Combination Chemoradiation Therapy: The Whole Is More Than the Sum of the Parts

For many years, oncologists have held the view that “radiation improves local control, but not survival.” Although this perspective is fairly common, it is not always accurate and does not recognize a more nuanced interplay between local control, systemic control, and cure. Solid tumors cannot be cured without achieving local control of the primary malignancy, and thus local control is a critical component of tumor cure. A more nuanced statement that could be true might be the following: “When surgery provides good local control, the local control advantage provided by radiation may not lead to a statistically significant survival advantage if the competing risk of distant metastases is very high or very low.” Radiation therapy also might not improve survival if systemic chemotherapy improved local control without radiation, or if salvage surgery were effective and local recurrence did not increase the risk of distant metastases. It is worth considering the relationship between local control and survival in several solid tumors. The initial randomized trials demonstrating the benefit of radiation in breast cancer suggested that irradiating the breast after lumpectomy, or the chest wall after mastectomy, improved local control but did not affect survival. The lack of a survival benefit, however, may have been attributable to a relatively small number of deaths in these studies. In fact, meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group suggest that improved local control does lead to improved cancer-specific and overall survival. In gastric cancer, the North American standard of care was established by Intergroup-0116, in which patients were randomly assigned to surgery alone versus surgery followed by adjuvant chemotherapy and radiation. In this study, the reduction in local and regional recurrences, from 47% to 24%, correlated closely with the improvement in overall survival, and the rate of distant metastases was similar in both arms. In fact, the observation that improved survival appeared attributable mainly to improved local control was the impetus for the successor Intergroup trial, CALGB 80101, which sought to further improve survival by more aggressively addressing the risk of distant metastases. Rectal cancer is a disease in which we frequently hear that radiation improves local control without affecting survival. Although there certainly are data that are consistent with this view, the totality of the data is more ambiguous. The results of NSABP R-02, for example, do support the hypothesis that radiation can improve local control without a survival benefit. In this trial, patients who underwent surgery for locally advanced rectal cancer were randomly assigned to postoperative chemotherapy or postoperative chemoradiotherapy. Patients who received radiation had a statistically significant improvement in local control without an improvement in disease-free or overall survival. However, not all rectal cancer studies have come to the same conclusion. The Swedish Rectal Cancer trial, in which patients were randomly assigned to surgery alone versus preoperative short course radiation, showed statistically significant improvements in local control, cancer-specific survival, and overall survival in the irradiated patients. Conversely, EORTC 22921, a 1,000-patient study using a 2 2 design testing both preand postoperative chemotherapy and radiation, failed to demonstrate a statistically significant survival benefit in patients who received adjuvant chemotherapy. Perhaps most significant is GITSG 7175, a four-arm trial in which patients were randomly assigned to surgery alone, adjuvant chemotherapy, adjuvant radiation therapy, or adjuvant chemotherapy and radiation. This trial established the benefit of adjuvant therapy for rectal cancer and was thus the last large US phase III trial to contain a surgery-alone arm. In this study, both radiation and chemotherapy provided similar magnitude, nonsignificant benefits in disease-free survival, whereas only the combined chemoradiation arm resulted in a statistically significant improvement compared with surgery alone. The mechanisms behind the synergistic effect of combining chemotherapy and radiation have been well documented, as reviewed by Seiwert et al. Clinical trials in many types of solid tumors have confirmed that concurrent administration of chemotherapy and radiation leads to a better outcome than sequential administration, or using either modality alone. Examples include non–small-cell lung cancer, cervical cancer, head and neck cancer, and anal cancer. Thus, understanding the patterns of failure can help us understand ways in which we can both improve tumor control and decrease morbidity. In esophageal cancer, the trials comparing neoadjuvant chemoradiotherapy with surgery alone have had mixed results. Although some demonstrated a benefit, most showed a nonsignificant trend in favor of neoadjuvant therapy, though recent meta-analyses have consistently favored the use of neoadjuvant therapy. Most recently, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated that preoperative carboplatin and paclitaxel with concurrent radiation is an extremely well-tolerated regimen with a higher rate of R0 resections (92% v 69%) and improved JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 5 FEBRUARY 1