cancer management - iarc.fr · al techniques. endoscopic and radiologi-cal technology has enabled...

Cancer managementCancer managementCancer management

Once cancer is diagnosed, the patient may require medicaltreatment and specialized care for months, and often years.The principal modes of therapy – surgery, radiotherapy andchemotherapy – may be given alone or in combination. Strongemphasis is now placed on the development of specializedcancer centres in which evidence-based multimodality thera-py is applied, subject to evaluation by appropriately designedtrials. After successful treatment, specific rehabilitation maybe needed. When cancer treatment is not curative, maintaining the high-est possible quality of life is paramount. For many patients,supportive and palliative care are essential and this ofteninvolves a range of professional services that extends beyondthe discipline of oncology.

666

WCR-S6.Q ( composition) 27/01/03 11:28

Although surgery for cancer was availablefor many years prior to the advent of othertherapies, the discipline of surgical oncolo-gy is not yet recognized in all countries asa speciality. Rather, surgical oncology is aconcept which has developed recently,evolving with the emergence of radiothera-py and chemotherapy as separate modali-ties (Radiotherapy, p277 and Medical on-cology, p281). The surgeon, who in thepast was performing solo in the treatmentof patients with cancer, has now becomepart of a team of players working togetherin a complex programme of multimodalanticancer therapies. Since a surgical oncologist cannot hope tomaster the whole field of solid cancers,especially in view of the high technicaldemands of such surgery, subspecializationin organ-based groupings, such as uppergastrointestinal and colorectal subspeciali-ties, has become necessary. Hyperspeciali-zation into hepato-pancreato-biliary, endo-crine and vascular surgery has also devel-oped. Tentative attempts to develop proce-

dure-based subgroupings, with new special-izations for surgeons devoted to one type ofprocedure, such as organ transplantation orvideo laparoscopy, have generally failed.There is now a tendency to recruit surgeonswho focus on one, or a few, organ sites.These specialists bring with them not onlybasic knowledge of the biology of cancerbut the ability to participate in multidiscipli-nary research and to collaborate with col-leagues from other disciplines.However, with the growing evidence thatcancer is rarely an organ-limited disease,both a disease-orientated approach andan organ-orientated approach are neces-sary to ensure optimal care for the cancerpatient. Surgical oncologists have promot-ed the standardization of surgical practiceaiming at the increase of life expectancy.Their participation in multi-centre clinicaltrials has provided the opportunity tocompare clinical results of surgery andoutcomes in the treatment of cancer [1,2].

Ethical and organizational aspectsTreatment of patients with cancer, of allages, requires a specific ethical and psy-chological approach. Most patients movethrough a state of denial and lateracceptance as the diagnosis and treat-ment of the disease progresses. A deci-sion to perform surgery may be madewhen the disease has already adverselyaffected the quality of the patient’s life.Cancer is often considered as a mutilat-ing, self-destructive process and surgeryis viewed frequently as either a lastchance salvage procedure or an addition-al insult to a ravaged body. Thus, fromthe patient’s perspective, the prospect ofsurgery is seen as a new burden, but alsoa chance of cure. Surgeons involved inthe care of cancer must help patients toregain their autonomy in decision-makingand self-determination. This insight hasvalue as a prelude to obtaining informedconsent for surgery and particularlybefore proposing to a patient that he orshe should enter a clinical trial. In prac-tice, patients often have greater confi-

dence in a well-structured and coordinat-ed multidisciplinary team than in a singlephysician. The changing relationship betweenpatients and surgeons due to the dis-semination of knowledge and to public

SURGICAL ONCOLOGY

272 Cancer management

SUMMARY

> Surgical oncology is emerging as a spe-cialist discipline; recent advances includemore precise identification of the tumourmargin, leading to reduced local recur-rence.

> New technology has facilitated minimalinvasive surgery, laparoscopy and fibre-optic endoscopy.

> The greatly elevated cancer risk in indivi-duals with familial cancer syndromesincreasingly raises the prospect of preven-tive surgery, e.g. mastectomy in carriers ofBRCA1/2 mutations and colectomy inpatients with familial adenomatosis coli.

> Surgical management is underpinned byrecognition of the whole patient, and notmerely focused on tumour excision.

Fig. 6.2 A patient undergoing electrolysis treat-ment for an unresectable liver tumour. Two plat-inum electrode catheters deliver a low dose elec-tric current causing local tumour ablation.

Fig. 6.1 Surgery can cure patients with solidtumours when the tumour is confined to theanatomic site of origin.

WCR-S6.Q ( composition) 27/01/03 11:28 72

awareness of cancer has given rise tonew attitudes towards operative risk.Many surgeons involved in the care ofcancer patients have had to change their“surgeon-centric” focus to a position of asurgical oncologist committed to an inte-grated approach to treatment of cancerwhich merges organ-orientated and dis-ease-orientated specializations. Suchsurgeons are therefore better placed toface new challenges. There is a general trend towards central-izing the care of cancer patients in hospi-tals where it is possible to muster multi-disciplinary teams. Radiation therapy andcytotoxic chemotherapy are often central-ized to oncology clinics with oncologicalsurgeons having the opportunity to focuson the surgical part of the treatment.However, since it is unrealistic and unde-sirable to deprive general surgery of itsrole in the treatment of cancer patients, itremains essential to improve the knowl-edge and expertise of general surgeons inoncological practice.

ContextSurgery for prevention of cancerSurgical resection of tumours with severedysplasia is a strategy for the preventionof cancer (Table 6.1). One striking exampleis total coloproctectomy in young asymp-tomatic patients with familial adenoma-tous polyposis (Fig. 6.4). Another exampleis total pancreatectomy in a patient withintraductal multifocal papillary mucinoustumour of the pancreas with areas ofmoderate to severe dysplasia (Fig. 6.5).Liver transplantation for advanced livercirrhosis, from which small, undetectablehepatocellular carcinomas may develop[3], may be considered a means to pre-vent liver cancer.

Surgery for cancer cureLocal control of the tumour, which meansthe total eradication of the primarytumour and disease involving regionallymphatics, is indispensable for obtaininga cure. Surgery is often the most appro-priate procedure for obtaining this goaland, from this point of view, remains thecornerstone in treatment [4]. Curative sur-gery is no longer synonymous, however,

with mutilating surgery. The general phi-losophy of cancer surgery has becomemore conservative than in the past, aslong as such conservation remains com-patible with an adequate resection of thetumour. The preoperative assessment,however, is of the utmost importancebefore subjecting a patient to a potential-ly hazardous operative procedure.Conservative surgery in breast cancer is aconspicuous example of how the need foradequate treatment has been reconciledwith preservation of the female breast andimproved quality of life. Radical mastecto-my, although effective, was accompaniedby the psychological trauma of breastamputation. This promoted evaluation of

more conservative procedures (Table 6.2)and it became apparent that partial mas-tectomy alone was followed by significantlocal recurrence rates. Results in the1980s and 1990s demonstrate that over-all and disease-free survival from breastcancer are equivalent for mastectomy andbreast-conserving surgery with postopera-tive radiotherapy for women with earlybreast cancer [5]. Breast conservationtherapy as an alternative to mastectomy isespecially important since, as a conse-quence of mammographic screening, theaverage size of invasive tumours hasdecreased while the incidence of non-invasive breast carcinoma has increased. In the case of stomach cancer, surgery is

Surgical oncology 273

Fig. 6.3 The liver of a cirrhotic patient demon-strating multifocal hepatocellular carcinoma.

Fig. 6.4 Operative specimen of total coloproctec-tomy for familial adenomatous polyposis in a 14 year old boy; numerous polyps are evident.

Table 6.1 Surgery as a means of cancer prevention. V.T. DeVita et al., (1997) Cancer: Principles and practice of oncology

© Lippincott, Williams & Wilkins.

Underlying condition Associated cancer Prophylactic treatment

Cryptorchidism Testicular Orchidopexy

Familial colon cancer Colon ColectomyFAP, familial adenomatous polyposis,or HNPCC, hereditary nonpolyposis colorectal cancer

Ulcerative colitis Colon Colectomy

Multiple endocrine neoplasia Medullary cancer ThyroidectomyMEN1, MEN2 of the thyroid

Familial breast cancer Breast MastectomyBRCA1, BRCA2

Familial ovarian cancer Ovary OophorectomyBRCAI

271 A 301 WORLD CANCER 17/06/03 15:29 Page 273

the only possible curative treatment andresults of gastrectomy have improvedsince 1970 (Table 6.3) [4]. Comparison offive-year survival shows dramatic differ-ences between Japanese and Americanresults (100% for Japan and 50% for theUSA for stage I cancer), which may in partdue be to differences in classification ofstage or in surgical technique. In Japan,extended lymph node dissection is stan-dard procedure and total gastrectomy anddissection of adjacent organs are morecommonly performed.

Palliative cancer surgeryIndications for palliative surgery havedecreased during the last decades withthe increasing emergence of intervention-al techniques. Endoscopic and radiologi-cal technology has enabled significant pal-liation of disabling symptoms, particularlyin the context of lumen-occluding com-pression by the tumour.

Technological advancesSurgical instrumentation has evolvedsteadily over the past two decades. Fibre-optic endoscopy, along with other newtechnologies, has had a significant impacton the development of modern surgery.Laparoscopy (endoscopic examination ofthe interior of the abdomen) has becomea mainstay in the diagnosis of intraperi-toneal non-Hodgkin lymphoma and peri-toneal carcinomatosis (widespread carci-noma in the abdominal cavity). Combinedwith ultrasonography, it plays an increas-ingly important role in the staging of manycancers, such as hepatic and pancreatictumours [6]. Moreover, new proceduresare still being explored in the treatment ofcancer. Early results of laparoscopicresection of colonic carcinoma seem to bepromising, although the sporadic reportsof port site recurrences need furtherinvestigation. Peripheral lung metastasescan be resected through thoracoscopy by

wedge resection. However, more specificdata are required to justify adoption oflaparoscopic and thoracoscopic proce-dures as standard operations in the fieldof cancer. Oncological principles shouldnot be compromised solely to accommo-date the technically complex tasks associ-ated with video-endoscopic techniques. Over recent years, non-operative ablativetechniques have also emerged. These aredesigned to facilitate local destruction oftumours either by chemical or physicalagents, such as arterial chemoemboliza-tion, alcohol injection, cryotherapy,radiofrequency ablation, electrolysis (Fig.6.2) and chemo-hyperthermia [7]. Theseprocedures can be used not only for palli-ation but also with a curative intent, as analternative to, or in combination with, sur-gical resection, according to the stage ofthe tumour and the general condition ofthe patient. Liver transplantation is now consideredthe best modality of treatment in carefullyselected cirrhotic patients with smallhepatocellular carcinoma confined to theliver (Fig. 6.3). Although still controversial,this new strategy, which treats bothtumour and cirrhosis, is now meeting withincreasing success and is becoming moreaccepted in developed countries. Never-theless, its application on a large scaleremains limited by the persistent shortageof donors and thus of organs available fortransplantation. Liver transplantation withliving, related donors has become a valu-able alternative to reduce the pressure onthe significant shortage of cadaveric livergrafts and has been applied to carefullyselected patients with a limited range ofmalignant liver tumours. In Asian coun-tries (particularly Japan and Hong Kong)where transplantation from cadavericdonors is nearly non-existent, this newstrategy is progressively being developedby specialized centres.

Role of surgical oncology in multi-modality therapySurgery remains the primary option forthe cure of many cancers. However, onoccasions, curative resection is impossi-ble or the prognosis following resectionremains unsatisfactory. To combat such


Period Resectability (%) Mortality (%) 5-yr survival (%)

Before 1970 37 15 38

Before 1980 53 13 52

Before 1990 48 5 55

Table 6.2 Halsted radical mastectomy and modified radical mastectomy in the treatment of breast cancer;use of the less drastic modified procedure has steadily increased.

Table 6.3 Survival and mortality following stomach cancer surgery have improved significantly.A.J.A. Bremers et al. (1999) Cancer Treatment Reviews, 25: 333-353.

Year Radical mastectomy (%) Modified radical mastectomy (%)

1972 47.9 27.7

1976 25.5 51.9

1977 20.9 55.4

1981 3.4 72.3

In a radical mastectomy, all the breast tissue is removed together with the pectoralis minor and major muscles and the axillarycontents; the pectoralis major is preserved in the modified procedure. American College of Surgeons, Commission on Cancer,Chicago, 1982.

WCR-S6.Q ( composition) 27/01/03 11:28 Page 274

expectation of poor outcome, adjuvanttherapies combining chemotherapy andradiotherapy have been developed and,when added to surgery, may be regardedas an integral part of modern surgicaloncology. Neoadjuvant use of radiotherapy hasbeen developed to help downstagetumours such as rectal carcinoma. Someirresectable tumours may becomeresectable following such treatment.Similar results can be obtained bychemotherapy in the management oflarge, awkwardly placed hepatic colorec-tal metastatic disease, and this cantransform certain tumours from irre-sectable to resectable lesions. Neo-adju-vant therapy may also decrease the rateof regional recurrence after curativeresection of aggressive carcinomas,exemplified by pancreatic exocrine ade-nocarcinoma [8].The goal of cytoreductive surgery is toremove as much as possible of thetumour mass. Such elimination of largeportions of known malignant deposits is

referred to as “debulking”. Cytoreduc-tive surgery is widely employed as theprimary treatment of ovarian cancer,with both five-year survival and mediansurvival better for patients with smallresidual masses. Some of these find-ings may, however, be a reflection ofpatients selected for surgery ratherthan a treatment-related change in thenatural history of disease. Cytoreduc-tive surgery is usually combined withsubsequent chemotherapy and radio-therapy. There is increasing use ofcytoreductive surgery and intraperi-toneal chemotherapy for peritoneal car-cinomatosis from ovarian cancer.Recent advances in intraoperativeradiotherapy have the potential to offeradditional strategies in the manage-ment of inaccessible or poorly resectedcancers, typified by tumours of the bil-iary tract. Biliary cholangiocarcinomascan be managed by the placement ofintraoperative radiotherapeutic sourcesas adjuvant treatment following eitherresection or failed resection.

