Aan dit artikel is enkele uren gewerkt. Mocht u ons willen helpen kanker-actueel online te houden dan kan dat met een machtiging of directe donatie via: http://kanker-actueel.nl/NL/donaties.html of al of niet anoniem op - rekeningnummer NL79 RABO 0372931138 t.n.v. Stichting Gezondheid Actueel in Terneuzen.

9 oktober 2017: Bron: BMJ 2017;359:j4530

Slechts de helft van de door de European Medicines Agency (EMA) officieel goedgekeurde nieuwe kankermedicijnen geven een mediane verbetering van de overall overleving. Maar die verbetering, als die er al is, blijkt marginaal met een mediane verbetering van overall overleving van 2,7 maanden. (variërend van 1 tot 5,8 maanden). Verbetering van kwaliteit van leven werd in de 23 studies waar dit ook als doel stond bereikt bij 48% (11 uit 23).

De Engelse onderzoekers, Courtney Davis en collega's zijn hard in hun conclusie: veel medicijnen worden beoordeeld en goedgekeurd op basis van ondeugdelijke resultaten of studiedoelen die geen goede voorspellers blijken voor de mate van overleving en/of kwaliteit van leven.

Conclusions: This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

De studieresultaten zijn afgelopen week gepubliceerd in BMJ.

In de periode 2009 tot en met 2013 gaf de EMA goedkeuring aan 48 kankermedicijnen voor 68 indicaties. Bv. olaparib werd goegekeurd voor zowel borstkankerpatiënten als eierstokkankerpatiënten met een BRCA 1 / 2 mutatie.  Bij 35 van de 68 indicaties bij een mediane follow-up van 5,4 jaar vonden de onderzoekers van deze nieuwe studie statistisch significante verbetering van de overleving of verbetering van de kwaliteit van leven. De medicatie voor de andere 33 indicaties liet geen verbetrring van de overall overleving zien en ook geen verbeterde kwaliteit van leven.

Hier een grafiek van de onderzochte medicijnen voor de 68 indicaties. Teskt gaat onder grafiek verder.

Table 1

Characteristics of approvals of cancer drug, 2009-13. Figures are numbers (percentage) of indications

CharacteristicsSolid tumours (n=51)Haematological tumours (n=17)
Type of marketing authorisation:
 First marketing authorisation 24 (47) 9 (53)
 Extension 27 (53) 8 (47)
Pathway of first marketing authorisation:
 Regular approval 19 (79) 4 (44)
 Conditional approval 5 (21) 5 (56)
 Orphan designation 3 (6) 8 (47)
Intent of treatment:
 Curative 6 (12) 1 (6)
 Non-curative 45 (88) 16 (94)

Wat de onderzoekers vooral benadrukken in hun studie is dat geen enkele studie die beslissend was voor de offciële goedkeuring en dus toelating tot de klinische praktijk als doel had ‘kwaliteit van leven’, zelfs niet als het onderzochte middel vooral palliatief werd ingezet.  In iets meer dan de helft van de indicaties was kwaliteit van leven een secundair doel van het onderzoek, maar de resultaten daarvan waren echt heel slecht: slechts in zeven studies was er sprake van een statistisch significante verbetering van de kwaliteit van leven.

Deze medicijnen gaven uiteindelijk een verbetering van kwaliteit van leven. Ik heb dit niet vertaald. Anders gebruik google translationknop rechtsboven dit artikel.

Box 2: Cancer drugs associated with benefit on health related quality of life (HRQoL)

Reported at time of market approval
  • Afatinib v pemetrexed/cisplatin (for the treatment of TKI-naive, EGFR mutation +ve, non-small cell lung cancer) significantly delayed the time to deterioration for cough and dyspnoea but not time to deterioration of pain. HRQoL was evaluated against prespecified components of the European Organisation for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30) questionnaire and lung cancer module QLQ-LC13. The study was open label43

  • Gefitnib (for the treatment of metastatic non-small cell lung cancer) showed significant benefits on quality of life compared with carboplatin plus paclitaxel, and with docetaxel on some measures, but not compared with placebo. HRQoL was assessed with the functional assessment of cancer therapy-lung (FACT-L), and trial outcome index (TOI), and symptom improvement by the lung cancer subscale (LCS). The active comparator trials were open label. The trial v placebo was double blind44

  • Tegafur, gimeracil, oteracil (S-1) (in combination with cisplatin for the treatment of advanced gastric cancer) showed a significant improvement over cisplatin/5-fluorouracil for only one of the subscales (physical wellbeing) of the functional assessment of cancer therapy-gastric (FACT-Ga) HRQOL instrument. The study was open label45

  • Vandetanib v placebo (for the treatment of metastatic medullary thyroid cancer) significantly improved “time to worsening of pain” (a composite endpoint based on patient reported analgesic use and responses to the brief pain inventory) but did not show a significant improvement for the functional assessment of cancer therapy-general (FACT-G) score. The study was double blind46

Reported in the postmarketing period
  • Crizotinib (for second line treatment of ALK mutation +ve advanced non-small cell lung cancer) showed significant improvements compared with pemetrexed across a range of HRQoL measures, including a significantly greater delay in time to worsening of symptoms. HRQoL was assessed with the European Organisation for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30) and the lung cancer module QLQ-LC13. The study was open label47

