evidence supports adjuvant radiotherapy in selected patients with rectal cancer
TRANSCRIPT
ANZ J. Surg.
2004;
74
: 152–157
ORIGINAL ARTICLE
PERSONAL VIEW
EVIDENCE SUPPORTS ADJUVANT RADIOTHERAPY IN SELECTED PATIENTS WITH RECTAL CANCER
P
ETER
G
IBBS
,* M
ICHAEL
W. C
HAO
,* I
AN
T. J
ONES
†
AND
D
ESMOND
Y
IP
‡
Departments of *Oncology and
†
Colorectal Surgery, Royal Melbourne Hospital, Melbourne, Victoria and
‡
Medical Oncology Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia
Background:
Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectalcancer and the impact of adjuvant radiation therapy (RT). With improvements in surgical technique apparently reducing the risk ofLR, the relevance of older data upon which the current recommendations for adjuvant RT are based has been questioned.
Methods:
A focused review was undertaken of the published literature on the risk of LR following surgery for rectal cancer andthe impact of adjuvant radiation. In particular the authors attempt to define how accurately the risk for an individual patient can bepredicted, trends in reported LR rates over the time period of randomized trials, and the relevance of changing surgical and RTtechniques.
Results:
Many of the perceived differences in published results can be explained by variations in study entry criteria, length offollow up and data recording. Comparisons between studies are most accurate when defined subsets of patients, such as those withstage III disease, followed for the same period of time, are considered. In parallel with improvements in surgical technique, whichmay have reduced the risk of LR, modifications to RT delivery have resulted in recent series not reporting an increased mortality inthose patients treated with modern RT techniques.
Conclusion:
All of the available evidence supports the use of adjuvant RT in selected patients with rectal cancer. Ongoing studieswill better define individual patient risk and the risk–benefit ratio of adjuvant RT.
Key words: adjuvant, cancer, morbidity, radiation, rectal, survival, therapy, toxicity.
Abbreviations
: 5-FU, 5-fluorouracil; APR, abdominoperineal resection; CMT, combined modality therapy; GITSG, Gastro-intestinal Tumour Study Group; MSI, microsatellite instability; LCRT, long-course radiation therapy; LR, local recurrence;NSABP, National Surgical Adjuvant Breast and Bowel Project; RT, radiation therapy; SCRT, short-course radiation therapy;TME, total mesorectal excision;
INTRODUCTION
In recent years an extensive literature has focused attention on theimportance of surgical technique, tumour staging and the optimalintegration of adjuvant therapy in optimizing the outcome forpatients with rectal cancer.
1
Since 1990, when the US NationalInstitutes of Health (NIH) recommended that all patients withstage II or III rectal cancer should receive postoperative chemo-therapy and radiation therapy (RT),
2
this has been common prac-tice. In the years since that conclusion was made, a large amountof data have been published and it is appropriate to reviewwhether this recommendation is still valid.
There are many factors that potentially could alter the originalrecommendation made by the NIH on the basis of early studies.These include (i) an improvement in surgical technique that led tosignificantly fewer patients experiencing local recurrence (LR);(ii) an awareness that the morbidity of adjuvant RT has beenunderreported, particularly with respect to bowel function; (iii) animprovement in RT technique that reduced the morbidity andminimized the mortality from adjuvant RT; and/or (iv) an
improvement in overall survival through the optimization of sys-temic chemotherapy resulting in a reduced risk of distant recur-rence. Arguably all of these have happened. To complicate anyeffort to assess the implications of these changes three ‘standard’RT options have emerged, including preoperative short-courseRT (SCRT; 25 Gy in five fractions over 5 days), postoperativelong-course RT (LCRT; 50.4 Gy in 28 fractions over 6 weeks)with chemotherapy, and preoperative LCRT with chemotherapy.
Recently Meagher and Ward published a provocative reviewof the role of adjuvant RT in rectal cancer in this Journal, con-cluding that current evidence does not support the routine use ofthis modality.
3
They argue that in the studies demonstrating asurvival advantage for adjuvant RT, the outcomes in the controlarm were unacceptably poor due to inferior surgical technique,and that with ‘modern surgery’ no survival advantage would havebeen demonstrated. Similarly, with declining LR rates the smallabsolute reduction in LR rates achieved with adjuvant RT is out-weighed by the significant morbidity (and mortality) associatedwith treatment. We present here a commentary on their analysisand a different perspective of the same literature.
CAN WE PREDICT THE RISK OF LOCAL RECURRENCE?