The futureTypically within more developed countries,there is now a range of fully equipped andstaffed specialist cancer hospitals ormajor centres with specialized cancerunits. Despite this infrastructure, in manycountries, surgical oncology still remainsapart on both a local and national level. Adoption of new technologies in cancersurgery should be guided by scientific evi-dence of benefit for the patient and cost-effectiveness in relation to current prac-tice. During the evaluation phase, accessto the technology should be restricted tomulti-centre controlled clinical trials with-in a critical academic oncology climate.Such a programme of action will safe-guard continuing progress in outcomes ofcancer care, while at the same time keep-ing the economic burden within reason-able and sustainable limits [2].

Surgical oncology 275

Fig. 6.5 Contrast-enhanced magnetic resonance imaging (MRI) of an intraductal papillary mucinoustumour of the pancreas in an adult patient who was subsequently treated by total pancreatectomy. 1 = common bile duct; 2 = pancreatic duct with multiple dilations caused by the presence of tumour tis-sue; R = right, L = left.

1

2


1. Vetto J, ed. (1999) Current Practice and Therapy inSurgical Oncology, Hagerstown, MD, Lippincott Williams &Wilkins Publishers.

2. Feig BW, Berger DH, Fuhrman GM, eds (1998) The M.D.Anderson Surgical Oncology Handbook, Hagerstown, MD,Lippincott Williams & Wilkins Publishers.

3. Mion F, Grozel L, Boillot O, Paliard P, Berger F (1996)Adult cirrhotic liver explants: precancerous lesions and unde-tected small hepatocellular carcinomas. Gastroenterology,111: 1587-1592.

4. Bremers AJ, Rutgers EJ, van de Velde CJ (1999) Cancersurgery: the last 25 years. Cancer Treat Rev, 25: 333-353.

5. Fisher B (1999) From Halsted to prevention and beyond:

advances in the management of breast cancer during thetwentieth century. Eur J Cancer, 35: 1963-1973.

6. Berry DP, Maddern GJ (2000) Other in situ ablativetechniques for unresectable liver tumours. Asian J Surg, 23:22-31.

7. Luck AJ, Maddern GJ (1999) Intraoperative abdominalultrasonography. Br J Surg, 86: 5-16.

8. Partensky C, Maddern GJ (1999) Pancreatectomy afterneoadjuvant chemoradiation for potentially resectableexocrine adenocarcinoma of the pancreas. In: Mornex F,Mazeron, JJ, Droz, JP, Marty, M eds, ConcomitantChemoradiation: Current Status and Future, Paris, Elsevier.

REFERENCESSociety of Surgical Oncology (USA): http://www.surgonc.org

European Society for Surgical Oncology:http://www.esso-surgeonline.be/

World Federation of Surgical Oncology Society:http://www.wfsos.com/

On-line Medical Dictionary (CancerWeb):http://cancerweb.ncl.ac.uk/omd/

WEBSITES

The prospects for telemedicine in cancertreatment primarily involve informationdistribution for quality assurance andsharing of medical technology resources.The Internet provides a powerful platformfor information and knowledge distribu-tion worldwide. Routine use of telemedi-cine is currently limited to developedcountries. The impact of telemedicine indeveloping countries remains limitedsince Internet access is often restricted.In developed countries, sharing of med-ical technology resources among healthcare institutions is likely to increasemarkedly with the development ofadvanced Internet-based services. Thesemay include remote diagnosis, telemed-ical services such as remote image pro-cessing (including 3D or virtual reality fordiagnosis or training), remote therapyplanning (e.g. in radiation therapy) andexpert system counterchecks (e.g. tomonitor treatment courses) which mayimprove treatment outcome at affordablecosts.

Today, with modern network capacities nolonger limiting electronic medical data trans-fer, the management of huge quantities ofinformation and quality assurance are themajor challenges in advanced medical infor-matics. Although much effort has beendirected towards the development of elec-tronic patient records, no truly authoritativestandard has thus far evolved (EuropeanCommittee for Standar- dization, TechnicalCommittee for Health Informatics,http://www.centc251.org/).

In developed countries, most hospitals relyon electronic data processing as the meansof delivering services. Individual medicaldepartments often employ their own digitalinformation systems. In most instances,these applications will have been imple-mented over many years without referenceto sharing, and communication, even with-in the hospital information system, may notbe practicable due to proprietary communi-cation standards. In effect, within a singlehealth care institution, relevant patientinformation is distributed in numerousinformation systems without properexchange capabilities. Attempts have been

made to utilize Web technology to createintegration platforms, with HL 7 as thecommunication standard (Health Level 7,http:// www.HL7.org). However, disad-vantages apply with respect to data han-dling, security and speed of performance.An alternative, as integration middleware,may be CORBA (Object ManagementGroup, http://www.omg.org/) but com-mercial applications still have to provetheir value in clinical routine.

Only broad distribution of electronic infra-structures in health care will allow theintegration of beneficial telemedical serv-ices into medical practice. In developedcountries, the evolution of electronicpatient records promises extensiveadvantages in terms of quality assuranceand cost-effectiveness of patient treat-ment. In developing countries, ubiquitousaccess to Internet information sourceswill help tremendously in the distributionof medical standards and knowledge(Ricke J and Bartelink H, Eur J Cancer 36,827-834, 2000; Wootton R ed., Europeantelemedicine 1998/99. Kensington publi-cations, London 1999).

TELEMEDICINE



It is estimated that 50% of all patients whoare diagnosed with cancer in the worldwould currently benefit at some stage oftheir illness from radiotherapy. This couldbe either as part of radical therapy withcurative intent or as palliation for pain orother symptoms. The delivery of radio-therapy requires long-term planning in theconstruction of facilities as well as spe-cialized doctors, physicists and techni-cians [1]. In many parts of the world facil-ities are very poor, even though upgradingis well within many health service budg-ets. The increasing reliability of modernequipment together with the reducingcosts of the associated sophisticatedcomputer planning facilities should resultin considerable global improvement overthe next decade.

RadiobiologyRadiotherapy is defined as the use of ion-izing radiation for the treatment of malig-nant disease. Modern high energy X-raymachines deliver radiation which is up toone hundred times more penetrating thanthe X-rays used for diagnosis and can be

delivered using tight beams to welldefined areas in the body. This allows forthe treatment of deep-seated tumourswith minimal radiation being delivered tosurrounding normal tissue. Although themajority of treatments given in this wayuse X- or gamma rays, ionizing radiationcan also be given by electron beam accel-erators or particle accelerators.The biological basis for the therapeuticeffect of radiation has been examinedextensively in both cell culture and animaltumours. Although there are correlationsfrom the laboratory, most clinical radio-therapy regimens are based on experi-ence rather than biological modelling.There is considerable heterogeneity bet-ween tumours which defies rigid predic-tion.Cell survival curves after the administra-tion of different doses of radiation havebeen used to explore the best way toenhance selectivity between normal andmalignant cells. Radiation causes pro-found DNA damage which is then repairedin most cells (Carcinogen activation andDNA repair, p89). The amount of damage

depends on the type of radiation used andis increased in the presence of oxygen.Many tumours are hypoxic, simplybecause they have outgrown their bloodsupply (Invasion and metastasis, p119)and this renders such tumours moreresistant to radiation damage. Differenttechniques to overcome this problem,such as the use of hyperbaric oxygen,hypoxic cell sensitizers and neutron radia-tion, have had only limited success. It is

RADIOTHERAPY

SUMMARY

> Radiotherapy is fundamental to the opti-mal management of cancer patients; itsefficacy is affected by technical (thenature and delivery of the beam) andbiological factors (tumour susceptibilitymodulated by hypoxia and drugs).

> Provision of radiotherapy services iscentral to national cancer control strate-gies, requiring long-term planning andappropriate assessment of health careresources.

> Without recourse to sophisticated tech-nology, effective radiotherapy for manycancers can be comprehensively provid-ed at moderate cost.

Fig. 6.7 A patient being prepared for treatment on a modern linear accelerator. © Varian Medical Systems.

Fig. 6.6 Schematic drawing of the inside of a lin-ear accelerator, indicating the wave-guide in whichelectrons are accelerated before hitting a target.©Varian Medical Systems.

Radiotherapy 277


likely that as more is understood aboutthe molecular genetics of cancer, theeffects of radiation will be more accurate-ly predictable. This will allow for more tai-lored and appropriate radiation schedulesand doses, with better efficacy and lesstoxicity.

EquipmentRadiotherapy equipment is complex andvaried [2]. The penetrating power of aradiotherapy beam is defined in terms ofits energy and is measured in electronvolts (eV). The simplest type of equipmentis a low energy orthovoltage machine thatbasically represents an enhanced diag-nostic X-ray machine. It can produce abeam of up to 250KeV. The problem inusing a standard X-ray tube to produce abeam of higher energy is the heat gener-

ated at the target site (the site at whichX-rays are generated by electron bom-bardment). Even with elaborate watercooling systems, target degradationoccurs rapidly at higher voltages.Although the penetration of such low volt-age beams is only 1-4 cm, they are effec-tive at treating superficial cancers of theskin and for palliating bone metastases.The application of multiple orthovoltagefields was used to treat deep tumours inthe past, but severe skin reactions and thelarge volume of normal tissue irradiatedposed severe problems.Isotope-based radiotherapy using gammaray-emitting sources produces beamswith a higher energy. Initially radium wasthe source used, but this was supersededby cobalt. Cobalt machines produce anenergy of 1.25 MeV and are very reliable.

The cobalt source is housed in a lead boxwith a shutter, which is opened electrical-ly. The only mechanical failure to beaddressed involves malfunction of theshutter mechanism. However there areproblems with radiological protection asthe sources need to be changed every fiveyears because of radioactive decay. Therehave also been several bizarre incidents indeveloping countries where stolen cobaltheads have been sold for scrap metalresulting in highly radioactive home andoffice furniture.Linear accelerators (Fig. 6.7) are now the“gold standard” for radiotherapy provi-sion. Electrons are accelerated down a lin-ear wave-guide of about a metre in lengthand then hit a target where their kineticenergy is transferred into X-rays. Suchmachines can reliably produce beams ofup to 20MeV energy. These beams passdirectly through the skin surface causinglittle or no skin reaction. In order to deliv-er maximal quantities of radiation to deeptumours while keeping normal tissue doselow it is necessary to use more than onebeam. The amount of energy given up byeach beam diminishes as it penetrates.With modern equipment and computerplanning facilities, excellent dose distribu-tion can usually be achieved in most partsof the body using three fields. The charac-teristics of the radiation produced and theapproximate equipment costs are shownin Table 6.4. The process by which the volume to beirradiated is identified by the radiothera-pist is called “planning”. Information istaken from clinical examination, plain X-rays, computed tomography (CT) andmagnetic resonance imaging (MRI) scansand used to identify the target high dosevolume. A simulator (a diagnostic appara-tus with the same characteristics as atreatment machine) is used to check theanatomical relationships. In many situa-tions, computed tomography planning sys-tems allow direct marking of the volumeon a computed tomography scan. For small volume, very accurate fields,such as those used for laryngeal or pitu-itary tumours, some form of patient immo-bilization shell is required. This is a thinperspex mask made to fit each patientTable 6.5 Radiotherapy treatment appropriate to particular cancers.

Tumour Total Dose Duration of No. of fractions(Gy) treatment (weeks) (dose (Gy) per fraction)

Prostate cancer 64 6 32 (2)

Glioblastoma 60 6 30 (2)

Oesophageal cancer 60 6 30 (2)

Laryngeal cancer 60 6 30 (2)

Pituitary tumour 50 5 25 (2)

Lung cancer 50 4 20 (2.5)

Hodgkin disease 40 4 20 (2)

Bone metastases 8 1 1 (8)

Table 6.4 Characteristics of radiotherapy equipment.

Equipment Energy 50% depth dose Approximate (depth at which electron beam machine cost

ionization is 50%) (million US$)

Orthovoltage 50-250 KeV 4 cm 0.2

Cobalt 1.25 MeV 9 cm 0.6

Linear accelerator 4-20 MeV 15 cm 1.0

Particle accelerator 4-20 MeV 5-20 cm 20 - 50



individually and onto which marks for theentry and exit points have been made. Inthis way, the set-up is reproduced identi-cally each day with no inaccuracy causedby slight shifts in the patient’s position orchanges in skin shape or contour due toweight loss that may occur during treat-ment. Radical radiotherapy is usually frac-tionated into small daily doses given fivedays a week. This allows a lethal dose tobe given to the tumour, whilst the normaltissues have time to recover and repairthe DNA damage caused by radiation. The relative merit of cobalt machines ascompared to linear accelerators is oftendebated. In the past there have been con-cerns regarding capital cost, reliability andclinical need for linear accelerator tech-nology in the developing world [3]. Recenttechnical advances in beam collimation,conformal therapy, modular design andthe ability to construct national andindeed international computer networksnow favour linear accelerators as theworkhorse for radiotherapy provision indeveloped countries. Although there aresome who still consider cobalt effective[4], most organizations, including the UK’sRoyal College of Radiologists, consider lin-ear accelerators to be the way forward [5].

