Journal club on Ca Anal Canal
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This document summarizes key findings from several clinical trials on the treatment of anal squamous cell carcinoma. The UKCCCR ACT I trial showed improved local control and colostomy-free survival with chemoradiation (CRT) compared to radiation alone. Subsequent trials found improved outcomes with mitomycin-C compared to 5-FU alone. The RTOG 98-11 and ACT II trials found no advantage to cisplatin over mitomycin-C in CRT or with maintenance chemotherapy. The current standard is CRT with 5-FU and mitomycin-C.
![RTOG 9811 ACT II (2x2 design)
Report time 5-yr 3-yr
pCR (%) No Bx 95 ~ 94.5
LRR (%) 33 ~ 25 13 ~ 11
RFS (%) 54 ~ 60 75 ~ 75
OS (%) 70 ~ 75 Adj 85 ~ 85
No 84 ~ 84
Col-rate (%) 19 10 Adj 5 ~ 5
No 4 ~ 4
Acute SE (%) 42 61 13 25
Ajani JA. JAMA 2008; 199: 1914-21.
James R. J Clin Oncol (Proc ASCO) 2009; 27: 797s [abstract LBA-4009].](https://image.slidesharecdn.com/journalclubanalcancerver5-200811123643/85/Journal-club-on-Ca-Anal-Canal-57-320.jpg)
![No benefit of
Neoadjuvant 5FU+CDDP, High-dose RT
Conroy T. J Clin Oncol 2009; 27: 176s [abstract 4033].
ACCORD-03 (2x2 design)
pCR (%) LRR (%) EFS (%) CFS (%) OS (%)
Neo Con Neo Con Neo Con Neo Con Neo Con
60 Gy 78 74 20 10 70 67 83 86 79 89
65-70 Gy 86 74 4 12 78 68 85 80 89 79](https://image.slidesharecdn.com/journalclubanalcancerver5-200811123643/85/Journal-club-on-Ca-Anal-Canal-68-320.jpg)
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Journal club on Ca Anal Canal
- 1. JOURNAL CLUB ON ANAL CARCINOMA Dr Manas Dubey Senior Resident Radiation Oncology HBCH & MPMMCC, Varanasi.
- 2. Introduction Squamous cell carcinoma of the anus is rare and least prevalent GI malignancy & accounts for only 1 – 2 % of all large bowel malignancy. Ratio of 1:2 for men to women with median age at diagnosis is 60 yrs.
- 3. Risk Factors HPV 16, 18, 33, 34, 35 HIV Smoking Multiple sexual partners, Receptive anal intercourse, History of Sexual transmitted disease
- 4. Pathology Squamous cell carcinoma ( most common- 85%) Adenocarcinoma (10-15%) Melanoma
- 6. Contd… Prior to the mid 1970s, the standard approach to anal cancer was abdominal perineal resection (APR), which required a permanent colostomy Long-term DFS results with a surgery alone approach were approximately 50%
- 7. Contd,… A review at the Mayo Clinic of 118 anal cancers treated with APR reported an OS rate of 70% and overall recurrence rate of 40%. Of these, greater than 80% established recurrence sites had local recurrence
- 8. Cotd… Many small trials using different forms of chemotherapy with varying types of radiotherapy Started by Nigro in 1973
- 9. Trials in anal cancer Nigro et al (1974-1983) UKCCCR Anal Canal Trial 1 (1996) EORTC trial (1997) RTOG 87–04 ACT II trialRTOG98-11
- 10. Chemo-RT Sx Chemo - 5FU 1000 mg/m2/d x 4 d - MMC 15 mg/m2 RT - 30 Gy in 15 F - Tumor + Pelvic + Inguinal Sx - APR in first 6 cases pCR 5/6 - Biopsy APR if positive Initial studies of Nigro Mmc- mitomycin c APR- abdominoperineal resection Pcr- pathologic complete response
- 11. 1974 1983 1985 Pt. 3 28 45 pCR 67 % 81 % 84 % DFS - 85 % 84 % Nigro ND. Dis Colon Rectum 1974; 17: 354-6. Nigro ND. Cancer 1983; 51: 1826-9. Leichman L. Am J Med 1985; 78: 211-5. Pcr- pathologic complete response DFS- Disease free survival
- 12. Contd… Nigro et al., from Wayne State University pioneered incorporating concurrent pelvic radiation therapy and chemotherapy 1980’s….primary treatment started moving away from the surgeons
- 13. CONTD.. Paradigm-changing discovery in the management of squamous cell carcinoma of the anal canal.
