Optimizing Neoadjuvant Therapy for Rectal Cancer With Oxaliplatin

Neoadjuvant chemoradiation (CRT) is standard treatment for stage II-III rectal cancer. Fluoropyrimidine-based CRT prolongs disease-free survival over adjuvant CRT and improves local control over both adjuvant CRT and neoadjuvant radiotherapy alone, but does not prolong overall survival. New approaches to neoadjuvant therapy may improve outcome in this disease. Oxaliplatin, a standard component of chemotherapy for the treatment of both resected and metastatic colon cancer, is a potent radiosensitizer with synergistic radiosensitizing activity in combination with 5-FU in preclinical studies. Early clinical trials showed promising activity with the addition oxaliplatin to 5-FU-based CRT in stage II-III rectal cancer; however, early data from phase III trials seem to be disappointing. This article reviews the existing literature and explores the potential role of oxaliplatin as part of neoadjuvant CRT for rectal cancer.

Abstract

Neoadjuvant chemoradiation (CRT) is standard treatment for stage II-III rectal cancer. Fluoropyrimidine-based CRT prolongs disease-free survival over adjuvant CRT and improves local control over both adjuvant CRT and neoadjuvant radiotherapy alone, but does not prolong overall survival. New approaches to neoadjuvant therapy may improve outcome in this disease. Oxaliplatin, a standard component of chemotherapy for the treatment of both resected and metastatic colon cancer, is a potent radiosensitizer with synergistic radiosensitizing activity in combination with 5-FU in preclinical studies. Early clinical trials showed promising activity with the addition oxaliplatin to 5-FU-based CRT in stage II-III rectal cancer; however, early data from phase III trials seem to be disappointing. This article reviews the existing literature and explores the potential role of oxaliplatin as part of neoadjuvant CRT for rectal cancer.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is approved for 1.0 contact hour. Approval as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/13355; and 4) view/print certificate.

Release date: March 15, 2013; Expiration date: March 15, 2014.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the role of oxaliplatin in the management of rectal cancer.
  • Describe the benefits and limitations of oxaliplatin in the neoadjuvant treatment of localized rectal cancer.

Rectal cancer occurs in 40,300 patients annually in the United States.1 Surgical resection is the only curative option. The lack of serosa covering the rectum and the proximity of the rectum to other pelvic organs promote local invasion of rectal tumors, and the location of the rectum in the pelvis can make complete resection technically difficult. Therefore, unlike colon cancer, rectal cancer tends to have a high local recurrence rate.2,3 Modern treatment strategies for stage II-III rectal cancer involve a multimodality approach aimed at minimizing morbidity, decreasing recurrence risk, and prolonging survival. Recently, the treatment paradigm shifted from adjuvant to predominantly neoadjuvant therapy based on improved local control and increased rates of sphincter preservation.4 This article focuses on the potential role for oxaliplatin in the neoadjuvant treatment of localized rectal cancer.

Neoadjuvant Chemoradiation Using 5-FU

Neoadjuvant fluoropyrimidine-based chemoradiotherapy (CRT) represents a standard treatment approach for patients with T3-4 and/or node-positive rectal cancer (stage II-III disease). Despite the lack of a survival benefit,5,6 phase III studies (EORTC 22921 and FFCD 9203) showed that the addition of 5-FU to neoadjuvant radiotherapy improves pathologic complete response (ypCR) and local control over radiotherapy alone.7-9 Similarly, phase III studies failed to show a survival benefit for the administration of neoadjuvant versus adjuvant CRT.4,10,11 This was confirmed by the recent update of the German CAO/ARO/AIO-94 study, showing no overall or disease-free survival benefit for neoadjuvant over adjuvant CRT after a median follow-up of 11 years.12 Neoadjuvant fluoropyrimidine-based CRT consistently decreases local recurrence risk, improves the odds of sphincter preservation, and improves ypCR compared with adjuvant CRT,4,11,12 which led to the adoption of neoadjuvant therapy as a standard of care.

Despite improved local control with neoadjuvant CRT, up to 35% of patients will have distant recurrence.13 Attempts to improve the efficacy of neoadjuvant CRT focus on treatment intensification through combining additional radiosensitizers such as oxaliplatin.

The Potential Role for Oxaliplatin in Neoadjuvant Chemoradiotherapy

Oxaliplatin is an important component of fluoropyrimidine-based chemotherapy in the treatment of colorectal cancer. In resected stage III colon cancer, adding oxaliplatin to fluoropyrimidines decreases recurrence risk14,15 and improves overall survival.14 In early-stage rectal cancer, the role of oxaliplatin is unclear.

