1. IMRT for the Treatment of Anal Cancer Kristen O’Donnell, MS3 December 12, 2007

2. Anal Cancer: Just the Facts Estimated new cases in the US in 2007 4,650 Estimated Deaths 690 Pathology ~80% Squamous cell carcinoma, Other 20% adenocarcinoma or melanoma. HPV associated, same pathogenic serotypes as cervical cancer, 16 & 18 (Jemal et al., 2007; Hansen and Roach, 2007)

3. Anal Cancer: Just the Facts Anatomy: 3-4 cm anal canal Anal verge to dentate line Lymph node drainage: Perirectal Internal iliac Inguinal nodes (Up-to-date; cancerbackup.org)

4. Staging T T0 Tis T1 <2 cm T2 >2 cm but <5 cm T3 >5 cm T4 invades adjacent organs N N0 N1 perirectal N2 unilateral internal iliac or inguinal N3 perirectal and inguinal and/or bilateral inguinal and/or internal iliac M M0 M1 distant metastases (Hansen and Roach, 2007)

5. Current Standard is Definitive Chemoradiotherapy for Anal Cancer Radiotherapy alone vs. Chemoradiotherapy. 45 Gy alone or w/ concomitant 5-FU and mitomycin UKCCCR, 1996: 585 epidermoid anal cancer patients with any stage disease randomized EORTC, 1997: 110 patients with stage IIIA- B anal cancer randomized (UKCCCR, 1996; Bartelink et al., 1997)

6. Current Standard is Definitive Chemoradiotherapy for Anal Cancer EORTC No significant difference in acute toxicity Diarrhea and skin reaction most common Better complete remission rates 54%  80% 18% improvement in locoregional control 32% improvement in Colostomy-free survival at 5 years UKCCCR Significantly decreases local recurrence 59%  36% local failure rate, Relative risk of 0.54 Decreases cancer related risk of death after 3 years 39%  28% anal cancer mortality, Relative risk 0.71 No significant overall survival benefit after 3 years Radiotherapy 58% and Chemoradiotherapy 65% (EORCT, Bartelink et al., 1997)

7. Current Standard is Definitive Chemoradiotherapy for Anal Cisplatin and 5-FU chemotherapy with radiation therapy is an alternative regimen Provides similar locoregional control, colostomy free survival and overall survival to 5-fu and mitomycin with radiotherapy Causes less toxicity (Hung et al., 2003) RTOG 98-11: Standard concomitant 5-FU/mitomycin chemRT vs. Induction with 5-FU/Cisplatin then 5- FU/Cisplatin + RT Reduced hematologic toxicity Decreased colostomy free survival Complicated by induction treatment design (Gunderson et al., 2006) Anal Cancer Trial II being conducted in the UK (Das et al., 2007)

8. Rates of Locoregional Recurrence with Definitive Chemoradiotherapy UKCCCR: 36% at 3 years EORTC: ~32% at 5 years M.D. Anderson: 14% at 3 years Study of 167 patients treated with definitive chemoRT for anal cancer. (Das et al., 2007)

9. Patterns of Locoregional Recurrence Das et al. at M.D. Anderson found : 75% Recurred at anus or rectum 21% Presacral and/or iliac regions 5/5 had RT field start at the bottom of the SI joints –3/5 recurred above RT field, 1/5 marginal, 1/5 recurred both above and within field 4% (1 patient) Inguinal recurrence Compared to cited 8-15% risk of inguinal recurrence in studies of patients not receiving inguinal RT. Locoregional control benefit from RT RT is very effective at inguinal nodes and iliac nodes with adequate treatment coverage. Need better local control at primary tumor site. How will IMRT change these statistics? (Das et al., 2007)

10. IMRT Utilizes detailed beam shaping Creates unique conformal distributions and sharp dose gradients Increase the ability to: Target specific volumes Limit normal tissue exposure Use in the treatment of head and neck, prostate and gynecologic cancers.

11. IMRT in anal cancer New application gaining support Early studies show reduced toxicity rates with comparable local control and survival statistics. Area of active study Radiation Therapy Oncology Group is currently enrolling for a phase II trial (RTOG 0529).

