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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%).

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VINCENZO TOMBOLINI CATTEDRA DI RADIOTERAPIA Università Sapienza di Roma

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  1. VINCENZO TOMBOLINI CATTEDRA DI RADIOTERAPIA Università Sapienza di Roma

  2. 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%)

  3. SELECTION OF PATIENTS FOR TREATMENT

  4. Prognostic Factors MCR (MunichCancerRegister): • 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, AnnOncol, 16, 664, 2005.

  5. CONCLUSIONI SELECTION OF PATIENTS FOR TREATMENT T3 tumors form a heterogeneous group tumors thatbarely extend beyond the lamina muscularispropria extend to or invade the mesorectalfascia 5-year OS Extramuralspread < 5mm 83.4% Extramural spread > 5 mm 54,1% (p = .0001) Merkel S, Mansmann U, Siassi M. et al. The prognosticinhomogeneity in pT3 rectal carcinomas. Int J ColorectalDis 2001;16:298 –304.

  6. CONCLUSIONI SELECTION OF PATIENTS FOR TREATMENT Itermediate risk group Neoplasmextending beyond the rectal wall = cT3-T4a or N1-2 M0 WITHOUT urresctable infiltration to surroding organs (cT4b) Valentini V. The right study design isneeded to find out wichpatients benefit from preoparitivechemioradiotherapy for intermediate stagedrectalcancer. Onkologie 2011; 34, 6-8.

  7. CONCLUSIONI SELECTION OF PATIENTS FOR TREATMENT N + poor prognosis? as the nodal burden increases, the prognosis also became poorercorrespondingly 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 Clin Oncol 2010;28:256 –263.

  8. CONCLUSIONI SELECTION OF PATIENTS FOR TREATMENT Extramuralvenousinvasion (EMVI) associatedwith: Local recurrence Livermetatases Relapse Free Survival Low-lyingtumorsrequiringabd- perineal resection (APR) worse survival rates than patients with low anterior resection. localrecurrence, cancer-specificsurvival 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.

  9. 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 SELECTION OF PATIENTS FOR TREATMENT Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectalcancer? J ClinOncol 2008;26:303–312.

  10. CONCLUSIONI Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging The ability to accuratelypredict these risk factors preoperatively would allow stratification of patients to receive neoadjuvant therapy.

  11. 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

  12. Stadio II-III • Mesorectal fascia involvement/potentialcircumferentialresectionmargins • 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.

  13. Mercury Study • 2 important markers analyzed with preoperative MRI • mrTRG (tumorregression grade with RMI) • CRM (circumferentialresectionmargin ) • 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

  14. Tumorregression grade (TRG)

  15. The impact of CR after Neo-Adjuvant Therapy Local relapse

  16. The impact of CR after Neo-Adjuvant Therapy DISTANT METASTASES

  17. The impact of CR after Neo-Adjuvant Therapy OVERALL SURVIVAL

  18. The impact of CR after Neo-Adjuvant Therapy Disease Free Survival

  19. MODERATE-RISK DISEASE Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging

  20. MODERATE-RISK DISEASE • Short-course RT (25 Gy/ 5 fractions 5-7 days Surgery) • Long-course chemoradiotherapyCRT (45–54 Gy in 25–30 fractions with concomitantfluropyrimidine-basedchemotherapy 5-6 week Surgery)

  21. MODERATE-RISK DISEASE Surgery alone versus preoperative Radiotherapy + Chemotherapy

  22. MODERATE-RISK DISEASE Phase III trials of short-course radiotherapy =

  23. MODERATE-RISK DISEASE Phase III trials of long-course radiotherapy with or without CT chemotherapy

  24. MODERATE-RISK DISEASE • Short-course RTand Long-course chemoradiotherapyCRT Benefits in local control, but NOT IN OS (apart from the Swedish Cancer trial) Lack of impact on reducing distant recurrences?

  25. 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 • PreoperativeCRT versus postoperative CRT • (CAO/ARO/AIO-94) GermanRectalStudy 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 • PreoperativeCRT versus preoperative RT • EORTC 22921 5 ysLR 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

  26. MODERATE-RISK DISEASE Complications 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° cancer RT+ TME = 14% TME = 9%

  27. Stadio II It has been suggested that some patients with disease 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 +adjuvantchemotherapy. Can we have confidence in the clinical staging?

