Advanced Colorectal Liver Metastases and Surgery After Preoperative Chemotherapy: Is Response-Based Selection Enough?
Authors: Nicola Personeni, Guido Torzilli, Armando Santoro
Journal: Journal of Clinical Oncology (2011)

To judge preliminary efficacy, single-arm phase II studies rely on historical controls.We completely agree with Ajani et al 1 that betweentrial comparisons are difficult.However, the best conceivable historical control is a trial in exactly the same setting (centers, investigators) with the same patient population (eligibility criteria, staging methods) and-apart from cetuximab-the same treatment regimen, identical end points, and pathologic response assessments.Because our SAKK 75/02 and 75/06 trials meet all of these criteria, we use it to set the bar-or, if the authors prefer, as a calibration mark. 3 Both the pathCR rate (26% v 32%) and the rate of responders (pathCR plus TRG2: 47% v 68%) were higher in the SAKK 75/06 study as compared with the previous trial without cetuximab.For us, this was a clear but still preliminary sign of efficacy.Ajani et al 1 raise a fundamental question: When during the develop-mentofanewtreatmentistheoptimaltimepointtoembarkonaphaseIII trial?The short answer is that before beginning a randomized controlled trial, safety and preliminary promising efficacy of a given regimen need to be established.By choosing toxicity as a primary end point and by escalating the complex trimodal treatment in cohorts, safety of chemoimmunoradiation therapy in this carefully selected patient population was clearly shown. 2 Additionally, we previously published our report on the larger SAKK 75/02 phase II trial 3 ; in that study, the same multimodal regimen (without cetuximab) showed a high feasibility rate in a multicenter, community-based setting.The ongoing phase III trial sponsored by SAKK, Multimodal Therapy With and Without Cetuximab in Patients With Locally Advanced Esophageal Carcinoma is a European collabora-tiveeffortwiththeGermanEsophagealCancerStudyGroup,theAustrian Working Party of Medical Oncology, and in the near future, the Fe ´de ´ration Francophone de Cance ´rologie Digestive.So far, more than 50 patients have been randomly assigned.In suggesting a treatment algorithm that is based on biologic subsets, Ajani et al 1 give us, hopefully, a glimpse into the future.Although some spectacular progress has been made in biologic subsets of several tumor types, unfortunately, in esophageal cancer, we are not there yet.Esophageal cancer is not only relatively rare, it is also a particularly heterogenous disease with different histologies in a heterogenous patient population, and treatment involves surgery, radiotherapy, and systemic treatment.These many variables define a number of subsets that first need to be identified.TheresearchapproachasoutlinedbyAjanietalisprobablybest suited for diseases with high incidence and fewer variables, such as breast and colon cancer, whereas for esophageal cancer, we and our coinvestigators are convinced that a more pragmatic research approach is more appropriate.However, we will be among the first to celebrate with Ajani et al once treatment can be targeted to defined subgroups.In the meantime, we will attempt to define biologic subgroups through translational projects in the ongoing phase III trial.