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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

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Endo-HDR (if randomized to this arm)

Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

capecitabine and IMRT (if randomized to this arm)

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

IMRT (intensity modulated radiation therapy)

* 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.

FOLFOX6

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.

Surgery

Amol K Narang, M.D.

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).

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.

Chemoradiation or Brachytherapy for Rectal Cancer

Chemoradiation OR Brachytherapy for RECTal Cancer

Pathologic complete response rate is reported as the number of patients who achieve pathologic complete response after the treatment for each arm.

As per the NCCN guidelines, pathologic response is graded by the system recommended by the AJCC Cancer Staging Manual and CAP guidelines:

* Complete response - no remaining viable cancer cells
* Moderate response - only small clusters/single cancer cells remain
* Minimal response - residual cancer remaining, but with predominant fibrosis
* Poor response - minimal/no tumor kills, extensive residual cancer

Number of participants with grade 3 or higher adverse events will be listed by relationship.

Grading is by CTCAE 4 guidelines.

Relationship, as determined by PI, is unrelated/unlikely/possible/probable/definite.

Patients were given the EORTC QLQ-C30 at baseline, preop, postop, and at follow ups Y1-5. The forms were scored as per the manual available at EORTC. Raw scores are transformed to fall in a range of 0-100. Generally, higher scores on QoL scales represent higher levels of QoL.

The scores are reported as the mean of the Global Health Status/QoL scale score when more than 1 patient completed the form for a time point. If only 1 form was available for a time point, then the score for that form is reported.

Assessing the difference time to death rates among study participants.

Compare distant metastasis for both Endo-HDR and CRT.

Compare progression free survival for both Endo-HDR and CRT.

Compare locoregional control for both Endo-HDR and CRT.

Nucletron

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Patients will receive IMRT along with capecitabine.

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection capecitabine and IMRT (if randomized to this arm): Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

IMRT (intensity modulated radiation therapy): 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

FOLFOX6: \* 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

Surgery: 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.

IMRT and Capecitabine

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection:

Endo-HDR: Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

FOLFOX6: \* 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;

Surgery: 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.

Endo-HDR

Patients will receive IMRT along with capecitabine.

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection

capecitabine and IMRT (if randomized to this arm): Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

IMRT (intensity modulated radiation therapy): 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

FOLFOX6: \* 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

Surgery: 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.

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection

Endo-HDR (if randomized to this arm): Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

FOLFOX6: \* 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

Surgery: 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.

Total

Age, Categorical

Sex: Female, Male

white/caucasian

Race/Ethnicity, Customized

United States

Region of Enrollment

met baseline enrollment requirements as per protocol

Amol Narang, MD

Number of Patients With Pathologic Complete Response

Grade: 3; Relationship: probable

Grade: 3; Relationship: possible

Grade 3; Relationship: Unlikely

Number of Participants With Grade 3 or Higher Adverse Events

baseline

pre-op

post-op

year 1

year 2

year 3

year 4

year 5

3 patients randomised to IMRT arm had at least 1 form completed. 5 patients randomised to the ENDO arm had at least 1 form completed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Spots Global Cancer Trial Database for capecitabine and imrt (if randomized to this arm)