- 15. UKCCCR ACT I UKCCCR- UK coordination committee for cancer research
- 18. Contd…N= 577 CCRT 45 Gy/20-25 + 5- Fu+ MMC RT Alone 45Gy/20-25 A 5-fluorouracil (1000 mg/m2 over 24 hours on days 1–4 and on Days 22-25) infusion was started at least 2 hours before the first radiation fraction. Mitomycin 12 mg/m2 was given by intravenous bolus injection on day 1 only
- 19. Contd… Dose of 45 Gy was given with anterior and posterior opposed fields. The recommended target volume included the anus and inguinal lymph nodes,.
- 20. Assesment… Response Assesment < 50% Response - Radical Surgery If 50% response or a complete remission- Give boost RT (15Gy/6#) • Tumour response was assessed 6 weeks after completion of the first radiotherapy course • A second assessment of tumour response was recommended 2 months after completion of boost radiotherapy
- 21. End points Primary End point- Local failure Secondary end points- overall survival cause-specific survival
- 23. Clinical response 6 weeks after initial treatment Response Radiotherapy CMT COMPLETE RESPONSE 76 (30%) 100 (39%) >50% 157 (62%) 138 (53%) <50% 22 (9%) 21 (8%)
- 24. CONTD… After a median follow-up of 42 months, Local failure 61% Radiotherapy Alone vs 36% CMT patients. There was no overall survival advantage
- 25. Local failures
- 26. Morbidity
- 27. CONTD….
- 29. Results RT alone CMT Locoregional control 41% 66% Colostomy free survival 20% 30% Overall survival 27% 33%
- 30. EORTC 22861
- 31. EORTC 22861 (N= 103) - CRT scheme: 45 Gy/ 25 fx +/- 5FU 750 mg/m2 ; D1-5, 29-33 MMC 15mg/m2; D1 6 weeks gap 15 Gy (CR) or 20 Gy boost (PR) Patient characteristics Treatment scheme CR- complete response PR- Partial Response
- 32. Chemoradiation Treatment 1 2 3 4 65RT week 5FU MMC 750mg/m2 d1-5 & 29-33 24 hour continuous iv infusion 15mg/m2 d1 only iv bolus, max single dose 20 mg MMC- Mitomycin -C Boost radiotherapy 6 week gap
- 33. EORTC 22861 XRT XRT + 5 FU-MMC p value Complete response 54% 80% Local Failure rate (5 years) 50% 32% 0.02 Colostomy free survival Increase by 32% (see graph) 0.03 DFS (5 years) Estimated improvement by 18% OS 54% 58% 0,17 Colostomy-free survival
- 34. RTOG 8704
- 35. US (RTOG 8704) (N=291) - CRT schedule: 45 -50,4Gy 5FU 1000 mg/m2;D1-4, 29-32 +/- MMC 10mg/m2; D1&29 4-6 weeks gap If residual disease: 9 Gy boost/5FU/cisplatin100 mg/m² Patient characteristics Treatment scheme
- 36. US (RTOG-8704) XRT+ 5 FU (n=145) XRT + 5 FU-MMC (n=146) p value Complete response 86% 92,2% Colostomy- free survival 59% 71% 0.014 Colostomy rate 22% 9% 0.002 DFS 51% 73% OS 71% 78,1% 0.31
- 37. Take home message with these 3 Randomized controlled trials Chemoradiation is superior to Radiotherapy alone MitoMycin-C improved Complete response rate and decreased 4-yr colostomy rate
- 39. • Poor results in T3-4 by 5FU+MMC • Standard Chemo-RT in SCCA - H+N - Esophagus - Cervix Cisplatin (CDDP) CDDP- Cis-Dichloro-Diamine- Platinum
- 40. Intergroup RTOG 98-11 R CMT 45 to 59 Gy + 5-FU/Mito 5-FU-CDDP 2 cycles RT 45 to 59 + 5-FU/CDDP T2-4 N0 N+ Upfront CT and comparing MMC with Cisplatin CMT- Combined modality treatment R- Randomization