DosimetryRadiation can be measured in severalways. In the early days, techniques suchas film blackening, skin erythema and

measuring changes in chemicals con-tained in pastilles placed on the skin,gave an approximate indication of dose.In 1937 the “Roentgen” was defined,reflecting the energy of the beam meas-ured in an ionization chamber. This didnot, however, reflect absorbed dose in atarget volume in a patient. The “Rad”was the first unit of absorbed dose, with1 rad representing the absorption of 100ergs of energy per gram of tissue. Thecurrent unit using the S.I. system(International System of Units) is theGray (Gy) which is the equivalent of 100rads. Most fractionation schemes areexpressed in centi-Gray (cGy), which isthe same as 1 rad.Different types of radiation – X-rays ofdifferent energy, neutrons and particles– have different biological effects on tis-sue even though the same dose may begiven. This has to be taken into accountin radiation safety calculations. For radi-ological protection the “Sievert” is used.This is calculated from the absorbeddose in cGy multiplied by a quality factorQ, which is 1.0 for most X-rays, 10 forneutrons and 20 for alpha particles.In prescribing radiation, the timing, frac-tionation and volume to be treated are allinterdependent. Many radical radiothera-py plans use a dose of approximately 60Gy given in 30 daily fractions of 2Gy eachday, Monday to Friday, over six weeks.Palliative treatments may be given with

much larger fractions over a short periodof time, using a lower total dose. For con-trol of bone pain, a single large fractionof 8 Gy may be used. When the size ofeach fraction is increased the amount ofnormal tissue damage also rises becauseof the reduced time for the normal repairprocesses to work. Therefore the biologi-cal effects of giving the same total doseover a short period of time are muchgreater than giving it over a longer periodof time. Various complex formulae havebeen developed to relate time dose andfraction size. The radiotherapist choosesa dose based on the type of tumour,whether treatment is radical or palliativeand the volume and type of normal tissueincluded (Table 6.5). The total amount of radiation toleratedby different parts of the body variesenormously. There are several tissues inthe body that have a poor capacity torepair following exposure to radiation.The most sensitive are the lens of theeye, the spinal cord, lung, kidney andsmall intestine. Depending on thepatient’s general condition and expecta-tion of cure, it is often necessary to con-struct elaborate plans to avoid thesestructures. More recently, conformalplans which correspond precisely to theshape of the tumour have become wide-ly available (Fig. 6.8). Such plans reducenormal tissue toxicity and allow the actu-al tumour dose to be escalated, increas-

Fig. 6.8 Conformal radiotherapy to a pleural mesothelioma. A The calculated dose distribution in the axial or transverse view. B An example of one Beam's EyeView (BEV). The BEV at this particular gantry angle has a crescent shape that conforms to the target volume. C Different Beam's Eye Views (BEVs) that aredelivered in one conformal X-ray arc field. ©Varian Medical Systems

A B C

Radiotherapy 279


ing the chance of tumour eradication,provided no metastases are present.

BrachytherapyThis literally means “short distance treat-ment” and is used to describe techniqueswhere radioactive sources are placeddirectly through or in contact with a tumour.Such systems for the treatment of cervicalcancer are very effective. This cancer iscommon in many parts of the developingworld and, if better education could result inearlier presentation, more women would becurable by this relatively low-tech proce-dure. Basically rods of caesium or other iso-tope are placed directly into the uterus withfurther radioactive material inserted into

the vaginal vault. In this way a pear-shapeddeposition of high intensity radiation isdelivered over a two- to three-day period.More sophisticated after-loading systemsare available in which the isotope, in theform of cobalt or iridium beads, is insertedinto guides by a hydraulic system. Thisreduces unwanted exposure of staff and rel-atives to radiation.Iridium 191 wires are flexible and can beinserted directly into tumours of the tongue,buccal mucosa, anus and breast. This givesa very high dose of radiation precisely to thetumour. The wires remain in position forthree to five days and the results are oftenas good as found with more expensiveexternal radiotherapy systems.

Side effects of radiotherapyMost patients tolerate radiotherapy relativelywell. Problems arise from the intrinsic sensi-tivity of normal tissue inevitably included inthe treatment volume. Mucous membranesbecame oedematous and painful, skin reac-tion leads in extreme cases to ulceration andscarring. Abdominal radiation causes enteri-tis and diarrhoea. The general acute effectsof radiation include radiation sickness andgeneral debility. Good nursing care withdrugs to control sickness, headaches, diar-rhoea and oedema can effectively controlmost problems. The delivery of high qualityradiotherapy requires teamwork between arange of professionals to maximize its bene-fits and reduce the severity of its side effects.

1. Porter A, Aref A, Chodounsky Z, Elzawawy A,Manatrakul N, Ngoma T, Orton C, Van't Hooft E, Sikora K(1999) A global strategy for radiotherapy: a WHO consulta-tion. Clin Oncol (R Coll Radiol ), 11: 368-370.

2. Price P, Sikora K, eds (2000) Treatment of Cancer, 4thEdition, London, Chapman and Hall.

3. Borras C, Stovall J, eds (1993) Design Requirements forMegavoltage Radiotherapy X-Ray Machines for Cancer

Treatment in Developing Countries, New Mexico: LosAlamos Laboratories.

4. Van Dyk F, Battista J (1996) Cobalt 60: an old modali-ty, a renewed challenge. Curr Oncol 3: 23-34.

5. Royal College of Radiologists (1998) Equipment,Workload and Staffing for Radiotherapy in the UK, London

REFERENCESInternational Society of Radiology:http://www.isradiology.org

The Royal College of Radiologists (UK):http://www.rcr.ac.uk

European Association and Congress of Radiology:http://www.eurorad.org

Cancer BACUP (UK): Understanding Radiotherapy:http://www.cancerbacup.org.uk/info/radiotherapy.htm

WEBSITES

The Edinburgh Declaration of 1988 (WorldConference on Medical Education, Lancet2:464, 1988) aimed to change the charac-ter of medical education so that “it trulyreflects the defined needs of the societyin which it is situated”. The total burden ofcancer on the global community and thehealth care professions is increasing.These realities are prompting increasedefforts in cancer control, and medical stu-dent cancer education must be an integralpart of this effort. The International UnionAgainst Cancer (UICC) monograph(Robinson E et al., Cancer Education forundergraduate medical students : curricu-la from around the world, UICC, Geneva1994) describes global concerns aboutthe status of medical student education

about cancer, and provides a series ofmodel curricula. The continued orientation of most medicalstudent curricula around traditionaldepartment-discipline areas rather thancommunity or patient needs inhibits thedevelopment of clinical service-based inte-grated teaching. It also inhibits the incor-poration of new knowledge about cancerbiology and epidemiology and improvedcancer treatments into medical studenteducation. Medical educators stress theimportance of medical students' experi-ence as a major determinant of lifetimeapproaches to cancer. Initial perspectivesmay not be greatly affected by postgradu-ate training. For many doctors, their onlyformal cancer education is that gained as amedical student, partly because cancermanagement and control does not fallsquarely on any of the individual postgrad-uate educational bodies. It is clearly impor-

tant that medical students should beappropriately educated about cancer. Thejoint UICC/WHO statement (Undergrad-uate education in cancer, UICC/WHOWorkshop, Geneva, 1981), to the effectthat “in most countries there is a signifi-cant gap between the actual cure rates ofvarious cancers and the maximum curerates obtaining through utilizing currentavailable knowledge”, is sobering. Animportant first step in the reform of med-ical student cancer education is theappointment of a cancer education com-mittee or co-ordinator in all medicalschools. A reorganization of the existingsyllabus with the introduction of prob-lem-based learning relating to cancerbiology, cancer prevention, diagnosis,treatment and symptom control, wouldrectify many of the deficiencies identifiedin surveys of medical student cancer edu-cation.

CANCER EDUCATION IN MEDICAL COURSES



CHEMOTHERAPY

The use of chemotherapy to treat cancerbegan in 1943 following the observation ofleukopenia (reduction in number of leuko-cytes) in military personnel exposed tomustard gas after an explosion of a battle-ship in Bari harbour. This alkylating agentwas adapted for intravenous use and pro-duced dramatic but short-lived responsesin patients with lymphoma and leukaemia.Other agents, such as the folic acid andpyrimidine inhibitors, followed and thearmamentarium rapidly grew. It was rec-ognized that drug resistance developedwhen single agents were used, so combi-

nation chemotherapy became standard.During the 1950s and 1960s, majorstrides were made in the treatment ofleukaemias, lymphomas and choriocarci-nomas with many patients being com-pletely cured. New drugs were discoveredfollowing extensive screening pro-grammes – the vinca alkaloids from theperiwinkle, the anthracyclines from fungiand platinum drugs from experiments onthe effects of electric currents on bacteri-al growth. The 1970s and 1980s broughteffective drug combinations for testicularcancer and many childhood malignancies.Thus chemotherapy is now given in thesetting of paediatric malignancy, germ celltumours (Cancers of the male reproduc-tive tract, p208) and some types of lym-phoma (Lymphoma, p237) with curativeintent. Chemotherapy may be adminis-tered prior to surgery (neoadjuvant) tofacilitate resection and prevent metasta-sis or after surgical debulking (adjuvant)to reduce the risk of distant relapse.Adjuvant chemotherapy for breast andcolon cancer was proven to be beneficialin large-scale randomized trials followedby sophisticated meta-analyses [1]. Thevalue of chemotherapy in improving thequality of life of patients, by palliatingsymptoms and pain, even in the absenceof survival advantage, is evident.

New drugs have been launched and newcombinations put together. However,many challenges remain (Table 6.6).Despite many new agents becoming avail-able, often at great cost, the gains interms of cure rates have been small.Fashions for high dose chemotherapy with

MEDICAL ONCOLOGY

SUMMARY

> The efficacy of chemotherapy variesmarkedly depending upon the malignan-cy. Some, such as testicular seminoma,leukaemias and malignant lymphomasare highly responsive, while minimalresponse tumours include those of thebrain (glioblastoma), lung and pancreas.

> WHO has identified a list of essentialanticancer drugs.

> Drugs are typically used in combination,based on and progressively improved byrandomized trials.

> Inherent or induced drug resistance limitsefficacy.

> Most currently-used drugs inhibit DNAsynthesis and/or cell division, inducingapoptosis. Drugs that target tumour-specific signalling pathways, includingthe tryrosine kinase inhibitor Gleevecfor stromal tumours and acute myeloidleukaemia, are being developed.

> New approaches include gene therapyand novel strategies for immunotherapy,but clinical results thus far are largelydisappointing.

High complete response High complete response Low complete response

High cure Low cure Low cure

Hodgkin disease Acute myeloid leukaemia Non small cell lung cancer

Acute lymphoblastic leukaemia Breast cancer Colon cancer

Testicular cancer Ovarian cancer Stomach cancer

Choriocarcinoma Small cell lung cancer Prostate cancer

Childhood cancer Sarcoma Pancreatic cancer

Burkitt lymphoma Myeloma Glioblastoma

Table 6.6 Chemotherapy for advanced cancer: the current situation.

Medical oncology 281

Fig. 6.9 Chemotherapeutic drugs for injectionmay be available as ampoules (as shown) orready-prepared in a syringe.


bone marrow transplantation, the use ofmarrow support factors, biological thera-pies such as monoclonal antibodies orcytokines, have resulted in little overallgain but considerable expense. The driv-ing force for medical oncology comesfrom the USA, which spends 60% of theworld’s cancer drug budget but has only4% of its population (Fig. 6.11). Huge cul-tural differences exist in the use ofchemotherapy, with USA-trained physi-cians following aggressive regimens forpatients who in other countries would sim-ply be offered palliative care. This has cre-ated a tremendous dilemma for thoseresponsible for health care budgets. Forexample, the use of paclitaxel in patientswith metastatic breast cancer will prolongsurvival by six months at a cost ofUS$12,000. In many countries this wouldfar exceed the total health care consump-tion throughout a cancer patient’s life. Yetthe pressure to use expensive patenteddrugs is enormous. Conferences, traveland educational events sponsored by thedrug industry rarely give a real perspec-tive on the effective prioritization of can-cer care for poorer countries.

The biological basisIn respect of their molecular structure,drugs currently used in cancer chemother-apy represent an enormous range of struc-tural diversity. Anticancer drugs may becharacterized as being toxic to, and henceable to cause the death of, dividing cells.Many agents for which a mechanism ormechanisms of action is relatively clearinterfere with biological processes neces-

sary for cell division, specifically includingthe synthesis of DNA or RNA (Fig. 6.12).Antimetabolites limit synthesis of nucleicacid precursors. In this way methotrexateinhibits dihydrofolate reductase, therebylimiting synthesis of reduced folate, whichis necessary for production of purines andpyrimidines. Similar agents include 5-fluo-rouracil and cytarabine. After synthesis, themacromolecular processing of DNA isdependent upon topoisomerases and theseenzymes are specifically inhibited by anumber of classes of drugs, includinganthracyclines (doxorubicin, daunorubicinand epirubicin), epipodophyllotoxins(etoposide and teniposide) and the camp-tothecins (irinotecan and topotecan). Somedrugs cause structural damage to matureDNA, as exemplified by alkylating agents(cyclophosphamide, chloroambucil andprocarbazine) and platinum derivatives (cis-platin and carboplatin). Functioning of themitotic spindle is variously affected byvinca alkaloids (vincristine and vinblastine)and the taxanes (paclitaxel and relatedcompounds). Hormonal agents such astamoxifen affect proliferation of hormonal-ly responsive cells and are thus effective inbreast cancer. Otherwise, pharmacologicalmechanisms such as those summarizedabove often fail to account for the markeddifferences in responsiveness of particulartumour types to the various agents, and for

which no mechanistic insight may be avail-able. Cytotoxic drugs evoke drug resistance.Tumours (relative to normal tissue) may beinherently resistant or acquire resistanceas a consequence of treatment. Suchresistance may be anticipated to includedrugs of similar structure, but oftenextends to multiple classes of structurallyunrelated agents (Box: Resistance to can-cer chemotherapy, p285). The phenome-non has been extensively studied experi-mentally, by selection of cell populationsable to proliferate in the presence of a highdrug concentration. While relevant proces-ses have been revealed, including produc-tion of the multidrug resistant protein 1(which mediates drug transport out ofcells), the extent to which these processeslimit patient responses is still being deter-mined.

DeliveryIncreasingly, chemotherapy can be givenentirely in a day care or outpatient setting.This reduces costs and is preferred bymost patients and their families. Prior toinitiation, the goal of therapy must be real-istically defined. Prognostic factors such asthe stage of the disease, the sites of metas-tases, the general medical condition of thepatient, the willingness to accept any likelytoxicity and the availability of the neces-sary facilities to treat complications mustall be considered. It is essential to careful-ly document the degree of involvement atkey sites so that the response to drugs canbe measured. Although a particular tumourmay be curable in some circumstances,not all patients with that tumour type willbe cured. The risk-benefit concept needsto be discussed beforehand. Increasingly,cancer patients are being given more infor-mation about their disease and the optionsavailable. An honest appraisal of cost-effectiveness is vital in countries where thefull cost of drugs is paid for by the patient.Cancer chemotherapy requires access tolaboratory facilities to monitor at leastblood counts, liver and renal function andtumour markers. Nurse-led chemotherapysuites are very effective and liked bypatients. Clear protocols must be in placeand adapted to local circumstances.


Fig. 6.10 Crystals of cisplatin: more than 90% ofpatients with advanced germ cell tumours are cur-able since the introduction of cisplatin-basedchemotherapy.

