vincenzo tombolini cattedra di radioterapia università sapienza di roma

VINCENZO TOMBOLINI CATTEDRA DI RADIOTERAPIA

Università Sapienza di Roma

Rectum Carcinoma• CANCER WITH EXTENDING FROM THE

ANAL MARGIN UP TO A MAXIMUM OF 15 cm (measured with a rigid sigmoidoscope)

LOWER RECTUM

• UP TO 4 – 5 cm FROM ANAL MARGIN (rare 6-7%)

SELECTION OF

PATIENTS FOR

TREATMENT

Prognostic Factors MCR (Munich Cancer Register):

• STAGE UICC: REMAINS THE MOST IMPORTANT PROGNOSTIC FACTOR EVEN WHEN CHECKED BY AGE, TYPE OF SURGERY AND ADJUVANT THERAPIES

IMPORTANCE OF CLINICAL STAGING

INFLUENCES THERAPEUTIC DECISIONS Kerr J et al, Ann Oncol, 16, 664, 2005.

CONCLUSIONI

SELECTION OF PATIENTS FOR TREATMENT• T3 tumors form a heterogeneous group

– tumors that barely extend beyond the lamina muscularis propria

– extend to or invade the mesorectal fascia

5-year OS– Extramural spread < 5mm 83.4% – Extramural spread > 5 mm 54,1%

(p = .0001)(p = .0001)

Merkel S, Mansmann U, Siassi M. et al. The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 2001;16:298 –304.

CONCLUSIONI SELECTION OF PATIENTS FOR TREATMENT

• Itermediate risk group – Neoplasm extending beyond the rectal wall = cT3-

T4a or N1-2 M0– WITHOUT urresctable infiltration to surroding organs

(cT4b)

Valentini V. The right study design is needed to find out wich patients benefit from preoparitive chemioradiotherapy for intermediate staged rectal cancer. Onkologie 2011; 34, 6-8.

CONCLUSIONI

SELECTION OF PATIENTS FOR TREATMENT• N + poor prognosis?

– as the nodal burden increases, the prognosis also became poorer correspondingly

3,791 patients PORT 5-year OS

– T3 N0 75% – T3 N1 60% – T3 N2 44%

5-year OS– T3 N0 64 % – T3 N1 52,4 % – T3 N2 47,5 %

Gunderson LL, Sargent DJ, Tepper JE et al. Impact of T and Nstage and treatment on survival and relapse in adjuvant rectal cancer:Apooled analysis.J Clin Oncol 2004;22:1785–1796.

Gunderson LL, Jessup JM, Sargent DJ et al. Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J ClinOncol 2010;28:256 –263.

CONCLUSIONI

SELECTION OF PATIENTS FOR TREATMENT•Extramural venous invasion (EMVI) associated with:

– Local recurrence– Liver metatases– Relapse Free Survival

•Low-lying tumors requiring abd- perineal resection (APR) worse survival rates than patients with low anterior resection.

– local recurrence, – cancer-specific survival– OS

Dresen RC, Peters EE, Rutten HJ et al.. Eur J Surg Oncol 2009;35: 1071–1077.Ouchi K, Sugawara T, Ono H et al. Cancer 1996;78:2313–2317. Smith NJ, Barbachano Y, Norman AR et al.Br J Surg 2008;95:229 –236

den DM, Putter H, Collette L et al. The abdominoperineal resection itself is associated with an adverse outcome: The European experience based on a pooled analysis of five European randomised clinicaltrials on rectal cancer. Eur J Cancer 2009;45: 1175–1183.

• Histological evidence of tumor within 1 mm of the potential circumferential resection margin (CRM) strongly predicts– local recurrence – poor survival

Total mesorectal excision (TME) is a standard surgical tecnique

The plane of dissection is formed by the mesorectal fascia (encloses the fatty mesorectum)

This fascia forms CRM

Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008;26:303–312.

SELECTION OF PATIENTS FOR TREATMENT

CONCLUSIONI

Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging

The ability to accurately predict these risk factors preoperatively would allow stratification of patients to receive neoadjuvant therapy.

MRI

•Can highlight the invasion of the MRF•Can predict the potential CRM•Can highlight the TRG (Tumor Regression Grade)•Can distinguish between good and poor prognosis after neoadjuvant therapy and•Can be related to the long-term results

Stadio II-III

Mesorectal fascia involvement/potential circumferential resection margins

•Treatment strategy is dependent on MRF involvement.•CRM can be defined only postoperatively by the surgical plane.•MRI is the method of choice for the prediction of positivity of MRFs•MDCT seems to be equivalent to MRI only in tumours in the mid/high rectum.