Oxaliplatin as a Radiosensitizer

Oxaliplatin enhances radiation-induced cytotoxicity through several mechanisms, including causing DNA damage via formation of both inter- and intrastrand crosslinks, induction of G2/M cell-cycle arrest, and blockade of DNA replication and inhibition of transcription,16,17 which ultimately result in synergistic induction of irreparable DNA damage.18,19 Preclinical data indicate potent radiosensitizing properties of oxaliplatin.20,21 Subsequent investigations suggest synergism between oxaliplatin and radiation, specifically in colon cancer cells, but data conflict regarding the appropriate sequencing.22,23 In colon cancer cell lines, the addition of oxaliplatin to 5-FU resulted in synergistic radiosensitizing activity. These data generated interest in integrating oxaliplatin into standard CRT in the clinical setting.

Early Clinical Trials of Neoadjuvant 5-FU, Oxaliplatin, and Radiation in Rectal Cancer

Multiple phase I studies of fluoropyrimidine-based CRT in combination with oxaliplatin are summarized in Table 1.24-34 Several dosing schedules of oxaliplatin were combined with either capecitabine or 5-FU (bolus or infusional) at various doses, along with either 45.0 or 50.4 Gy of radiotherapy. Grade 3 diarrhea was the most consistently reported dose-limiting toxicity. In general, results suggested that oxaliplatin could be safely added to fluoropyrimidine-based CRT at a weekly dose of 50 to 60 mg/m2, allowing for a greater dose density. Reported ypCR ranged from 0% to 26% in those studies.26,30-34

Phase II studies investigated various combinations and dosing schedules of fluoropyrimidine, oxaliplatin, and radiation, and are summarized in Table 2.24,27-29,35-43 Most studies primarily evaluated ypCR and surgical outcomes, including sphincter preservation and postoperative complication rates. Reported ypCR rates varied between 7% and 28%,24,27-29,38,44 comparing favorably with rates of 8% to 15% among historical controls treated with fluoropyrimidines only.4,9,11 Overall, regimens including weekly oxaliplatin seemed to produce higher rates of ypCR.27,29,45 Grade 3/4 diarrhea was the most frequently reported toxicity, with incidences of 8% to 38%. The combination of continuous infusion 5-FU and weekly oxaliplatin resulted in the highest rates of grade 3/4 diarrhea.27,36,45 Rates of sphincter preservation, when reported, ranged from 32% to 73%. Acceptable rates of postoperative complications (ranging from 0%-39%) were reported and included wound dehiscence, infection, and bleeding. Postoperative mortality rates (within 60 days of surgery) were low, with most studies reporting no intra- or postoperative deaths. These results generated interest in investigating the combination in phase III studies.

Table 1

Summary of Phase I Clinical Trials of Oxaliplatin- and Fluoropyrimidine-Based Chemoradiation

Table 1
Table 2

Summary of Published Phase II Clinical Trials of Fluoropyrimidine-Based Chemoradiation With Oxaliplatin in Stage II-III Rectal Cancer

Table 2

Phase III Trials of CRT With Oxaliplatin

Four phase III trials evaluated the addition of oxaliplatin to fluoropyrimidine-based CRT as neoadjuvant therapy for stage II-III rectal cancer, showing overall increased toxicity and mixed preliminary efficacy results (Table 3). Final efficacy data regarding primary outcomes are not yet available for 3 of these trials.

The French ACCORD12/Prodige2 trial46 randomized 598 patients with resectable cT3-4,N0-2 rectal cancer to neoadjuvant CRT with capecitabine (radiotherapy dose of 45 Gy) versus capecitabine plus weekly oxaliplatin (radiotherapy dose of 50 Gy), with the primary end point of ypCR. Of patients receiving oxaliplatin, 59% required dose modifications, compared with 50% of patients in the control arm. Trends toward improved ypCR (P=.09) and reduction in ypT4 tumors (P=.087) were observed with oxaliplatin. When patients experiencing a major response and those with a few residual malignant cells (TRG 2) were included, pathologic response rates were 39.8% versus 28.9% in favor of oxaliplatin (P=.008). Sphincter preservation was 75% in each arm. In an exploratory analysis of circumferential resection margin (CRM) status, in which a positive margin was defined as tumor located 2 mm or less (as opposed to the conventional definition of <1 mm) from the rectal margin, a significant decrease in the rate of positive CRM was seen with the addition of oxaliplatin (19.3% vs. 9%; P=.02). Intraoperative evidence of distant metastatic disease was found in 4.2% of patients treated with capecitabine only versus 2.8% in those who also received oxaliplatin. Grade 3/4 toxicities, particularly diarrhea, were significantly increased with the combination therapy.