- 42. RTOG 98-11: OS & colostomy free survival Ajani, JAMA 2008
- 43. Intergroup RTOG 98-11: conclusions Cisplatin/5FU was not superior to MMC/5FU for DFS (primary endpoint) Cumulative colostomy rate was significantly worse in the cisplatin/5FU arm than the MMC/5FU arm OS in both arms was similar MMC/5FU remains the standard of care for patients with anal canal carcinoma
- 46. ACT II Trial Randomized trial of 950 Patients RT in both arms (50.4 Gy in 28 fractions) with concurrent infusional 5-FU (1000 mg/m2 per day on days 1 to 4 and 29 to 32) and either cisplatin (60 mg/m2 on days 1 and 29) or mitomycin (12 mg/m2 day 1 only )
- 47. Contd… Second randomization to receive or not receive maintenance chemotherapy starting four weeks after chemoradiotherapy Two courses of cisplatin plus 5-FU, administered four weeks apart
- 48. Factorial Design 1. Chemoradiation Comparison MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance N=471 N=469 versusMMC CisP
- 49. MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance N=446 N=448 No maintenance versus Maintenance Factorial Design 2. Maintenance Comparison
- 50. Radiotherapy 50.4 Gy in 28 fractions over 5 ½ weeks (no gap) Phase I 30.6 Gy in 17 fractions Parallel opposed 3cm below inf. tumour (or margin) Anal bolus Phase II GTV + 3cm 19.8Gy in 11 fractions N0 groins Planned volume (canal) Direct field (margin only) N+ groins all GTV +3cm Anal bolus
- 51. Chemoradiation Treatment 1 2 3 4 65RT week 5FU MMC 1 2 3 4 65RT week 5FU CisP 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion 12mg/m2 d1 only iv bolus, max single dose 20 mg 60mg/m2 d1 & 29 iv infusion 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion
- 52. Maintenance Treatment Week 5FU CisP Starts 4 wks after end of primary CRT 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion 60mg/m2 d1 & 29 iv infusion 1 2 3 4
- 53. CRT Comparison Complete Response at 6 months 0 20% 40% 60% 80% 100% MMC CisP P=0.53 94.5% 95.4% MMC CisP
- 54. CRT Comparison Colostomy rate at 3 years P=0.26 Includes colostomies for toxicity and pre treatment colostomies not reversed 0 20 40 60 80 100 MMC CisP 13.7% 11.3%
- 55. Take home message No proven advantage to induction chemo exists (RTOG 98011) CRT comparison (ACT II) No evidence for superior CR rate with cisplatin Maintenance comparison (ACT II) No statistically significant difference in RFS, OS or cause specific survival
- 56. 5FU+CDDP vs 5FU+MMC RTOG 9811 ACT II (2x2 design) Pt. 682 940 Stage Except T1 TanyNany Arm 1 RT + 5FU + CDDP Neo 2 cycles (5FU+CDDP) RT + 5FU + CDDP ± Adj 2 cycles (5FU+CDDP) Arm 2 RT + 5FU + MMC RT + 5FU + MMC ± Adj 2 cycles (5FU+CDDP) RT dose 45 Gy ± boost to 55-59 Gy 50.4 Gy
- 57. RTOG 9811 ACT II (2x2 design) Report time 5-yr 3-yr pCR (%) No Bx 95 ~ 94.5 LRR (%) 33 ~ 25 13 ~ 11 RFS (%) 54 ~ 60 75 ~ 75 OS (%) 70 ~ 75 Adj 85 ~ 85 No 84 ~ 84 Col-rate (%) 19 10 Adj 5 ~ 5 No 4 ~ 4 Acute SE (%) 42 61 13 25 Ajani JA. JAMA 2008; 199: 1914-21. James R. J Clin Oncol (Proc ASCO) 2009; 27: 797s [abstract LBA-4009].
