A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma

Our plain-English summary of A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma, by V. Kovac, M. Zwitter, M. Rajer, et al (Anti-cancer Drugs, 2012).

The study

• Authors: V. Kovac, M. Zwitter, M. Rajer, A. Marin, A. Debeljak, U. Smrdel, M. Vrankar
• Journal: Anti-cancer Drugs
• Published: 2012;23(2):230-8
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.

In plain English

This phase II trial in Slovenia, without a comparison group, enrolled 78 patients with malignant pleural mesothelioma between December 2002 and May 2008. The planned treatment was low-dose gemcitabine as a 6-hour infusion plus cisplatin for four three-week cycles. Patients without progression or serious toxicity then received two cycles of gemcitabine alone, and 62 (79.5%) completed all six cycles. Sixty patients (76.9%) had some asbestos exposure, 47 of them heavy or professional. Tumours disappeared in 4 patients (5.1%) and shrank partly in 35 (44.9%), a response rate of 39 of 78 (50%). Median progression-free survival was 8.0 months (confidence interval 6.9 to 9.0). Median overall survival was 17.0 months (confidence interval 14.7 to 19.2). At three years, 19.8% were alive. Severe (grade 3 or 4) neutropenia occurred in 18 patients, and there were no treatment-related deaths. At cycle 3, 70 patients (89.7%) reported feeling the same or better. Only the epitheloid tumour type was significantly linked to longer survival. The authors noted that, without randomization, comparison with other treatments is only speculative. They concluded the treatment should be explored further, citing acceptable toxicity and reasonable cost.

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: Nonrandomized (single-group) phase II clinical trial using Simon's two-stage design
• Who was studied: 78 patients (58 men, 20 women, aged 33 to 82, median 58) with malignant pleural mesothelioma, recruited in Slovenia between December 2002 and May 2008
• Exposure: Chemotherapy, not asbestos, was the exposure studied. The plan was gemcitabine 250 mg/m2 as a 6-hour infusion on days 1 and 8 plus cisplatin 75 mg/m2 on day 2 of a 3-week cycle, for four cycles. Two further cycles of gemcitabine alone followed for patients without progression or serious toxicity. Asbestos exposure was recorded as a patient characteristic, and no fiber types were reported.
• Main results:
  • The two gemcitabine-only cycles after cycle 4 were given only to patients not showing progression and without serious toxicity
  • 62 of 78 patients (79.5%) completed all six cycles
  • 60 of 78 patients (76.9%) had some asbestos exposure: heavy/professional in 47, light/occasional in 6, and environmental in 7 (living within 10 km of the former asbestos factory in Anhovo)
  • Among all 78 patients, there was a complete response in 4 (5.1%) and a partial response in 35 (44.9%), for a combined response rate of 39 (50%)
  • Minimal response or stable disease was seen in 35 patients (44.9%). The disease progressed during treatment in 4 patients (5.1%).
  • Median progression-free survival for all 78 patients was 8.0 months (confidence interval 6.9 to 9.0)
  • Median overall survival for all 78 patients was 17.0 months (confidence interval 14.7 to 19.2)
  • One-year, two-year and three-year survival rates were 67.3%, 32.7% and 19.8%
  • Grade 3 neutropenia occurred in 16 patients (20.5%) and grade 4 in 2 (2.6%). There was no febrile neutropenia and there were no treatment-related deaths.
  • Reversible thrombocytosis with platelets above 1000 x 10^9 per litre occurred in 10 patients (12.8%). Two of these developed grade 2 deep vein thrombosis.
  • Grade 2 alopecia (hair loss) occurred in 60 patients (76.9%)
  • At cycle 3, 70 patients (89.7%) reported equal or better well-being
  • Patients with epitheloid histology had a median progression-free survival of 9.0 months vs 7.0 months for other types (P = 0.049), and a median overall survival of 17.0 vs 14.0 months (P = 0.010)
  • Differences in progression-free and overall survival by age, sex, performance status and stage were not statistically significant
  • Among 27 patients given the same or similar treatment again after relapse, an objective response was confirmed in 22 (81.5%)
• The authors' conclusion: The authors concluded that, because of acceptable toxicity, remarkable activity and reasonable cost, this treatment should be further explored.
• Limitations the authors state:
  • The nonrandomized design and relatively small trial size make comparison with other treatment schedules only speculative
  • PET-CT was not available and MRI was rarely used, so the real stage of disease may have been higher than recorded in many patients
  • Few patients had surgery, and selection for surgery was biased, so their outcomes cannot be compared with those of other patients
  • The contribution of the two extra cycles of gemcitabine alone to the treatment outcome is uncertain

Topics

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

Medical terms in this study, explained in our Lexicon: Gemcitabine, Cisplatin, Pleural Mesothelioma, Lung Cancer, Biopsy, Performance Status, Informed Consent, Sarcomatoid.

Related studies

• 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)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors — C.A. Johnson, D. Kilpatrick, et al. (1997)
• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052) — M.E. O'Brien, R.M. Gaafar, et al. (2013)
• Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma — R. Maruyama, F. Shoji, et al. (2005)
• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)

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