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Gastrointest Cancer Res. 2012 Jan-Feb; 5(1): 3–12.
PMCID: PMC3348710

ACR Appropriateness Criteria®—Recurrent Rectal Cancer

ABSTRACT

The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions. These Criteria are reviewed every 2 years by a multidisciplinary expert panel. The development and review of these guidelines includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Local recurrence of rectal cancer can result in devastating symptoms for patients, including intractable pain and discharge. Prior treatment can limit subsequent treatment options. Preoperative 5-FU based chemoradiotherapy is the treatment of choice for patients with a local recurrence who did not receive adjuvant therapy after initial resection or who might have received chemotherapy alone. Chemoradiotherapy followed by evaluation for surgery is the preferred treatment for patients who have undergone previous radiotherapy after surgery. The inclusion of surgery has resulted in the best outcomes in a majority of studies. Palliative chemoradiotherapy is appropriate for patients who have received previous radiotherapy whose recurrent disease is considered inoperable. Radiotherapy can be delivered on a standard or hyperfractionated treatment schedule.

Newer systemic treatments have improved response rates and given physicians more options for treating patients in this difficult situation. The use of induction chemotherapy prior to radiotherapy is an evolving treatment option. Specialized treatment modalities should be used at institutions with experience in these techniques and preferably in patients enrolled in clinical trials.

Key words: Appropriateness Criteria, Local recurrent rectal cancer, chemoradiotherapy, re-irradiation

SUMMARY OF LITERATURE REVIEW

Introduction / Background

Local or regional failure in rectal cancer presents a major dilemma. Therapy strategies for patients with local pelvic recurrences are individualized, depending on the site of local recurrence as well as the type of therapy previously received. For new patients with recurrences at the anastomoses from a previous low anterior resection who had heretofore not received adjuvant radiotherapy (RT), appropriate treatment would include either repeat resection followed by postoperative combined-modality therapy (CMT) or preoperative CMT followed by surgical intervention with or without intraoperative radiotherapy if technically and medically feasible. For those patients having previously received pelvic radiotherapy limited reirradiation with our without chemotherapy and intraoperative radiotherapy (IORT) is an option.

Radiotherapy vs. Chemoradiotherapy

In the setting of a patient presenting with a local pelvic or perineal scar recurrence after abdominal-perineal resection (APR), surgery remains an option, followed by CMT if the patient had not previously been treated. Type of primary surgery, symptoms, location of the recurrence, and whether the tumor is fixed to adjacent structures affect overall prognosis, with a median survival of 28 months with a R0 resection compared to 12 months with an R1 or R2 resection [1]. Postoperative morbidity can be high in patients undergoing radical resection, including sacrectomy [2]. Alternatively, preoperative RT with curative intent could also be given for local recurrences in the setting of a previous APR. Patients with poor performance status could be treated with palliative CMT alone. 5-Fluorouracil (5-FU) is generally incorporated with RT in an effort to increase radioresponsiveness; however, the effectiveness of chemoradiotherapy compared to radiotherapyt alone in this setting or in patients with other sites of pelvic recurrence is debatable.

Shumate et al [3] reported on the MD Anderson Cancer Center's experience with locally advanced or recurrent rectal cancer. A retrospective comparison was made between patients treated preoperatively with radiotherapy alone from 1977-1986 and patients receiving chemoradiotherapy that included continuous infusion of cisplatin alone, 5-FU, or both beginning in 1987. It was not possible to determine the advantage of chemoradiotherapy in patients with locally recurrent rectal cancer, as all but one patient received CMT; however, chemoradiotherapy did not appear to increase operative morbidity in this group of patients or in patients with locally advanced primary disease. The authors suggested that CMT may have facilitated sphincter-sparing surgery with improved tumor downstaging; however, improvements in surgical techniques may have also contributed.

