Locally Advanced Rectal Cancer: What Does the Local Treatment Response Tell Us About the Global Picture?

Abstract

Historically, both local as well as distant failure rates were unsatisfactory for locally advanced rectal tumors after surgery alone (1Swedish Rectal Cancer TrialImproved survival with preoperative radiotherapy in resectable rectal cancer.N Engl J Med. 1997; 336: 980-987Crossref PubMed Scopus (2266) Google Scholar). Significant progress has been made on the local front with the introduction of mesorectal excision as well as neoadjuvant short-course radiation therapy or long-course chemoradiotherapy. In the German CAO/ARO/AIO-94 trial, patients with clinical stage II or III rectal carcinoma treated with neoadjuvant radiation therapy and infusional 5-fluorouracil (5-FU), surgery, and 4 cycles of adjuvant bolus 5-FU had a 7.1% rate of local–regional failure at 10 years (2Sauer 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: 1926-1933Crossref PubMed Scopus (1300) Google Scholar). The long-term control result from this trial provides an important benchmark for patients with clinical stage II and III rectal cancer going forward. The CAO/ARO/AIO-94 study also provides another important and concerning benchmark statistic: nearly 30% of the patients treated with neoadjuvant therapy developed distant metastatic disease by 10 years (2Sauer 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: 1926-1933Crossref PubMed Scopus (1300) Google Scholar). Thus, locally advanced rectal adenocarcinoma would seem to be a prime candidate for true multimodality therapy, with a calling for effective systemic therapy above and beyond what is delivered as a radiosensitizer concurrently with radiation therapy during neoadjuvant therapy. The integration of local–radiation and surgery–therapies and systemic therapy is founded on the principle of spatial cooperation and is the basis for many common cancer treatment algorithms (3Steel G.G. Peckham M.J. Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity.Int J Radiat Oncol Biol Phys. 1979; 5: 85-91Abstract Full Text PDF PubMed Scopus (803) Google Scholar). Adjuvant chemotherapy for resected rectal cancer would seem all the more natural given the data from adjuvant colon cancer trials, which showed first the superiority of adjuvant 5-FU and leucovorin (LV) relative to surgery alone, and subsequently the value of adding oxaliplatin to 5-FU/LV (4International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigatorsEfficacy of adjuvant fluorouracil and folinic acid in colon cancer.Lancet. 1995; 345: 939-944Crossref PubMed Scopus (983) Google Scholar, 5Andre T. Boni C. Navarro M. et al.Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.J Clin Oncol. 2009; 27: 3109-3116Crossref PubMed Scopus (1645) Google Scholar). However, multiple clinical trials that have addressed the use of chemotherapy specifically in rectal (as opposed to colon) adenocarcinoma patients treated with neoadjuvant therapy have not shown a clear benefit for its use (6Breugom A.J. Swets M. Bosset J.F. et al.Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: A systematic review and meta-analysis of individual patient data.Lancet Oncol. 2015; 16: 200-207Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). A recent meta-analysis evaluated nearly 1200 patients from 4 randomized trials that studied the role of adjuvant chemotherapy in patients with rectal cancer who had undergone preoperative radiation or chemoradiation therapy (6Breugom A.J. Swets M. Bosset J.F. et al.Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: A systematic review and meta-analysis of individual patient data.Lancet Oncol. 2015; 16: 200-207Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). Only 1 of the studies, which contributed the fewest number of patients to the analysis, incorporated oxaliplatin in the adjuvant chemotherapy regimen. Adjuvant chemotherapy did not yield any statistically significant improvement in distant disease control or disease-free or overall survival. There was a suggestion of improvement in disease-free survival with the use of adjuvant chemotherapy only in the highest rectal tumors (tumors from 10 to 15 cm from the anal verge). As investigators continue to extrapolate from data in colon cancer, different consensus guidelines have different recommendations regarding the role of adjuvant chemotherapy in rectal cancer patients (eg the National Comprehensive Cancer Network guidelines and the 2nd European Rectal Cancer Consensus Conference report [7Valentini V. Aristei A. Glimelius B. et al.Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2).Radiother Oncol. 