Treatment of the Future, Today?

DOI: 10.1200/JCO.2012.45.5923 A patient in her early 60s was referred to me for a discussion of adjuvant chemotherapy after she underwent a lobectomy for clinical stage I adenocarcinoma of the lung. Unfortunately, pathologic evaluation revealed hilar lymph node involvement, which upstaged her to pathologic stage II disease. This should have been a fairly routine discussion. Several well-done, phase III randomized clinical trials have demonstrated an improvement in overall survival with the use of adjuvant cisplatin-based chemotherapy versus observation alone after resection of stages II and III non–small-cell lung cancer (NSCLC), and such treatment has been the standard of care since 2004. She was upset by the fact that the cancer was a higher stage than initially thought and was terribly afraid of the potential adverse effects of chemotherapy. She truly saw the higher stage of cancer as a death sentence. I assured her that the complete surgical resection she had already undergone offered her a 50% chance of cure and that adjuvant chemotherapy could improve the cure rate by another 5% to 10%. The chemotherapy would amount to throwing the kitchen sink at the cancer to do all we could to prevent it from recurring. Her husband voraciously wrote down my every word and asked a multitude of pointed questions. Despite my best efforts to explain her situation and my recommendation for adjuvant treatment, they left my office still despondent and unsure of how to proceed, so I suggested a return office visit in a couple of weeks, when she had more fully recovered from surgery and more thoroughly digested the information I had shared with them. The next week, her husband called to tell me that they had sought a second opinion and that this new oncologist had asked for the molecular profile of the tumor (epidermal growth factor receptor (EGFR) mutation, KRAS mutation, and EML4-ALK rearrangement). He was quite upset that I had not discussed molecular analysis during my initial visit with them, and it was clear from his tone that he felt I had not given his wife all of the available options. I could already feel his confidence in my professional abilities eroding. At first, I did not know what to say. I am an academic thoracic oncologist. I keep up on the lung cancer literature. I know that presently, all of the data that justify molecular profiling and the use of targeted therapy, such as gefitinib, erlotinib, and crizotinib, are from studies in patients with metastatic NSCLC. In fact, all of these agents were approved by the US Food and Drug Administration only in the setting of metastatic disease. I assured him that molecular testing was not relevant in his wife’s situation, that there was no proven benefit for targeted therapy in the postoperative setting, and that adjuvant cisplatin-based chemotherapy was still the best option for improving her long-term survival. Despite my explanations of the current state of our knowledge and standard of care, he cancelled the subsequent visit with me and the planned chemotherapy. The tumor tissue had indeed been sent for reflex molecular analysis and was positive for an EGFR sensitizing mutation. It can be rationally argued that reflex molecular analysis based on histology in patients who have undergone potentially curative therapy is not an appropriate use of medical resources, because there are no data justifying the use of adjuvant EGFR inhibitors in patients with completely resected NSCLC. Or are there? The oncologist with whom they had sought a second opinion had offered adjuvant erlotinib, given the patient’s reluctance to receive adjuvant chemotherapy. I felt panicked and uneasy. I knew that, thus far, data were available from only one randomized trial evaluating the adjuvant use of an EGFR inhibitor in patients with resected NSCLC and that this trial had demonstrated no survival benefit, even in the subset of patients with EGFRmutant tumors. Had I somehow missed a practicechanging clinical trial that had demonstrated a survival benefit for adjuvant EGFR inhibitors in patients with resected, EGFR-mutant NSCLC? A quick literature search revealed a recent article entitled, “Impact on Disease-Free Survival of Adjuvant Erlotinib or Gefitinib in Patients With Resected Lung Adenocarcinomas That Harbor EGFR Mutations.” This was a retrospective study in which 56 patients with resected, early-stage, EGFR-mutant NSCLC who had been treated with adjuvant EGFR inhibitors either in a phase II clinical trial or “at the discretion of their physicians” were compared with 111 similar patients who had not received adjuvant JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 30 NUMBER 32 NOVEMBER 1