Overgaard et al [4], reported on a randomized trial of RT alone (50 Gy/5 weeks + 10-20 Gy boost) or given simultaneously, with weekly 5-FU (600 mg/m2) given before treatment every Monday during the first 5 weeks in patients with locally recurrent or inoperable colorectal cancer. The addition of 5-FU failed to demonstrate any improvement in local response or diminish the development of distant metastasis. The acute complication rate increased to 33% vs. 13% after radiotherapy alone. Despite the lack of survival improvement in these studies, CMT is generally recommended in an effort to improve local control. Dose may be important, with higher doses producing greater symptomatic response [5].

Importance of Preoperative or Definitive Radiotherapy (with or without chemotherapy) in Patients With Locally Recurrent Rectal Cancer

Vermaas et al [6] compared the results of preoperative RT and surgery to surgery alone in patients with recurrent rectal cancer. Local control after preoperative treatment was statistically significantly higher at 3 and 5 years compared to the surgery-alone group. There was, however, no difference in overall or metastases-free survival between the groups. Larsen et al [7] evaluated preoperative and perioperative risk factors for morbidity and mortality after irradiation and surgery in patients >75 years of age with locally advanced or recurrent rectal cancer. They reported a 46% R0 resection rate in patients with recurrent cancers. Margin status was found to be predictive of disease-free survival rates in patients undergoing aggressive surgery including sacrectomy for recurrent rectal cancer [8]. They did, however, report a statistically significant 42% complication rate, with the rate being highest among patients who underwent sacrectomy. Surgery also provided a longer median survival time, 21 months, compared to combined RT and chemotherapy alone, 12 months, in a population-based study of 141 patients with recurrent rectal cancers [9]. A 57% 5-year survival rate was reported in 25 patients undergoing a curative resection.

Hu et al [10] investigated the use of 3-dimensional conformal RT combined with FOLFOX4 chemotherapy in 48 patients with unresectable recurrent rectal cancer. They reported a >90% relief in pain with a 56.5% overall response rate in the study group. They did report, however, more peripheral neuropathy in the study group compared to the control group. (See Variant 1 and Variant 2.)

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Clinical Condition: Recurrent Rectal Cancer
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Clinical Condition: Recurrent Rectal Cancer

Reirradiation

For patients with locally recurrent rectal cancer following high-dose pelvic radiotherapy, management decisions have generally been directed toward palliative care employing diverting colostomies and chemotherapy. Although historically considered unsafe, reirradiation in the pelvis has been investigated in select patients with locally recurrent rectal cancer, and it has been found to be reasonably well tolerated and to provide symptomatic relief in the majority of patients. Additionally, a significant percentage of patients were able to undergo radical surgical salvage, with a 2-year survival rate of 66% in this group [11]. An update from the same institution included 52 patients with recurrent rectal cancer who underwent reirradiation [12]. A 15% bowel obstruction rate and a 7% fistula rate were reported when reirradiation was combined with surgery [13]. The median reirradiation dose was 30.6 Gy. Twenty-two patients were treated in a hyperfractionated approach (1.2 Gy BID). Total cumulative doses ranged from 66.6-104.9 Gy with a median total dose of 84.4 Gy. The whole pelvis was not treated and small bowel and bladder were excluded from the reirradiation field. The actuarial survival at 2 years was 25%, decreasing to 14% at 3 years. Bleeding was stopped in 100% of patients, with palliation of pain seen in 65%. The incidences of RTOG® grade 3 and 4 late toxicity were 23% and 10%, respectively. The use of hyperfractionated RT resulted in reduced late toxicity in comparison to conventionally treated patients receiving once-daily irradiation. Pacelli et al [14] treated 58 patients for recurrent rectal cancer; patients who had undergone previous RT had received either 23.4 Gy in 1.8 Gy fractions or 1.2 Gy BID to 40.8 Gy. Intraoperative electron beam radiotherapy (IOERT) was delivered in 20 cases. They reported a 40% 5-year overall survival rate with 5-year overall survival greater in patients undergoing an R0 resection.

