Phase II Trial of Preoperative High-dose-rate Endorectal Brachytherapy and FOLFOX Chemotherapy for Rectal Cancer

Summary

Introduction and Rationale:

Over the past 30 years, major advances in adjuvant therapy and surgical techniques have
markedly improved cure rates for patients with locoregionally advanced rectal cancer such
that pelvic tumor control is over 90%. Preoperative chemoradiation consisting of 5 ½ weeks
of external beam radiotherapy combined with radiosensitizing 5-fluorouracil followed by
total mesorectal excision (TME) then adjuvant chemotherapy represents the current standard
of care. Despite improved survival and locoregional control, disease-free survival have
plateaued at rates of 70% because of the high incidence of distant metastasis in about 1/3
of patients.

Clearly, development of more effective systemic therapy approaches to eliminate
micrometastatic disease are needed to further improve survival outcomes. The incorporation
of oxaliplatin, combined with 5-fluorouracil (FOLFOX), as adjuvant treatment of resected
stage II-III colon cancer has led to clinically and statistically significant improvements
in disease-free and overall survival in colon cancer. In rectal cancer, FOLFOX has been used
primarily after TME but with compliance rates of typically 70%.

One approach to address systemic disease and improve compliance is to treat patients with
FOLFOX chemotherapy upfront prior to locoregional therapy. Moreover, incorporating an
effective radiation regimen with lower incidence of short and long-term side effects may
further enhance compliance to systemic therapy. External beam radiation therapy (EBRT) can
increase side effects both acute and chronic toxicity by exposing normal tissue nearby the
tumor such as the bladder, bowel, and sexual organs. An appealing technical alternative to
EBRT is a brachytherapy (BT) approach using a rectal applicator placed intraluminally in
direct contact with the tumor to deliver radiation while sparing adjacent normal organs and
decreasing exposure to the pelvic bone marrow. A rectal brachytherapy approach treating over
300 patients has been reported by the McGill group showing equivalent pelvic control, higher
pathologic complete response rates and lower short and long-term toxicity. The rectal
brachytherapy regimen consists of 4 daily treatments over one week given without
chemotherapy which significantly shortens treatment time and cost compared to a standard
course of fractionated external beam pelvic radiotherapy. One concern of the rectal
brachytherapy approach is that pelvic nodes typically covered in the external beam technique
may result in suboptimal outcomes. However, careful patterns of failure studies from a large
Dutch preoperative external beam randomized study have shown very low rates of isolated
pelvic nodal relapse and minimal benefit of external beam radiotherapy to decrease such
failure.

Proposal investigator propose combining pre-operative FOLFOX chemotherapy with high dose
rate endorectal brachytherapy followed by surgery and then additional FOLFOX chemotherapy to
further improve compliance.

Primary Endpoint The purpose of this study is to find out whether giving chemotherapy and a
new technique for delivering radiation therapy before surgery can improve compliance to
systemic therapy by 10% from a baseline of 70%.

Secondary Endpoints

1. Locoregional failure

2. Distant Metastasis

3. Bladder, Bowel, Sexual function and Bone Marrow Toxicity

4. Quality of Life

5. Pathologic complete response rates

6. Molecular changes on pre- and post-treatment tumor specimens

Study Design The treatment regimen would consist of 6 cycles of FOLFOX and HDR-ERBT (4
consecutive daily treatments to deliver 26Gy) followed in 6-8 weeks by TME surgery then an
additional 6 cycles of FOLFOX chemotherapy after recovery from surgery. HDR-ERBT will be
given after 4 cycles of FOLFOX.

*Brachytherapy will be given to subjects at Beth Israel Medical Center only.

Inclusion Criteria:

- Adenocarcinoma of the rectum

- T2/3 tumors at ≤ 12cm from the A-V margin (below the peritoneal reflection)

- Tumors with a lumen to allow the positioning of the rectal applicator.

- Tumor of less than 3.5cm thickness documented at the CT Simulator

- Patient should be a suitable candidate for surgery and chemotherapy

- ECOG/WHO performance status 0-1

- Age 18 or older

- No previous history of pelvic radiation or chemotherapy

- Adequate marrow reserve, with absolute neutrophil count greater than or equal to 1.5
x 109/L and platelets greater than or equal to 100 x 109/L.

- Serum creatinine <= 1.5 x ULN; bilirubin <= 1.5 x ULN; ALT<= 2.5 x ULN

- Non pregnant, non-lactating females under active contraception

- No peripheral neuropathy > grade 2

Exclusion Criteria:

- Evidence of necrotic pelvic nodes or ≥ 1 cm

- Evidence of distant metastasis

- Previous pelvic radiation

- Other cancer except for non-melanomatous carcinoma of the skin or CIS of the cervix.

- Presence of multiples small bowel loops trapped within the immediate tumor bed (post
hysterectomy or prostatectomy).

- Use of any investigational agent within the 4 weeks preceding enrolment

- Exposure to chemotherapy during the neoadjuvant phase

- Documented distant metastases

- Significant neuropathy

- History of allergic reactions to platin compounds or 5-FU or leucovorin

- Uncontrolled intercurrent illness such as active infection, congestive heart failure
or coronary artery disease.

- Psychiatric illness that would limit compliance with study requirements

- Pregnancy or lactation

- HIV infection