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Tumor-Treating Fields Plus Chemotherapy Improved Survival in Unresectable Malignant Pleural Mesothelioma


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The addition of tumor-treating fields to standard-of-care chemotherapy has been found to be safe and effective in the treatment of unresectable malignant pleural mesothelioma. Data presented at the 2019 Multidisciplinary Thoracic Cancers Symposium showed that patients receiving the combination of low-intensity alternating electric fields with pemetrexed and a platinum agent (cisplatin or carboplatin) for first-line treatment of malignant pleural mesothelioma had a median overall survival of 18.2 months, which was significantly longer than the historical control of 12.1 months.1

Authors of the study also reported no increase in systemic toxicity with the use of the alternating electric fields. The only adverse event related to tumor-treating fields was skin toxicity beneath the transducer arrays.


The median overall survival [with tumor-treating fields plus chemotherapy] was 18.2 months, which is an increase by more than 6 months with respect to the historical control.
— Federica Grosso, MD

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“Despite the lower rate of patients with epithelioid histology, overall survival was better than the reference pemetrexed/platinum arm in recent trials,” said Federica Grosso, MD, an oncologist at Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy. “The median overall survival was 18.2 months, which is an increase by more than 6 months with respect to the historical control.”

As Dr. Grosso reported, malignant pleural mesothelioma is a rare tumor of the mesothelial surfaces, with an increasing incidence worldwide. Despite years of research, however, the only approved regimen is the combination of pemetrexed plus cisplatin, which was established more than 15 years ago by Vogelzang et al; it yielded a median overall survival of just 1 year.2 Additional options are clearly needed, said Dr. Grosso, who noted that the combination of carboplatin and pemetrexed has shown similar outcomes.

Tumor-treating fields are an antimitotic locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device. These alternating electric fields disrupt spindle formation during metaphase and interfere with the localization of intracellular organelles during telophase. In newly diagnosed glioblastoma, tumor-treating fields significantly improved overall survival, with a delayed decline in quality of life, leading to approval by the U.S. Food and Drug Administration.3

“Preclinical data have shown that human mesothelioma cells are highly sensitive to tumor-treating fields at a frequency of 150 kHz, with a synergistic effect when combined with chemotherapy including cisplatin and pemetrexed,”4 said Dr. Grosso.

STELLAR Details

Based on these data, STELLAR was designed as a multicenter phase II study. Dr. Grosso and colleagues enrolled 80 patients with unresectable malignant pleural mesothelioma to receive tumor-treating fields at a frequency of 150 kHz. The planned duration was at least 18 hours/d along with up to 6 courses of either pemetrexed plus cisplatin or pemetrexed plus carboplatin, according to investigator choice.

Patients whose disease did not progress after combined treatment could then receive tumor-treating fields alone as maintenance therapy until disease progression, unacceptable toxicity, or death. The disease was assessed by abdominal and chest computerized tomography scan every 6 weeks, and follow-up data were collected every 3 weeks. The study’s primary endpoint was overall survival, and the sample size was calculated to detect an increase by 5.5 months vs historical data,2 with a power of 80%. Overall response rate, progression-free survival, and safety were the study’s secondary endpoints.

The investigators included all patients with pathologic evidence of unresectable malignant pleural mesothelioma of all histologic subtypes, measurable disease according to modified Response Evaluation Criteria in Solid Tumors (RECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1 in the analysis. Patients with implanted electronic medical devices or significant comorbidities as well as candidates for curative treatment were excluded from the study.

Improvement in Overall Survival

As Dr. Grosso reported, the median age of patients enrolled was 67 years, and 84% of patients were male. Histologic subtypes were well represented, said Dr. Grosso, who noted that 66% and 26% of patients had epithelioid and sarcomatoid/biphasic histologies, respectively. The median number of courses of tumor-treating fields was eight, and the median number of chemotherapy courses was six.

The median overall survival was 18.2 months, which met the threshold for significant extension in overall survival compared with historical control (hazard ratio = 0.663; P = .043). The overall survival rate at 1 year was 62%, and the median overall survival in epithelioid patients alone was 21.2 months. The median progression-free survival was 7.6 months, and the overall response rate as assessed by the investigators through modified RECIST was 40%.

MORE ON RARE THORACIC CANCERS

For more on treating rare thoracic cancers such as mesothelioma and thymic epithelial tumors, see an interview with Federica Grosso, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.

The treatment was also well tolerated, with the majority of toxicities related to chemotherapy. The median compliance with tumor-treating fields was 68%, said Dr. Grosso, which indicates that patients kept the device on for at least 16 h/d.

The only toxicity related to the tumor-treating-field device was skin toxicity (dermatitis beneath the transducer arrays), which was observed in 53 patients (66%). A total of 4 patients (5%) had grade 3 skin toxicity. “Skin toxicity resolved after treatment with topical corticosteroids or a short treatment break. No serious adverse event was related to tumor-treating fields,” Dr. Grosso concluded. 

DISCLOSURE: Dr. Grosso has received travel support from NovoCure, Boehringer Ingelheim, PharmaMar, Novartis, and Bristol-Myers Squibb; honoraria from Merck; research funding from the Italian Centro per la Prevenzione e Controllo delle Malattie, and the Associazione Famigliari e Vittime Amianto. The STELLAR study was sponsored by NovoCure, Haifa, Israel.

REFERENCES

1. Ceresoli GL, Aerts J, Madrzak J, et al: STELLAR: Final results of a phase 2 trial of tumor-treating fields with chemotherapy for first-line treatment of malignant pleural mesothelioma. 2019 Multidisciplinary Thoracic Cancers Symposium. Abstract 4. Presented March 14, 2019.

2. Vogelzang NJ, Rusthoven JJ, Symanowski, J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636-2644, 2003.

3. Stupp R, Taillibert S, Kanner A, et al: Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 318:2306-2316, 2017.

4. Giladi M, Weinberg U, Schneiderman RS, et al: Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol 41(suppl 6):S35-S41, 2014.


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