Valentini et al [15] evaluated the response rate, respectability rate, local control, and treatment-related toxicity of preoperative hyperfractionated chemoradiotherapy for patients with locally recurrent rectal cancer who had received previous radiotherapy. They found that 86.4% of patients had treatment completed without any interruption, with only a 5.1% rate of acute lower GI toxicity. They also reported a 39% 5-year survival rate. Juffermans et al [16] reported a 72% good or complete palliative effect for a median of 6 months in patients receiving reirradiation and hyperthermia. Henry et al [17] reported a median overall survival time of 38 months with an estimated 40% 5-year survival rate in patients having resection of isolated pelvic recurrences. In this study, 56 of 88 patients had additional radiotherapy, including 24 treated with brachytherapy, eight treated with IORT, and 24 treated with external beam radiation. Preoperative CEA and final margin status was a statistically significant predictor of outcome.

Hansen et al [18] reported on a cohort of 577 patients with local recurrence of rectal cancer wherein 35.2% received palliative RT, 71.4% had RT prior to additional resection with a 1.6% 30 day mortality. Only 17% of patients had RT prior to the recurrence, either preoperative (8%) or postoperative (9%) at the time of the treatment of the primary tumor. Patients received 50 Gy if they received definitive RT and 30 Gy if palliative RT. Patients undergoing an R0 resection had a 55% survival rate compared to 20% for patients who underwent R1 resection. Every effort should be made to obtain an R0 resection. Most studies have found completeness of resection to be an independent prognostic variable for survival [9,14,18-24].

Patients selected for this experimental approach might include those with locally recurrent disease alone or in combination with metastatic cancer, when suffering from intractable pain and/or bleeding. They should have a Karnofsky performance status (KPS) of ≥70% and have no prior history of bowel obstruction within the pelvis. The optimal reirradiation dose has yet to be determined; however, final cumulative dose decisions should be determined based on the initial radiation dose given, the amount of small bowel in the radiation treatment field, the distance in time to recurrence, and the volume previously treated, as well as the intended volume to be retreated with irradiation. When re-irradiating the pelvis, every effort should be made to limit the dose to the bowel or bladder. (See Variant 3.)

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Clinical Condition: Recurrent Rectal Cancer

Review of Intraoperative Radiotherapy

IORT provides an additional therapy option in patients with locally recurrent rectal cancer, including those who have received prior external beam pelvic radiation. IORT involves radiation treatment delivered during a surgical procedure to the tumor bed, with the advantage of sparing surrounding normal tissues. Radiation is delivered either by a linear accelerator, resulting in the production of electron beams (IOERT), or in the form of either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. LDR brachytherapy involves permanent placement of radioactive I-125 or Pd-103 seeds in the tumor bed.

HDR brachytherapy employs a machine housing a high-activity Ir192 source that can be connected to a multichannel applicator that can conform to the tumor bed [25-29]. With HDR IORT the dose distribution (depth and location) can be individualized by altering source dwell positions. A dose of 10-20 Gy can be delivered over several minutes, compared to hours with LDR brachytherapy. IOERT has been used in an effort to improve local control and quality of life. IOERT requires less planning and setup time when compared to HDR-IORT; however, it is more challenging for treating larger areas, and dosimetry planning is not as reliable. Ideally, each department could benefit from the flexibility of having both HDR-IORT and IOERT available to accommodate diverse cases [30].

