Colorectal cancer remains a leading cause of cancer-associated deaths in the U.S., and rectal cancer represents nearly one-third of this burden. For patients with stage II or III rectal cancer, the paradigm of preoperative chemoradiotherapy (chemoRT), followed by complete surgical resection (ideally in the setting of sphincter preservation), followed by adjuvant chemotherapy, represents the current standard of care in the U.S.1-3 This paradigm is supported by national consensus guidelines and major cancer professional societies.4 Through the use of quality controlled external beam radiotherapy and subsequent total mesorectal resection, local control rates remain consistently greater than 90 percent. Today, most patients who succumb to rectal cancer do so through distant failure and systemic metastases.
It is plausible to speculate that a treatment regimen that ensures all patients with high-risk rectal cancers receive optimal systemic therapy could lead to meaningful improvements in survival. Furthermore, for most patients today, systemic therapy (and thus potential eradication of occult micro-metastatic disease) does not begin until after recovery from surgery—close to three months from the time of initial diagnosis. However, little data are available to show that adjuvant systemic chemotherapy reduces the risk of distant failure in rectal cancer, as opposed to colon cancer. Interestingly, most contemporary randomized controlled trials show that 25 percent to 70 percent of rectal cancer patients never receive or complete their intended adjuvant systemic chemotherapy. This statistic is in contrast to most adjuvant colon cancer clinical trials, in which more than 75 percent of patients routinely receive the intended therapy. Even at NCCN centers (a network of regional centers with the capacity to provide comprehensive multimodality cancer therapy), nearly 20 percent of patients do not receive their intended rectal cancer adjuvant chemotherapy.5 It is thus likely that, for a variety of reasons, the rate of adjuvant therapy administration is similarly suboptimal among patients treated off trial and in general practice.
One way to effectively ensure that all patients receive intended and earlier systemic therapy is induction or neoadjuvant chemotherapy. Thus, a new clinical trial paradigm is emerging that uses total neoadjuvant therapy (TNT), which typically includes four months of FOLFOX systemic chemotherapy, followed by chemoRT, and ending with surgical resection (see Figure 1). In a randomized phase II study, this approach has demonstrated a significant improvement in compliance with delivery of all therapy and no untoward surgical complications.6 Postoperative recovery is thus unabated by the need to continue anti-cancer treatments.
Figure 1. NRG Oncology NRG-GI002 Schema
Study approach and aims
The NRG Oncology TNT clinical trial (NRG-GI002) is a randomized phase II platform study with parallel, non-comparative experimental arms with a single comparative control arm of neoadjuvant chemotherapy and chemoRT in locally advanced and high-risk rectal cancer (see Figure 1). Additional arms testing novel agents and unique hypotheses will be added through protocol amendments and compared with the continuously running control arm. Any novel arm demonstrating success against the control arm will be further tested in larger and more definitive randomized controlled trials. The primary endpoint is a novel pathologic endpoint of the neoadjuvant rectal (NAR) score,which measures pathologic response to TNT and has been shown to predict long-term survival endpoints.7 Such a pathologic endpoint allows trial outcomes to be assessed rapidly. The platform design of the trial allows for a systematic approach to study novel radiosensitizers, such as the poly(ADP-ribose) polymerase inhibitor veliparib; personalized treatment selection using novel targeted systemic therapeutics; and identification of patients at exceptionally high risk for recurrence. Hence, the TNT protocol will provide a clinical trial to support the testing of multiple parallel hypotheses and help justify more definitive randomized controlled studies only after the demonstration of substantive activity.
Patients must have biopsy-proven clinical stage II/III rectal adenocarcinoma. The disease must be clinically determined as “locally advanced” by any one of the following criteria:
- Distal location: cT3-4 ≤ 5 cm from the anal verge, any N
- Bulky: Any cT4 with the majority of tumor < 12cm from the anal verge or evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia
- High risk for metastatic disease with four or more regional lymph nodes (cN2)
- Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as planned by the primary surgeon)
Associated translational studies will correlate clinical outcomes with molecular, biomarker, and imaging interrogation.
The study is currently undergoing the pre-activation phase at the National Cancer Institute Cancer Trials Support Unit. It is expected to be available for all sites to open in October 2016. The study is endorsed by all cooperative groups, including the Alliance for Clinical Trials in Oncology. For more information, contact email@example.com.
- Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.
- Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926-1933.
- Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27(31):5124-5130.
- NCCN Guidelines. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed August 23, 2016.
- Khrizman P, Niland JC, ter Veer A, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: A national comprehensive cancer network analysis. J Clin Oncol. 2013;31(1):30-38.
- Fernandez-Martos C, Garcia-Albeniz X, Pericay C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: Long-term results of the Spanish GCR-3 phase II randomized trial. Ann Oncol. 2015;26(8):1722-1728.
- George TJ Jr, Allegra CJ, Yothers G. Neoadjuvant rectal (NAR) score: A new surrogate endpoint in rectal cancer clinical trials. Curr Colorectal Cancer Rep. 2015;11(5):275-280.