- 58. ACCORD 03 307 patients with stage II and III anal cancers randomized to one of four treatment arms: Group 1- 5FU & cisplatin f/b EBRT 45 GY+ 5FU & Cisplatin ->rest ->15 GY Group 2- 5FU & cisplatin f/b EBRT 45 GY+ 5FU & Cisplatin ->rest ->20 -25 GY Group 3- EBRT 45 GY+ 5FU & Cisplatin ->rest ->15 GY Group 4- EBRT 45 GY+ 5FU & Cisplatin ->rest ->20 -25 GY
- 59. Contd…. Results-no significant difference in 5 yr colostomy free survival (70 to 82%), No significant differences were seen between the arms in terms of LRF and OS
- 60. Contd… Induction CT does not improve outcomes, with the role of radiation dose escalation remaining uncertain.
- 61. Unsolved questions CRT for early stage (and very early) RT doses Gap Management of inguinal region Type and scheme of CT Optimizing RT delivery
- 63. Management of inguinal region (CMT) N negative • ENI 36 Gy if T within 1 cm from anal margin Invasion of anal margin Pelvic nodes involved N positive CMT 60 Gy
- 64. Primary Endpoints Chemoradiation (CRT) comparison Primary Endpoints • Complete response rate at 6 months • Acute Toxicity (CTC Grade 3 & 4) Maintenance comparison Primary Endpoint • Recurrence Free Survival Both comparisons Secondary Endpoints • Colostomy Rate • Cause-specific & Overall survival
- 65. Statistical Methods Sample Size Target sample size ~950 patients CRT Comparison • 5% increase of CR rate from 90% to 95% - CisP arm Maintenance Comparison • decrease of recurrence from 25% to 17.5% - maintenance arm Each with 80% power, p<0.05 Analysis 905/940 patients evaluable Median follow-up 3 yrs Intention to Treat
- 66. CONTD… APR 6 weeks after completion of the protocol. 28 patients treated no gross tumor seen IN 24/28 patients 12 patients underwent APR 14 patients lesions grossly disappeared, and so wide excision of the scar was performed,
- 67. Contd… ( N= 28) Parametre Abdominoperineal Resection Excision Of Scar No Biopsy No tumor found 7 14 Microscopic tumor only 1 0 Gross tumor 4 0 Total 12 14 2 (No tumor On clinical Evaluation)
- 68. No benefit of Neoadjuvant 5FU+CDDP, High-dose RT Conroy T. J Clin Oncol 2009; 27: 176s [abstract 4033]. ACCORD-03 (2x2 design) pCR (%) LRR (%) EFS (%) CFS (%) OS (%) Neo Con Neo Con Neo Con Neo Con Neo Con 60 Gy 78 74 20 10 70 67 83 86 79 89 65-70 Gy 86 74 4 12 78 68 85 80 89 79
- 74. Contd… Morbidity – early morbidity - Any report of morbidity during treatment or up to 2 months defined Late morbidity - more than 2 months from the end of treatment Local failure (Main end point) - Time of LF is the date of biopsy or of clinical determination of residual/recurrent locoregional disease LF assessed from 6 weeks after initial treatment