IMRT for the Treatment of Anal Cancer

Kristen O’Donnell, MS3

December 12, 2007

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)

Anal Cancer: Just the FactsAnatomy:

3-4 cm anal canal

Anal verge to dentate line

Lymph node drainage:

Perirectal

Internal iliac

Inguinal nodes

(Up-to-date; cancerbackup.org)

Staging

TT0

Tis

T1 <2 cm

T2 >2 cm but <5 cm

T3 >5 cm

T4 invades adjacent organs

NN0

N1 perirectal

N2 unilateral internal iliac or inguinal

N3 perirectal and inguinal and/or bilateral inguinal and/or internal iliac

MM0

M1 distant metastases(Hansen and Roach, 2007)

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)

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 control32% improvement in Colostomy-free survival at 5 years

UKCCCRSignificantly 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)

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 radiotherapyCauses 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 toxicityDecreased colostomy free survivalComplicated by induction treatment design (Gunderson et al., 2006)

Anal Cancer Trial II being conducted in the UK

(Das et al., 2007)

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)

Patterns of Locoregional Recurrence

Das et al. at M.D. Anderson found:75% Recurred at anus or rectum21% 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 recurrenceCompared 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)

IMRT

Utilizes detailed beam shapingCreates 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.

IMRT in anal cancer

New application gaining support

Early studies show reduced toxicity rates with comparable local control and survival statistics.

Area of active studyRadiation Therapy Oncology Group is currently enrolling for a phase II trial (RTOG 0529).

IMRT Dosimetry studiesChen 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)

IMRT Dosimetry studiesLin and Ben-Josef Designed 9-field, non-coplanar IMRT plans for 5 patients with anal cancerVolumes:

GTV=anal tumor and positive nodesCTV= GVT + inguinal and iliac nodesPTV=CTV + 5 mm expansion

IMRT planning, 1° priority=PTV coverage2° priority=limiting dose to organs at riskUtilized Equivalent uniform dose for optimization

(Lin and Ben-Josef, 2007) ASCO Abstract

IMRT Dosimetry studiesResults:

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

Perineum Genitalia Small Bowel

Bladder Femoral Necks

Pelvis Sacrum

Dose Constraint (Gy)

36 36 50 50 45 50 50

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

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

ToxicityAll patients had mild-mod dermatitis No treatment breaks due to GI or skin toxicityAll GI and bladder toxicities were ≤ grade 2.

– EORTC trial showed frequent grade 3 GI and skin toxicity

Hematologic toxicity unchangedslightly worse than rate in RTOG trial

(Milano et al., 2005; Bartelink et al., 1997)

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 treatment14/17 complete response2 year progression free survival 65%Overall survival 91%Colostomy free survival 82%Local control 82%Distant control 74%

(Milano et al., 2005)

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.

Toxicity58% 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 breaksBetter than the 48% in RTOG 98-11

Hematologic toxicities were severe and common Grade 3 and 4 in 58% of patients as worstSimilar to RTOG 98-11 rates of 60%

(Salama et al., 2007)

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.

ResponseComplete response in 92%Local recurrence rate 13% @ 18 months18-month colostomy free survival 83.7%18-month distant recurrence free survival 92.3%

(Salama et al., 2007)

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.

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