The Italian STAR-01 trial47 randomized 747 patients with cT3-4 and/or cN1-2 rectal cancer to either CRT with continuous infusion 5-FU or continuous infusion 5-FU plus weekly oxaliplatin, with the primary end point of overall survival and a preplanned interim analysis of ypCR. Among the patients in the latter group, 83% received 5 doses of oxaliplatin and 66% received all 6 doses, with 15% of patients requiring dose reductions. Among those in the combination arm, 80% received the full planned cumulative dose of 5-FU and 84% received the full dose of radiation, compared with 90% and 92%, respectively, in the 5-FU only arm (P<.001 for both comparisons). More than 90% of patients on each arm were able to receive the planned 45 Gy of radiation. Seventeen percent of patients receiving oxaliplatin and 5-FU versus 4% of patients receiving 5-FU only discontinued treatment because of toxicity. Interim analysis revealed a ypCR rate of 16% on both arms (P=.904), with a significantly increased incidence of grade 3/4 toxicities with oxaliplatin versus 5-FU, predominantly diarrhea (15% vs. 4%, respectively). Postoperative complications were equally low on both arms. Intra-abdominal metastases were observed at surgery in 16 patients treated with 5-FU versus 2 patients treated with oxaliplatin. Survival data are still pending.

The German CAO/ARO/AIO-04 study48 randomized 1265 patients with rectal cancer and clinical evidence of nodal or perirectal fat involvement to either neoadjuvant infusional 5-FU-based CRT followed by adjuvant bolus 5-FU versus infusional 5-FU and oxaliplatin-based CRT followed by adjuvant FOLFOX, with the primary end point of disease-free survival. Treatment compliance with radiation and chemotherapy was similar in both groups, with 85% of patients receiving the full planned dose of oxaliplatin. Fewer patients required dose reductions in the oxaliplatin group than in the 5-FU group (15% vs. 21%, respectively); it must be kept in mind that a relatively more toxic 5-FU regimen was used in the control arm of this trial, resulting in higher rates of grade 3/4 toxicity than among other 5-FU controls in phase III studies. Ninety-four percent of patients in the oxaliplatin group and 96% of patients in the 5-FU group received the full planned dose of radiation. In an analysis of secondary end points, ypCR was significantly improved with oxaliplatin, with no significant differences in grade 3/4 toxicities or postoperative complications. Data regarding the primary end point are still pending.

The U.S. NSABP R-04 trial49 randomized 1608 patients to receive neoadjuvant CRT with 50.4 Gy of radiation therapy, plus either infusional 5-FU or capecitabine, with or without weekly oxaliplatin. The original primary end point of local tumor control at 3 years was replaced with a composite of ypCR and disease-free survival. Preliminary results suggested increased grade 3/4 diarrhea with oxaliplatin (15.4% vs. 6.6%), with no improvement in ypCR (20.9% vs. 19.1%) and no difference in sphincter preservation or surgical downstaging.

Finally, the recently completed PETACC-6 trial evaluated the addition of oxaliplatin to capecitabine-based neoadjuvant CRT and adjuvant CT (Clinical-Trials.gov identifier: NCT00766155). Patients with locally advanced rectal cancer (T3-4 or N0-1) were randomized to receive either neoadjuvant CRT with capecitabine alone followed by adjuvant capecitabine, or neoadjuvant CRT with capecitabine and oxaliplatin followed by adjuvant capecitabine and oxaliplatin, with the primary outcome of disease-free survival. Data from this trial are still pending.

The available data indicate increased toxicity without added benefit from oxaliplatin, and therefore do not support its use in standard neoadjuvant CRT regimens for the treatment of rectal cancer. This recommendation may change when final data on local control and long-term survival are available from the 3 trials with currently immature data.

Table 3

Summary of Completed Phase III Trials of Chemoradiotherapy With Oxaliplatin in Stage II-III Rectal Cancer

Table 3

The Potential Use of Oxaliplatin Combined With 5-FU Without the Use of Radiation in the Neoadjuvant Treatment of Rectal Cancer

Although no survival benefit has been demonstrated in phase III studies, the inclusion of radiation in the neoadjuvant therapy of rectal cancer represents the current standard of care, based primarily on the reduction of local recurrence and improvement in rates of sphincter preservation, both of which are significant quality-of-life benefits for patients. However, the use of radiation is also associated with the potential for significant short-term toxicity50 and long-term morbidity, including infertility and sexual dysfunction, abdominal fibrosis, autonomic nerve injuries resulting in abnormal bowel and bladder function, increased risk for pelvic fractures, and decreased bone marrow reserve, which would be potentially detrimental to therapy in the setting of recurrent or metastatic disease.4,50-53 Therefore, it is logical to question whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer, or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy.54