Fig. 6.11 The global cancer drug market.



Fig. 6.12 Summary of the mechanisms and sites of action of selected cancer chemotherapeutic drugs.

6-MERCAPTOPURINE6-THIOGUANINE

Inhibit purine ringsynthesis (6-MP)

Abnormal DNA fromfalse precursor

METHOTREXATE

Inhibits dihydrofolatereductase

PROCARBAZINE

Multiple mechanismsof DNA damage

ALKYLATING AGENTS

Cross-link DNA

L-ASPARAGINASE

Deaminates L-asparagine

VINCA ALKALOIDS

Inhibit microtubules

TAXANES

Stabilize microtubules

ANITIBIOTICS

Direct binding toDNA, often by inter-calation

Some of these drugsalso inhibit topoiso-merase II

5-FLUOROURACIL

Inhibits thymidylatesynthetase

PURINE SYNTHESIS PYRIMIDINE SYNTHESIS

RIBONUCLEOTIDES

DEOXYRIBONUCLEOTIDES

DNA

RNA

PROTEINS

ENZYMES MICROTUBULES

HYDROXYUREA

Inhibits ribonucleo-tide reductase

CYTARABINE

Inhibits DNA poly-merase

ETOPOSIDE

Inhibits topoiso-merase II


For many curable cancers, the initial ther-apy is the most important. Any dosereduction, delay or drug substitution canadversely affect response rate. Managersand patients must understand that reduc-ing the drug dosage or number of cyclesto save money is unacceptable. Adjuvantchemotherapy is now of proven value inbreast and colon cancer. Again, rigidadherence to protocols is essential tomaximize results.Recently several high cost drugs havebeen marketed for common cancers.Although capable of a significant responserate in patients with metastatic disease,

such responses may be of short durationand may only prolong survival by weeks. Towhat extent some of these new agentsshould replace older and cheaper genericagents has not yet been determined in welldesigned trials with relevant endpoints,which include cost benefit analysis [2].Inevitably this will have a subjective elementand will vary with the overall allocation ofcancer treatment resources in a country.

Categories of effectivenessProtocols for drug use, and the determi-nation of which agents should be used inthe treatment of which cancers, has fre-

quently been determined empirically.Clinical trials are developed for this pur-pose, and recognized standards, extend-ing from informed patient consentthrough to adequate statistical analysis,have been established for such trials.Often, cytotoxic drugs are employed (usu-ally in combination) at the maximum pos-sible dose. Dosage is limited by toxicity:the consequence of the agent reaching,and hence affecting, normal tissue.Certain toxicity, such as hair loss, may beof limited significance but death of prolif-erating cells in the gut, bone marrow orother sites may provoke nausea, myelo-suppression or other adverse effects.There are more than 200 types of cancerand these respond variably to chemother-apy. Tumours can be split into five cate-gories with regard to the relative useful-ness of chemotherapy (Table 6.7). Thisprovides a basis for examining the overallhealth gain of defined interventions. Thiswill of course change as new drugs withgreater efficacy are introduced.Category 1: Tumours for which there isevidence that the use of a single or acombination of drugs used alone or withother therapeutic modalities will result incure as defined by a normal life span insome and prolongation of survival in mostpatients.Category 2: Tumours where the averagesurvival is prolonged when chemotherapyis used as an adjuvant to local surgery orradiotherapy in the early stages of dis-ease.Category 3: Tumours where there is evi-dence that a single drug or a combinationwill produce clinically useful responses inmore than 20% of patients. Prolongationof survival occurs in most respondingpatients but may be of short duration.Category 4: Tumours where local controlmay be improved by using chemotherapybefore, during or after surgery and radio-therapy.Category 5: Tumours for which there arecurrently no effective drugs. Objectiveresponses occur in less than 20% ofpatients and there is no evidence of sur-vival benefit in randomized controlled tri-als when compared to best supportivecare.


Fig. 6.13 Combination chemotherapy is more effective than a single agent for treatment of Hodgkin dis-ease. (ABVD = adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine; BEACOPP = bleomycin,etoposide, adriamycin [doxorubicin], cyclophosphamide, oncovin [vincristine], procarbazine and pred-nisone; COPP = cyclophosphamide, oncovin [vincristine], procarbazine and prednisone).

Responsiveness Cancer(in decreasing order of efficacy)

Category 1 Germ cell, leukaemias, lymphomas, choriocarcinoma

Category 2 Breast, colorectal, ovarian, osteosarcoma, Ewing’ssarcomas, Wilms tumour

Category 3 Lung, bladder, prostate, stomach, cervical

Category 4 Head and neck

Category 5 Liver, melanoma, pancreatic, brain, renal, thyroid

Table 6.7 Categorization of cancer by effectiveness of chemotherapy.



While many anticancer drugs, either aloneor in combination, dramatically affect thecourse of malignant disease, success isfar from universal. Certain tumour typesare relatively refractory to anticancerdrugs. In other instances, a markedresponse to treatment occurs but, overtime, the disease process recurs anddrugs, both those originally used andagents not previously employed, are inef-fective. This phenomenon is referred to as“drug resistance”, sub-categorized aseither inherent or acquired, as appropri-ate.To understand, and ultimately circum-vent, drug resistance, massive resourceshave been directed toward elucidatingmechanisms. The primary focus has beenmalignant tumour cell cultures which areresistant to particular drugs, or cell popu-lations which acquire resistance as aresult of being cultured in the presence ofprogressively increasing drug concentra-tions. Such cultures partially reflect theclinical behaviour of tumours, particularlyto the extent that cultures “selected”using one drug also exhibit resistance tosome, but not all, other drugs.Mechanisms of drug resistance in cul-tured cells have been elucidated.Typically, resistance is attributable tomutation or altered expression of geneswhose products mediate the transport ofa drug(s) into or out of the cell, the metab-olism and hence the intracellular concen-tration of the drug, and the structural orenzymatic protein to which the drug bindsto cause cytotoxicity, sometimes calledthe target. Thus the multidrug resistancegene MDR1 encodes P-glycoprotein whichmediates the transport of a family of “nat-ural product drugs” (including vinca alka-loids and epipodophyllotoxins, but exclud-ing, for example, cisplatin) out of the cellthereby reducing their intracellular con-centration and hence cytotoxicity (Tan Bet al., Curr Opin Oncol, 12: 450-458,2000). Agents tending to inhibit P-glyco-protein, and hence restore drug sensitivi-

ty, have been identified (Szabó D et al.,Anticancer Res, 20: 4261-4274, 2000;Persidis A, Nat Biotechnology, 17: 94-5,1999). Depending upon drug concentra-tions employed in the selection process,overexpression of P-glycoprotein may beachieved through increased concentrationof messenger RNA with or without amplifi-cation of the MDR1 gene. Altered expres-sion of genes affecting apoptosis may alsoaccount for resistance (e.g. Helmbach H etal., Int J Cancer, 93: 617-22, 2001). Geneamplification and related effects arerestricted to malignant cells, and are con-sidered to reflect the genomic instabilitythat is characteristic of cancer biology.Exploitation of drug resistance mecha-nisms to improve clinical outcome forpatients with relevant cancers has beenlimited. Surveys have been undertaken toestablish overexpression of “resistance”genes in particular tumour types, and suchstudies may be applied to individualtumours as a basis for designing therapy.

Drug resistance mechanisms operating inclinical cancer are demonstrable.However, the findings overall are com-plex: few specific generalizations can bemade and effective therapy is oftenrestricted to individual cases. Likewise,the results of clinical trials of MDR1inhibitors, or novel drugs specificallydeveloped to circumvent particular resist-ance processes, have not become thedominant features of cancer chemothera-py. However, accumulated knowledgetends to confirm the efficacy of drug com-binations rather than single agents asoffering the best basis for cancerchemotherapy. Indeed, the vulnerabilityof single agents to resistance mecha-nisms has been demonstrated in relationto the drug STI-571 (“Gleevec”) which wasdeveloped to specifically inhibit the geneproduct which has a critical role in the eti-ology of chronic myeloid leukaemia(McCormick F, Nature, 412, 281-282,2001).

RESISTANCE TO CANCER CHEMOTHERAPY

Table 6.10 Some causes of cytotoxic drug resistance.

Class of compound Resistance mechanism(s)

AntimetabolitesMethotrexate Defect in active transportation

Polyglutamation defect Increased DHFR

5-Fluorouracil (5-FU) Alterations in activating enzymesIncreased thymidylate synthaseIncreased dUMP

Alkylating agentsMustard derivatives Decreased cellular uptake

Increased cellular gluathione Enhanced DNA repair

Nitrosoureas Enhanced DNA repair via guanine-O6-alkyl transferaseDecreased cellular uptake

Platinum derivatives Increased cellular gluathione Enhanced DNA repair

Anthracyclines and like agents P-glycoproteinAltered topoisomerase-II activity Increased cellular gluathione

Natural alkaloidsTaxanes Alterations in tubulin

P-glycoprotein



Most of the world’s most common can-cers fall into category 3 (Table 6.7).

Prioritizing cancer careChemotherapy is only one of manyapproaches to cancer control (Cancercontrol, p303). In all environments, skilledprioritization is necessary to maximize theoverall benefit of medical intervention.This must include the prevention, educa-tion, early diagnosis, and the other treat-ment modalities outlined elsewhere.Recently, the WHO has published its rec-ommendations for prioritizing anticancerdrugs with the creation of an essentialdrugs list [3]. The drugs were banded bytheir utility in treating category 1, 2 and 3tumours and related to the global inci-dence of the responding tumours.Thirteen drugs were identified which pro-vide beneficial outcomes against certaincancers, with a further four drugs neces-sary to treat leukaemia. Thus 17 drugs canbe considered as the first priority (Table6.8). All are generic and relatively cheapand should be made widely availablebefore the more recent, heavily promotedhigh cost drugs are purchased.A second group of drugs is listed as prior-ity 2. These have well documented bene-fits in certain clinical situations but arenot truly essential, as either drugs frompriority 1 can be used as substitutes ortheir effects are only palliative. Cheaperand simpler forms of palliation with radio-therapy or analgesics may be more appro-priate in low resource environments. Fewof these drugs are available as generics. The practical problems in assessing therole of a particular drug are exemplified bythe case of the taxanes – paclitaxel anddocetaxel. A randomized controlled trial inthe USA demonstrated a 13-month sur-vival advantage for women given paclitax-el and cisplatinum as first-line treatmentfor ovarian cancer when compared tocyclophosphamide and cisplatinum, thepreviously most widely used treatment[4]. The additional cost of paclitaxel perquality-adjusted life year may be as muchas US$ 20,000 per patient. Whether torecommend the routine use of paclitaxelin this situation must relate to the totalhealth care economy of a country [5]. Of

course the wealthy will simply buy thedrug or go abroad for it, but state healthcare systems will increasingly have to takerationing decisions - something politicianstry to avoid. The suggestion is often madethat the pharmaceutical industry shouldmake more effort to create a pricing struc-ture that reflects local economies.Unfortunately parallel importing – the pur-chasing of a drug in a low-priced countryand exporting it to one in which the priceis high and selling it for profit – is a flour-ishing trade. This makes imaginative pric-ing schemes unpopular with major manu-facturers who would see price erosion intheir most profitable markets.The drugs in the priority 3 group arerecent, expensive and some are of lowefficacy. About 50% of patients withmetastatic breast cancer respond to doc-etaxel but the duration of benefit is usual-ly only about six months. A similar order ofbenefit is seen with gemcitabine for non-small cell lung cancer, irinotecan for col-orectal cancer and luteinizing hormone-releasing hormone (LHRH) agonists forprostate cancer. Manufacturers dissemi-nate positive information through pressreleases and by using public relationsagencies which support patient advocacygroups, as well as the more conventionaladvertising in medical journals. This fuelsdemand and disturbs the financing of pub-

lic sector drug supply. Education of politi-cal decision-makers as well as the publicis essential to correct this imbalance. Agood example is the common desire toinvest in stem cell rescue systems in thedeveloping world. Although there is com-pelling evidence for a strong relationshipbetween dose intensity of chemotherapyand tumour response rate, there is nogood randomized data to show that doseescalation with bone marrow support pro-

Fig. 6.14 Prediction for likely changes in approaches to chemotherapy, 2000 – 2025.

Table 6.8

The WHO essential cancer drug list

Bleomycin Procarbazine

Chlorambucil Tamoxifen

Cyclophosphamide Vincristine

Doxorubicin Vinblastine

Etoposide Cytarabine

5-Fluorouracil Dactinomycin

Methotrexate Daunorubicin

Prednisolone 6-Mercaptopurine

Cisplatinum Plus two anti-emetics



duces more cures in common cancers.The cost is enormous, often exceedingUS$ 50,000 per patient.

Drugs for supportive careMost effective cancer chemotherapy hassignificant side-effects. Effective anti-emetics are available and should be rou-tinely administered in advance with mostchemotherapy combinations. Steroids(prednisolone or dexamethasone), adopamine receptor antagonist (domperi-done, metoclopramide) and a 5-hydrox-ytryptamine (5-HT3) receptor antagonist(ondansetron, granisetron) are essential.Local pricing should be used to deter-mine choice within each category.

Neutropenia (subnormal levels of circu-lating neutrophils) and the risk of infec-tion is one of the most common dose-lim-iting side-effects of cancer chemothera-py, leading to reduced dosages, delayedcycles and reduced effectiveness.Recom- binant colony stimulating factorsare available which mobilize marrowstem cells. There is little evidence thattheir routine use enhances the overalleffectiveness of standard chemotherapyand yet two are billion dollar block-busters. A wide range of relatively cheap drugs isavailable for the relief of the many symp-toms experienced by cancer patients.Especially important are the opioid anal-

gesics, which are often strictly controlledand unavailable in many countries. Theeducation of politicians, legislators andhealth care professionals is necessary toreduce the immense amount of needlesssuffering caused globally by inadequateanalgesic use (Palliative care, p297).