  • Erlotinib (for first line treatment of EGFR mutation +ve metastatic non-small cell lung cancer) showed clinically relevant and significant improvements compared with gemcitabine/carboplatin in total functional assessment of cancer therapy-lung (FACT-L), trial outcome index (TOI), and lung cancer subscale (LCS) scores. The study was open label48

  • Nilotinib v imatinib (for patients with newly diagnosed Ph+ chronic myeloid leukaemia) reported a significant quality of life improvement with respect to some categories of low grade adverse events. HRQoL was assessed with generic SF-36 and leukaemia specific functional assessment of cancer therapy-leukaemia (FACT-Leu) surveys. The study was open label42

  • Ofatumumab (in patients with chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab) showed significant improvements v “physician’s choice” with respect to fatigue but not side effects of treatment or effects of disease. HRQoL was evaluated according to three prespecified domains of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-C30) and the chronic lymphocytic leukaemia module QLQ-CLL16 (fatigue, side effects of treatment, and effects of disease). The study was open label49

  • Pazopanib (for first line treatment of advanced renal cell carcinoma) significantly improved HRQoL compared with sunitinib with respect to 11 of 14 HRQoL domains. HRQoL was assessed with the functional assessment of chronic illness therapy-fatigue (FACIT-F) questionnaire, the National Comprehensive Cancer Network/functional assessment of cancer therapy-kidney symptom index 19 (NCCN-FACT FKSI-19), and the cancer therapy satisfaction questionnaire. The study was open label50

Het overzicht van de belangrijkste onderzochte medicijnen, is wel klein maar hopelijk nog wel te lezen:

Medicijnen goedgekeurd BMJ studie

Fig 1 Magnitude of overall survival benefit at the time of EMA approval. Figure excludes seven indications for which median overall survival could not be estimated at time of marketing authorisation: mifamurtide for resectable non-metastatic osteosarcoma after complete resection (+chemo); pertuzumab for 1st line HER2+mBC; pomalidomide for 3rd line (+dexamethasone) relapsed and refractory multiple myeloma; rituximab for 1st line CLL (+chemo); trastuzumab for HER2+ BC (+taxane) after adjuvant chemo; trastuzumab for HER2+BC (+adjuvant chemo); and trastuzumab for HER2+locally advanced BC (+neoadjuvant chemo and as monotherapy adjuvantly). Box 1 shows abbreviations used

Hier een grafiek van de efectiviteit van de goedgekeurde medicijnen nadat zij op de markt kwamen:

Fig 2 Availability of benefits on overall survival and quality of life of cancer drugs approved 2009-13. Box 1 shows abbreviations used

Medicijnen BMJ studie na goedkeuring

Deborah Cohen, verbonden aan BMJ, heeft in de studies die zij beoordeelden een heleboel fouten geconstateerd, zoals methodologische fouten in het ontwerp, de uitvoering, de analyse en de verslaglegging. Die zijn volgens haar allemaal door de EMA over het hoofd gezien.

Dat medicijnen op ondeugdelijke gronden worden toegelaten, heeft volgens Deborah Cohen ernstige gevolgen. Zij geeft twee voorbeelden. De eerste: een publicatie met statistisch hoopgevende resultaten leidt tot onrealistische verwachtingen bij kankerpatiënten en ook bij oncologen. En het tweede uunt dat Deborah Cohen maakt: het ontbreken van een goed onderbouwd bewijs van de effectiviteit brengt de betalende instanties en regeringen in een moeilijk parket in hun onderhandelingen met de producenten van de medciijnen. Wat te doen met de financiering van deze dure geneesmiddelen?

Al met al dus een ontluisterend beeld. Dat alleen maar bevestigd dat de kankerpatient zelf totaal onbelangrijk is in het wetenschappelijke onderzoek

Het volledige studierapport: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13 is gratis in te zien.

Hier het abstract met referentielijst:

This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4530 (Published 04 October 2017) Cite this as: BMJ 2017;359:j4530

  1. Courtney Davis, senior lecturer1,
  2. Huseyin Naci, assistant professor of health policy2,
  3. Evrim Gurpinar, MSc candidate in international health policy 2,
  4. Elita Poplavska, assistant professor3,
  5. Ashlyn Pinto, MSc candidate in global health2,
  6. Ajay Aggarwal, academic clinical oncologist4 5
Author affiliations
  1. 1Department of Global Health and Social Medicine, King’s College London, London WC2R 2LS, UK
  2. 2LSE Health, Department of Health Policy, London School of Economics and Political Science, London, UK
  3. 3Faculty of Pharmacy, Riga Stradins University, Riga, Latvia
  4. 4Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
  5. 5Institute of Cancer Policy, King’s College London, London, UK
  1. Correspondence: C Davis courtney.davis@kcl.ac.uk
  • Accepted 28 September 2017

Abstract

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.

Design Retrospective cohort study.

Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.

Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs.

Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%).

Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

  • Transparency: The lead author affirms that this manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

References


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