Data suggest that a more aggressive surgical approach (total mesorectal excision [TME]) also significantly reduces local recurrence rates.55-57 Advances in surgical technique in the past decade, including the increasing use of TME, have resulted in higher complete resection rates and fewer positive margins,58 raising the question of whether radiation is still necessary for all patients. In addition, advances in systemic therapy for colorectal cancer, including the addition of oxaliplatin to fluoropyrimidines, have resulted in improved response rates as high as 70%,59-61 which could be potentially beneficial in the neoadjuvant setting. With better local control, an increasing percentage of patients with rectal cancer will experience relapse at a systemic level, providing a rationale for the investigation of oxaliplatin-based systemic therapy without radiotherapy for patients at lower risk of local recurrence, specifically those without truly locally advanced disease or those with limited nodal involvement (T3,N0 or T3,N1) undergoing TME. Lower rates of intra-abdominal metastases discovered at surgery in patients treated with oxaliplatin on the ACCORD12, STAR-01, and AIO trials46-48 suggest that adding this agent to neoadjuvant therapy may improve control of micrometastatic disease. The role of neoadjuvant oxaliplatin plus fluoro-pyrimidines without radiation in select patients with rectal cancer is currently under investigation in the phase II/III NCCTG N1048 trial (ClinicalTrials.gov identifier: NCT01515787).

Conclusions

Promising preclinical and early clinical results failed to translate into a clear benefit to adding oxaliplatin as a radiosensitizer in CRT regimens for patients with rectal cancer. Although the results from 3 of 4 phase III studies are not yet mature, current data suggest that oxaliplatin adds toxicity in the absence of added clinical benefit, and therefore should not be used as part of standard preoperative CRT. The reason for this lack of benefit is unclear but may relate to undertreatment and tumor cell repopulation during treatment breaks, as a result of added toxicity from oxaliplatin necessitating more dose reductions and interruptions in treatment. Another possibility is that the addition of oxaliplatin to 5-FU does not further enhance the radiosensitizing effect already achieved by 5-FU alone.

The choice of ypCR as a surrogate end point for survival in some studies may also explain the apparent failure of oxaliplatin to improve outcomes. The association between ypCR and response and long-term clinical outcomes has not been firmly established,6,11,44,62-73 and therefore ypCR does not represent a valid surrogate end point for survival in phase III trials of therapy for rectal cancer. Finally, the possibility exists that only select patients, such as those with tumors underexpressing the protein ERCC-1, which repairs platinum-induced DNA damage, will achieve benefit from oxaliplatin.

If oxaliplatin ultimately demonstrates improvement in long-term clinical outcomes (such as disease-free and overall survivals) with prolonged follow-up from phase III trials, its integration into standard neoadjuvant CRT should then be considered. However, maintaining dose intensity may prove difficult given the added toxicities. A regimen containing lower cumulative doses of oxaliplatin and 5-FU (200 and 7000 mg/m2, respectively), and a treatment schedule that allows for a chemotherapy break, such as used in the AIO-04 trial, may help improve treatment compliance.

The potential for improved control of micro-metastatic disease observed in phase III studies of neoadjuvant oxaliplatin-based CRT and high response rates with fluoropyrimidines plus oxaliplatin in the metastatic setting suggest a rationale for the continued investigation of oxaliplatin in rectal cancer, potentially in the context of induction chemotherapy before or exclusive of CRT, as is currently under investigation in the N1048 study, or in the adjuvant setting in which a recent meta-analysis suggests a significant disease-free and overall survival benefit for fluoropyrimidine-based therapy over observation after curative surgery.74 Current NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer support the use of adjuvant FOLFOX after neoadjuvant CRT for T3-4 or node-positive tumors, largely based on extrapolation from stage III colon cancer data (to view the most recent version of these guidelines, visit NCCN.org).75 A need also exists for a more personalized approach to rectal cancer treatment to help develop predictive biomarkers (such as ERCC-1) to identify patients who may benefit from oxaliplatin-based therapies. Finally, available evidence does not support the use of ypCR as a primary end point for phase III trials.

In conclusion, the current standard is to not include oxaliplatin in preoperative CRT regimens for the treatment of rectal cancer. This recommendation may change after data on survival from phase III trials are reported.

Dr. Martin has disclosed that she has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Bekaii-Saab has disclosed that he is a consultant for sanofi-aventis.
EDITORKerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer NetworkMs. Green has disclosed that she has no relevant financial relationships.
CE AUTHORSNicole B. Harrold, BS, Manager, Continuing Education and GrantsMs. Harrold has disclosed that she has no relevant financial relationships.Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information OperationsMs. Gregory has disclosed that she has no relevant financial relationships.

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Correspondence: Tanios Bekaii-Saab, MD, A454 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. E-mail: Tanios.saab@osumc.edu

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