A number of factors interact to determine the risk of LR follow-ing a potentially curative resection for rectal cancer. Some ofthese are readily quantifiable and some are not. The quality of thesurgeon and the type of operation he/she performs are both signif-
P. Gibbs
MD, FRACP;
M. W. Chao
FRACR;
I. T. Jones
FRACS, FRCS;
D. Yip
FRACP.
Correspondence: Dr P. Gibbs, Oncology Department, c/- Post Office RMH,Parkville, Vic. 3050, Australia.Email: [email protected]
Accepted for publication 13 August 2003.
RECTAL CANCER: EVIDENCE FOR ADJUVANT RT 153
icant factors,
4
reflected in the wide range of published LR rates.However, LR cannot be regarded ‘largely as a failure of surgicaltechnique’ as argued by some.
5
Irrespective of the surgeon,the likelihood of an LR will also reflect tumour stage (both Tand N stage),
6
tumour distance from the anal verge, and tumourbiology.
7,8
With respect to tumour stage (staging criteria are summarizedin Tables 1–3), a pelvic relapse may result from direct tumour
extension (reflected by increasing T stage) or spread to regionallymph nodes (reflected by N stage) and the risk can be quantifiedbased on these two variables. The most powerful prognosticinformation is achieved when these two variables are consideredtogether, best illustrated in a recent analysis of 2551 patientstreated in three US adjuvant rectal cancer studies.
6
These trialsemployed similar eligibility criteria and all patients receivedadjuvant RT. Within any T stage, increasing N stage was associ-ated with an increased risk of LR, a similar trend being observedwithin any N stage with increasing T stage. Following adjuvantchemotherapy and RT, patients with a T
3
N
0
or T
1–2
N
1
tumour hadan LR rate of 6–8% at 5 years, those with T
3
N
1
tumours had anLR rate of 11% and for T
3
N
2
or T
4
N
0–2
tumours the LR rate was15–22%. Clearly the enthusiasm for recommending adjuvant RTshould be based on a consideration of both the T stage and theN stage.
The biology of rectal cancer is a critical but as yet largelyunexplored prognostic factor. Some factors that may reflectadverse tumour biology are evident in the routine pathologyreport, including poor tumour differentiation or the presence oflymphovascular invasion.
9
A current major focus of research is anattempt to define specific biological markers that will predictpatient outcomes. Some of these also may predict the likelybenefit from treatment. For example the presence of a mutated
ras
oncogene is associated with increased malignant potential,and decreased survival rates in patients with stage III and IVlesions.
7
The potential role of p53 as a prognostic factor, or apredictive factor of response to chemoradiotherapy, is the subjectof ongoing study. The presence of microsatellite instability (MSI)is associated with a significantly better prognosis and may alsopredict which patients are likely to benefit from adjuvant chemo-therapy.
8
Although none of these markers have become part ofstandard pathologic analysis, many are being prospectivelystudied in current adjuvant studies that will better define theirpotential utility.
WHAT IS THE TRUE RATE OF LOCAL RECURRENCE FOR RECTAL CANCER?
A wide range of LR rates has been reported in the literature,
10
partlyreflecting surgical skill and the type of surgery performed, but mul-tiple other variables will also influence this outcome. Differingpatient populations, variable definitions of LR and the rigour offollow up are just some of the factors that influence the reported LRrates and also confound any comparison between series.
1
Direct comparisons of the LR rates achieved in preoperativeand postoperative studies are potentially the most misleading.The two large preoperative series of SCRT included all patientswith potentially resectable rectal cancer.
11,12
No attempt wasmade to exclude early stage patients (good prognosis) who wouldhave been excluded from postoperative series, but in the Dutchstudy the 57 patients with a positive surgical margin (bad prog-nosis) were excluded from the analysis. The Dutch investigatorsreported that the overall risk of LR following TME surgery alonewas an apparently impressive 8.2% at 2 years of follow up. How-ever, this is a combined result from the LR rate of 15% forpatients with stage III cancer (36% of the total) and the muchlower LR rates for patients with earlier stage cancers (56% of thetotal patients enrolled). Also, 30% of patients in the Dutch studyhad tumours at 10–15 cm from the anal verge. Few of thesepatients experienced an LR
12
and many would have beenexcluded from other adjuvant series of rectal cancer (12 cm from
Table 3.
Clinicopathologic staging system (ACPS) and Dukes staging
Maximum spread ACPS stage
Dukes stage
Mucosa AO –Submucosa or muscularis propria A ABeyond muscularis propria B BRegional nodes involved C CTumour transected (histologic) D A,B or C†Distant metastases (clinical or histological) D (D)‡
†
Staging dependent on extent of tumour spread through the rectal wall.
