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Rectal cancer chemo and radiotherapy trials
The document discusses several trials evaluating preoperative chemoradiotherapy versus postoperative chemoradiotherapy or radiotherapy alone for rectal cancer. Some key trials found that preoperative therapy improved local recurrence rates and survival compared to postoperative or no adjuvant therapy. Longer intervals between preoperative radiotherapy and surgery were associated with higher rates of tumor downstaging. Adding oxaliplatin or chemotherapy without radiation improved survival outcomes in some trials. Ongoing studies are exploring chemotherapy alone and targeted agents in rectal cancer.
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Rectal cancer chemo and radiotherapy trials
- 1. PROF.S.SUBBIAH et al CHEMOAND RADIOTHERAPY TRIALS IN RECTAL CANCER Department of Surgical Oncology Centre for Oncology GRH,Royapettah
- 2. PROF.S.SUBBIAH et al Objectives •Whether trimodality therapy improves survival • If CRT should be given pre operatively or post operatively • Precisely which patients should be irradiated • Duration of adjuvant therapy • When to operate
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- 4. PROF.S.SUBBIAH et al •7.5 years consecutive series • 115 pts • At an average of 4·2 years postoperatively, three pelvic recurrences have developed but there have been no staple-line recurrences in patients who had "curative" surgery.
- 5. PROF.S.SUBBIAH et al Recommendations •Tendency to "cone" the dissection plane towards the rectal wall posteriorly and laterally has been condemned by Toddl • Most rectal carcinomas can be treated without destruction of the anal sphincters, provided that the mesorectum is completely excised.
- 6. PROF.S.SUBBIAH et al •1168 patients from 70 hospitals throughout Sweden who were randomly assigned to treatment groups, 908 (78 percent; 454 in each group) were treated with curative intent • one week of preoperative irradiation, followed by surgery within the next week (radiotherapy-plus-surgery group), or to surgery with no additional radiotherapy (surgery alone group)
- 7. PROF.S.SUBBIAH et al 25Gy delivered in 5 fractions for five days
- 8. PROF.S.SUBBIAH et al •At 5 years follow up, Local recurrence rate was 11% in preop RT group and 27% in surgery only group. • Translated to both improved OS and cancer specific survival in all Duke’s stages
- 9. PROF.S.SUBBIAH et al •1805 pts • SCRT followed by TME versus TME alone • LRR at 2 years- 2.4% vs 8.2% • But OS was 82% vs 81.8%
- 10. PROF.S.SUBBIAH et al •preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone • The effect of radiotherapy became stronger as the distance from the anal verge increased
- 11. PROF.S.SUBBIAH et al •Improved 10-year survival in patients with a negative circumferential margin and TNM stage III • For patients with a negative resection margin, the effect of radiotherapy led to an improved cancer specific survival, which was nullified by an increase in other causes of death, resulting in similar overall survival rates
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- 13. PROF.S.SUBBIAH et al •T3/T4-N+ • 50.4 Gy- 1.8Gy/# plus 5FU – 1000mg/sq.m as 120 hrs continuous infusion on first and fifth week of RT • Surgery after six weeks • Post operatively four five day cycles of 5FU – 500mg/sq.m • Post op CRT was similar with a 5Gy boost
- 14. PROF.S.SUBBIAH et al •421 patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. • The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). • The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative- treatment group (P=0.006). • Grade 3 and 4 toxicity with radiotherapy in post op setting
- 15. PROF.S.SUBBIAH et al •arm 1, preop RT 45 Gy in 5 weeks • arm 2, preop RT plus two 5-day CT courses (fluorouracil 350 mg/m2 /d and leucovorin 20 mg/m2 /d) in the first and fifth week of RT • arm 3, preop RT plus four postoperative CT courses • arm 4, preop RT and CT plus postoperative CT
- 16. PROF.S.SUBBIAH et al •1011 patients were entered onto the trial • 505 received preop RT (arms 1 and 3), and 506 received preop RT-CT (arms 2 and 4). • Median interval to surgery was 5.4 weeks.
