In this issue of ONCOLOGY, Drs. Patel, Puthillath, Yang, and Fakih discuss the evolution of adjuvant therapy for locally advanced rectal cancer from postoperative to preoperative radiation and provide a fairly comprehensive review of the data on adjuvant/neoadjuvant chemoradiation for rectal cancer. The authors then attempt to critically evaluate the use of combination chemotherapy regimens in the neoadjuvant setting, asking the question, “Is more better?”
Neoadjuvant Chemoradiation as ‘Standard of Care’ for Locally Advanced Rectal Cancer
The shift in paradigm from adjuvant to neoadjuvant (preoperative) therapy for rectal cancer has been driven by numerous theoretical and empiric advantages. These include improved response to radiotherapy due to better oxygenation, decreased risk of seeding at surgery, increased chance for a complete pathologic surgical resection (R0), increased likelihood of sphincter-sparing, and improved patient tolerance. If chemotherapy is considered, there can be better delivery due to intact vasculature as well as earlier systemic treatment of occult metastatic disease.
These benefits have been borne out in clinical studies, most notably from the recent German Rectal Trial, which demonstrated an improvement in local relapse rates and reduced acute and overall toxicity using preoperative vs postoperative chemoradiation. This phase III randomized trial has established the “standard of care” for T3/4 or N+ rectal cancer as neoadjuvant infusional 5-FU with conventionally fractionated radiotherapy to 5,040 cGy.
Subsequent publications of the European Organisation for Research and Treatment of Cancer (EORTC) 22921 and Fédération Francophone de Cancérologie Digestive (FFCD) 9203 further confirmed the benefit of combining 5-FU–based chemotherapy with preoperative radiation.[2,3] This practice had been a de facto standard in the United States due in large part to an overwhelming lack of equipoise by North American investigators, who were reluctant to participate in the Radiation Therapy Oncology Group (RTOG) and National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials designed in the 1990s to address this very clinical issue. Moreover, neoadjuvant approaches with conventional radiation fractionation schemes have been less widely practiced in Europe, where the short-course radiation regimen of 5 Gy in five fractions had been previously shown to improve local control rates even among patients undergoing a total mesorectal excision.
Pitfalls in Extrapolating From the Metastatic Setting to Adjuvant/Neoadjuvant Therapy
Undoubtedly, the next step is to improve our current standard of care. Given the multitude of new chemotherapy combinations and molecularly targeted systemic therapies being investigated in metastatic colorectal cancer, it is natural to consider incorporating these regimens into the adjuvant/neoadjuvant setting.
However, it must be remembered that the endpoints and goals of therapy differ significantly between curative patients receiving neoadjuvant therapy and patients receiving chemotherapy for noncurative disease. Surrogate endpoints such as response rates, time to progression, and progression-free survival (PFS) can be evaluated for patients with measurable metastatic disease, and multidrug regimens may be found to have more of an impact on these endpoints than single agents when the impact is measured in weeks to months. Moreover, many patients with metastatic disease may have received initial chemotherapy with single-agent fluorouracil(Drug information on fluorouracil) (5-FU) and may have developed variable degrees of cross-resistance, necessitating multidrug regimens and combinations with targeted agents to overcome resistant tumor cells in the clinical setting of recurrent disease.
In the neoadjuvant setting, we are treating patients with the intention of cure at 5 years. The incremental improvement—ie, a few more months in PFS—that comes with the addition of more cytotoxic chemotherapy and targeted agents in the metastatic setting will be hard to detect in the adjuvant setting. This was evident from the MOSAIC trial, a large randomized phase III trial evaluating the addition of oxaliplatin(Drug information on oxaliplatin) (Eloxatin) to 5-FU/leucovorin (LV) for patients with stage II/III colon cancer. With over 2,200 patients, a 3-year disease-free survival benefit was shown for the addition of oxaliplatin. However, in a subset analysis of stage II patients, the benefit was not statistically significant. Thus, even with large phase III trials, it is difficult to demonstrate the impact of additional chemotherapy in the adjuvant setting.