‡
Dukes did not describe a D stage
Table 2.
TNM staging
T N M
Stage IT
1
N
0
M
0
T
2
N
0
M
0
Stage IIT
3
N
0
M
0
T
4
N
0
M
0
Stage IIIAny T N
1
M
0
Any T N
2
M
0
Stage IVAny T Any N M
1
TNM, tumour, node, metastasis.
Table 1.
TNM stages
TNM Tumour extent
T Spread of tumourTis Carcinoma
in situ
T
1
SubmucosaT
2
Muscularis propriaT
3
Subserosa, non-peritonealized pericolic/perirectal tissueT
4
Other organs or structures/visceral peritoneumN Regional lymph nodesN
0
No regional lymph node metastasesN
1
1–3 positive regional nodesN
2
4 or more positive regional nodesM Distant metastasesM
0
No distant metastasesM
1
Distant metastases
TNM, tumour, node, metastasis.
154 GIBBS
ET AL
.
the anal verge is the maximum distance for inclusion in mostpostoperative adjuvant therapy studies). By the authors’ estimate20–50% of LR had not occurred at the time of this initial analysis,implying that the ultimate overall LR rate will be in the range of10–16% and for stage III cancers it would be 18–30%. In con-trast, stage III cancers, with the attendant increased risk of LR,are dominant in postoperative series.
13–18
Based on the reportedLR rates for each tumour stage in the Dutch study if this serieshad been made up of one-third stage II and two-thirds stage IIIcancers, typical of the patients enrolled in the postoperative USstudies, the LR rate in the surgery alone arm at 2 years would havebeen 11.9% and the projected overall LR rate would be14.3–23.8%. In comparison the LR rate was 24% in the surgeryalone arm of the original Gastrointestinal Tumour Study Group(GITSG) study wherein 66% had stage III rectal cancer (Table 4).
13
It is possible to define subsets of patients within the group whowere routinely offered adjuvant RT based on the risk of LR.
4
TheIntergroup retrospective review found that patients with a T
3
N
0
orT
1–2
N
1–2
tumour had a 6–8% chance of LR following adjuvantchemotherapy and RT.
9
Based on the two randomized trials thathave demonstrated that combined modality therapy reduces therisk of LR by 54–60%,
13,16
the risk of LR following surgery alonewould have been in the order of 12–16%. Without knowledge ofa referring surgeon’s LR rate in routine clinical practice, whichmay be much higher than this figure, an argument could be madethat all of these patients should still be offered adjuvant RT.
WHAT RELEVANCE DO THE REPORTED LR RATES HAVE TO ROUTINE CLINICAL
PRACTICE?
Although data from randomized trials, such as the Dutch study,help to define standard practice, many questions remain for thesurgeon when considering whether to refer a patient for anopinion regarding adjuvant RT. With few exceptions, individualcolorectal surgeons do not know the rate of LR in their own prac-tice. How is the treating medical or radiation oncologist to knowof the surgical expertise of the referring surgeon? If in doubtshould they overestimate the surgeon’s abilities? Even for thesurgeon of average ability can the LR rates achieved in carefullyconducted clinical trials that enrol selected patients be reproducedin routine clinical practice?
What are we to make of series from individual surgeons orcentres that report LR rates far below that reported in prospectiverandomized series?
19–22
As with the preoperative series previ-
ously discussed these include many early stage cancers, typically30% of patients having stage A cancers, and may include highrectal and rectosigmoid tumours.
21
Therefore they cannot bedirectly compared with results achieved in postoperative seriesdue to marked differences in the entry criteria. These series mayalso demonstrate one extreme of the spectrum of LR rates,achieved by good surgeons with a high caseload, and therefore donot represent the results achieved by the average surgeon with asmaller caseload, let alone the less competent surgeon. Thepotential for selective reporting also needs to be consideredbecause surgeons are less likely to publish what they consider tobe poor results. As level IV evidence they should not be used todefine routine care.
We would strongly recommend that individual surgeons con-sider personal audits of rectal cancer surgery outcomes. Leader-ship in this issue is currently being shown by the ColorectalSurgery Society of Australia, who are considering initiatives toimplement national standards for data collection. Ultimatelyroutine data collection may become mandatory
HAS IMPROVED SURGERY REDUCED THE RATE OF LOCAL RECURRENCE IN THE
MODERN ERA?