• 2 important markers analyzed with preoperative MRI1.mrTRG (tumor regression grade with RMI)2.CRM (circumferential resection margin )

predict survival opportunity to a multidisciplinary team to

provide a therapeutic option before surgery .

• ypT e CRM postoperatori e (non lo status di N) sono importanti per predire l’andamento dei pazienti

Mercury Study

Tumor regression grade (TRG)

The impact of CR after Neo-Adjuvant Therapy

Local relapse


DISTANT METASTASES


OVERALL SURVIVAL


Disease Free Survival

MODERATE-RISK DISEASE

Prognostic classification of rectal cancer based on pretreatment staging magnetic

resonance imaging


Short-course RT (25 Gy/ 5 fractions 5-7 days Surgery)

Long-course chemoradiotherapy CRT (45–54 Gy in 25–30 fractions with concomitant fluropyrimidine-based chemotherapy 5-6 week Surgery)


Surgery alone versus preoperative Radiotherapy +

Chemotherapy

MODERATE-RISK DISEASEPhase III trials of short-courseshort-course radiotherapy

=

MODERATE-RISK DISEASEPhase III trials of long-course

radiotherapy with or without CT chemotherapy

MODERATE-RISK DISEASEShort-course RT and Long-course chemoradiotherapy CRT

Benefits in local control, but NOT IN OS

(apart from the Swedish Cancer trial) Lack of impact on reducing distant

recurrences?

Preoperative SCRT versus preoperative CRT•Polish trial Local failure, DFS, or OS = NS•Australasian trial Local failure, DFS, or OS = NS (trend > LC in CRT)

No difference in OS,DFS, LF

Preoperative CRT versus postoperative CRT•(CAO/ARO/AIO-94) German Rectal Study Group after 11 years of follow-up (T3 LR = 7.1% vs. 10.1% in the pre- and postoperative arms, respectively; p .048)

Local recurrence rates reduced in the preoperative Arm No difference in DFS or OS rates

Preoperative CRT versus preoperative RT•EORTC 22921 5 ys LR 8.7% for preoperative CRT vs 17.1% for preoperative RT (p.002); OS = NS; Acute G 3-4 toxicity 13,9% preoperative CRT; 7.4% for preoperative RT (p.001)•FFCD- 9203 LR 8.1% for preoperative CRT; 16.5% for preoperative RT (p .004); OS = NS; Acute G 3-4 toxicity: 14,6 % preoperative CRT; 2.7% for preoperative RT (p.05)

Local recurrence rates reduced in the CRT Arm No difference in DFS or OS rates

MODERATE-RISK DISEASEComplications of RT e CRT

•Acute side effects and surgical complications only slightly increased •Long-term toxicity more problematic.

fecal incontinence,bowel obstruction, sexual dysfunction second cancer (compromise long-term

survival) Dutch TME study: follow-up 12 years

2° cancerRT+ TME = 14%TME = 9%

Stadio II

It has been suggested that some patients withdisease at lower risk of local recurrence (eg, proximal rectal cancer staged as cT3, cN0, M0, characterized by clear margins and favorable prognostic features) may be adequately treated with surgery + adjuvant chemotherapy.

Can we have confidence in the clinical staging?

Stadio II

ConclusionThe accuracy of preoperative ERUS/MRI for staging mid to distal mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CH-RT and perhaps as many as 30% to 40%, when one accounts for the downstaging encountered with preoperative CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CH-RT.Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CH-RT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.

188 pt RT-CT preop. 22% pN+

Stadio II

Weakness of nodal staging by imaging?

Is better a short course RT?

MODERATE-RISK DISEASEWhat can we change?

• Capecitabine incorporated in CRT in clinical practice

– comparing capecitabine with 5-FU-based CRT • Lancet Oncol 2012;13:579 –588. Trend toward improved survival in the

capecitabine arm, perhaps because of fewer distant metastases. > DFS in favor of capecitabine•J Clin Oncol 2011;29:3503. No significant difference in (pCR) rate between capecitabine and 5-FU with or without oxaliplatin.