The endpoints for evaluating the benefit of combination chemotherapy agents in neoadjuvant therapy have been tailored to allow for earlier assessment of efficacy. For example, pathologic complete response (pCR) following preoperative chemoradiation is predictive of overall survival[6-11] and therefore should be an appropriate surrogate for evaluating the effect of neoadjuvant chemoradiation regimens for rectal cancer.
The wide array of new cytotoxic and targeted agents has propagated numerous small phase II studies evaluating pCR rates. While these phase II studies may be sufficient to detect small differences in pCR rates, larger, well-designed phase III trials will be needed to determine whether these improvements in pathologic response translate into survival benefits. As noted by the authors, future neoadjuvant chemoradiation trials should also focus on clinically relevant endpoints such as sphincter preservation and toxicity.
Individualization of Neoadjuvant Therapy
The neoadjuvant approach is particularly appealing for assessing the biology of the tumor and for identifying active regimens that can then be used for the patient in the postoperative setting. Preoperative therapy also allows us to identify predictive and prognostic markers for treatment response. This leads to the potential for individualizing treatment regimens using information about the tumor and the patient.
Basic prognostic information such as tumor stage, histologic grade, and location are being reinforced by the use of biomarkers that may help us to identify patients who are most likely to benefit from certain drugs. Mutations in the K-ras gene have been associated with a lack of response to epidermal growth factor receptor (EGFR) inhibitors and an overall worse prognosis in colorectal cancer.[12-13] The mutation is easily identified and can be used to select appropriate patients for EGFR-inhibitor therapy. Other biomarkers such as p27 and microsatellite instability, among many other factors, are being investigated for their role as predictive or prognostic markers.
The use of molecular imaging to evaluate treatment response early during neoadjuvant therapy may also help tailor therapy to the individual biology of the tumor. Early 18F-fluorodeoxyglucose (FDG)–positron-emission tomography (PET) responses have been shown to be prognostic for survival in the treatment of Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and esophageal cancer.[14-18] For rectal cancer, FDG-PET scans performed after chemoradiation may not predict pathologic response, but early PET scan evaluations, even after 12 days of chemoradiation, may correlate better with pathologic response at the time of surgery. This approach is being considered in the treatment of esophageal cancers, where early response determined by PET scans during induction chemotherapy can be used to change the treatment course and/or chemotherapy regimen.
Finally, patient-specific risk factors such as age, performance status, and other medical comorbidities, must be considered when adding chemotherapy or targeted agents to neoadjuvant therapy. The benefits of bevacizumab(Drug information on bevacizumab) are likely to be outweighed by cardiovascular or thrombotic risks in the patient with a history of cardiac disease. For young, premenopausal women who are trying to preserve fertility, the risks and benefits of pelvic irradiation must be addressed. For small, mobile, proximal ultrasound T3, N0 tumors, the argument could be made to avoid radiotherapy for a young woman.
Individualization of care is clearly the direction in which we are heading in oncology. More rational choices for neoadjuvant therapy in rectal cancer based on prognostic and predictive markers, including microarray technology—available prior to therapy or early enough in the treatment course to allow for alterations in therapy—will lead to fewer patients receiving ineffective and potentially toxic therapy. Basically, the smart use of innovative treatment planning and delivery of radiotherapy, coupled with selective use of systemic agents based on validated tissue-array information, may eventually lead to increased tumor cell death and less toxicity, resulting in an enhanced therapeutic ratio.
In the meantime, in the absence of better markers, we agree with the authors, that more is not always better. Despite the constant drive to push the field forward by adding newer and better therapies, we need to weigh the incremental benefits in relation to both the human costs of added toxicity and the societal costs of financing these expensive new drugs.
—Karyn A. Goodman, MD
—Charles R. Thomas, Jr, MD
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