Data from trials conducted mostly in the 1970s and 1980s established the paradigm that optimal treatment of rectal cancer requires a combination of radiation therapy, chemotherapy, and surgery.1 Virtually all of these trials, however, demonstrated that radiotherapy added only to the local control rate—an important endpoint in its own right—while only one outlier trial, the Swedish Rectal Cancer Trial, demonstrated an overall survival benefit for radiotherapy.2 That trial utilized a short-course radiation schedule of 500 cGy daily for 5 consecutive days, with no chemotherapy as part of the treatment strategy in either arm.
Heretical Question
About a decade ago, our group noted an interesting phenomenon. We had three patients over a short period of time who had either medical contraindications to pelvic radiotherapy or suspected extrapelvic metastases, and so were treated with FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin) chemotherapy as an initial maneuver. These three patients underwent endoscopic evaluation 2 to 3 months into therapy for the purpose of assuring that the tumors were not at risk of obstruction. In each case, either a complete or near-complete clinical response was seen.
At operation, two of the three had a pathologically confirmed complete response, and the third had only rare viable tumor cells seen, for a near-complete pathologic response, and these patients remained recurrence-free in follow-up. This led us to ask a heretical question: Do we need to be radiating the pelvises of all patients with locally advanced rectal cancer?
Our pilot data, recently reported in the Journal of Clinical Oncology3 and reviewed in this issue of The ASCO Post, suggest that a sizable proportion of patients with stage II or III rectal cancer might be able to be safely treated without the added long- and short-term toxicities, or the added expense, of pelvic radiotherapy. Our findings are hypothesis-generating, and serve as the basis for a phase III National Cancer Institute cooperative group trial, which is now open and accruing patients.
Pilot Study
Our pilot study included 32 patients with rectal cancer at our institution who would otherwise have received preoperative chemotherapy plus radiotherapy. We treated them with neoadjuvant FOLFOX plus bevacizumab (Avastin). In addition, selective use of preoperative chemotherapy/radiotherapy was administered only for patients in whom tumor progression was seen after 12 weeks of chemotherapy. All patients subsequently had surgery and then 12 additional weeks of the same chemotherapy.
Two patients discontinued treatment early due to cardiac events. One went on to receive standard preoperative chemotherapy plus pelvic radiotherapy, followed by total mesorectal excision and then standard FOLFOX chemotherapy; she remained free of recurrence. The other was found to have substantial coronary artery disease, had a coronary stent placed, and received preoperative radiotherapy alone. He subsequently developed pulmonary metastases.
Thirty patients completed the planned 3-month course of chemotherapy. None showed progression, and all 30 went on to have an R0 resection. One patient with 14 positive nodes was given postoperative radiotherapy. Eight of the original 32 (25%) were found to have a pathologic complete response to chemotherapy alone, with no viable tumor identifiable in the surgical specimen.
With a minimum follow-up of 4 years from the date of operation, none of the 30 patients treated with preoperative chemotherapy only had a local recurrence of tumor. Four patients developed distant metastatic disease, all in the lung. One of these patients had had a pathologic complete response in the rectum, and developed a solitary lung metastasis 18 months later, which was resected; she remains cancer-free 4 years later.
Key Changes
What has changed in the past several decades to allow us to question the continued universality of the role of radiotherapy?
First, the quality of surgery has changed dramatically with the understanding that total mesorectal excision is the appropriate operation for removal of a locally advanced rectal tumor.4 Older surgical techniques called for a blunt dissection of the rectum off of the pelvic sidewall, with avulsion of the rectosacral ligament. This led to a tearing of the outer surface of the mesorectum, a fatty sheath that surrounds the rectum and contains the regional lymph nodes, and greatly increased the chance for residual tumor to be left at the local site. A total mesorectal excision involves a sharp dissection of the outer surface of the mesorectum, creating a surgical plane and resulting in an intact mesorectum, and a far cleaner removal of local-regional nodes.
The second major change is in the quality of chemotherapy. The use of infusional rather than bolus 5-FU and the addition of oxaliplatin have meaningfully improved the activity of chemotherapy for rectal cancer.
A third factor is the vast improvement in the accuracy of presurgical staging. With the advent of endorectal ultrasound and high-quality rectal magnetic resonance imaging, a far more accurate assessment of local invasiveness and, to a lesser extent, nodal involvement allows for more accurate delineation of locally resectable vs locally invasive tumors. The dramatic improvement in the accuracy of computed tomography imaging also allows for a far more sensitive and specific identification of synchronous small-volume stage IV disease.
The final factor that supports investigation of a non–universal radiotherapy approach is the observed increased, and as yet, unexplained sensitivity of the primary tumor to garden variety FOLFOX chemotherapy. Chau et al had previously reported outstanding activity of capecitabine/oxaliplatin when used as an initial maneuver in the treatment of locally advanced rectal cancer, with an 88% radiologic response rate, prior to planned capecitabine plus radiotherapy.5 Our group had also noted this increased sensitivity of the primary.6
Role of Bevacizumab
Our trial was initiated before the results of the colon adjuvant trials with bevacizumab were known. We chose to include bevacizumab in our pilot trial with the plan that if the colon adjuvant trials were positive, we would take bevacizumab forward in our rectal strategies, whereas if they were negative, we would drop the bevacizumab going forward. Both large-scale trials of bevacizumab in the adjuvant setting were subsequently found to be decidedly negative.7,8
In addition, results of a 1,400-patient randomized trial that became available after our rectal trial had started showed that bevacizumab had absolutely no impact on the objective response rate of capecitabine/oxaliplatin or FOLFOX in the metastatic setting.9 We therefore do not believe that bevacizumab had any contribution to our promising results, and we do not advocate its use in the adjuvant or neoadjuvant setting.
PROSPECT Trial
Our preliminary results have led to the current Alliance phase III study known as the PROSPECT trial (Preoperative Radiation Or Selective Preoperative Evaluation of Chemotherapy and Total mesorectal excision). This trial is randomly assigning patients to a standard arm of preoperative pelvic radiotherapy with concurrent capecitabine vs preoperative FOLFOX for 12 weeks. For patients experiencing less than an estimated 20% reduction in tumor volume on preoperative FOLFOX, preoperative radiotherapy with capecitabine is then given, while those with acceptable tumor reduction go on to total mesorectal excision without radiotherapy. Postoperative care in each arm is at the discretion of the treating physician.
This trial is open to rectal cancer patients with stage II or III rectal cancer and tumors above 5 cm from the anal verge. The study is widely available throughout North America, and consideration of this trial for all eligible patients is strongly encouraged. ■
Disclosure: Dr. Saltz reported no potential conflicts of interest.
References
1. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Nat Cancer Inst 80:21-29, 1988.
2. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997.
3. Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: A pilot trial. J Clin Oncol 32:513-518, 2014.
4. Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133:894-899, 1998.
5. Chau I, Brown G, Cunningham D, et al: Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging–defined poor-risk rectal cancer. J Clin Oncol 24:668-674, 2006.
6. Cercek A, Weiser MR, Goodman K, et al: Complete pathologic response in the primary of rectal or colon cancer treated with FOLFOX without radiation. J Clin Oncol 28 (suppl), abstract 3649, 2010.
7. Allegra CJ, Yothers G, O’Connell MJ, et al: Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol 31:359-364, 2013.
8. de Gramont A, Van Cutsem E, Schmoll H-J, et al: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): A phase 3 randomised controlled trial. Lancet Oncol 13:1225-1233, 2012.
9. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013-2019, 2008.