2009; 92: 148-163Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar]). Why has adjuvant chemotherapy proven to have a role in adjuvant treatment for colon cancer but not in rectal cancer? One potential answer lies in the adjuvant chemotherapy regimen. In 3 of the 4 aforementioned studies, only 5-FU/LV or capecitabine was delivered adjuvantly, as opposed to the 5-FU plus oxaliplatin combination therapy commonly used in adjuvant colon cancer treatment. The recently reported ADORE trial showed a disease-free survival benefit to adjuvant 5-FU/LV plus oxaliplatin over 5-FU/LV alone in patients with resected pathologic stage II or III rectal cancer after preoperative chemoradiotherapy (8Hong Y.S. Nam B.H. Kim K.P. et al.Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after peroperative chemoradiotherapy (ADORE): An open-label, multicenter, phase 2, randomized controlled trial.Lancet Oncol. 2014; 15: 1245-1253Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). Of note, compliance with the adjuvant chemotherapy was very high in both arms of this study. Another answer may lie in this issue of compliance. For example, in the European Organization for Research and Treatment of Cancer 22921 trial, only 43% of patients assigned to receive postoperative chemotherapy received the intended course of adjuvant treatment (9Bosset J.F. Collette L. Calais G. et al.Chemotherapy with preoperative radiotherapy in rectal cancer.N Engl J Med. 2006; 11: 1114-1123Crossref Scopus (2080) Google Scholar). Patients undergoing rectal cancer surgery may have delays in initiation of adjuvant chemotherapy secondary to wound and other postoperative complications that lead to prolonged hospital stays and recovery periods. Significant delays in initiating chemotherapy have previously been associated with inferior survival outcomes in rectal cancer (10Cheung W.Y. Neville B.A. Earle C.C. Etiology of delays in the initiation of adjuvant chemotherapy and their impact on outcomes for stage II and III rectal cancer.Dis Colon Rectum. 2009; 52: 1054-1063Crossref PubMed Scopus (2) Google Scholar). To address this issue, investigators have begun to study the value of sequencing “full systemic therapy” before surgery, (11Perez K. Safran H. Sikov W. et al.Complete neoadjuvant treatment for rectal cancer: The Brown University Oncology Group CONTRE study.Am J Clin Oncol. 2014; (In press)Google Scholar). Finally, fundamental differences in tumorigenesis and chemosensitivity may exist between colon and rectal tumors, although recent data would suggest that these in-continuity structures share many similarities in tumor development (12Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5612) Google Scholar). There may be a flip side to the poor distant control rates seen in locally advanced rectal cancer, and that is the subject of the report by Park et al in this issue of the International Journal of Radiation Oncology • Biology • Physics (13Park I.J. Kim D.Y. Kim H.C. et al.Role of adjuvant chemotherapy in ypT0-2N0 patients treated with preoperative chemoradiotherapy and radical resection for rectal cancer.Int J Radiat Oncol Biol Phys. 2015; : 534-541Google Scholar). Previous studies have shown that patients who undergo neoadjuvant therapy and are found to have no remaining viable tumor—a pathologic complete response—in their surgical specimen have high rates of disease-free survival (and relatively low rates of developing metastatic disease) independent of the use of adjuvant chemotherapy (14Capirci C. Valentini V. Cionini L. et al.Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: Long-term analysis of 566 ypCR patients.Int J Radiat Oncol Biol Phys. 2008; 72: 99-107Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar). In an update of the CAO/ARO/AIO-94 trial, patients with a pathologic complete response to neoadjuvant therapy had a 10.5% incidence of developing distant metastases, compared with 39.6% in patients with poor histologic response (using the Dworak criteria) (15Fokas E. Liersch T. Fietkay R. et al.Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: Updated results of the CAO/ARO/AIO-94 trial.J Clin Oncol. 