•Increase Tumor downstaging with SCRT– SCRT followed by a delay of 6–8 weeks may allow tumor

downstaging and be a useful alternative to CRT• Polish study randomized: 154patients 55 Gy preoperative SCRT followed by surgery either 7–10 days or 4–5 weeks after RT 5-year survival rates 63% and 73% for the immediate and delayed surgery groups, respectively (p .24). The longer time interval resulted in greater downstaging rate (44.2% vs. 13%) better survival

•The ongoing Stockholm III trial SCRT with immediate (1–10 days) or delayed (4 –7

weeks) surgery


Neoadjuvant chemotherapy• Schrag et al, 2010

– exclude those with T4 or bulky disease (Schrag et al) – avoid radiotherapy-associated toxicity – 6 cycles of neoadjuvant folinic acid, fluorouracil, and oxaliplatin

(FOLFOX) + bevacziumab– stable or progressive disease after chemotherapy CRT– Selective postoperative CRT in a positive CRM– pCR rate of 27% (31 pt)

• GEMCAD 0801, 2012– 88% radiological response, – 100% R0 resection – 15% pCR

Schrag D, Weiser MR, Goodman KA et al. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin 2010;28:3511.

Fernandez-Martos C, Estevan R, Salud A et al.Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial. J Clin Oncol 2012;30:3586.


Neoadjuvant chemotherapy: ongoing trials• North Central Cancer Treatment Group (NCCTG-N1048)

– 1060 pt cT2N1, T3N0, T3N1. Not below 5 cm– neoadjuvant FOLFOX followed by TME if > 20% tumor regression

versus CRT

• Phase II BACCHUS (NCT01650428)– moderate-risk rectal cancers (cT3-T4, N0-N2 tumors 4 cm

from anal verge with a non threatened CRM or V2) – 6 cycles of bevacizumab + FOLFOX versus folinic acid, 5-

fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) followed by TME

• Phase II trial, COPERNICUS (NCT01263171)– neoadjuvant chemotherapy followed by SCRT for those with

moderate-risk disease.

HIGH-RISK DISEASE

Prognostic classification of rectal cancer based on pretreatment staging magnetic

resonance imaging

HIGH-RISK DISEASE• Potentially involved or threatened CRM •Increased risk of both local and distant recurrence • Poorer prognosis.

Local Recurrence rates from 40% to10% but… 5-year distant metastasis rates of about 30%

Long-course CRT with a radiation dose of 45–54 Gy and concomitant fluoropyrimidine chemotherapy is now widely accepted as standard practice

Intensification of CRT•Radiation dose escalation•More effective radiation sensitizers

HIGH-RISK DISEASEWhat can we change?

Radiation dose escalation•Radiation doses to the pelvis restricted by:

potential small bowel toxicity, sphincter preservation, risks of surgical morbidity, including anastomotic

dehiscenceFrench ACCORD12/0405 PRODIGE 2 J Clin Oncol 2012;30:4558–4565.•45 Gy vs 50 Gy (CAPOX) No Difference

The introduction of IMRT•Highly conformal dose distributions •Minimize the doses to adjacent critical pelvic structures.


Radiation dose escalation Kaplan-Meier curves stratified for the treatment factors: radiotherapy dose


Radiation dose escalation with IMRT•Phase II Radiation Therapy Oncology Group (RTOG) 0822 study

Alternative methods of radiotherapy: contact radiotherapy and endorectal brachytherapy•Lyon R 96–02 randomized trial RCT, 88 pt EBRT, 39Gyin 13 fractions or the same EBRT plus endocavitary contactradiotherapy boost (85 Gy in 3 fractions). The 10-year rate ofpermanent colostomy halved in the contact RT group compared with EBRT alone.


Phase III trials of neoadjuvant chemoradiation with oxaliplatin and 5-FU/capecitabine

• Adding oxaliplatin to fluoropyrmidine-based CRT

HIGH-RISK DISEASEA pathological complete response was achieved in 23.75% of 80 patientsLocal recurrences were observed in 8.75%Distant metastases in 21.25%

Chemotherapy consisted of a 2-h oxaliplatin infusion (50 mg/m2) on the first day of each week of radiotherapy, and five daily continuous infusions of 5-FU (200 mg/m2per die). Patients received five or six cycles of oxaliplatin,

HIGH-RISK DISEASE• Intensification of Chemotherapy or More

effective radiation sensitizers•Irinotecan-based CRT•Targeted agents:

antiangiogenic antibody bevacizumab antiepidermal growth factor receptor inhibitors cetuximab

and panitumumab,


• Currently little room for further improvement with additional radiosensitizing agents

• Systemic relapse is responsible for the majority of deaths in patients with rectal cancer

• Alternative strategies to reduce distant metastases

NEW PERSPECTIVES

• During and after CRT identify those with a cCR and a

‘true pCR’ who may be spared radical surgery

• Indentify a subgroup in moderate risk that should not do therapy

• Indentify a subgroup in high risk that should have upfront chemotherapy, (particularly patients who are likely to require chemotherapy as part of their treatment strategy): neoadjuvant chemotherapy CRT TME adjuvant chemotherapy.