Intraoperative Radiotherapy

Abuchaibe et al [31] reported that the extent of surgical resection was the most important factor for improving local control in patients undergoing IORT, with a local control rate of 50% and a 2-year actuarial local relapse-free survival rate of 56% reported in this group of patients. Overall, including patients unable to undergo a complete resection, the 2-year actuarial local relapse-free survival rate was only 14%. Similar findings have been reported at other centers incorporating IORT for recurrent rectal cancer with distant metastatic rates remaining high [32-33]. Use of IOERT with close or positive resection margins has historically resulted in inferior outcomes in patients with locally recurrent rectal cancer [14,32,34]. Dresen et al [19] reported on 57 patients receiving reirradiation of 30.6 Gy with IOERT. The IOERT dose was dependent upon the completeness of resection with patients having a R0 resection receiving 10 Gy, patients with a R1 resection receiving 12.5 Gy, patients with an R2 resection and <2 cm residual tumor receiving 15 Gy, and those with >2 cm receiving 17.5 Gy. Five-year overall survival was 48.4% in those patients undergoing a R0 resection. Radical resection and the stage of the primary tumor were the only factors predicting overall survival in multivariate analysis. Ferenschild et al [20] reported 3- and 5-year rates of local control to be 49% and 34%, respectively, in patients receiving 10 Gy IOERT and 50 Gy external bean radiotherapy (EBRT). Once again, those patients undergoing complete resection fared better than those with an incomplete resection. Haddock et al [35] from the Mayo Clinic reported on a retrospective analysis of 51 patients with recurrent rectal cancer having received previous EBRT (median dose 50.4 Gy; range, 27-70 Gy) treated with surgery and IOERT ± additional EBRT. The median IOERT dose was 20 Gy (range, 10-30 Gy). They reported a 72% actuarial central control rate with a median, 2- and 5-year actuarial survival of 23 months, 48% and 12%, respectively. Thirty-two percent of patients developed neuropathy. which was the most common radiation-induced toxicity. Seven patients developed ureteral narrowing or obstruction; all but one patient who developed a complication received ≥20 Gy IOERT.

Re-recurrence was found to be higher in a series of patients undergoing retreatment for recurrent rectal cancer if they had an R1/R2 resection as compared to an R0 resection [23]. Reirradiation was incorporated with regional hyperthermia in 24 patients with recurrent rectal cancer. Patients received a median dose of 39.6 (range, 30-45) Gy combined with 5-FU [36]. The local progression-free survival interval was 15 months, with a 1-year overall survival rate of 87% and 1-year local progression-free survival rate of 61%. Grade-5 acute toxicity occurred in 12.5% of patients. .

Toxicity attributable to IORT can be difficult to distinguish from disease-related toxicity. RTOG® 85-08 reported a 16% significant 2-year actuarial complication rate in 42 patients with advanced or recurrent rectal cancer who received IORT as a component of their treatment [37]. Although Vermaas et al reported a 27% local control rate in 11 patients treated with IORT having received previous EBRT; they also reported a high morbidity rate. In addition, Dresen et al reported a 4.8% mortality rate, Ferenschild et al had 17/25 patients with postoperative morbidity and Kanemitsu et al had an 81% surgical morbidity rate emphasizing this procedure needs to be performed in highly selected good performance status patients. [19-21,38]. Multiple single-institution studies have now demonstrated improved local control and in some cases survival when IORT is combined with preoperative chemoradiotherapy and aggressive surgery [30,39-41].

Additional studies are needed to determine how to combine external beam radiation and IORT optimally with modern systemic chemotherapy to improve quality of life, limit toxicity, and improve survival in patients with recurrent rectal cancer.

High-Dose–Rate Intraoperative Radiation Therapy

Nuyttens et al [26] reported a 14% local failure rate within the HDR-IORT field in 37 patients with close or positive margins following resection. Therefore, controversy exists as to the importance of final margin status in patients undergoing HDR-IORT [17,25-26]. Heriot et al [42] had 12 of 160 patients with recurrent rectal cancer receive 10 Gy HDR-IORT. The presence of involved lymph nodes, the use of HDR-IORT and R1 resection portended impaired survival; on multivariate analysis, R1 resection and use of HDR-IORT resulted in impaired survival. The poor survival is most likely a result of use of HDR-IORT in patients not obtaining R0 resection.

