Drug–Radiotherapy Combination Trial Developments—Response

Abstract

In a recent issue of Clinical Cancer Research, we reviewed and discussed key methodologic basic and clinical research aspects that could inform precision drug–radiotherapy trial optimization (1). We thank the University of Michigan (Ann Arbor, MI) group for underlining that radiotherapy-gemcitabine combination could still be used at full drug dosage (weekly 1,000 mg/m) while modifying radiotherapy parameters. The authors should be congratulated for their continuous efforts in refining chemoradiation modalities in pancreatic cancer. The gemcitabine example is emblematic because in the first phase II trial assessing thoracic radiotherapy and full-dose gemcitabine association in non–small cell lung cancer (NSCLC), gemcitabine dose was not derived from phase I studies involving radiotherapy. Unacceptable severe toxicities, including 38% toxic deaths were described (2), supporting the role of adequate in vivo models to assess the impact of the combination on normal tissue and the importance of dose escalation trials. Phase I studies subsequently evaluated concomitant gemcitabine delivered at lower doses in numerous malignancies (1). At the same time, radiotherapy concepts and techniques have constantly progressed. Radiotherapy technical improvements (intensity modulated radiotherapy, image-guided radiotherapy, stereotactic radiotherapy, protons, etc.) translated into more accurate radiation delivery resulting in less toxicity to normal tissues (1). Radiotherapy dose escalation trials have, therefore, evaluated radiotherapy parameters, with or without systemic treatments (3, 4). The first phase I trial associating gemcitabine and IMRT delivered at the primary site and regional lymphatics did not permit escalation of either the radiotherapy or gemcitabine dose (5). Historically, treatment volumes included adjacent uninvolved nodal regions (elective node irradiation, ENI). Because smaller radiotherapy fields lead to reduced toxicity without jeopardizing outcomes, ENI has been abandoned in several tumor types, including pancreatic cancer. Reducing toxicities allows treatments intensification, both of radiotherapy (moderate hypofractionation or ultra-hypofractionation with SRT) and drugs (as the example of full-dose gemcitabine or newer combinations). Reducing radiotherapy fields and sparing lymph nodes could also mitigate severe lymphopenia, presented as a poor prognostic factor in many recent studies (1). Protons might better preserve the therapeutic ratio in this setting. Precise radiotherapy techniques, doses, and volumes (as shown in Fig. 2 of our review; ref. 1) are important parameters in clinical trial design. Radiotherapy data (volumes, dosimetric constraints, etc.) should be recorded and quality analyses should be applied (1). In the PACIFIC study, which validated consolidation immunotherapy after concurrent thoracic chemoradiotherapy in locally advanced NSCLC (1), radiotherapy data were missing and only the delivered dose was available. A greater incidence of severe toxicity could be observed in real-life practice, reinforcing the need of well-structured, carefully designed early clinical research.