The impact of pCR after neoadjuvant therapies

The challenge remains to identify those with a cCR and a ‘true pCR’ who may be spared radical surgery and, similarly, patients with a pCR who may benefit from adjuvant chemotherapy to minimize the risk of subsequent local or distant failure.

Disegno e valutazione sperimentalestudio Sapienza (A.Laghi-V.Tombolini)

• RM con diffusione

Mezzo previsionale di risposta al trattamento neo-adj?

mrTRG-1 (Assenza di ogni segnale tumorale) mrTRG-2 (tumore residuo minimo, cicatrice predominante)mrTRG-3 (aree miste di fibrosi a basso segnale e intensità di segnale intermedio > 50% ma senza predominanza di segnale tumorale)mrTRG-4 (Intensità di segnale predominante a carattere tumorale minima intensità di segnale basso di tipo tumorale)mrTRG-5 (assenza di fibrosi; visibilità solo di segnale tumorale)

Disegno e valutazione sperimentale

• RM con diffusione– Day -1

Stadio RM = cT3cN2a (> 3<6 N+)

CRM < 1 mm


• RM con diffusione– Day 15

mrTRG 2/3



mrTRG 2/3


• Intervento chirurgico

– Resezione anteriore del retto

E.I. Risposta patologica completa= ypT0, ypN0


• RM con diffusione– Day -1

Stadio RM = cT2-N1b (>1<3N+)



mrTRG 2



mrTRG 1 o 2?

Disegno e valutazione sperimentale• Intervento chirurgico

– Resezione anteriore del retto

E.I. Risposta patologica completa

• RM di controllo– Negativa per recidiva/residuo di malattia

Refertazione attuale1. Descrizione morfologica2. Localizzazione3. Dimensione4. Lesione anulare5. Ulcerazione6. Perforazione7. Mucinoso8. Posizione dominante sul bordo di

invasione tumorale9. Distanza del bordo inferiore dal

margine anale10. Distanza dal bordo inferiore del

tumore al m.pubo-rettale11. Estensione trasversale del tumore12. Estensione longitudinale del tumore13. Rapporto tumore-riflessione

peritoneale14. Caratteristiche RM

1. Segnale T12. Segnale T23. Diffusione4. Perfusione

15. Stadiazione T1. Rm T2. Si estende oltre la muscolare propria3. Infiltrazione del peritoneo4. Infiltrazione organi extraperitoneali

16. Se retto basso o ultrabasso ( a livello o sotto dell’anello pubo-rettale)

1. Piano intersfinterico-mesorettale2. Sfintere esterno3. m.. Pubo-rettale

17. Stadiazione N (numero e sede)18. Stato dei margini di resezione

circonferenziale (MRC)1. Distanza minima del T dalla fascia Mesorettale

(FMR): mm2. Posizione in base ai quadranti dell’orologio3. Distanza minima di una linfoadenopatia

secondaria dalla FMR: mm4. MRC invaso

19. Infiltrazione venosa ExtramuraliRm cT cN

CONCLUSIONI• Un approccio ottimale nella diagnosi e

nella terapia Ca del retto prevede un approccio multidisciplinare ed integrato

• Negli ultimi 30 anni si sono avuti notevoli progressi nella OS e DFS

• Ancora esistono dubbi sull’approccio «ideale» o «standard»

• Diagnosi precoce e stadiazione corretta sono indispensabili per una terapia ottimale

A Watch-and-Wait Approach to the Management of Rectal CancerPrajnan Das,

Bruce D. Minsky and Prajnan Das, October 15, 2013

Instead of routine surgery in selected rectal cancer patients who have a clinical complete response

(cCR) after chemoradiation.

vincenzo tombolini cattedra di radioterapia università sapienza di roma

Documents

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adjuvant rectal cancer

eur j cancer

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j clin oncol