- 17. PROF.S.SUBBIAH et al •After preop RT-CT, tumors were smaller • Less advanced pT and pN stages • Had small numbers of examined nodes • Less frequent LVN invasions • Mucinous tumors increased after preop RT-CT
- 18. PROF.S.SUBBIAH et al •80 centres in four countries. • 1350 patients with operable adenocarcinoma of the rectum were randomly assigned • Short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or • Initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fl uorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). • The primary outcome measure was local recurrence
- 19. PROF.S.SUBBIAH et al •Median follow-up of surviving patients was 4 years. • 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). • Reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy • Relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy • Overall survival did not differ between the groups
- 20. PROF.S.SUBBIAH et al •cT3–4 or any node-positive disease randomized to two groups • A control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m² on days 1–5 and 29–33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m² on days 1–5 and 29);
- 21. PROF.S.SUBBIAH et al •Investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m² on days 1–14 and 22–35) and oxaliplatin (50 mg/m² on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m² on days 1 and 15), leucovorin (400 mg/m² on days 1 and 15), and infusional fl uorouracil (2400 mg/m² on days 1–2 and 15–16).
- 22. PROF.S.SUBBIAH et al •Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3–4 or cN1–2 rectal cancer compared with former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94).
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- 24. PROF.S.SUBBIAH et al •Clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens • Continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m2 , 5 days per week), with or without intravenous oxaliplatin (50 mg/m2 once per week for 5 weeks) or • Oral capecitabine (825 mg/m2 twice per day, 5 days per week), with or without oxaliplatin (50 mg/m2 once per week for 5 weeks)
- 25. PROF.S.SUBBIAH et al •Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. • Adding oxaliplatin did not improve surgical outcomes but added significant toxicity
- 26. PROF.S.SUBBIAH et al Inconclusion of three trials, STAR -01, NSABP – R04 and ACCORD 12 • No difference in pathological response, sphincter saving or surgical downstaging • More grade 3 and 4 adverse events
- 27. PROF.S.SUBBIAH et al LyonR90-01 - Influence of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing Surgery for Rectal Cancer
- 28. PROF.S.SUBBIAH et al •Population (n = 210) – Carcinoma rectum stage T2-3, NX, M0, were randomized before radiotherapy • Intervention (n = 99) – Short interval (SI) surgery (2 weeks) • Comparator (n = 102) – Long interval (LI) surgery (6-8 weeks) • Both arms received- total dose 39 Gy/ 3 Gy/fraction in 13 fractions deliveredover 17 days
- 29. PROF.S.SUBBIAH et al •Outcomes – Median FU -33 months • long interval between preoperativeradiotherapyand surgery was associated with a significantly better clinical tumor response (53.1% in the SI group v 71.7% in the LI group, P = .007) and pathologicdownstaging (10.3% in the SI group v 26% in the LI group, P = .005). • No differences in morbidity, local relapse, and short-term survival between the two groups. • No difference in Sphincter sparing surgeries
- 30.
- 31. PROF.S.SUBBIAH et al •The median follow-up was 17.2 years. The 5-, 10-, 15-and 17-year overall survival rates were, respectively, 66.8%, 48.7%, 40.0%, and 34.0% for the SI group and, respectively, 67.1%, 53.5%, 41.9%, and 34.0% for the LI group. • There were no significant differences between groups in terms of survival or local recurrences • The radiation-induced sterilization rate of the preoperative cancer specimen was a marker of good prognosis. The interval duration (the treatment being the same) although it is modifying the sterilization rate has no impact on survival
- 32. PROF.S.SUBBIAH et al StockholmIII- Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer ( non inferiority trial) • Population: Resectable rectal cancer • Intervention and Comparator: • 3 arm randomization (n=840) (included grp 1 (n=129), grp 2 (n=128) and grp 3 (n=128)) • 2 arm randomization (n=455) (included grp 1 (n=228) & grp 2 (n=227)) • RT 5x5 Gy + surgery within 1 week (SRT) • RT 5x5 Gy + surgery after 4-8 weeks (SRT- D) • RT 25x2 Gy + surgery after 4-8 weeks (LRT-D)
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- 34. PROF.S.SUBBIAH et al StockholmIII • Outcomes: 5 year survival • Median time to recurrence – grp 1 – 33.4 months, grp 2 – 19.3 months, grp 3 – 33.4 months. • No OS or DFS benefit noted • Postoperativecomplicationswas similar between all arms when the three-arm randomization was analyzed. • However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short- course radiotherapy (53% vs 41%) • Short-course radiotherapy with delay to surgery is a useful alternative to conventionalshort-course radiotherapy with immediate surgery.