It has generally been accepted that improved operative techniquewill reduce the risk of LR. Attention has focused on the need for aTME although some have questioned the need for this tech-nique.
22
There are, however, no prospective randomized studiesto support this and indeed it would be unethical to perform such astudy, so we must rely on indirect comparisons between series.The critical question is whether the quality of surgery in theAmerican series
13,14
that led to the recommendation for adjuvantRT is so poor that these results have been invalidated.
The LR rates in two series of SCRT from Europe are strikinglydifferent. In a Swedish series, where the type of surgery was notmandated, the LR rate following surgery alone was 27% at5 years.
11
In the Dutch series, where all surgeons were taughtTME, the LR rate at 2 years was 8.2% (and projected to be10–16% at 5 years).
12
This is a striking difference, but may reflectmore than simply a difference in operative technique. For exam-ple, if only the patients from the Swedish series that underwent a‘curative resection’ are considered, the LR rate in the surgeryalone group drops to 23% because the Swedish investigators,unlike the Dutch, did not exclude patients with a positive resec-tion margin from their analyses.
Table 4.
US studies of adjuvant RT for rectal cancer
Years of accrual Follow up(years)
LR surgery alone(%)
LR with CMT(%)
Overall survival with CMT
(%)
GITSG GI 7175
13
1975–80 8 24 11 58Krook
et al
.
14
1980–86 7 – 14 57GITSG GI 7180
15
1981–85 3 – 16 52O’Connell
et al
.
16
1986–90 – – – 60 (bolus 5-FU)70 (infusional 5-FU)
NSABP R02
17
1987–92 5 – 8 65INT0114
18
1990–92 5 – 14 647 17
RT, radiation therapy; LR, local recurrence; CMT, combined modality therapy; 5-FU, 5-fluorouracil.Only two series included a surgery alone control arm. The series by O’Connell
et al
.
16
did not report figures for LR.
RECTAL CANCER: EVIDENCE FOR ADJUVANT RT 155
The important question, for which there is no answer, is whatrelevance do results from Europe have to results achieved byAmerican surgeons, upon which the current recommendations foradjuvant therapy are based.
13–16
Has surgery improved, as it hasin Europe? Results from another European series, a relativelyrecent postoperative series from Norway, support the notion thatprior to the widespread adoption of TME European results mayhave been inferior to those achieved in older US studies, with anLR rate of 30% in the control arm.
23
This is despite more thanhalf of the patients having Dukes B cancers. Also, how do theresults achieved by surgeons in Australia compare to thosereported in US or European series. Data from individual surgeonsor centres
21,22
compares favourably with the published literatureand results from a large Australian cohort study
24
appear equiva-lent to those achieved in the control arm of a large US series.
25
Another way to address this question of whether or not surgeryhas improved to the same extent in the US as it has in Europe isto look for a trend over time in the LR rates reported in US series(Table 4). There is only one study with a surgery-alone controlarm, so no comparisons can be made between surgery alone arms.An alternative is to compare the LR rates achieved in the chemo-therapy plus RT arms because this consisted of bolus 5-fluoro-uracil (FU) and a similar RT schedule in each case. The NationalSurgical Adjuvant Breast and Bowel Project (NSABP) R-02 studystands out with an LR rate of only 8% at 5 years.
17
However, in amore recent US series using equivalent adjuvant treatment(INT0114),
19
the LR rate was much higher (17% at 7 years),which is at the upper range of that reported in earlier studies. Is itpossible that the LR rates in the NSABP series were a one-offresult? Are there reasons why these rates were lower thanexpected? First, in that study the patients were censored (no longerfollowed for study purposes) after the first sign of recurrence, sothat LR were recorded only if they were the first site of diseaserelapse. (Although the number of LR that occur following docu-mentation of distant recurrences is rarely reported, in the Dutchseries one in six LR occurred after a distant recurrence).
10
Second,there may have been a selection bias in the NSABP study, whichbegan accrual following the initial publication from GITSG,
13
which had demonstrated that adjuvant RT significantly reducesthe risk of LR. Investigators may have been reluctant to enrolpatients at high risk of LR into a study where half of the patientsdid not receive adjuvant RT
.
Finally, the quality of data collectionin that series has been questioned.
17
In summary, there is no cleartrend over time toward lower rates of LR in the patients treatedwith 5-FU and RT, suggesting that the LR rates achieved withsurgery alone would also be steady.
WHAT IS THE IMPACT OF ADJUVANT RADIATION THERAPY ON LOCAL
RECURRENCE?
