A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies

Our plain-English summary of A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies, by J.P. Delord, E. Raymond, M. Chaouche, et al (Annals of Oncology, 2000).

The study

• Authors: J.P. Delord, E. Raymond, M. Chaouche, P. Ruffie, M. Ducreux, S. Faivre, V. Boige, T. Le Chevalier, O. Rixe, E. Baudin, P. Pautier, J.M. Rodier, N. Chouaki, B. Escudier, L. Kayitalire, J.P. Armand
• Journal: Annals of Oncology
• Published: 2000;11(1):73-9
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers.

Patients And Methods: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male:female ratio 25:11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m2 to 1500/30 mg/m2.

Results: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m2. One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles.

Conclusions: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m2 at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.

In plain English

This was a phase I (dose-finding) study of two chemotherapy drugs, gemcitabine and vinorelbine, given together by vein on days 1 and 8 of each three-week cycle. It was done at the Institut Gustave-Roussy in France in 36 patients with advanced solid tumors that had not responded to standard treatment. Some had mesothelioma, but the article does not give their total number and says nothing about asbestos exposure. Doses rose step by step from 800/20 to 1500/30 mg/m2 (gemcitabine/vinorelbine). The main dose-limiting side effect was neutropenia, a drop in infection-fighting white blood cells. At the highest dose, 3 of 12 patients had a dose-limiting side effect in the first cycle. Grade 3-4 neutropenia occurred in 22.9% of 48 cycles, and one patient died after neutropenia with septic shock. Of 34 patients assessed, one with advanced mesothelioma had a partial tumor response lasting 16 weeks. One with pancreatic cancer had an 80% partial response. The authors concluded the drugs can be combined at 1500 and 30 mg/m2. They noted that measuring effectiveness was not the study's aim.

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 dose-escalation (dose-finding) clinical trial
• Who was studied: 36 patients (25 men, 11 women; Table 2 gives median age 62, range 34-73) with histologically proven advanced solid tumors refractory to standard treatment, at the Institut Gustave-Roussy, Villejuif, France. Tumor sites included pancreas, head and neck, thyroid, chest (10, including mesothelioma), ovary and others. The total number of mesothelioma patients is not stated.
• Exposure: Not an asbestos exposure study. Patients received the chemotherapy drugs gemcitabine (800-1500 mg/m2) and vinorelbine (20-30 mg/m2) as 30-minute intravenous infusions on days 1 and 8 of a 21-day cycle, with vinorelbine given first.
• Main results:
  • Neutropenia was the dose-limiting toxicity.
  • At dose level 6 (1500/30 mg/m2), 3 of 12 patients had a dose-limiting toxicity in the first cycle, so this level was taken as the recommended dose.
  • At dose level 6, over 48 cycles there were 5 episodes of grade 4 neutropenia (10.4%) and 6 of grade 3 neutropenia (12.5%), 22.9% grade 3-4 in total.
  • One patient at dose level 6 had febrile grade 4 neutropenia with septic shock and died at day 16.
  • Reversible grade 3 liver toxicity occurred in two patients during the first cycle, at dose levels 1 and 6.
  • Flu-like syndromes occurred in 10 of 85 cycles (12%) at dose levels 1-5 and in 15 of 48 cycles (31%) at the recommended dose level.
  • Thirty-four patients were evaluable for tumor response.
  • One patient with advanced mesothelioma had a partial response lasting 16 weeks after 6 courses at dose level 2.
  • The discussion reports tumor stabilization and clinical benefit in 10 patients, 3 of them with mesothelioma.
  • One patient with pancreatic adenocarcinoma that had progressed on 5-fluorouracil and cisplatin had an 80% partial response after four courses.
• The authors' conclusion: The authors concluded that gemcitabine and vinorelbine can be combined on days 1 and 8 every three weeks at 1500 and 30 mg/m2. They said the responses in a pancreatic cancer patient and a mesothelioma patient support further evaluation in tumors resistant to standard drugs.
• Limitations the authors state:
  • The authors state that the study was not designed to assess how well the combination works against tumors.

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine, Vinorelbine, Clinical Trial, Sarcoma, Carcinoma, Neutropenia, Chemotherapy, Cisplatin.

Related studies

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• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)
• Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma — M.G. Zauderer, S.L. Kass, et al. (2014)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)
• Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose — M. Van Nuland, H. Rosing, et al. (2020)
• BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma — S. Busacca, M. Sheaff, et al. (2012)

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