Future developmentsSeveral pieces of technology are comingtogether to drive forward chemotherapyin the next decade [6]. Molecular biologyhas provided some remarkable new tar-gets for drug design. The Human GenomeProject will yield huge volumes of infor-mation to categorize cancer risk and todefine likely responses to treatment(Box: Impact of the Human GenomeProject, p324). Understanding and meas-uring gene expression patterns will leadto novel agents to interfere with signaltransduction, gene transcription, apopto-sis and angiogenesis. Gene therapy (Box:Gene therapy for cancer, 289) holdspromise to correct the basic defects thatlead to cancer. It is likely that use of newtherapeutic approaches centring onmolecular biology will increase rapidly inthe near future (Fig. 6.14) but advanceswill be expensive to implement. There isno doubt that the treatment of cancer isset to improve dramatically over the nextdecade. The greatest challenge facing allof us is how to fund the implementationof an equitable system of cancer care inan increasingly material world.

IMMUNOTHERAPY

Treatment of cancer with vaccines tostimulate the host’s own immune systemto reject the cancer has been a goal oftumour immunologists for much of the20th century. Apart from vaccines andthe administration of other agents suchas bacterial products, which constitute“active” immunotherapy, exogenousimmunity may be provided by the givingof antibodies or lymphoreticular cells in“passive” immunotherapy. Progress hasbeen substantial but there is still a longway to go before immunotherapy isaccepted as an important modality in the

Fig. 6.15 Tumour cells are under selective pressure to escape the body’s growth-restricting mechanisms.Upper panel: complex three-way interactions occur between tumour cells, their microenvironment andthe immune system. Neighbouring stromal cells transfer nutrients and growth-stimulatory signals to can-cer cells and stimulate vascularization. Cells of the innate and adaptive immune systems may attack can-cer cells. Lower panel: different mechanisms may lead to evasion or counter-attack of cancer cellstowards the immune system, including impaired antigen presentation, limited activation of cytotoxic T-cells, expression of Fas ligand which kills tumour-infiltrating cytoxic T-cells, natural killer cells, granu-locytes or macrophages and production of mucins which block T-cell proliferation.

Immune system

Activated T cell

Stromal cellsCancer cells

Cytokinereceptors

DF3/MUC1

B7-1/2

MHC I

RCAS1receptor

Growtharrest

Proliferation

Cell death

RCAS1Cytokines

CTLA4

CD28

TCR

DcR3Fas (CD95)

FasL (CD95L)

FasL

Integrins, growthfactors, cytokines

Myeloid cells, natural killercells, activated lymphocytes Immune escape,

clonal expansion,vascularization

Immune escape Tumour cell



treatment of cancer. The problems largelystem from the fact that most cancer anti-gens (proteins displayed on the tumourcell surface which elicit a response fromthe host immune system) are alsoexpressed in normal tissue, albeit at dif-ferent levels or developmental stages (e.g.reappearance of fetal antigens such asalpha-fetoprotein and carcinoembryonicantigen). This lack of “foreignness” hasmeant that immunization against tumourshas proved difficult. It is also clear that themethod by which the antigen is presentedto the immune system is critical in that T-cells can be “tolerized” to the tumour anti-gen, rather than activated. Immuneresponses can be qualitatively differentand vary in their ability to reject tumours.The determinants of these differentresponses by the immune system arebecoming better understood and arebecoming incorporated into the designand administration of vaccines. On theother hand, the plasticity of the genome oftumour cells allows for the rapid genera-tion of antigen-loss variants, which insome cases exceeds the adaptiveprocesses of the immune system.Products of the tumour cell may havedirect suppressive effects on immuneresponses. Certain tumour cells alsoappear resistant to programmed celldeath induced by the immune cells.

Problems to be overcome inimmunotherapyThere are inherent problems which limitthe effectiveness of immune therapy (Fig.6.15). Cancer cells can receive nutrientsand growth-stimulatory signals fromneighbouring stromal cells and stimulateneovascularization. Cells of both theinnate (or non-specific, e.g. myeloid cellssuch as macrophages and neutrophils)and adaptive (or acquired, requiring theproduction of antibodies, e.g. lymphoidcells such as T-, B- and natural killer cells)immune systems may attack cancer cells.Myeloid cells can attack tumour cells in anantigen- and major histocompatibilitycomplex (MHC)-independent way, forexample, natural killer (NK) cells are trig-gered by cells lacking MHC class I mole-cules. In contrast, cytotoxic T lymphocytes

must be activated by antigen-derived pep-tides presented by MHC molecules. Thelack of “foreignness” of a tumour isreflected in the number of precursor T-cells that are available in the host to rejectthe tumour. The higher the number of T-cells that recognize the tumour, the morelikely it is that tumour rejection will occur.An extreme example of this is the rejec-tion of allotransplants (grafts between twogenetically different individuals) due tothe host’s possession of a high frequency(approximately 1 in 300) of precursorsagainst alloantigens. Although it is unlike-ly that immunization against a singletumour cell antigen will achieve this fre-quency of T-cells, it is quite possible thatimmunization against several antigens willsummate to these levels. It has long been suspected that T-cells incancer patients were tolerant to tumourantigens. Impaired antigen presentationresults in limited cytotoxic T lymphocyteactivation. This may follow from theexpression of decoy receptor DcR3 oncancer cells and the neutralization of Fasligand (CD95L) produced by cytotoxic Tlymphocytes and natural killer cells (Fig.6.15, lower panel). Expression of Fas lig-and may kill tumour-infiltrating cytotoxic T

lymphocytes, natural killer cells, granulo-cytes or macrophages. Mucins, such asDF3/MUC1, or the new ligand RCAS1 (agrowth inhibitory molecule expressed inmany ovarian and uterine carcinomas),may block T-cell proliferation, adding tothe arsenal of weapons that tumours mayuse to evade control by the immune sys-tem.Measurement of tolerance has been facil-itated by the introduction of tetramertechnology. Tetramers are formed by link-ing biotinylated human leukocyte antigen(HLA) class I molecules to avidin and thenadding peptides to the complex that arerecognized by T-cells. Studies in trans-genic mouse models and in melanomapatients have shown that tolerance of T-cells appears to correlate with low avid-ity of the T-cell receptor for the corre-sponding antigen [7].In addition to the requirement for a highfrequency of high avidity T-cells targetedagainst the antigen, it is also importantthat the responding T-cells producecytokines, such as IFN-γ and IL-2, thatrecruit type 1 helper T-cell (TH1)-mediat-ed responses, rather than IL-4- and IL-10-recruited type 2 helper T-cell (TH2)responses, which induce antibody pro-

Fig. 6.16 Generation of cytotoxic T lymphocyte activity is dependent on interaction with mature dendri-tic cells (a distinct set of antigen-producing cells). CTL = cytotoxic T cell, THL = T-helper cell.

CD4TH1 cell

CD8CTL

CD8CTL

CD8

CD8

CD4Tumour cell Costimuli

Presentation

Presentation

Antigen Processing

Dendritic cell

Mature dendritic cell

CD40L, lipopoly-saccharide, viruses

Cofactor

Antigen isshed by the

tumour

Tumourcelllysis



,

Technology developed for manipulation ofgenetic material in an experimental con-text gave rise to the notion of alteringgene structure or expression in the con-text of clinical treatment. Adenosinedeaminase deficiency was the first inher-ited disease for which clinical gene thera-py was performed (Blaese RM et al.,Science, 270: 475-80, 1995). Infusion of T- cells in which the adenosine deaminasegene had been retrovirally transferred ledto sustained detection of transduced andfunctional T-cells at least in two cases.Advancing knowledge about the geneticlesions present in cancer cells hasallowed the emergence of gene therapy asa new method of intervention against can-cer, which is targeted at the level of geneexpression. Gene therapy has the poten-tial to achieve a much higher level ofspecificity of action than conventionaldrug therapeutics owing to pinpoint tar-geting of control and regulatory mecha-nisms of gene expression (Gomez-NavarroJ et al., Eur J Cancer, 35: 2039-2057,1999).A number of strategies for cancer genetherapy have been developed to the pointof phase I or II trials: Mutation compensation – includes replace -ment of a deficient function, e.g. of atumour suppressor gene (e.g. retinoblas-toma) by administering the wild-typegene, or ablating the function of a domi-nant oncogene (e.g. E1A). However,tumours are typically heterogeneous intheir patterns of oncogene/tumour sup-pressor gene expression and possessmore than one abnormality. Developmentof such therapy may require the “perma-nent” expression of the modified gene.Molecular chemotherapy – includes deliv-ery of a gene which is toxic to a cancercell (e.g. thymidine kinase), or increasesits sensitivity to conventional therapies(e.g. the P450 gene sensitizes breast can-cer to cyclophosphamide), or protectsbone marrow from myelosuppression

induced by chemotherapy. Problems to beovercome include a low transfection ratewhen the vector is injected loco-regionally,dose-limiting toxicity and the appearanceof drug-resistant subpopulations.Genetic immunopotentiation – attempts toenhance the anti-tumour activity of cells ofthe immune system (e.g. tumour-infiltrat-ing lymphocytes) or to increase theimmunogenicity of the tumour cell itself(e.g. transfer of granulocyte-macrophagecolony stimulating factor (GM-CSF), the B7family of co-stimulatory molecules, ormajor histocompatibility complex (MHC)).Obstacles to success include low transferrate, tolerance of tumour antigens, andinhibition of immune response.The promise of gene therapy has been real-ized in limited contexts. Primary immuno-deficiencies have long been considered asa possible experimental field for gene ther-apy. As noted, adenosine deaminase defi-ciency was the first inherited disease forwhich clinical gene therapy was per-formed. The low number of cells trans-duced with the required gene, however,was not sufficient to provide sustainedclinical benefit.Nevertheless, Severe Combined Immuno-deficiencies (SCID) represent unique con-ditions in which currently available vectorscan still be considered for a therapeuticapproach. This assumption is based on theexpected selective advantage conferred totransduced cells in this setting. X-linkedSCID is characterized by an absence ofmature T and natural killer (NK) lympho-cytes due to gamma c chain cytokinereceptor deficiency. The ability of gamma cchain-transduced CD34+ cells from SCID-X1 patients to mature into T-cells (Hacein-Bey S et al., Blood, 92: 4090-7, 1998), aswell as NK cells (Cavazzana-Calvo M et al.,Blood, 88: 3901-9, 1996), sets the basis fora clinical trial of ex-vivo gene transfer intoCD34+ cells from SCID-X1 patients.The clinical trial was approved in January1999 and initiated in March of the sameyear. Five patients were enrolled. Ex-vivogene transfer led to an infection rate ofCD34+ cells of 40% and 14 - 26.5 x 106/kgCD34+ cells were infused back to the

patients without prior chemoablation. Inall patients but one, T lymphocyte countswere detected from day 30 and rose pro-gressively to reach values ≥ 3500/µl forthe first two patients (Cavazzana-Calvo Met al., Science, 288: 669-72, 2000) andabout 4800/µl for the fourth patient.These results are promising, althoughpreliminary, and may open the door totreatment of other immunodeficiencies,and possibly cancer, by ex-vivo genetransfer.

Website:

Clinical trials in human gene transfer, Office of

Biotechnology Activities, NIH:

http://www4.od.nih.gov/oba/clinicaltrial.htm

GENE THERAPY FOR CANCER

Control

Macro Histopathology

Treatedwith a virus carrying the

FHIT gene

Fig. 6.17 Tumours are evident in the forestomach(Fst) and at the squamocolumnar junction (SCJ)with the hindstomach (Hst) in mice who possessonly one normal copy of the FHIT tumour suppres-sor gene. Oral administration of a virus carrying awildtype FHIT gene results in a substantial reduc-tion in numbers and size of these tumours, andnear normal stomach epithelia. K.R. Dumon et al.(2001) Proc Natl Acad Sci USA 98:3346-51.



duction. It is clear that tumour cells arenot passive targets for destruction by theimmune system but become selectedpartly on the basis of products whichinhibit host responses (Table 6.9).

Principles of immunotherapyThe considerations above and the experi-ence gained from past studies onimmunotherapy suggest it is possible toformulate principles that might apply irre-spective of the cancer under study. Immunization at sites removed from thetumour reduces the influence of thetumour on the antigen-presenting cell.Administration of a vaccine can be opti-mized in terms of dose, frequency andduration. Adjuvants (substances mixedwith an antigen to enhance the immuneresponse to this antigen) may increasenumbers of antigen-presenting cells andprocessing thereby.Induction of high affinity T-cell responsesis becoming an important objective andunderlies much of the interest in the useof dendritic cell vaccines. This is becausestudies in several animal models haveshown it is possible to break tolerance byimmunization with the antigen displayedon dendritic cells that have been activatedby suitable agents, such as CD40 ligand,TNF-α and others [8-10]. Figure 6.16 illus-trates recent concepts of how helper T-cells may act to cause maturation of den-dritic cells to a stage where they caninduce cytotoxic T-cell activity. Dendriticcells are induced to mature by interactionwith helper T-cells which express theCD40 ligand. Dendritic cells can also bematured by lipopolysaccharide, TNF-α andviruses. Activated cytotoxic T lymphocytescan kill tumour cells expressing the rele-vant antigens. Tumour cells may inhibitdendritic cell maturation by release of fac-tors such as interleukin IL-10 and vascularendothelial growth factor.Immunization with low doses of antigen,such as with plasmid DNA, also appears tofavour the induction of high affinity T-cells.The optimal antigens to be used in vac-cines will differ between different types ofcancer but in general the aim is to includeantigens that are expressed at relativelyhigh concentrations on the tumour cell

and against which there are relatively highnumbers of precursor cells [11-13].Increasing the relative numbers of T-cellstargeted against a particular antigen hasnot proven an easy task and approachesto this include depletion of overall T-cellnumbers prior to immunization. The mosteffective antigens in animal models havebeen individual-specific antigens. Thesame may apply in humans but use ofautologous tumours cells or tumourextracts (derived from the host’s owntumour) has practical difficulties in mostpatients. The general aim, however, is touse antigens in the vaccine which willincrease the number of T-cells above therequired threshold for rejection of thetumour.

