Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer

Our plain-English summary of Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer, by L.L. Herscher, S.M. Hahn, G. Kroog, et al (Journal of Clinical Oncology, 1998).

The study

• Authors: L.L. Herscher, S.M. Hahn, G. Kroog, H. Pass, B. Temeck, B. Goldspiel, J. Cook, J.B. Mitchell, J. Liebmann
• Journal: Journal of Clinical Oncology
• Published: 1998;16(2):635-41
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies.

Patients And Methods: Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment.

Results: Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion.

Conclusion: The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation.

In plain English

This was a phase I trial of the cancer drug paclitaxel given at the same time as chest radiation. Its aim was to find the highest dose patients could tolerate. Thirty patients took part. Twenty-seven had unresectable mesothelioma and three had advanced or recurrent non-small-cell lung cancer. Paclitaxel was given as a continuous 120-hour infusion every 3 weeks during radiation, at doses from 90 to 120 mg/m2. The maximum tolerated dose was 105 mg/m2. At 120 mg/m2, two patients developed grade 4 neutropenia, a severe fall in infection-fighting white blood cells. Neither developed fever or infection. Three patients had allergic (hypersensitivity) reactions. Six had a persistent dry cough treated with cough medicine. One developed nerve damage that caused low blood pressure on standing, which was attributed to paclitaxel. Biopsies from five mesothelioma patients showed no significant build-up of cells in mitosis, the effect the drug was expected to produce. Twenty-five patients had died, and median survival after treatment was 5 months. The authors concluded the regimen was well tolerated and deserved further evaluation. They noted that poor survival may have prevented a proper assessment of late side effects.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I clinical trial (dose-escalation study of paclitaxel with concurrent radiation therapy)
• Who was studied: 30 patients: 27 with unresectable mesothelioma and 3 with stage IIIB or recurrent non-small-cell lung cancer (27 male, 3 female; median age 59, range 39 to 78)
• Exposure: Treatment, not asbestos: paclitaxel as a 120-hour continuous infusion every 3 weeks (90 to 120 mg/m2) during thoracic radiation. Mesothelioma patients received a total tumor dose of 5,760 to 6,300 cGy. The article does not report asbestos exposure.
• Main results:
  • The maximum tolerated dose of paclitaxel with radiation, across all patients, was 105 mg/m2 over 5 days
  • Two patients at the 120 mg/m2 dose level developed grade 4 neutropenia, the dose-limiting toxicity
  • Neither patient with grade 4 neutropenia developed fever or other infectious complications
  • Three of the 30 patients developed a hypersensitivity (allergic) reaction
  • Six patients had a persistent dry cough lasting more than 3 months, treated with antitussive medication; no patients required corticosteroids
  • One patient developed severe orthostatic hypotension, attributed to an autonomic neuropathy caused by paclitaxel
  • Five patients, all with mesothelioma and accessible chest wall masses, had biopsies; no tumor showed a significant G2/M (mitotic) block
  • 25 of the 30 patients had died; median survival after completion of treatment was 5 months (range 1.5 to 22 months)
  • Of the mesothelioma patients, four were alive, and only one of these was without evidence of disease at 14 months
• The authors' conclusion: The authors concluded that continuous-infusion paclitaxel given with large-field lung irradiation was well tolerated and deserved continued evaluation
• Limitations the authors state:
  • Poor patient survival may not have allowed adequate assessment of late toxicity
  • Other factors that may affect radiosensitization, such as the tumor's inherent radiosensitivity and effects of other agents on the cell cycle, were not addressed

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Lung Cancer, Pleural Mesothelioma, Neutropenia.

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