This is one of the least disputed aspects of any discussion of adju-vant RT. The recent meta-analysis, which included many olderseries, found that preoperative RT reduced the risk of LR byapproximately 50% and postoperative RT by approximately33%.
26
However, the results of recent randomized trials suggestthat the impact using modern RT techniques is probably greater.In the recently published Swedish study the reduction in LRwas 60% (27–11%)
11
and in the Dutch series it was 71%(8.2–2.4%).
12
This reduction was maintained irrespective of thebaseline risk.
5
With respect to the most recent postoperativeseries, which compared surgery alone with adjuvant chemo-
therapy and radiotherapy in the GITSG study the risk reductionwas 54% (24% down to 11%),
13
and in a single European seriesby Tveit
et al
. it was 60% (30% to 12%).
23
DOES ADJUVANT RT INFLUENCE OVERALL SURVIVAL?
Meagher and Ward have concluded that adjuvant RT has noimpact on overall survival,
3
partly due to a meta-analysis of adju-vant RT studies that found no improvement in overall survival
26
and partly due to the results from the Dutch series.
12
The meta-analysis did demonstrate that cancer-related survivalis improved by 20% with adjuvant RT, but in this analysis therewas no impact on overall survival due to substantial RT-relatedmortality. In other words, gains in survival resulting from theimpact of RT on risk of recurrence were cancelled out by RT-related deaths in the patients who did not have recurrent cancer.This meta-analysis, however, includes many older series whereinRT techniques were inferior to those employed in modern prac-tice. If with modern RT techniques there was minimal RT-relatedmortality and the anti-tumour efficacy were maintained, then themeta-analysis suggests that adjuvant RT would significantlyimprove patient survival.
Is there evidence of reduced RT-related mortality in modernseries? There are no randomized data to demonstrate this but,as is the case for TME surgery, there is considerable non-randomized data to support this suggestion and a randomized trialwould be unethical. In the Swedish study, in which RT techniquewas not mandated, a retrospective analysis found that the in-hospital mortality rate in patients treated with the old two-fieldRT technique (using only anteroposterior (AP) fields), was 15%compared to 3% in those patients treated with a modern four-fieldtechnique.
11
Therefore, while there was a significant difference insurgery-related mortality overall between RT and surgery alonepatients, this was largely due to an exceptionally high mortalityrate in the patients treated with an old technique. Consistent withthis, in the recently reported Dutch series there was no differencein postoperative mortality between all patients receiving RT andthose in the surgery alone control arm.
12
Also, if RT-related mortality is reduced with modern tech-niques, and older techniques were employed in the original USstudies, then a larger difference in survival would have been dem-onstrated between the surgery alone and adjuvant therapy arms inthese trials, if modern techniques had been used. If it is valid toargue that these studies employed inferior surgery that increasedthe risk of local recurrence in the control arm, as Meagher andWard have done, then it can also be argued that improved adju-vant RT techniques would further improve survival in the treat-ment arm.
In the Swedish preoperative RT study adjuvant RT substan-tially improved 5 year survival rates, from 48% to 58%.11 Thiswas despite the use of inferior RT techniques that resulted inincreased postoperative mortality in the RT arm. In the Dutchseries, where outcomes in the control arm are far superior, therehas not been and almost certainly will not be an overall survivaladvantage demonstrated, despite superior RT techniques beingused. Too much focus, however, should not be placed on thissingle series. It would seem premature to conclude that adjuvantRT does not improve survival based on an early analysis of onestudy that suggests this and to ignore all of the previous data,including the Swedish study, that suggest adjuvant RT improvescancer related survival. As discussed here the Dutch study
156 GIBBS ET AL.
includes many patients with early stage cancer or high rectalcancer for whom the likelihood of survival with surgery alone isalready high, and including these patients may mask a small butsignificant improvement in survival for the high-risk patients. Ofconsiderable interest therefore would be a subset analysis ofthese data, when it is mature, looking at the impact of RT on sur-vival in the patients most at risk of LR and death, those withstage III disease.
WHAT IS THE RISK OF LOCAL RECURRENCE AS AN ISOLATED EVENT?