Cancer vaccine trialsMelanoma remains the most studiedhuman cancer, in terms of potential fortreatment by immunotherapy. A numberof phase III (comparison of the relativevalue of the new drug with the currentstandard treatment) and phase I/II trials(initial evaluation of a drug's safety andpharmacokinetics, generally in patientswith advanced disease/focus on theactivity of the new product as a single

agent in a noncomparative, open study)have been conducted. Multiple centreshave reported phase III trials based onuse of whole cells or lysates of wholecells [14]. Most recently, the emphasis invaccine development has shifted to theuse of well-defined antigens in vaccines,such as peptide epitopes recognized byT-cells or whole proteins [7].Immunotherapy with dendritic cells isalso being tested in a number of centres. The objective of inducing apoptosis bythe TNF family of ligands has receivedvery little attention as a therapeuticstrategy in immunotherapy but may holdthe key to whether the immunotherapy issuccessful or not. Interferon-α2 (IFN-α2)is able to induce TRAIL (TNF-relatedapoptosis-inducing ligand) (Apoptosis,p113) on a variety of different lympho-cytes such CD4 T-cells, natural killercells and monocytes [15].

Broad perspectivesInsights into the complexity of tumourcells and the host immune system aregradually evolving. The lack of foreignnessof most tumour antigens, tolerance of theimmune system to the antigens andrelease of immunosuppressive factors by

Table 6.9 Mechanisms involved in inhibition of host immune responses to tumours.

Mechanism Factors involved

Inhibition of antigen Vascular endothelial growth factor (VEGF), presentation interleukin-10 (IL-10)

Inhibition of cytokine IL-10, transforming growth factor-β (TGF-β)production α- melanocyte-stimulating hormone

Tolerance of T cells Tumour antigen, hydrogen peroxide,lack of co-stimulation

Inhibition of migration of leu- Prostaglandin E2, VEGFkocytes from blood vessels

Tumour-mediated destruction Fas Ligand, Tumour necrosis factor-related of T cells apoptosis-inducing ligand (TRAIL)

Resistance of tumour cells IL-10, immunoselection of human leukocyte to killing antigen (HLA) and antigen loss variants


tumour cells provides a formidable prob-lem to development of effective vaccinetherapy. Most of the existing phase III tri-als are based on use of whole cell orlysates of whole cells and were initiatedbefore some of the more recent conceptsin tumour immunology were known. Theresults of three randomized trials inpatients with melanoma have shown nosubstantial benefit from vaccine therapybut several major studies have yet to becompleted. The advent of many “start-up”biotechnology companies and new infor-mation about cancer antigens has gener-ated many new approaches in cancer vac-cine therapy, particularly in the use ofdendritic cell vaccines. The next few yearspromise therefore to be an exciting periodin the evolution of immunotherapy.

HORMONAL THERAPYAdjuvant endocrine therapy is a standardcomponent in the management of

tumours of the breast and prostate gland. In breast cancer, anti-estrogenic treat-ment is recommended for all post-menopausal women with newly-diagnosedmetastatic disease if the tumour biopsyshows evidence of estrogen receptor (ER)or progesterone receptor (PR) expression.Similarly, this treatment is given if thereceptor status is unknown, whereasER/PR-negative carcinomas are not treat-ed since they cannot be expected torespond. For many years, tamoxifen hasbeen the drug of choice as many clinicaltrials have shown that it significantlyincreases progression-free survival; it mayalso prevent or delay the development ofbreast cancer in high-risk women [16]. Assecond-line treatment, the selective aro-matase inhibitor anastrozole has beenshown to be similarly effective. About one-quarter of breast carcinomas overexpressthe HER2/neu protein (the ERBB2 geneproduct) and these may respond to thera-

py with a monoclonal antibody (Herceptin)that binds to the receptor. Prostate cancer was the first human neo-plasm to be successfully treated with hor-monal therapy, which has been used in thetreatment of advanced disease for morethan six decades. Androgen suppressionmay be achieved by luteinizing hormone-releasing hormone (LHRH) agonists orsurgical orchidectomy. The majority ofpatients with metastatic prostate cancershow an initial response, often with signif-icant relief of symptoms, but treatment israrely curative and in most cases tumoursbecome resistant to anti-androgen thera-py.Hormonal therapy, commonly with prog-estational agents, is also indicated anduseful in the treatment of metastatic can-cer of the endometrium, being associatedwith significant improvements in survival.


1. Early Breast Cancer Trialists' Collaborative Group(1992) Systemic treatment of early breast cancer by hor-monal, cytotoxic, or immune therapy. 133 randomised tri-als involving 31,000 recurrences and 24,000 deaths among75,000 women. Lancet, 339: 71-85.

2. NCI/ASCO (1998) Integrating economic analysis intocancer clinical trials: the National Cancer Institute-American Society of Clinical Oncology EconomicsWorkbook. J Natl Cancer Inst Monogr, 1-28.

3. Sikora K, Advani S, Koroltchouk V, Magrath I, Levy L,Pinedo H, Schwartsmann G, Tattersall M, Yan S (1999)Essential drugs for cancer therapy: a World HealthOrganization consultation. Ann Oncol, 10: 385-390.

4. McGuire W, Neugut AI, Arikian S, Doyle J, Dezii CM(1997) Analysis of the cost-effectiveness of paclitaxel asalternative combination therapy for advanced ovarian can-cer. J Clin Oncol, 15: 640-645.

5. Sikora K (1999) Developing a global strategy for can-cer. Eur J Cancer, 35: 24-31.

6. Sikora K (1998) Cancer. In: Marinker M, Peckham,Meds, Clinical futures, London, BMJ Books, 74-95.

7. Hersey P (2003) Principles in immunotherapy ofmelanoma. In: Thompson JF, Morton DL, Kroon, BBR eds,Textbook of Melanoma: Pathology, Diagnosis andManagement, Martin Dunitz.

8. Lanzavecchia A (1998) Immunology. Licence to kill.Nature, 393: 413-414.

9. Sotomayor EM, Borrello I, Tubb E, Rattis FM, Bien H, LuZ, Fein S, Schoenberger S, Levitsky HI (1999) Conversionof tumor-specific CD4+ T-cell tolerance to T-cell primingthrough in vivo ligation of CD40. Nat Med, 5: 780-787.

10. Diehl L, den Boer AT, Schoenberger SP, van der VoortEI, Schumacher TN, Melief CJ, Offringa R, Toes RE (1999)CD40 activation in vivo overcomes peptide-induced periph-eral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med, 5: 774-779.

11. Boon T, van der Bruggen P (1996) Human tumor anti-gens recognized by T lymphocytes. J Exp Med, 183: 725-729.

12. Rosenberg SA (1999) A new era for cancerimmunotherapy based on the genes that encode cancerantigens. Immunity, 10: 281-287.

13. Gilboa E (1999) The makings of a tumor rejection anti-gen. Immunity, 11: 263-270.

14. Hersey P (2002) Advances in non-surgical treatmentof melanoma. Expert Opin Investig Drugs, 11:75-85.

15. Nguyen T, Thomas WD, Zhang XD, Sanders J, HerseyP (2000) Immunologically mediated tumor cell apoptosis.The role of TRAIL in T cell and cytokine mediated respons-es to melanoma. Forum (Genova ), 10: 243-252.

16. O'Regan RM, Jordan VC (2002) The evolution oftamoxifen therapy in breast cancer: selective oestrogen-receptor modulators and downregulators. Lancet Oncol, 3:207-214.

REFERENCESDrug Information: a guide to prescription and over-the-counter medications (USA):http://www.nlm.nih.gov/medlineplus/druginformation.html

US Food and Drug Administration Oncology Tools website:http://www.fda.gov/cder/cancer/

American Society of Clinical Oncology:http://www.asco.org

WEBSITES


DefinitionContemporary medicine places an empha-sis on comprehensive patient care. In thecancer patient, this encompasses not onlythe patient’s immediate condition andtreatment, but also longer-term effects,physical disabilities, vocational issues andsocial reintegration.Rehabilitation is the process of returning aperson to their highest level of functionfollowing illness, injury or other debilitat-ing events, the physical, psychological,social and vocational effects of which canlead to impairment, disability or handicap[1]. Impairment results from a loss or abnor-mality of physiological or anatomicalstructure or function [2]. These can be theclinical features or manifestations of a dis-ease, such as weakness or confusion froma brain tumour [3].A disability is a restriction or lack of abili-ty to perform a task or activity within thenormal range. This is the functional con-sequence of the impairment. An examplemay be the inability to walk due to weak-ness caused by a brain tumour.A handicap results from the interaction of aperson with their environment leading to adisadvantage in performing a role otherwisenormal for an individual. An example wouldbe the inability to continue work as a mail

carrier due to the inability to walk fromweakness caused by a brain tumour. Cancer rehabilitation is the process bywhich those with cancer maximize theirfunction and minimize their disability fromthe impairments of cancer, while attemptingto maintain their quality of life (Table 6.11).Quality of life can be defined as a sense ofwell-being from current life experiences“in the context of the value systems inwhich they live, and in relation to theirgoals and concerns.” [5].

Overall perspectiveDue to earlier diagnosis and improve-ments in treatment, people are livinglonger following the diagnosis of cancer.The average five-year survival rate for can-cer patients is 50% in developed coun-tries, 30% in developing countries.However, cancer patients are frequentlyleft with deficits in mobility, cognition andself-care. Cancer rehabilitation helps peo-ple live better with cancer. There is thusan increasing need for rehabilitation pro-fessionals to care for cancer patients andsurvivors [4].Cancer rehabilitation can improve qualityof life by eliminating or decreasing the

REHABILITATION


SUMMARY

> Rehabilitation involves restoring cancerpatients to their highest achievable levelof physical and psycho-intellectualcapacity despite the impact of disease,thus improving quality of life.

> Medical, physical, cultural, financial andemotional needs of individuals must beconsidered.

> A comprehensive interdisciplinary teamprovides the optimal means.

Table 6.11

Objectives of cancer rehabilitation

Maximize functional abilities.

Minimize disability from cancer-relatedimpairments.

Maintain quality of life.

Provide treatments for symptom control.

Fig. 6.18 Occupational therapy focuses on therestoration of bodily functions, mechanical move-ments and increasing patients’ quality of life. Von Kantor and Associates, Fort Lauderdale, USA.

Table 6.12 The number of physiatrists (physical medicine and rehabilitation specialists) certified by theAmerican Board of Physical Medicine and Rehabilitation has increased six-fold since 1975.

Year Physiatrists certified

No. certified in that year Total certified

1975 65 1,163

1978 114 1,469

1980 101 1,709

1985 166 2,378

1990 287 3,454

1995 298 4,940

1998 317 5,886

1999 334 6,220


“burden of care” needed for cancerpatients. Quality of life is subjectivelydefined by each individual but usuallyincludes a sense of dignity. Dignity maysimply be using a commode rather than abedpan, being able to dress oneself, orbeing able to get from bed to chair with lit-tle assistance. Cancer rehabilitationstrives to enable patients to keep theirrespect and dignity. Due to the aggressive nature of many can-cers, treatment has rightly been the focusof most clinicians. However, there canalso be tremendous disability associatedwith cancer and its treatments, and thusrehabilitation is appropriate for patientsthroughout their disease. It is importantthat the primary care physician, medicaloncologist, surgeon, radiation oncologistand palliative care physician are aware ofthe benefits of rehabilitation, minimizingdisability as early as possible in the courseof the disease. However, unlike diseasesand injuries traditionally seen in rehabili-tation medicine, cancer can be progres-sive in nature, and medical interventionsmay be ongoing. Cancer rehabilitation must balance thebenefits of continued rehabilitation thera-pies with the physiological effects oftumour progression and advanced cancertreatments. With advanced cancer, furthertherapies may not be able to make appre-ciable differences in function and actuallyprevent patients from doing things theywant to do by expending their limited timeand energy resources. Therefore, as withmany other treatments for cancerpatients, it is very important to recognizewhen “enough is enough”. In patients withadvanced cancer, rehabilitation can oftenprovide an objective view of the patientthrough their functional abilities and activ-ity, thus providing important informationfor palliative care-type decisions(Palliative care, p297).It is important to know of further plannedcancer treatments as these can impactupon the patient’s condition and abilities.Aggressive chemotherapy can result infatigue, decreased nutritional intake andimmunosuppression, which can affectfunction as well as participation in a reha-bilitation programme. Surgery to debulk

or remove tumour can lead to neurologicaland musculoskeletal deficits, not to men-tion other complications associated withmajor surgery in a high-risk population. Ifmajor surgery is planned for the nearfuture, therapy to address current func-tional deficits may be wasted as otherdeficits may be acquired after surgery. Itmay therefore often be advantageous todelay intensive rehabilitation until thesetreatments are completed.

Responsibility for rehabilitationDue to complex medical, physical, social,financial and emotional issues, cancerrehabilitation is best facilitated by a com-prehensive interdisciplinary team. Effec-tive communication and teamwork isessential in formulating and carrying outplans to achieve successful rehabilitationoutcomes. Team members may include aphysiatrist (i.e. a physical medicine andrehabilitation specialist), the primary carephysician, a medical oncologist, surgeon,radiation oncologist, physical therapist,occupational therapist, speech therapist,case manager, social worker, nutritionist,rehabilitation nurse and chaplain (Table6.13).The physiatrist can diagnose and treatdeficits in neuromuscular function, pre-scribe physical, occupational and speechtherapies, prescribe therapeutic modali-ties such as tens (a method of producingelectroanalgesia through electrodes ap-plied to the skin) and ultrasound, performjoint and soft tissue injections for symp-tom control, perform electrodiagnosticstudies, and coordinate the comprehen-sive rehabilitation programme created bythe interdisciplinary team to meet theneeds of the patient (Table 6.14). The physical therapist can evaluatepatient strength, range of motion andfunctional mobility, and follow this byappropriate treatments. The occupational therapist can evaluatedeficits in activities of daily living such asfeeding, grooming, bathing, dressing andtoileting, and again follow this withappropriate treatments. The speech therapist can evaluatedeficits in communication, cognition andswallowing. Proposed treatments may

include oral strengthening exercises, useof laryngeal or oesophageal speech tech-niques, alternative communicationdevices, aphasia education and swallow-ing strategies. A nutritionist or dietician can evaluatethe current nutritional status of thepatient and make recommendations ondietary needs based on maintaining cur-rent activity level and also, if possible,increasing strength and endurance.Dietary recommendations may includesupplements or additional tube feeding ifthe nutritional needs of the patient arenot being met. Rehabilitation nursing provides the nec-essary medical and surgical nursing carefor complicated rehabilitation inpatients.They must also reinforce mobility andself-care techniques taught by the othertherapists and provide family educationin skin care, bowel and bladder manage-ment, medication administration, feedingtube use, wound care and many otherpatient care issues. The social worker assists with issues ofpatient and family adjustment to the can-

Rehabilitation 293

Fig. 6.19 In the TRAM flap procedure, the transrectus abdominus muscle, which lies in the lowerabdomen, is used to reconstruct the breast aftermastectomy. Arrows indicate the resulting abdom-inal scar.


cer and its associated disability.Frequently, community resources, familyand friends need to be mobilized for a safedischarge of the patient from hospital. Thesocial worker is familiar with agencies andcharities that can provide financial assis-tance as well as equipment and services,if needed. The case manager can assist patients withhome health and equipment referrals,obtain insurance approvals for inpatientrehabilitation hospitalization, and addressquestions regarding insurance coverage.The chaplain can provide supportive spiri-tual services to patients and their familieswho are having a difficult time coping withthe uncertainty of their disease.It is feasible for knowledgeable primarycare physicians, oncologists, or surgeonsto coordinate appropriate rehabilitationcare. However the time and resourcesnecessary to put together the appropriaterehabilitation team are often not available.

