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Ann Thorac Surg 2005;80:1183-1184
© 2005 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160
(Email: jpiehler{at}kumc.edu).
Esophageal cancer remains highly lethal, with surgical resection generally offering benefit to only small subsets of patients, usually those with fortuitously discovered early stage disease. Perhaps as a consequence of resultant therapeutic frustration, thoracic surgeons have widely accepted a management strategy incorporating induction chemotherapy or chemoradiation prior to resection despite the absence of convincing supportive data that such is preferable to surgery alone. One is forced to rely on analyses or meta-analyses of single institution experiences, usually based on historical controls, or to creatively dissect the data in the few available phase III studies to generate any conviction of benefit. Nevertheless, fueled by the documented benefits of such preoperative therapy in other venues, such as bronchogenic carcinoma, there is sufficient consensus of benefit that randomized trials addressing the subject have been abandoned due to the unattractiveness of the control arm. Therefore the prevailing standard practice (including at this surgeon's institution) is that induction therapy is offered to almost all patients with potentially resectable disease beyond superficial invasion. Despite this tenuous foundation, the debate has largely moved beyond the question of the benefit of induction therapy and is now focusing on relative effectiveness of the virtually limitless permutations and combinations of chemotherapy and radiation therapy that can be administered prior to resection.
Alas, such is not totally irrational. Numerous studies have documented that those patients who respond to induction therapy, and in particular those with a complete pathologic response, have superior survival to partial responders and especially to nonresponders after subsequent resection. Indeed, the outcome of those who receive ineffective induction therapy may be worse than those treated with surgery alone. Therefore a reasonable goal is to identify those patients who are likely to respond to induction therapy (offering alternative strategies to others) and to optimize the preoperative regimen to maximize response.
It is in this light that the study by de Manzoni and colleagues [1] should be assessed. This is a well-written analysis of two sequential groups of patients with squamous cell carcinoma of the thoracic esophagus treated by two induction chemoradiation protocols, followed by resection. The primary conclusion of the comparison, that the more intensive regimen was associated with a greater likelihood of complete (R0) resection, complete pathologic response, and improved survival,has been amply documented in the literature and would be anticipated by most readers; the induction protocol utilizing two cycles of cisplatin and 5-fluorouracil chemotherapy (one cycle concurrent with radiation) with 30 Gy radiation has been long ago relegated to historical status due to compromised local control and survival compared with more aggressive protocols such as that used in the authors' more recent cohort (three cycles of chemotherapy, two being concurrent, and 50 Gy of radiation). Therefore, at a minimum, the study offers further documentation that at least some progress has been achieved in managing this cancer and that the quest to optimize preoperative therapy has legitimacy.
There are several strengths of the study that deserve mention. The analysis is limited to squamous cell carcinoma without the confounding effects of including patients with adenocarcinoma. Inclusion criteria and operative technique were consistent throughout, and not one of the 177 patients was lost to follow-up. Tolerance of the induction regimens was excellent, with 92% of patients completing therapy, leading to high operability. Survival curves are constructed on an intention to treat basis, including mortality related to the induction protocols and to resection. In the more aggressively treated recent cohort, R0 resections were achieved in 84% (associated with a noteworthy 5-year survival of 43%), there was reasonable operative mortality, and complete pathologic tumor response was seen in 30% (5-year survival of 75%).
On the other hand, there are limitations to the study, several of which are a consequence of a relatively small patient cohort that compromises statistical analysis. The reaffirmation that nonresponders gained no survival advantage with the more intense regimen underscores the need to identify those more likely to benefit from the induction protocols. Positron emission tomographic scanning was not used as a staging modality, and there is evidence that the degree of persistent tumor metabolic activity at interval restaging may predict pathologic response. Regression analysis documented the expected favorable survival impact of low cTNM stage, but data linking specific pretreatment stage to induction response and then to survival is limited to those with cT4 disease. These issues are pertinent, as 17% of group A and 21% of group B had cT1N0 or cT2N0 disease, stages which are treated in many institutions with surgery alone with a high expectation of R0 resection and good outcome. Their inclusion in this study can be justified, but without stage-specific analysis, they have the potential to favorably bias the outcome data. Specific identification of which clinical stages are most likely to respond would be important in the design of future treatment algorithms. Similarly, the study does not discuss the pattern of disease recurrence, knowledge of which could offer some insight into the relative contributions of chemotherapy and radiation in explaining the benefit of the more aggressive regimen. In most institutions utilizing induction protocols similar to the authors' group B, the majority of recurrences are systemic with locoregional control having been achieved by the combination of the preoperative therapy and wide resection, including lymph node dissection. The fact that complete pathologic responders in group B had a better outcome than those in group A suggests that the added chemotherapy provided better systemic control, but interpretation is hampered by the absence of stage-specific data.
So where do we go from here? We need more solid data to help predict those patients who are likely to respond to induction therapy, and a means of confirming this response as early as possible. Regarding the therapy itself, given that most patients currently fail with systemic disease, further intensification of the radiotherapy component, either through dose escalation or hyperfractionation schemes, is unlikely to provide major survival improvement and could be associated with increased treatment-related complications. Newer induction chemotherapy options utilizing other platinum derivatives, irinotecan, and taxanes, amongst others, are being investigated in phase II trials. Molecular profiling of tumors has the potential to predict response to specific agents, and targeted therapy may have benefit beyond cytotoxic drugs. Hopefully these options will translate into an increased likelihood of response to induction therapy with subsequent survival benefit.
This study demonstrates that progress has been made in the management of selected patients with esophageal cancer and suggests some promise for the future. Unfortunately, it also reminds us of the many gaps in our knowledge that must be filled before we can meaningfully impact this disease.
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