Mesothelioma - asbestkanker informatie: Alimta en dubbele chemo met als aanvulling B12 en foliumzuur zorgt voor opmerkelijke resultaten bij inoperabele mesothelioma

Lees ook dit artikel: https://kanker-actueel.nl/dendritische-celtherapie-heeft-succes-bij-patienten-met-mesothelioma-asbestkanker-erasmus-doet-oproep-dat-meer-patienten-zich-aanmelden-voor-de-studie.html

1 april 2017: Lees ook dit artikel:

https://kanker-actueel.nl/NL/pembrolizumab-een-anti-pd-medicijn-geeft-uitstekende-resultaten-bij-zwaar-voorbehandelde-patienten-met-mesothelioma.html

Juni 2002: Tijdens ASCO, het grote internationale congres dat afgelopen maand (mei 2002) plaatsvond in Amerika werden de studieresultaten van onderstaande Phase III studie bekendgemaakt en gepresenteerd als ideale aanpak voor inoperabele mesothelioma. Natuurlijk (daar is op te verdienen en lopen patenten op) werd de nadruk gelegd op de dubbele chemo - cisplatin en pemetrexed - maar niet minder belangrijk lijkt de constatering dat de groep die als aanvulling vitamine B12 en foliumzuur het veruit het beste deed. De voedingssuppletie zorgde voor veel minder bijwerkingen en daardoor werd de effectiviteit van de behandeling vergroot. De conclusie lijkt dan ook dat deze aanpak met dubbele chemo alleen voor succes zorgt met als aanvulling voedingsuppletie om zo de bijwerkingen te verminderen en de effectiviteit van de behandeling te vergroten.

Bron website van ASCO:

Unresectable Mesothelioma: A New Standard of Care
Robert S. Mocharnuk, MD

Every year, 2000-3000 new cases of mesotheliomas are diagnosed in the United States. Directly related to asbestos exposure, the annual incidence of mesotheliomas is expected to rise worldwide until the year 2020, at which time most countries will have developed and completed asbestos eradication programs. In the meantime, this traditionally fatal malignancy is yielding to the efforts of a handful of investigators committed to changing the natural course of this disease.

Dr. Nicholas Vogelzang, from the University of Chicago, is one of them. A phase 3 international study, comparing single-agent cisplatin (75 mg/m2) every 3 weeks vs the multitargeted antifolate pemetrexed, given as a 500-mg/m2 IV bolus over 10 minutes with cisplatin (75 mg/m2) every 3 weeks, built on solid phase 1 trials showing response rates of 44%, 32%, and 25% when pemetrexed was combined with cisplatin, carboplatin, and raltitrexed, respectively.[1] Previously, these trials enrolled few patients over extended periods of time, due to the relative rarity of this disease.

In this study, 472 patients were enrolled between April 1999 and March 2001, of which 452 were randomized. The first 70 randomized patients received no vitamin B12 or folate supplements. Thereafter, the increased mortality rate associated with use of pemetrexed, compared with cisplatin alone, prompted the study reviewers to issue replacement regimen guidelines for folic acid and B12 on December 2, 1999. During this transition period, an additional 47 patients received partial supplementation, whereas full vitamin B12 and folate supplementation was given to the remaining 331 patients enrolled thereafter.

There are 448 patients evaluable, with a median follow-up of 9 months, and 304/448 have died. A 30% or more 2-dimensional reduction in pleural rind bulk by CT scanning constituted a response. Response rates are summarized in the Table.

Table. Cisplatin vs Combination Pemetrexed/Cisplatin in Unresectable Mesotheliomas
Unsupplemented or partially supplemented Fully supplemented
Regimen Cisplatin Cisplatin/Pemetrexed Cisplatin Cisplatin/Pemetrexed
Patient number 59 58 163 168
Response rate 9% 21% 20% 46%
Median survival time 9.3 months 12.1 months 10 months 13.3 months
Time to progressive disease 3.9 months 5.7 months 3.9 months 6.1 months

Not surprisingly, adverse hematologic side effects were more common with the combination regimen vs single-agent cisplatin (grades 3 and 4 neutropenia 28% vs 2%, grades 3 and 4 thrombocytopenia 6% vs 0%), although the incidence of febrile neutropenia was only 2% greater (2% vs 0%). Moreover, hematologic toxicity was significantly reduced with the addition of supplemental B12 and folic acid. Pulmonary function studies measuring vital capacity, dyspnea, and pain scores all improved to a greater degree among patients treated with the combination drug regimen.

Dr. Vogelzang concluded that combination of pemetrexed and cisplatin is superior to single-agent cisplatin as assessed by response rate, median survival time, time to disease progression, and quality-of-life scores, and these results are not altered, but enhanced (via reduction in hematologic toxicity) by the addition of vitamin supplementation. The large and diverse numbers of patients included in this trial lend credence to the argument that pemetrexed and cisplatin should be considered as standard of care for advanced mesotheliomas.

In support of Dr. Vogelzang's conclusions, Dr. Valerie Rusch from Memorial Sloan-Kettering Cancer Center, New York, NY, hailed these findings as an antidote to the generally nihilistic approach oncologists take in treating this disease. In addition to Dr. Vogelzang's work with new combination therapy and improved patient selection criteria, there are other causes for optimism in the management of malignant mesothelioma. These include the recent acceptance and adoption of a TNM staging system, an expanding knowledge base about the biologic workings and natural history of this disease, reductions in surgical mortality, and a greater reliance on multidisciplinary management.

Dr. Rusch commended Dr. Vogelzang for seeing to completion the first phase 3 study in this field. Equally impressive are the large numbers of diverse patients enrolled in such a timely manner, the clarity of eligibility criteria, the consideration of prognostic factors, the careful and thoughtful standards by which responses are measured, use of supplemental (nonradiologic) measures of response, and incorporation of a new therapeutic agent into first-line treatment. While combination treatment is more toxic than single-agent therapy, these side effects are tolerable, particularly in light of the benefits accrued. The trial results appear to confirm previous trial experience with single-agent cisplatin and should become the standard by which other treatments are compared.

Questions that have yet to be answered include whether homocysteine levels will vary among different populations worldwide, what are the optimal supplemental vitamin doses, what influence vitamin supplementation will have on the cisplatin arm only as it relates to drug-induced neuropathy, what influence does histology have on response and survival, what effect this combination will have in the neoadjuvant setting of potentially respectable tumors, and what will be the effects of adding other targeted therapies to this regimen. No amount of optimism can change the fact that mesotheliomas remain a deadly and practically universal fatal disease...but there is now a glimmer of hope where none existed before.

Reference
Vogelzang NJ, Rusthoven J, Paoletti P, et al. Phase III single-blinded study of pemetrexed + cisplatin vs cisplatin alone in chemonaive patients with malignant pleural mesothelioma. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 5.