The context of cancer rehabilitationAs previously stated, cancer rehabilitationshould occur throughout the course of thedisease to lessen and prevent disability. Arehabilitation programme can be pre-scribed prior to surgery or treatment toimprove conditioning or toleration of thetreatment. Specific therapies may be pre-scribed to maintain strength or range ofmotion in an area that may be adverselyaffected by proposed treatments. A reha-bilitation programme is often initiated dur-

ing active ongoing treatment to limit theadverse physical affects of the treatmentand also provide the patient with an activerole that he/she can play in the recoveryprocess. Rehabilitation frequently occursafter surgery or chemotherapy when theeffects of disease and treatment have ledto deconditioning or specific functionaldeficits. Rehabilitation for advanced can-cer patients with significant tumour bur-den may focus on therapies designed toimprove basic mobility and self-care.

Finally, rehabilitation for terminal cancerpatients may focus on family training forbasic care-giving, bowel and bladderissues, skin care, pain control, and pallia-tive care measures.Cancer rehabilitation can be performed invarious settings depending on the extentof the cancer and the extent of the dis-ability. For ambulatory patients with focalweaknesses, physical and occupationaltherapists can improve mobility and self-care issues. For patients requiring hospi-talization, a comprehensive interdiscipli-nary team may be used to coordinatemobility, self-care, cognitive, nutritionaland patient care issues prior to dischargeand return home. For advanced cancerpatients, the same interdisciplinary teamcan help teach family members and carershow to move and care for the patient,enabling the patient to spend quality timein familiar surroundings.Outpatient therapies can be obtained inthe office, clinic or therapy gym. Inpatientrehabilitation can occur in a rehabilitationunit that is part of a general hospital orcan occur in a free standing rehabilitationhospital with cancer patient experience.Due to extensive medical issues inadvanced cancer patients, it is beneficialto have ready access to surgical and med-ical consultants as well as medical oncol-ogists for urgent assistance. End-stagecancer rehabilitation can be given in therehabilitation unit, palliative care unit orhospice. At any stage of disease, quality oflife is the goal of cancer rehabilitation,which can also be arranged at home aslong as it is safe for the patient and family.


Table 6.14

Rehabilitation interventions

Physical therapy for strengthening, range of motion exercises, gait training.

Occupational therapy for training in activities of daily living such as bathing, grooming,dressing, toileting.

Speech therapy for cognitive assessment and training, swallowing evaluation and treat-ment.

Orthotic devices for functional assistance and pain control.

Pharmacological treatments for pain, spasticity, bowel and bladder control.

Joint injections, trigger point injections, botulism toxin injections for symptom control.

Table 6.13

Interdisciplinary rehabilitation team

Physiatrist (rehabilitation physician)

Primary care physician, medical oncolo-gist, surgeon, radiation oncologist

Rehabilitation nurse

Physical therapist

Occupational therapist

Speech therapist

Nutritionist

Case manager

Social worker

Chaplain


Rehabilitation 295

A 90-year-old patient with lower legmalignant fibrohistiocytoma is one monthpost-resection, with resulting difficultiesin balance and gait. After appropriatetests and studies are performed to ruleout post-operative infection, deep venousthrombosis or cancer recurrence, areview of the patient’s history reveals thathe is tripping over the toes of his affectedleg. Physical examination reveals weak-ness in the ankle and toe dorsiflexors ofthe affected leg. An orthotist (specialist inorthopaedic appliances) may be contact-ed to fabricate an ankle foot orthosis, pro-viding dorsiflexion assistance. Physicaltherapy can then provide gait trainingwith the orthosis and a device such as acane or walker. Stretching exercises ofthe ankle plantar flexors will also beimportant to prevent a plantar flexion con-tracture. These measures can reduce thefall risk in this elderly patient. Finally,occupational therapy can evaluate thepatient and make sure he can dress hislower extremities, providing an adaptivereacher or other equipment as necessary.

A 42-year-old woman with breast cancertreated with modified radical mastectomyfollowed by transrectus abdominus mus-cle flap reconstruction is now sufferingright shoulder stiffness and right armswelling, 8 weeks after surgery. Assumingappropriate tests and studies have beenperformed to rule out recurrence of dis-ease, post-operative wound infection orvenous thrombosis, a likely diagnosiswould be lymphoedema, secondary tosurgical lymph node dissection. Exam-ination of the right upper extremity wouldinclude assessment of strength, sensa-tion, and range of motion. A quantitativemeasurement of oedema may be accom-plished by circumferential measurementsof the arm at measured distances fromthe elbow and wrist. Deficits in range ofmotion can be addressed with a physicalor occupational therapy exercise pro-gramme. Lymphoedema can be treatedwith compression wrapping, a compres-

sion garment and/or manual lymphdrainage exercises. Medications to treatneuropathic pain may be prescribed.Finally, patient education in lymphoedemamanagement and prevention with recom-mendations on activity modification can bereinforced.

A 60-year-old male patient with metastaticrenal cell cancer to the spine with resultingspinal cord compression and paraplegia(paralysis of the legs and lower part of thebody) is hospitalized for palliative radiationtreatments to the spine. The patient’sdeficits resulting from his paraplegia mayinclude impaired mobility and self care,impaired sensation to his lower trunk, andneurogenic bowel and bladder (dysfunctionof the bowel and bladder due to a malfunc-tion of the relevant nerves). Although hisprognosis is poor, a brief concentrated inpa-tient rehabilitation programme can greatlyimprove his quality of life by teaching himhow to do more for himself, and teachingloved ones how to care for him when hebecomes unable to do so. Physical therapycan instruct the patient on bed mobility, ontransfer techniques from the bed to wheel-chair, on wheelchair use, and also provide arange of motion exercises for spasticitymanagement. Occupational therapy caninstruct the patient in upper extremity tech-niques to facilitate bathing, grooming, toi-leting and dressing as a paraplegic.Rehabilitation nursing can teach the patientand family a skin maintenance programme,urinary catheterization for bladder manage-ment, as well as techniques and medica-tions to manage neurogenic bowel. Patientand family education would also be benefi-cial in the areas of deep venous thrombosisprevention, autonomic dysreflexia preven-tion and management, and energy conser-vation. An in-patient rehabilitation pro-gramme with concomitant radiation thera-py may be completed within 1-2 weeks,resulting in a paraplegic patient who is ableto perform wheelchair mobility and self carewithout physical assistance.

A 33-year-old patient with left frontalglioblastoma multiforme has been treated

with craniotomy (operation on the skull)for tumour resection with resulting righthemiplegia and aphasia (speech dysfunc-tion). The patient may have deficits inmobility, self-care and communication.He may be depressed. He may also havedysphagia and be at risk from aspiration(breathing foreign material into thelungs). A speech therapist can assess hisspeech and cognition, providing assistedcommunication as appropriate. A swal-low evaluation with radiographic con-trast can provide evidence of aspiration,and diet modifications, swallowingstrategies, or a feeding tube may be rec-ommended. Physical therapy canaddress mobility issues such as trans-fers from bed to chair and ambulation asappropriate. A cane, walker or wheel-chair may be necessary depending on thedegree of weakness. Occupational thera-py can address self-care abilities associ-ated with the hemiparesis such as feed-ing, grooming, bathing, and toileting.Both physical therapy and occupationaltherapy can provide a stretching andstrengthening programme for the affect-ed side. Rehabilitation nursing can assistin assessment of bowel and bladder func-tion and assessment of skin integrity. Itwill be necessary to teach the patientand family how to maintain these areasin the home setting. When the patienthas reached a level of functioning withmobility and self-care that is safe forhome discharge, it may be beneficial tocontinue some therapies as an outpa-tient. These can reinforce concepts andtechniques learned in the hospital andalso provide an opportunity to problem-solve difficulties encountered in thehome setting. With the nature of thistumour, it is likely that further neurolog-ic deterioration in the future will lead tofurther functional deficits. It is importantto plan for this decline, providing thepatient and family with necessary educa-tion and equipment. It is also possiblethat this patient will have brain irradia-tion, repeat surgery or chemotherapy, allof which require further rehabilitationassistance.

CASE EXAMPLES



1. Garden FH, Gillis TA (1996) Principles of CancerRehabilitation. In: Braddom RL, Buschbacher R.M. eds,Physical Medicine and Rehabilitation, Philadelphia,Saunders, 1199-1214.

2. World Health Organization (1980) InternationalClassification of Impairments, Disabilities, and Handicaps,Geneva, WHO.

3. Levin V, Gillis TA, Yadav R, Guo Y (2002) Rehabilitationof Patients with Neurological Tumours and Tumour-related

Disabilities. In: Levin V ed., Cancer in the Nervous System.2nd Edition, Oxford University Press.

4. Conference Report (2001) Cancer Rehabilitation in theNew Millenium (Supplement). Cancer, 92: 970-1048.

5. WHO QOL Group (1998) The World Health OrganizationQuality of Life Assessment (WHO QOL): development andgeneral psychometric properties. Soc Sci Med, 46: 1569-1585.

REFERENCESAmerican Academy of Physical Medicine andRehabilitation:http://www.aapmr.org/

WEBSITE


Death from cancer, which is usually pre-ceded by significant morbidity, may occur:- at the time of diagnosis (especially whendiagnosed at an advanced stage as is thenorm in less industrialized countries); - during treatment with some major symp-toms the direct result of anticancer treat-ment (surgery, radiotherapy, chemothera-py); - when disease is progressive with less orno effectiveness for anticancer treatment(even if available).In all stages, the patient needs compre-hensive care and a patient with an eventu-ally fatal disease requires good palliativecare from the time of diagnosis. Compre-hensive care should proceed concurrentlywith anticancer treatment, whether withcurative or palliative intent. This approachto palliative care – as relevant to theentire care of a patient with probablyeventually fatal disease – is in sharp con-trast to other models of cancer care,

specifically including those in which pallia-tive care is squeezed into a small sectionof the overall management.

Principles of palliative careGoals for patients with probably incurabledisease should relate to optimum qualityof life as well as achievable prolongationof life, but not to immortality. Hope is notfostered by unrealistic goals; rather, theseforeshadow emotional despair.Decisions should concern the overall careof the patient, including anticancer thera-pies, where evidence indicates that per-sonal benefit should ensue (tumourresponse closely but not wholly parallelspatient benefit) and truly informed con-sent is given by the patient under normalcircumstances, or by a duly qualified rep-resentative if the patient is incompetent[1-4].Advances in palliative medicine and pallia-tive nursing in the last two decades havemarkedly increased the options for thera-py that may be provided to patients withcomplications of advanced disease, suchas gastrointestinal obstruction. Apartfrom these broad considerations, the fol-lowing specific issues must be addressedin the context of palliative care for a par-ticular patient:- relief of major symptoms in all stages ofdisease, especially cancer pain relief;- comprehensive care for patients actual-ly close to death;- support for family during the illness andafter the death of the patient.

The adequacy of palliative care Evaluation of palliative care may be relat-ed to structural issues (e.g. personnel,facilities, drugs), processes (modes ofdelivery of care) or outcomes [5]. In prac-tice, evaluation properly involves a combi-nation of all three categories which maybe assessed at the local, national andinternational level [6].Evaluation should include consideration of:- availability of essential drugs, notablyoral morphine;

- availability of educated professionalswho can serve as a resource for existinghealth services and families, and edu-cation/training systems [7];- evidence of sound decision-making withdue regard for the patient’s wishes;- measurement of major symptoms andtheir relief (especially pain), in the courseof anticancer treatment as well as on ces-sation.The USA has undertaken significantresearch in “End of Life Care”, which hashighlighted deficiencies. An authoritativeCommittee on Care at the End of Life pre-pared a comprehensive report for theInstitute of Medicine, Washington, DC, enti-tled Approaching Death [8]. This reportoffers a blueprint for change relevant at aglobal level. Especially significant is themodel of care proposed (“mixed manage-ment”) with palliative care in its core dimen-sions present from time of diagnosis ofeventually fatal illness, and not tied to prog-nosis (involving failure of all available anti-cancer treatment). This constitutes a radi-cally new approach, with far reaching impli-cations for clinical practice, education,research, quality assurance and administra-tors (and funding agencies), and for spe-cialist palliative care practitioners.

PALLIATIVE CARE

Palliative care 297

SUMMARY

> Central to palliative care are symptomrelief and support for the patients andtheir families, including regard for emo-tional, cultural and other needs.

> A role for palliative care is best consid-ered early in the course of disease, pos-sibly at diagnosis.

> Optimal palliative care depends on ade-quate infrastructure (personnel, facili-ties, drugs) and methodology (modes ofdelivery, dose adjustment by thepatient); its outcome should be evaluat-ed.

> Adequate pain control is an essentialcomponent of cancer care. Supportivetreatment is not limited to immediatemedical needs but should also takeaccount of individual and communitytraditions.

Fig. 6.20 At all stages of disease, the cancerpatient needs comprehensive care. Mary PotterHospice, North Adelaide, South Australia.


