Chemoradiation or Brachytherapy for Rectal Cancer

Locally advanced rectal carcinoma continues to be a major oncologic problem in the United
States with approximately 40,000 new cases diagnosed in 2011. For stage II/III rectal
carcinoma, adjuvant chemoradiation(1-3) and total mesorectal excision (TME) (4, 5)represent
the major treatment advances that have increased cure rates over the past 30 years.

In the setting of TME, a landmark phase III German trial of stage II/III rectal cancer
patients established neoadjuvant 5FU-based chemoradiation (NCRT) as standard of care over the
same regimen given post-operatively(6). The preoperative arm showed superior local control
(6% vs. 13% p=0.006), a complete pathologic response of 8%, a higher rate of sphincter
preservation and less grade 3 toxicity compared to post-operative treatment. However,
disease-free and overall survival (76% versus 74%, respectively) were no different because of
the high rate of distant metastasis occurring in over 1/3 of patients (5yr DM 36 vs
38%,p=0.84). Importantly, those attaining a pathologic complete response had a decreased rate
of distant metastasis and improved disease-free survival. Drawbacks to the regimen include
acute grade 3 or 4 toxicity in 27% of patients, low compliance rates with postoperative
chemotherapy (27 - 50%), and an overall decline in anorectal function shown by long-term
studies(6).

Given the excellent locoregional control reported in TME surgical series, several trials have
investigated whether certain patients may be spared preoperative radiotherapy(7-9). Two large
randomized trials by Dutch and British investigators showed that a short preoperative course
of hypofractionated EBRT (25 Gy in 5 fractions) followed by TME surgery decreased
locoregional recurrence by 2/3 as compared to patients treated with TME surgery alone. In the
Dutch trial, patients with mid and distal rectal cancers were most likely to benefit from
radiotherapy. In these patients, preoperative radiation was shown to decrease locoregional
recurrence by 5-fold (10% to 2%); however, the hypofractionated preoperative EBRT regimen was
associated with a significant increase in acute and chronic morbidity. Indeed, the Dutch
study revealed that irradiated patients, when compared to surgery alone, had more perineal
wound healing problems after abdominoperineal resection (29% vs. 19%), worsening
deterioration of anal sphincter dysfunction, and more severe long-term effects related to
sexual functioning both in males (p=0.004) and females (p<0.002)(10-12). Birgisson
Additionally, colleagues have reported a consistent negative impact on bowel function in
those patients undergoing sphincter preservation(13). In reviewing the long-term data of the
Swedish short course preoperative EBRT rectal cancer trial, Birgisson also reported a higher
incidence of secondary tumors (9.5%) in patients treated with preoperative radiation when
compared to patients having surgery alone (4.3%)(14).

Modern approaches to address the risk of distant metastasis and poor compliance with adjuvant
systemic chemotherapy (following NCRT) have incorporated newer effective chemotherapy agents
earlier in the treatment protocol. For example, oxaliplatin has been one of the most widely
studied agents as a result of its proven efficacy when combined with 5-fluorouracil and
leucovorin (FOLFOX) both in the metastatic and adjuvant settings for colon cancer(15).
Initial phase II studies with the addition of oxaliplatin to standard 5-FU based NCRT
appeared to show improved pathologic complete response rates compared to standard NCRT.
However, two phase III trials clearly show that the addition of oxaliplatin during 5FU-based
NCRT does not significantly improve pathologic complete response, locoregional control,
distant metastasis or survival but does increase acute grade 3-4 toxicity by two to
three-fold(16, 17).

