IMRT for the Treatment of Anal Cancer

1
IMRT for the Treatment of Anal Cancer

• Kristen ODonnell, 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

• N
• N0
• N1 perirectal
• N2 unilateral internal iliac or inguinal
• N3 perirectal and inguinal and/or bilateral
  inguinal and/or internal iliac

• T
• T0
• Tis
• T1 lt2 cm
• T2 gt2 cm but lt5 cm
• T3 gt5 cm
• T4 invades adjacent organs

• 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)
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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)
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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)
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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.

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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
• GTVanal tumor and positive nodes
• CTV GVT inguinal and iliac nodes
• PTVCTV 5 mm expansion
• IMRT planning,
• 1 priorityPTV coverage
• 2 prioritylimiting dose to organs at risk
• Utilized Equivalent uniform dose for optimization
• (Lin and Ben-Josef, 2007) ASCO Abstract

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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

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
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)
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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 _at_ 18 months
• 18-month colostomy free survival 83.7
• 18-month distant recurrence free survival 92.3

(Salama et al., 2007)
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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