12. IMRT Dosimetry studies Chen et al. Conventional AP/ PA pelvic fields vs. Conformal avoidance IMRT planning in 2 patients Same PTV with IMRT plan assigned dose constraints for femoral heads and external genitalia. Comparable PTV coverage: IMRT plan: 97-98% of PTV at 90% prescribed dose Conventional AP/PA: 94% of PTV at 90% prescribed dose IMRT spared femoral heads 58-59% vs. 71-72% of prescribed dose and genitalia 55-63% vs. 78-97% with conventional planning (Chen et al. 2005)

13. IMRT Dosimetry studies Lin and Ben-Josef Designed 9-field, non- coplanar IMRT plans for 5 patients with anal cancer Volumes: GTV=anal tumor and positive nodes CTV= GVT + inguinal and iliac nodes PTV=CTV + 5 mm expansion IMRT planning, 1° priority=PTV coverage 2° priority=limiting dose to organs at risk Utilized Equivalent uniform dose for optimization (Lin and Ben-Josef, 2007) ASCO Abstract

14. IMRT Dosimetry studies Results: Homogenous dose coverage 95% of PTV receiving 99% of prescribed dose IMRT to treat anal cancer should decrease toxicity and has potential to improve local control. (Lin and Ben-Josef, 2007) ASCO Abstract PerineumGenitaliaSmall Bowel BladderFemoral Necks PelvisSacrum Dose Constraint (Gy) 36 50 4550 Mean dose with IMRT (Gy) 13.5 ±5.9 19.4 ±16.1 18.9 ± 8.2 28.8 ± 3.2 15.9 ± 2.3 15.9 ± 1.3 24.8 ± 2.4

15. Clinical use of IMRT for anal cancer Single institution study of 17 anal cancer patients treated with definitive chemoRT using IMRT planning. Comparative dosimetric analysis of 7 patients: IMRT planning vs. 3-D AP/PA planning Significant reduction in small bowel, bladder and perineum doses Toxicity All patients had mild-mod dermatitis No treatment breaks due to GI or skin toxicity All GI and bladder toxicities were ≤ grade 2. –EORTC trial showed frequent grade 3 GI and skin toxicity Hematologic toxicity unchanged  slightly worse than rate in RTOG trial (Milano et al., 2005; Bartelink et al., 1997)

16. Clinical use of IMRT for anal cancer Single institution study of 17 anal cancer patients treated with definitive chemoRT using IMRT planning Similar outcomes to standard treatment 14/17 complete response 2 year progression free survival 65% Overall survival 91% Colostomy free survival 82% Local control 82% Distant control 74% (Milano et al., 2005)

17. Multicenter experience with IMRT for anal cancer 53 patients treated at three academic medical centers with IMRT and chemotherapy for definitive treatment of anal cancer. Toxicity 58% completed treatment without interruption Improved GI toxicity rates and severity Grade 3 in 15% with no Grade 4 RTOG 98-11: 34% of patients had Grade 3 - 4 Dermatologic, Grade 3 in 38% Similar to studies with 2-wk treatment breaks Better than the 48% in RTOG 98-11 Hematologic toxicities were severe and common Grade 3 and 4 in 58% of patients as worst Similar to RTOG 98-11 rates of 60% (Salama et al., 2007)

18. Multicenter experience with IMRT for anal cancer 53 patients treated at three academic medical centers with IMRT and chemotherapy for definitive treatment of anal cancer. Response Complete response in 92% Local recurrence rate 13% @ 18 months 18-month colostomy free survival 83.7% 18-month distant recurrence free survival 92.3% (Salama et al., 2007)

19. Summary Dosimetric studies and small clinical trials have shown reduced dosing and toxicity to normal structures with the use of IMRT. No decreases in treatment effectiveness or local control rates have been detected. Limited sample sizes and duration of follow-up minimize the ability to detect small variations in local control rates.

20. Future Studies using IMRT for Anal Cancer RTOG 0529 A Phase II Evaluation of Dose-Painted IMRT in Combination with 5-Fluorouracil and Mitomycin- C for Reduction of Acute Morbidity in Carcinoma of the Anal Canal. 59 patients with histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anal canal; Stage 2-4 and N0- N3 stage. Currently enrolling