  28. Stadio II Conclusion The accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvementdespite CH-RT and perhaps as many as 30% to 40%, when one accounts for the downstagingencountered 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+

  29. Stadio II Weakness of nodalstaging by imaging? Isbetter a short course RT?

  30. MODERATE-RISK DISEASE What can wechange? • Capecitabine incorporated in CRT in clinicalpractice • comparingcapecitabine 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 ClinOncol 2011;29:3503. No significantdifference in (pCR) rate between capecitabine and 5-FU with or withoutoxaliplatin. • Increase Tumordownstaging with SCRT • SCRT followed by a delay of 6–8 weeks may allow tumor downstaging and be a useful alternative to CRT • Polishstudyrandomized: 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

  31. MODERATE-RISK DISEASE What can we change? 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.

  32. MODERATE-RISK DISEASE What can we change? 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.

  33. HIGH-RISK DISEASE Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging

  34. HIGH-RISK DISEASE • Potentiallyinvolved 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

  35. HIGH-RISK DISEASE What can we change? • Radiation dose escalation • Radiation doses to the pelvis restricted by: • potential small bowel toxicity, • sphincter preservation, • risks of surgical morbidity, including anastomoticdehiscence • French ACCORD12/0405 PRODIGE 2 J ClinOncol 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.

  36. IMRT

  37. HIGH-RISK DISEASE What can we change? Radiation dose escalation Kaplan-Meier curves stratified for the treatment factors: radiotherapy dose

  38. HIGH-RISK DISEASE What can we change? • Radiation dose escalation with IMRT • Phase II Radiation Therapy Oncology Group (RTOG) 0822 study • Alternative methods of radiotherapy: contact radiotherapy and endorectalbrachytherapy • Lyon R 96–02 randomized trial  RCT, 88 pt EBRT, 39 • Gyin 13 fractions or the same EBRT plus endocavitary contact • radiotherapy boost (85 Gy in 3 fractions). The 10-year rate of • permanent colostomy halved in the contact RT group compared with EBRT alone.

  39. HIGH-RISK DISEASE What can we change? • Adding oxaliplatin to fluoropyrmidine-based CRT Phase III trials of neoadjuvant chemoradiation with oxaliplatin and 5-FU/capecitabine

  40. HIGH-RISK DISEASE A pathological complete response was achieved in 23.75% of 80 patients Local 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,

  41. HIGH-RISK DISEASE • Intensification of Chemotherapy or More effectiveradiationsensitizers • Irinotecan-based CRT • Targetedagents: • antiangiogenic antibody bevacizumab • antiepidermal growth factor receptor inhibitors cetuximaband panitumumab,

  42. HIGH-RISK DISEASE What can we change? • 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

  43. NEW PERSPECTIVES • During and after CRTidentify those with a cCR and a ‘true pCR’ who may be spared radical surgery • Indentify a subgroup in moderate risk thatshouldnot do therapy • Indentify a subgroup in high risk thatshould • haveupfrontchemotherapy, (particularly • patients who are likely to require chemotherapy as part • of their treatment strategy): neoadjuvant • chemotherapy CRT TME adjuvant • chemotherapy.

  44. The impact of pCRafter neoadjuvant therapies The challenge remains to identify those with a cCR and a ‘true pCR’who may be spared radical surgeryand, similarly, patients with a pCR who may benefit from adjuvant chemotherapy to minimize the risk of subsequent local or distantfailure.

  45. Disegno e valutazione sperimentalestudio Sapienza (A.Laghi-V.Tombolini) RM con diffusione  Mezzo previsionale di risposta al trattamento neo-adj?

  46. 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)

  47. Disegno e valutazione sperimentale RM con diffusione Day -1 Stadio RM = cT3cN2a (> 3<6 N+) CRM < 1 mm

  48. Disegno e valutazione sperimentale RM con diffusione Day 15 mrTRG 2/3

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