2014; 32: 1554-1562Crossref PubMed Scopus (272) Google Scholar). Such results demonstrate the interpatient heterogeneity common to this and other cancers. This important finding with tumors demonstrating complete pathologic response may well apply to patients who have any degree of significant tumor “downstaging” (reduced pathologic stage relative to clinical stage) after neoadjuvant treatment, and that is indeed suggested by the results of this study. Data from 1016 patients treated were pooled together in a multi-institutional effort. Patients initially had locally advanced rectal cancer (clinical stages are not provided in the report) and were found to have posttreatment pathologic stages of T0-2N0 (ypT0-2N0) (postoperative stage 0 or I cancer). A variety of chemotherapy regimens were given concurrently with the radiation. Approximately 90% of these patients proceeded to adjuvant chemotherapy (with various agents), and 10% did not. Five-year distant metastasis rates were low in both groups (6.9% with adjuvant chemotherapy and 10.6% without, P=.17), as were local recurrence rates (2.5% with adjuvant chemotherapy and 5.4% without). In multivariate analysis, the use of adjuvant chemotherapy was not associated with relapse-free survival (hazard ratio 0.62, P=.28), although the confidence intervals were wide (0.26-1.49). In propensity score analysis, adjuvant chemotherapy was again not associated with a statistically significant decrease in rate of distant metastases, nor did it affect relapse-free survival. In a separate analysis evaluating not downstaging of tumor invasiveness but rather the histologic response, use of adjuvant chemotherapy was of borderline importance for patients with poor tumor regression grade. With the limitations of retrospective data analysis kept in mind, the results of Park et al are thought-provoking. One hypothesis generated from this study is that we can use the results of neoadjuvant therapy—the established approach to clinical stage II and III rectal cancer on the basis of the CAO/ARO/AIO-94 results—to select a group of patients for whom the risk of distant disease progression is low and for whom the addition of adjuvant chemotherapy may carry more risks than benefits. Why patients who have significant tumor downstaging may have low rates of distant progression, even without adjuvant chemotherapy, is unclear. Perhaps some of these patients have been overstaged with conventional imaging and were never destined to have a high risk for developing distant disease. Perhaps the chemotherapy used during the neoadjuvant chemoradiation course is indeed sufficient to eradicate or prevent the growth of micrometastases that are as “treatment sensitive” as their source; or it may be that tumors that have chemoradiotherapy-sensitive primary sites do not aggressively seed distant sites despite aggressive local growth—in other words, downstaging is a prognostic, not necessarily predictive, sign. Also, substantial killing or alteration of the primary site may affect growth of distant disease through immune-mediated mechanisms (15Fokas E. Liersch T. Fietkay R. et al.Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: Updated results of the CAO/ARO/AIO-94 trial.J Clin Oncol. 2014; 32: 1554-1562Crossref PubMed Scopus (272) Google Scholar). Thus, we are left with the reminder, common in contemporary oncology, that we are not providing adequate adjuvant therapy to many patients and are over-treating others. Clearly, further clinical study is necessary to determine which groups of patients undergoing standard chemoradiotherapy are likely or unlikely to benefit from further chemotherapy. Defining a “good response” to neoadjuvant treatment will be part of this process—“downstaging” is somewhat nebulous and arbitrarily defined and depends in part on the quality and reproducibility of clinical staging, as well as the length of the break period. Additionally, is there a predictive bell curve derived from the surgical specimens? Are patients on the extreme ends of the spectrum—those with pathologic complete response and those with minimal regression—the ones least likely to benefit from adjuvant 5-FU-based chemotherapy regimens, whereas those with an “intermediate” response the ones most likely to benefit from it? Whether the degree of histologic response to chemoradiotherapy (histologic tumor regression grading) can outperform physical downstaging as a biomarker also remains to be seen. Finally, the value of downstaging and/or histologic response relative to other prognostic and predictive biomarkers will need evaluation. Rectal cancer management is in a state of evolution. Distant disease progression remains a significant challenge for patients and clinicians and must be a focus of continued preclinical and clinical study. However, studies such as the one by Yu et al serve to remind us of the heterogeneity of this disease and may allow us to take advantage of a special variety of biomarker that emerges from the treatment itself. Role of Adjuvant Chemotherapy in ypT0-2N0 Patients Treated with Preoperative Chemoradiation Therapy and Radical Resection for Rectal CancerInternational Journal of Radiation Oncology, Biology, PhysicsVol. 92Issue 3PreviewTo explore the role of adjuvant chemotherapy for patients with ypT0-2N0 rectal cancer treated by preoperative chemoradiation therapy (PCRT) and radical resection. Full-Text PDF