Adjuvant Therapy for a 3.9-cm Adenocarcinoma of the Lung

By Rebecca Heist Massachusetts General Hospital Cancer Center Rebecca Heist Despite successful surgery in this otherwise healthy middle-aged woman, recurrent lung cancer remains her highest risk for death. Five-year survival for stage IB (pT2aN0) lung cancer is 58% [1]. Barely more than half of patients who undergo a successful surgery, as this patient did, will be alive at 5 years. That is a sobering statistic, and anything that can improve this patient's chance for survival should be considered. So, what about adjuvant chemotherapy? This patient with significant risk of recurrent lung cancer should not be denied adjuvant chemotherapy simply because her tumor measures 1 mm less than what is widely considered the cutoff for offering treatment. It is true that patients with higher stage of disease see more benefit with adjuvant chemotherapy; this has been borne out in all three of the large clinical trials that have shown a benefit with cisplatin-based adjuvant chemotherapy (International Adjuvant Lung Cancer Trial, or IALT [2]; JBR.10 [3]; Adjuvant Navelbine International Trialist Association [ANITA] [4]) and in a pooled meta-analysis of cisplatin-based studies [5]. Benefit is also seen with adjuvant chemotherapy in node-negative patients who have a large tumor. Although visceral pleural involvement itself would not be a trigger for adjuvant chemotherapy, the large size of her primary tumor would be. Multiple analyses have shown improvement in overall survival with adjuvant chemotherapy if tumor size is greater than or equal to 4 cm (Cancer and Leukemia Group B [6] and JBR.10 [7]). Notably, 5-year survival for patients with tumors 4 cm or larger was 59% in the observation arm and 79% with chemotherapy in JBR.10 [7]. A 3.9-cm tumor is, in my mind, close enough to 4 cm to fall within the rubric of deriving benefit from chemotherapy. The choice of chemotherapy warrants some discussion. Although the most common regimen that has been studied is cisplatin combined with vinorelbine, as used in JBR.10 and ANITA, IALT allowed multiple other agents in combination with platinum, including vindesine, vinblastine, and etoposide, and the most common regimen in that trial was actually what we think of as an “old” regimen, cisplatin-etoposide. Ongoing clinical trials such as ECOG-1505 (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00324805","term_id":"NCT00324805"}}NCT00324805) allow multiple different adjuvant chemotherapy backbones, including cisplatin-vinorelbine, cisplatin-docetaxel, cisplatin-gemcitabine, and cisplatin-pemetrexed. With the efficacy of pemetrexed in the nonsquamous setting in metastatic disease [8], earlier use of this agent in the adjuvant setting in patients with nonsquamous histology would be warranted. I would treat with cisplatin-pemetrexed in this case, given the efficacy of pemetrexed in the nonsquamous setting in advanced disease and the tolerability of this regimen. Notably, the patient is a never-smoker and molecular testing for driver mutations such as EGFR and ALK would be of high interest. Whether adjuvant erlotinib in the setting of an EGFR mutation or adjuvant crizotinib in the setting of ALK translocation should be recommended is an unanswered question; randomized trials specifically targeting these populations have not yet been done, although several are planned. Interestingly, a phase II study of surgically resected patients with EGFR mutations who received adjuvant erlotinib for 2 years reported 2-year disease-free survival of 94% [9]. Enthusiasm for adjuvant tyrosine kinase inhibitors in this setting must be tempered by the results of several large trials that showed no benefit and perhaps a suggestion of harm. In a molecularly unselected population, Southwest Oncology Group's SWOG 0023 trial showed a detriment to maintenance gefitinib in stage III disease after chemotherapy and radiation [10]. BR.19 was a phase III study randomly assigning molecularly unselected patients to either adjuvant gefitinib or placebo in stage IB–IIIA disease instead of or following adjuvant chemotherapy. This trial was closed after the results of SWOG 0023 were reported. Preliminary results of BR.19 showed no benefit to gefitinib and, in fact, a trend toward worse disease-free survival and overall survival; somewhat surprisingly, in the subset of EGFR-mutation-positive patients, overall survival was inferior with adjuvant gefitinib as well [11]. Although these studies have their flaws (e.g. nonmolecularly selected, premature closure, subset analyses of small numbers for EGFR mutation), their results lend credence to the position that adjuvant tyrosine kinase inhibitors should be given only in the setting of an appropriately targeted clinical trial. Enrollment in clinical trials attempting to definitively answer this question would be ideal if such driver mutations were found.