Meagher and Ward suggest that LR usually occurs in the contextof distant recurrence and is therefore of limited clinical signifi-cance, but this is not evident in four recently published series. Inthe Dutch series 50% of patients diagnosed with an LR did nothave a distant recurrence at the time.12 In the US Intergroup study(INT0114)18 almost 70% of patients diagnosed with an LR hadno other sites of disease.27 A retrospective Italian series reportedthat of 81 patients with an LR, 36 (44%) did not have a simulta-neous distant relapse.28 In an Australian series 17 of 41 LR (41%)occurred as an isolated event.22
It is important also to examine the trend in risk of distantrecurrence. If fewer patients relapse and die from disease atdistant sites due to improvements in adjuvant chemotherapythen the relative importance of local disease is increased. Exam-ining the same American series previously discussed (Table 4)for trends in overall survival, it appears that patient survival isimproving. In the O’Connell et al. study that defined the currentstandard of infusional 5-FU concurrent with RT, 70% ofpatients were alive at 5 years,16 an absolute improvement of10% over the bolus 5-FU and RT arm. In the three earlierstudies of bolus 5-FU and RT the 5 year survivals were in therange of 52–58%.13–15
WHAT IS THE MORBIDITY AND MORTALITY OF ADJUVANT RADIATION THERAPY?
We agree with Meagher and Ward that the morbidity of adjuvantRT is substantial and previously was underreported. Appropri-ately the focus of their discussion is on bowel function, but otherdocumented complications include pelvic fractures, small bowelobstruction, perineal sepsis and vascular events. Again it is rele-vant to note that the morbidity and mortality from adjuvant RThas significantly decreased in parallel with improvements in tech-nique, particularly moving from using only anterior and posteriorfields to a multifield approach, modifying the field treated andmore precise planning. Data on the morbidity related to RT andquality of life are now routinely collected as an important end-point in prospective studies and the Dutch investigators devotedan entire paper to reporting the acute toxicity experienced in theirstudy.29 Further definition of the true morbidity of adjuvant RT,particularly the late effects on bowel function, is critical to theongoing cost/benefit debate.
Clearly bowel function is not an issue for patients requiring anabdominoperineal resection (APR). Notably patients with lowrectal cancer also have the highest risk of LR.6 In older studiesthe APR rate varied from 50 to 68%13–15 and in more recent USseries it was 42%17 and 47%.18 The current rate of APR for Aus-tralian surgeons is unknown but we would estimate that 10–30%of patients will require an APR, and therefore not be at risk ofimpaired bowel function following adjuvant RT.
SHOULD WE BE USING COMBINED MODALITY THERAPY FOR LOCALLY ADVANCED DISEASE?
Contrary to what is argued by Meagher and Ward we suggest thatthe literature demonstrates that treating locally advanced unre-sectable rectal cancers is of benefit. Multiple series have demon-strated that this approach results in a significant number of long-term survivors whereas few long-term survivors are seen follow-ing surgery alone.30–35 The largest experience and longest medianfollow up of patients receiving preoperative combined modalitytherapy (CMT) for locally advanced cancer has been reported bythe Massachusetts General Hospital (MGH).30 In patients achiev-ing negative margins 82% remained free of locoregional recur-rence compared with 17% in patients with positive margins,stressing the importance of obtaining negative margins. The5 year disease-free survival was 63% for patients with negativemargins and 32% for patients with positive margins. This dem-onstrates that even when negative margins cannot be achieved,a surprisingly high number of patients (almost one-third) willremain disease free at 5 years. Clearly microscopic residualdisease is preferable to gross residual disease. The MGH experi-ence is not an isolated series and similar data have been reportedby investigators from the Mayo clinic,31 Memorial Sloan Ketter-ing,32 Munich,33 Heidelberg,34 and Eindhoven.35
CONCLUDING COMMENTS
Recommendations for the use of adjuvant therapy in patientswith rectal cancer can be based only on the available literature,with the strongest evidence coming from randomized studies.With reference to the factors that could alter the initial NIH rec-ommendation for adjuvant RT (as outlined in our introduction),we would suggest that (i) despite modern surgery LR rates indefined patients remain high; (ii) the toxicity from adjuvant RTis underreported but is substantially less with modern tech-niques; (iii) modern RT does not significantly increase the riskof postoperative mortality, reduces LR rates by more than 50%and may improve overall survival; and (iv) 5 year survival hasimproved by an absolute 12–18%13–16 following improvementsin adjuvant chemotherapy, increasing the relative importance oflocal control. In summary, although it is difficult to weigh upthe reduced LR rates due to improved surgery versus theimprovements in adjuvant RT, we would strongly suggest thatthe original recommendation remains valid. The possible excep-tions are those with T3N0 and T1–2N1 tumours, but based on thecurrent literature adjuvant treatment should still be discussedwith these patients.
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