- 35. PROF.S.SUBBIAH et al Habr-Gamaetal. - Watch and Wait Approach Following Extended Neoadjuvant Chemoradiation for Distal Rectal Cancer • Population (n=72): T2-4, N0-2, M0 distal rectal cancer who completed Neoadjuvant chemoradiotherapy (54 Gy and 5-fluorouracil/ leucovorin delivered in 6 cycles every 21 days). Patients were assessed for tumor response at 10 weeks from radiation completion • Intervention: Patients with complete clinical response were not immediately operated on and were monitored • Comparator: Patients with incomplete clinical response were referred to immediate surgery.
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- 37. PROF.S.SUBBIAH et al Habr-Gammaet al. • Outcomes: MedianFU- 56 months. • Forty-seven (68%) patients had initial complete clinical response (i.e after 10 weeks). Of these, 8 developedlocal regrowth within the first 12 months of follow-up (17%). • 39 (57%) sustained complete clinicalresponse (i.e after 12 months). • An additional 4 patients (10%) developedlate local recurrences (>12 months of follow-up). • Overall, 35 patients neverunderwent surgery (51%).
- 38. PROF.S.SUBBIAH et al Therectal cancer and preoperative induction therapy followed by dedicated operation (RAPIDO) trail
- 39. PROF.S.SUBBIAH et al •It is a multicenter trial (54 centers) • phase 3 randomized trail • 920 patients • Median follow up of 4.6yrs • Standard vs experimental ( SCRT – Chemo – surgery )
- 40. PROF.S.SUBBIAH et al •Primary end point – disease related treatment failure • At 3yrs - 30.4 % vs 23.7% • P = 0.019 • Distant metastasis at 3 yrs 26.8% vs 20% • Over all survival 88.8% vs 89.1% • pCR is 14.3% vs 28.4% • Ro resection rates are similar
- 41. PROF.S.SUBBIAH et al •Surgical complications are similar ( anastomotic leaks more in experimental arm but not statistically significant) • Quality of life is similar
- 42. PROF.S.SUBBIAH et al PRODIGE23 – A French trail • Phase 3 RCT • N= 461 • Standard vs experimental mFOLFIRINOX – CRT - surgery – Adjuvant chemo • Median follow up of 46months
- 43. PROF.S.SUBBIAH et al •Primary end point – 3yr DFS • 68.5 vs 75.7% • P=0.019 • pCR – 11.7 vs 27.5% • 3 yr Metastasis free survival 71.7 vs 78.8% • 3 yr OS 87.8 vs 90.8%
- 44. PROF.S.SUBBIAH et al Chemotherapywithout radiation • OPRA trial – initiating treatment with chemoRT may improve colostomy free survival • FORWARC trial– neoadjuvant FOLFOX without RT had lower rates of pCR • PROSPECT trial – ongoing. Chemotherapy alone in stage II or III high rectal cancer in patients with atleast 20% tumor regression following neoadjuvant treatment
- 45. PROF.S.SUBBIAH et al Targetedagents • EXPERT-C trial – additition of cetuximab to capecitabine based chemoRT. Improvement in OS in KRAS exon2/3 wild type tumors • SAKK41/07 trial – panitumumab in pre operative setting. pCR 53% vs 32%. More grade 3 toxicity • RaP/STAR -03 study – pCR not met
- 46. PROF.S.SUBBIAH et al cT1-2N0 • pT1-2,N0 – no further treatment • pT3,N0 • Observation – less than 2 mm invasion of mesorectum , well or moderately differentiated, no LVSI, upper rectal • FOLFOX/CAPEOX – margin neg proximal tumors • Capecitabine +RT followed by FOLFOX • pT4/N+- sandwich regimen – chemotherapy + concurrent chemoRT + addn chemotherapy • Total duration – 6 months
- 47. PROF.S.SUBBIAH et al •T3, N any with clear CRM and T1-2,N1-2 • chemoRT/ short course RT – transabdominal resection – adjuvant chemotherapy • long course RT – restaging • short course RT – within 1 week or > 6 to 8 weeks Wait and watch Total neoadjuvant therapy FOLFOXIRI not recommended
- 48. PROF.S.SUBBIAH et al •cT3, N any + threatened CRM and T4, N any chemoRT – restaging at 6 weeks • bulky residue – 12 to 16 weeks chemo restaging and transabdominal resection and addn chemotherapy • clear CRM – surgery and adj chemo