Chemoradiation or Brachytherapy for Rectal Cancer
Condition: Rectal Cancer
MeSH terms: Rectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      This research is being done to compare the effectiveness of high dose endorectal
      brachytherapy (END-HDR) and the standard treatment option of chemoradiation with Capecitabine
      in the treatment of cancer of the lowest part of the bowel (rectum).
    

Detailed description: 
      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 and total mesorectal excision (TME) 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. 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.

      Given the excellent locoregional control reported in TME surgical series, several trials have
      investigated whether certain patients may be spared preoperative radiotherapy. 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). Additionally, colleagues
      have reported a consistent negative impact on bowel function in those patients undergoing
      sphincter preservation. 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%).

      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. 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.

      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. 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). 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. 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.
    

Intervention name(s): Endo-HDR (if randomized to this arm); capecitabine and IMRT (if randomized to this arm); IMRT (intensity modulated radiation therapy); FOLFOX6; Surgery
Intervention type(s): Radiation; Drug; Radiation; Drug; Procedure
Intervention description(s): Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy; Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy; Patients will receive IMRT along with capecitabine. External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications; Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus An outpatient, 46 hour continuous IV infusion provided by a home IV infusion company. The 5FU is delivered by a small pump worn in a fanny pack around the waist. The home IV infusion company will arrange your disconnect at the end of the infusion.; After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine:
Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam.
Mobility of tumor as assessed if possible by rectal exam Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.
Other intervention name(s): Xeloda; Oxaliplatin, Leucovorin, 5 Fluorouracil
Intervention MeSH terms: Leucovorin; Capecitabine; Fluorouracil; Oxaliplatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Endorectal Brachytherapy Radiation Therapy; Intensity Modulated Radiation Therapy and Capecitabine