A Phase I Study of Concurrent External Beam Radiotherapy with Weekly Topotecan for Primary Treatment of Locally Advanced Lung Cancers
Authors: Dennie Jones, Claire Verschraegen, Thomas Schroeder
Journal: Journal of Thoracic Oncology (2012)

The optimal treatment of patients with locally advanced lung cancer remains to be defined. Combined modality treatment, usually with concomitant chemotherapy and radiation therapy, is administered usually as definitive therapy for patients who are poor surgical candidates. Currently, available data indicate that combined modality therapy, when feasible, is superior to either single modality alone; concomitantly administered chemotherapy and radiation therapy are superior to sequential therapy, although at the risk of increased toxicities.1,2 We initiated this phase I trial of weekly intravenous topotecan in increasing dosing cohorts with a standard fractionation regimen of external beam thoracic radiation in patients with stage IIIA/B lung cancer to determine the profile of adverse effects and a potential phase II dose. Prior treatment (except chest radiotherapy) for metastatic disease was allowed, provided treatment had reduced the burden of such disease to that which could be encompassed within a tolerable radiation port. Other eligibility criteria included an Eastern Cooperative Oncology Group Performance Status ⩽ 2; aged 18 years or older; and adequate end-organ function. All patients were required to provide a signed informed consent form approved by the University of New Mexico Institutional Review Board. Patients were entered in successive cohorts of 3–6 into escalating dose levels. Topotecan was administered intravenously over 30 minutes, once a week during the radiation. The starting dose for the first cohort was 2 mg/m2/wk. The planned increment between cohorts was 1 mg/m2/wk if no toxicity related to topotecan occurred, and 0.5 mg/m2 if grades 1–2 toxicity occurred. All patients received a total radiation dose of 63 Gray as 1.8 Gray in 35 daily fractions with a 3D conformal technique. Elective irradiation of any 18-fluorodeoxyglucose-nonavid lymph node was not allowed unless the short axis of the node of interest was >1.5 cm on the computed tomography scan. Radiotherapy interruptions were only permitted for grade 4 esophagitis/mucositis or skin toxicity and/or ≥grade 3 pulmonary toxicity. The protocol was terminated prematurely as two out of the first six patients (both in the second dose cohort) in this study experience severe pneumonitis, and one of the cases was fatal. This precluded further evaluation of this dose (3 mg/m2/wk) and schedule or any additional planned dose escalation. Five of the patients were able to complete therapy as planned. Three of the patients experienced a complete remission by positron emission tomography criteria with resolution of all FDG-avid disease, and two of them experienced complete remission by computed tomography criteria. One patient is still alive and free of disease at last evaluation at 32 months. The remainder succumbed to their disease at a median of 11 months (range, 3–32 months). A phase II topotecan dose of 2 mg/m2/wk with external beam thoracic radiation therapy could be further evaluated, but is likely to be below an optimal antineoplastic dose, at least as a single agent. Other regimens utilizing alternate topotecan doses and schedules have been shown to be better tolerated and should form the basis of regimens for further investigation with radiation therapy.3–5