One approach to limit toxicity from external beam radiotherapy is the use of intensity
modulated radiation therapy (IMRT). IMRT can limit radiation dose to normal rectum (above and
below the tumor) and surrounding organs at risk (OARs) such as bladder and sexual organs.
IMRT utilizes multiple beams of radiation to treat the rectal tumor plus a margin and limits
dose to OARs. While IMRT decreases radiation dose to normal structures, it requires an
additional 2-3 cm margin for microscopic extension (clinical treatment volume=CTV), set-up
error, and rectal motion (planning treatment volume=PTV). Furthermore, IMRT still requires
5-6 weeks of radiation with concurrent chemotherapy, is substantially more expensive than
conformal radiation, and is especially prohibitive in countries where access to technology
necessary for IMRT is limited (20). Based on the preliminary results of RTOG 0822 and others,
it still remains to be determined whether IMRT confers a statistically significant
improvement in pCR, toxicity rates and QOL relative to standard NCRT.

A novel approach to limit radiation toxicity is the use of high dose rate endorectal
brachytherapy (Endo-HDR) (21). Endo-HDR involves the placement of a silicon multicatheter
applicator within the rectum to deliver large doses to the rectal tumor and mesorectum with
rapid dose fall off to the surrounding organs. An Iridium 192 high dose rate brachytherapy
source attached to a wire is inserted into each catheter to deliver a high dose of radiation
therapy the tumor. High dose rate brachytherapy has been well established in various
malignancies (prostate, uterine, sarcoma, head and neck) to escalate radiation dose to the
tumor over a short period of time while sparing normal tissue. Compared with NCRT and IMRT,
Endo-HDR delivers treatment internally to the tumor without having to pass through
surrounding normal tissue and organs. It requires smaller margins (CTV/PTV=~1 cm) on the
tumor since the applicator is positioned under fiducial guidance over the tumor without need
for a margin for organ motion allowing greater sparing of OARs (22). Furthermore, the area of
the rectum exposed to high dose radiotherapy is surgically removed at the time of resection
which further minimizes chronic toxicity. Important structures that may be spared include
bone marrow, small bowel, bladder, the autonomic nerves, sexual organs, anal sphincter and
skin. Considering that 1/3 of patients will develop metastases, limiting bone marrow toxicity
may contribute to better compliance with systemic treatment and allow for a better treatment
strategy to target systemic recurrence. Another distinct advantage of Endo-HDR is the
shortened treatment time (1 versus 6 weeks). Endo-HDR therefore provides a major logistic
advantage for patients who may benefit from neoadjuvant therapy but who are geographically
distant from radiation centers, elderly, or medically infirmed.

Inclusion Criteria:

- Confirmed adenocarcinoma of the rectum

- Appropriate tumor staging and location

- Patients should be suitable candidates for surgery and chemotherapy

- ECOG/WHO performance status 0-1

- Patients must be 18 years or older

- No previous history of pelvic radiation

- Patients must have acceptable organ and marrow function

- Non pregnant, non-breast feeding females under active contraception

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

- Evidence of distant metastatic disease

- Evidence of sphincter invasion on MRI

- Prior history of radiation to the pelvis

- Prior malignancy except for adequately treated basal cell or squamous cell skin
cancer, cervical carcinoma in situ, DCIS, or other cancer from which the patient has
been disease free for at least 3 years

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

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

- Previous exposure to chemotherapy for rectal cancer

- Uncontrolled intercurrent illness including but not limited to, ongoing or active
infections (or infections requiring systemic treatment), symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements

- Pregnant and breastfeeding women are excluded, as well as women of child-bearing
potential who are unwilling or unable to use an acceptable method of birth control
(hormonal or barrier method of birth control; abstinence) to avoid pregnancy for the
duration of the study. Should a woman become pregnant or suspect she is pregnant while
participating in this study she should inform her treating physician immediately.

- Women who are not post-menopausal and have a positive urine or serum pregnancy test or
refuse to take a pregnancy test.

- Contraindication for safe MRI, implants, or other conditions that interfere with
imaging required for the study (e.g., pacemaker or non-MRI compatible hip prostheses).
Note: Subjects with bilateral hip implants are not eligible for the study. Subjects
with a unilateral hip implant may be eligible assuming the implant is MRI compatible
and does not present artifact on MRI in the areas of interest.

- Subject is pacemaker dependent.