Cancer pain relief varies and in someinstances is largely deficient, even incountries with adequate resources andspecialist palliative care services. The bar-riers to cancer pain relief have been codi-fied and include physician attitudes, avail-ability of crucial drugs, and communitybarriers, particularly in relation to the useof morphine. Fear of patients becomingaddicted often remains a barrier at thephysician level, and also at the communi-ty level, despite the fact that such addic-tion is virtually unknown if opioid drugsare used correctly for cancer pain relief.The renowned Wisconsin Cancer PainInitiative involved drug regulators as wellas health professionals in its initial stagesand has shown to the satisfaction of allthat increased availability of morphine forcancer pain relief did not increase drugdiversion in the community. In less developed countries, the publichealth approach to pain relief may be theonly basis for palliative care, the benefitbeing not merely islands of excellence,but general population coverage. Thisapproach has proved valuable in coun-tries such as Spain, where the service setup in Catalonia is a model of excellencerelying on mobilization of the communityand its resources within mainstreamhealth care [9].Nations should be encouraged to developnational guidelines indicating the impor-tance of cancer pain relief; such guide-

lines exist in many countries today. WHOguidelines have stressed the importanceof:- a national policy to make drugs avail-able for cancer pain relief;- actual availability of drugs at the com-munity level as well as in hospitals;- an education programme.These may be regarded as three sides ofa triangle and must all be present if can-cer pain relief is to be achieved. Drugssuch as oral morphine should be availablereadily, with ease of prescription and nogeographic or time restrictions. Use ofmorphine as part of the treatment of can-cer pain relief should be dictated by thenature and severity of the pain and not bythe prognosis.The International Narcotics Control Boardhas strongly supported the liberalizationof the availability of morphine for cancerpain relief and has taken the “ensuring ofan adequate supply of controlled drugsfor medical purposes” as “a principalobjective of the international drug controltreaties” [10]. Unfortunately, the dramat-ic increases in morphine use in the lastten years are frequently not correlatedwith the incidence of advanced cancer:pain relief is almost certainly seriouslyinadequate, but data are scarce.Some procedural changes have beenfound to improve the likelihood of cancerpain relief:- the listing of pain as a vital sign to be

measured in hospital charts;- public education to increase the expec-tations of pain relief;- some system of cancer pain monitoringat a community and national level;- projecting cancer care as a social justiceissue: WHO has recognized cancer painrelief as a right.There is now the need for a coherent ini-tiative to consolidate the earlier gainsachieved by WHO and to prevent unnec-essary suffering for many more peopleworldwide, particularly where strategiesfor cancer pain relief at low cost exist.

The organization of palliative careGood palliative care is not necessarilydependent upon the existence of special-ist palliative care services, but implies themobilization of services and recognitionof priorities within whatever the main-stream health care system is. In somedeveloped countries, specialist palliativecare services are a prominent feature ofhealth care delivery and serve as cata-lysts and resources for patients and fam-ilies with problems more difficult thanaverage.Reference has already been made to thepublic health approach with mobilizationof the whole health care system to carefor those patients with eventually fataldisease at all locations. This implies allo-cation of adequate resources to patientsin this category.


Fig. 6.21 Worldwide morphine consumption nearly tripled between 1984 and 1999, largely as a result of increasing emphasis by WHO on the need to use mor-phine in the treatment of cancer-related pain.

1984 1999

>10 mg/person

1-10 mg/person

<1mg/persondata not available

>10 mg/person

1-10 mg/person

<1mg/person

data not available


WHO has recommended that in developedcountries one half of the availableresources for cancer care should be devot-ed to palliative care, i.e. that the resourcesavailable for palliative care should equalthe combined resources available for allanticancer treatment – surgery, radiother-apy and chemotherapy. WHO recommend-ed that in less developed countries at least80% of resources should be available forpalliative care, noting that there is no othermeasure which can improve the quality oflife of the population as much as widelyavailable palliative care.

Palliative care and cancer pain world-wideGlobal improvements in palliative care donot depend so much upon the creation ofspecialized palliative care services sepa-rate from mainstream health care, butupon the permeation of the whole healthcare system by the principles of palliativecare. This in turn is dependent upon amajor planning exercise with administra-tive, education and research implications.Specialized demonstration programmesare justified to assist in this undertaking.There is now a vast store of information

concerning developments in palliativecare internationally, whether involvingspecialized palliative care services ormainstream health care systems andguidelines have been developed by rele-vant authorities, including theInternational Association of Hospice andPalliative Care.There are problems in all contexts, butimprovements have begun to be recog-nized. Less developed countries vary withregard to palliative care services. In devel-oped countries the problem is that ofpatchy application of the vast body of

Palliative care 299

A majority of cancer patients in most devel-oped countries probably use complemen-tary therapies as adjuncts to mainstreamcare for symptom management and qualityof life. A smaller proportion use “alterna-tive” remedies, unproved methods thattypically are invasive, biologically active,and often promoted as literal alternativesto evidence-based oncology treatment.These methods tend to involve consider-able travel and expense. Many are associ-ated with significant risks of adverseevents or substantial delays in receipt ofneeded care. Many alternatives, such ashigh-dose vitamin C supplements, specialdiets, shark cartilage, Iscador, and laetrile,have been studied and found ineffective.

Conversely, the benefits of some comple-mentary therapies are well documented.Randomized trials support the value ofhypnosis and acupuncture for pain andnausea, of relaxation therapies, musictherapy and massage for anxiety, pain anddepression, of yoga, tai chi and medita-tion for improved strength and stability.These and other complementary thera-pies increasingly are provided in main-stream cancer programmes. Some com-plementary therapies, such as psycholog-ical support, humour therapy and spiritu-al assistance, have been available fordecades as “supportive” care in oncology

medicine. In this sense, complementarymedicine may be seen as an extension andexpansion of earlier efforts to focus onpatients’ broader needs (Cassileth BR, TheAlternative Medicine Handbook: TheComplete Reference Guide to Alternativeand Complementary Therapies, WW Norton& Company, 1998).

Botanicals hold largely untapped promise,requiring serious research to documenttheir value against cancer or capacity toenhance well-being (Duke JA, The GreenPharmacy, New York, Rodale Press, 1997;Tyler VE, Herbs of Choice: The TherapeuticUse of Phytomedicinals, 1993 and Tyler VE,The Honest Herbal: A Sensible Guide To TheUse of Herbs and Related Remedies, 1994,both by Pharmaceutical Press).

However, many herbal remedies are toxicor contaminated, or interact negativelywith pharmaceuticals. St. John’s Wort, forexample, a useful herb for mild and moder-ate depression, is now known to decreaseblood levels of protease inhibitors,cyclosporine and other immunosuppres-sive drugs, birth control pills, cholesterolmedications, Coumadin, and chemothera-peutic agents. Such problems require thatoncologists remain vigilant to potentialinteractions many, if not most, of which,remain undocumented. It is probably safestfor patients to stop herbs and other non-prescription products during receipt of can-cer treatments.

Both the helpful and the problematic com-ponents of complementary and alterna-tive medicine are likely to persist in can-cer medicine. The challenge for the physi-cian and for the patient is to promote andutilize beneficial complementary thera-pies and discard disproved alternatives.In recent years, increasingly greater inte-gration of complementary and conven-tional medicine has occurred, creatingintegrative medicine. This synthesis ofthe best of complementary therapies andmainstream care lights the way to themore comprehensive, humane, and need-ed cancer care that hopefully will charac-terize the future of oncology.

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Fig. 6.23 Massage as a form of relaxation therapy



1. Adequacy of resources for care (espe-cially and at least pain relief) from timeof diagnosis of probably incurable can-cer, in comparison with resources foranticancer treatment (surgery radiother-apy, chemotherapy and the related diag-nostic and monitoring processes). This is an issue throughout the worldbut precise information is needed. It isworth the attention of health econo-mists with an understanding of WHOprinciples.

2. Being allowed to die – and allowingoneself to die: an issue in high technolo-gy environments. Attention should be given to the circum-stances in which futile treatment shouldneither be initiated nor maintained.

3. Education of professionals, especiallydoctors, with respect to the clinical sci-

ence, attitudes and skills essential forcontemporary palliative care. The courage and excellence of the USAnational programme for doctors through-out the country may have global signifi-cance.

4. Increasing incidence of cancer (espe-cially the less curable types), notably inless industrialized countries, associatedwith the ageing of the population and con-tinuing high levels of cigarette smokingand industrial pollution. In such circumstances the balancebetween attempts to cure and carebecomes more crucial, and delivery ofcare must be efficient, effective and sus-tainable at the level of the whole popula-tion in need: a massive challenge.

5. Assessment of adequacy of palliativecare at total community level.

6. Ethical issues relating to the disparityof care available in different circum-

stances throughout the world (differ-ences between countries and withincountries): can we continue to toleratesuch disparities in this millennium?Daniel Callaghan, the founder of therevered Hastings Institute for Ethics hasrecently written: “The greatest impor-tance of palliative care medicine is notsimply the benefit it can bring at the endof life, but its recasting of the goals ofmedicine, trying to better balance careand cure, and in all of life not just at itsend… Most needed is what I call a ‘sus-tainable medicine’… that accepts deathas part of the human condition, that isnot obsessed with the struggle againstdisease, that understands progress aslearning better how to live with, and diewith, mortality as a fundamental markof the human condition” (Callaghan D, JPalliat Care, 8: 3-4, 2000; Callaghan D,The troubled dream of life, New York,1993).

EMERGING ISSUES IN PALLIATIVE CARE

existing clinical science. Whether or notappropriate patients are referred to spe-cialist palliative care services, as shouldbe the case in difficult situations,depends on referral patterns and this factmay impede the delivery of optimum pal-liative care.The obstacles to the achievement of a“good” level of cancer pain relief commu-nity-wide in all countries, but especiallydeveloping countries, include not only thediffusion of knowledge regarding cancerpain relief, policy change concerning drugavailability, and education of health pro-fessionals and the public, but also moresubtle and sensitive issues. There arecountless examples of delays in imple-mentation which are only explicable interms of cultural factors which must berespected and understood.Some of these profound issues are spiri-tual and philosophical, and are felt espe-cially keenly in developing countries.Questions such as the following may be

unspoken, or rarely articulated:- Does the adoption of a recognized strat-egy for cancer pain relief run the risk ofdamaging the spiritual fabric of our socie-ty, of destroying our way of thinking aboutthe meaning of life, of suffering, of death?- When we are so short of resources, whyshould we spend so much time, moneyand trouble on pain treatment in thosewho can no longer work, instead of tryingto cure more people?- Why is cancer pain relief still so poor inthe West, even in prestigious cancer cen-tres?These matters need discussion in situa-tions of trust, and in an atmosphere ofpartnership. It is essential that those seeking to intro-duce the WHO approach to pain relief aredeeply aware of the personal, cultural andspiritual context into which this newmode of thinking and acting is to be intro-duced. The beneficial outcomes to thepatients and their families are so signifi-

cant that these outcomes themselvesmay be the key tool for change: suchchange must come from within the com-munity. However, wise leadership fromsenior administrators and clinicians canhave dramatic consequences.The challenge now in achieving better lev-els of global cancer pain relief is a moreappropriate understanding of the psycho-logical matrix within which the means torelieve that pain must operate. Awarenessof the total ecological matrix – with its his-torical, social, economic, psychologicaland spiritual components – is essential ifcancer pain relief is to be achieved. Insome respects, psychological and spiritualdevelopment in some so-called developingcountries is far in advance of the rest ofthe globe – and there is a need for all torecognize exchange-in-partnership as themost promising means of advance for thethird millennium.Those working in the policy area ofhealth care and with patients should


Palliative care 301

1. Doyle D, Hanks GW, MacDonald N, eds (1997) OxfordTextbook of Palliative Medicine, 2nd Edition, Oxford,Oxford University Press.

2. World Health Organization (1986). Cancer Pain Reliefand Palliative Care, Geneva, WHO.

3. World Health Organization (1996). Cancer Pain Reliefand Palliative Care, Geneva, WHO.

4. World Health Organization (1998). Symptom Relief inTerminal Illness, Geneva, WHO.

5. Higginson I, ed. (1993) Clinical Audit in Palliative Care,Oxford, Radcliffe Medical Press.

6. World Health Organization (2002). National CancerControl Programmes: Policies and ManagementGuidelines, 2nd Edition, Geneva, WHO.

7. American Medical Association Institute of Ethics(1999) EPEC Project. Education for Physicians on End ofLife Care, Chicago.

8. Field MJ, Cassel CK, eds (1997) Approaching Death:Improving Care at the End of Life (Committee on Care atthe End of Life, Division of Health Care Services, Instituteof Medicine), Washington, D.C., National Academy Press.

9. Gomez-Batiste X, Fontanals MD, Roca J, Borras JM,Viladiu P, Stjernsward J, Ruis E (1996) Catalonia WHOdemonstration project on palliative care implementation1990-1995: Results in 1995. J Pain Symptom Management,12: 73-78.

10. International Narcotics Control Board (1999) Reportof the International Narcotics Control Board for 1999,Vienna, United Nations Publications.

REFERENCESThe Macmillan Cancer Relief charity, UK:http://www.macmillan.org.uk/framed.html

National Hospice and Palliative Care Organization, USA:http://www.nhpco.org/

International Association of Hospice and Palliative Care, USA:http://www.hospicecare.com

American Pain Foundation:http://www.painfoundation.org/

Education for Physicians on the End of Life Care (EPEC):http://[email protected]

The WHO Collaborating Center for Policy andCommunications:http://www.medsch.wisc.edu/painpolicy

Cancer Pain Release (publication of the WHO global com-munications programme to improve cancer pain controland palliative and supportive care):http://www.whocancerpain.wisc.edu/

WEBSITES

understand not only the technicalaspects but also the cultural and spiritu-al significance of new approaches to thepatient experiencing pain, the need forrecognition (not hiding) of the pain, andthe obligation to relieve relievable dis-tress, without denying (and indeed con-firming) the precious values forming thefabric of society. Cancer pain relief, andpalliative care in general, give expressionto the compassion which is one of themost basic values within all human soci-eties.

Fig. 6.22 The worldwide medical consumption of morphine is increasing.


cancer management - iarc.fr · al techniques. endoscopic and radiologi-cal technology has enabled...

Documents