Pelvic Radiotherapy With Concurrent Neoadjuvant FOLFOX for Patients With Newly Diagnosed Rectal Adenocarcinoma

The current standard of care for treatment of locally advanced rectal cancer consists of
neoadjuvant whole pelvic RT with radiosensitizing single-agent 5-FU followed by surgery and
adjuvant full dose chemotherapy (typically FOLFOX). For all clinical T3, T4, and/or lymph
node positive rectal cancer patients the standard neoadjuvant radiation dose per fraction is
180 cGy delivered on consecutive weekdays over 5.5 weeks for a total of 5040 cGy. A
potentially paradigm-changing approach is currently being investigated in a phase II/III
trial in which neoadjuvant RT is omitting in favor of using full dose FOLFOX chemotherapy
based on provocative data published from Memorial Sloan Kettering Cancer Center. We
hypothesize that whole pelvic LDFRT using 40 cGy fractions for a total of 960 cGy can be
safely added concurrently to neoadjuvant full dose FOLFOX as an alternative to standard
neoadjuvant 5-FU chemoradiation. We further hypothesize that using LDFRT as a
chemopotentiatior will significantly increase the pCR rate as reported by the Memorial Sloan
Kettering pilot study of 27%. Lastly, due to the significantly lower radiation dose per
fraction and lower total radiation dose we expect that this novel strategy will not cause
higher rates of severe toxicity compared to neoadjuvant FOLFOX alone.

Specifically, this phase II trial intends to determine whether 6 cycles of neoadjuvant FOLFOX
with concurrent LDFRT followed by comprehensive restaging and TME achieves favorable outcomes
for patients with T3N0M0, T3N1M0, or T2N1M0 rectal cancer. As mentioned above, the current
standard of care for all locally advanced rectal cancer patients includes radiosensitizing
5-FU and concurrent whole pelvic RT to 5040 Gy in 180 Gy once daily fractions. Per the
proposed protocol, T3N0M0, T3N1M0, or T2N1M0 rectal cancer patients who are eligible to
undergo a low anterior resection would receive whole pelvic RT to 960 cGy in 40 cGy fractions
delivered twice daily on days 1-2 of each cycle of FOLFOX chemotherapy for a total of 6
cycles.

Eligible study subjects include adults who are candidates for curative intent
sphincter-sparing surgery and who lack high-risk features, particularly tumor encroaching
upon the mesorectal fascia (within 3 mm) as determined by pre-treatment endoscopic ultrasound
(EUS) and/or magnetic resonance imaging (MRI) or distal rectal tumors (<5 cm from the anal
verge).

Inclusion Criteria:

1. ≥ 18 years old at diagnosis.

2. ECOG Performance Status 0, 1, or 2.

3. Biopsy-proven diagnosis of rectal adenocarcinoma.

4. Radiographically measurable or clinically evaluable disease by CT scan of
chest/abdomen/pelvis with and without contrast ≤ 28 days prior to registration.

5. Clinical AJCC 7th edition stage T2N1M0, T3N0M0 or T3N1M0 based on physical
examination, CT scan chest/abdomen/pelvis, and pelvic MRI or endorectal ultrasound.

6. Preoperative proctoscopy confirming tumor extent as no less than 5 cm and no greater
than 12 cm from the anal verge.

7. Evaluation by a surgical oncologist, radiation oncologist, and medical oncologist ≤ 28
days prior to registration.

8. Confirmation by a surgeon that the patient is able to undergo a low anterior resection
with total mesorectal excision ≤ 28 days prior to registration.

9. In the absence of a being treated on a clinical trial, the patient would be
recommended to receive neoadjuvant chemoradiation followed by curative intent surgery.

10. The following laboratory values obtained ≤ 28 days prior to registration:

- Absolute neutrophil count (ANC) ≥ 1500/mm3.

- Platelet count ≥ 100,000/mm3.

- Hemoglobin > 8.0 g/dL. May transfuse to meet eligibility.

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN).

- SGOT (AST) ≤ 3 x ULN.

- SGPT (ALT) ≤ 3 x ULN.

- Creatinine ≤ 1.5 x ULN.

11. Negative pregnancy test (B-HCG) within 7 days prior to registration for women of
childbearing potential.

12. Did the patient provide study-specific informed consent prior to study entry?

13. Willingness to return to the enrolling medical site for all study assessments.

Exclusion Criteria:

1. Clinical T4 tumor.

2. Primary surgeon indicates the need for an abdominal perineal resection (APR) at
baseline.

3. Previous pelvic RT.

4. Autoimmune disease such as scleroderma, lupus, or inflammatory bowel disease.

5. Tumor < 3 mm from the mesorectal fascia as seen on MRI or endorectal ultrasound.

6. Tumor-induced symptomatic bowel obstruction.

7. Chemotherapy (including hormonal therapy) within the past 5 years from date of
registration.

8. Other invasive malignancies within past 5 years from date of registration.

9. Pregnant or nursing women.

10. Men or women of childbearing potential who are unwilling to employ adequate
contraception.

11. Other co-morbid conditions that, based on the judgment of the physicians obtaining
informed consent, would make the patient inappropriate for this study.

12. Any conditions that would preclude a patient from completing all study assessments.