By adjusting the sequencing of currently available treatments, improved compliance with therapy is ensured, and novel scientific and clinically relevant hypotheses can be further explored.
Rectal cancer represents nearly one-third of all colorectal cancer cases in the United States, and it continues to be a leading cause of cancer-associated deaths annually. While screening is an important part of efforts to reduce the adverse effects of this disease, optimal treatment after diagnosis is also important. The best treatment requires a truly multidisciplinary and multimodal team of experts. In this review, Dr. Salem and colleagues review the data supporting the current standards of care for rectal cancer. For patients with stage II or III rectal cancer, the paradigm of preoperative chemoradiotherapy (CRT) followed by complete surgical resection (ideally with sphincter function preservation) followed by adjuvant chemotherapy is the approach that is the most well established in the United States.[2-4] With this approach, and with the use of quality-controlled external beam radiotherapy and subsequent total mesorectal resection, local control rates for the majority of patients remain consistently greater than 90%. Thus, the overwhelming majority of patients who succumb to rectal cancer do so because of distant failure.
There is controversy regarding the absolute benefits of systemic chemotherapy in rectal cancer because of the limited clinical trial data demonstrating a survival benefit from its adjuvant use. In addition to favorable patient selection and inconsistent baseline staging methods, most of the contemporary randomized controlled trials have failed to deliver or complete the intended adjuvant systemic chemotherapy in 25% to 70% of patients. This is in contrast to the majority of the clinical trials of adjuvant therapy for colon cancer, in which over 75% of patients routinely receive the intended therapy. Even at National Comprehensive Cancer Network (NCCN) centers (a network of eight regional centers with the demonstrated capacity to provide comprehensive multimodality cancer therapy), nearly 20% of rectal cancer patients seen in regular clinical practice do not receive their intended adjuvant chemotherapy. One can only speculate on the rate of adjuvant therapy administration in the general population of patients treated off protocol and outside of NCCN centers. The reasons for the low rate of adjuvant therapy administration in rectal cancer patients are varied.
It is plausible that the demonstration of meaningful improvements in rectal cancer patient survival will remain elusive until clinical trial designs and standard treatment protocols ensure that all patients obtain optimal systemic therapy as part of their treatment. Moreover, for most patients today, systemic therapy (and thus sterilization of occult micrometastatic disease) does not begin until they have recovered from surgery-nearly 3 months after the time of initial diagnosis. One way to effectively ensure that all patients receive intended (and earlier) systemic therapy is to incorporate induction or neoadjuvant chemotherapy. Thus, a new clinical trial paradigm is emerging that utilizes “total neoadjuvant therapy” (TNT), which typically includes 4 months of FOLFOX (folinic acid, fluorouracil, and oxaliplatin) systemic chemotherapy followed by CRT, then ending with surgical resection. In a relatively small randomized phase II study, this approach demonstrated a significant improvement in compliance with delivery of all therapy and no untoward complications. Through use of this approach, we are already seeing some exciting glimmers of real hope for patients.
Based on favorable findings from several pilot studies utilizing TNT, clinical trials are currently underway or in development to improve the efficacy of chemotherapy, improve the efficacy of radiotherapy, or selectively reduce or eliminate either radiotherapy or surgery. The National Clinical Trials Network (NCTN) Alliance PROSPECT trial (ClinicalTrials.gov identifier: NCT01515787) is testing the selective elimination of radiotherapy in those patients who demonstrate tumor downstaging with neoadjuvant chemotherapy alone. This randomized controlled trial has the potential to change the standard of care for a population of patients with favorably staged and chemotherapy-sensitive rectal cancers.
Alternatively, the “watch-and-wait” approach is being formally tested after very intriguing preliminary data suggested that patients who undergo TNT with chemotherapy and CRT and who achieve a clinical complete response may be able to avoid immediate surgery and instead be closely monitored. For those who fail to achieve a durable remission, salvage surgical resection in the event of a documented local recurrence appears feasible. A multicenter clinical trial (ClinicalTrials.gov identifier: NCT02008656) is looking to validate those findings and, importantly, is also testing the sequencing of induction chemotherapy followed by CRT vs CRT followed by chemotherapy prior to consideration of immediate surgery.
Finally, the NRG Oncology TNT clinical trial (NRG GI-002; ClinicalTrials.gov identifier pending) is a randomized phase II platform study that has parallel, noncomparative experimental arms and a single comparative control arm of neoadjuvant chemotherapy and CRT in locally advanced and high-risk rectal cancer. It will provide a systematic approach to the study of novel radiosensitizers (eg, the poly [ADP-ribose] polymerase [PARP] inhibitor veliparib), personalized treatment selection to identify patients at exceptionally high risk for recurrence, and the use of novel targeted systemic therapeutics. Because rectal cancer is a tumor type that allows serial biopsies during clinical care without operative risk to the patient, there is an inherent opportunity for scientific discovery through the correlation of clinical outcomes with molecular and biomarker interrogation. The TNT protocol will support the testing of multiple parallel hypotheses and will make it possible for more definitive randomized controlled studies to be made contingent on a prior demonstration of substantive activity.
By adjusting the sequencing of currently available treatments, improved compliance with therapy is ensured, and novel scientific and clinically relevant hypotheses can be further explored. Despite the challenges of predicting the future, the current generation of US clinical trials aspire to dramatically change the status quo in rectal cancer management.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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