Permanent Seed Implants

Another method of IORT is the use of permanent I-125 seeds. Wang et al [43] treated 13 patients with a median minimal peripheral dose of 140 Gy (range, 120-160) with a median pain-free interval of 7 (range, 0-14) months. All but one of the patients in the study had received previous radiotherapy, with four patients receiving radiotherapy twice with doses ranging from 80-120 Gy. The 1- and 2-year local control rates were 14.4% and 0% respectively. Grade 4 complications were noted in two (15.4%) patients—one developed a cutaneous fistula and the other developed a fistula after disease recurrence.. Five patients developed fibrosis, and one developed perineal edema. All side effects were observed within the first 12 months.

Stereotactic Body Radiotherapy

Stereotactic body radiotherapy (SBRT) has been used to treat well-demarcated lesions in the brain, lung, and liver. SBRT is being used to treat tumors in additional anatomic areas as experience grows in the use of this technique. Kim et al [22] used the Cyberknife system to treat 23 patients with nodal recurrence of rectal cancer. The delivered a median dose of 39 Gy (range, 30-51) in three fractions. They reported overall survival of 25% with a local control rate of 74%. One patient was reported to have developed severe radiation-related toxicity. (See Variant 4.)

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Clinical Condition: Recurrent Rectal Cancer

Patient selection is crucial and should be determined in a multidisciplinary setting prior to offering treatment for recurrent rectal cancer. Patients with central recurrence have been demonstrated to have the best outcomes, while palliative RT is beneficial for patients with side-wall recurrence. Demonstrated expertise in the use of each specific modality is critical, given the high morbidity rates with IORT.

SUMMARY

The treatment of patients with recurrent rectal cancer is complex and dependent upon many factors including, but not limited to, a history of previous radiotherapy to the pelvis. Newer systemic treatments have improved response rates and given physicians more options in the treatment of patients in this clinically challenging setting. The use of induction chemotherapy prior to radiotherapy is an evolving treatment option. Specialized treatment modalities, such as IORT, and focused treatments, including cyberknife, should be used at institutions with experience in these techniques and preferably in patients enrolled in clinical trials. Preoperative chemotherapy with a 5-FU–based regimen followed by surgical reevaluation is the most appropriate treatment option in patients with recurrent disease who have not received prior radiotherapy. Patients with good performance status presenting with liver metastasis who have not undergone prior radiotherapy to the pelvic area may benefit from preoperative chemoradiotherapy followed by reevaluation for surgery and resection of the liver metastasis. Reduced-dose radiotherapy, either given daily or hyperfractionated, combined with chemotherapy and reevaluation for resection is the preferred choice of treatment for patients with recurrent rectal cancer who have received prior radiotherapy to the pelvis. The use of induction chemotherapy prior to radiotherapy may be appropriate for select patients presenting asymptomatically. IORT, either with electron beam or with high–dose-rate afterloading catheters could be used in selected centers with the appropriate experience in patients who have unresectable recurrent rectal cancer.

For additional information on ACR Appropriateness Criteria®, refer to http://www.acr.org/ac.

PUBLISHER'S NOTE

The ACR Appropriateness Criteria® on Recurrent Rectal Cancer are presented in these pages as a service to readers through a special arrangement between the publisher of Gastrointestinal Cancer Research (GCR) and the American College of Radiology. These criteria have not undergone peer review by GCR. All verbatim content, conclusions, and recommendations contained herein remain the sole responsibility, and intellectual property, of the American College of Radiology as follows:

Copyright © 2012 American College of Radiology All rights reserved. No part of these ACR Appropriateness Criteria® may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any information storage retrieval system, except under circumstances considered “fair use” as designed by US Copyright law, without written permission from the American College of Radiology.

Copyright © 2012 by the International Society of Gastrointestinal Oncology (ISGIO). No images, reproductions, or facsimiles of the pages containing this article as designed, laid out, published by, and nominally identified or associated with GCR and ISGIO may be reproduced, distributed, or transmitted without written permission from the Publisher and the American College of Radiology.

Footnotes

The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria® through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document.

Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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