OTRA MIRADA DE LAS TERAPIAS DIRIGIDAS EN CÁNCER COLORRECTAL METASTÁTICO

Esta es una transcripción del Comité del NICE (National Institute for Health and Care Exellence) Inglés, en el cual analizan las terapias dirigidas en cáncer de colon y su relación con el costo que tienen y los pocos beneficios que se obtienen. Es de hacer notar que no analizan los pacientes que se benefician, ya que esto se sabría si se publicara el NNT (Número de pacientes a tratar, para obtener un resultado). Esta Institución basa sus resultados en comparar los resultados de los grupos de tratamiento en conjunto y los gastos que de ello se derivan.

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Key conclusion
Cetuximab monotherapy or combination chemotherapy, bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy, and panitumumab monotherapy are not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy. This is because:
·                             It was not possible to confirm by how much bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy would extend life when used as second-line therapy, and evidence from previous assessments of bevacizumab with other combination regimens or for first-line treatment does not allow a justification for a positive recommendation in this appraisal.
·                             The ICERs for cetuximab monotherapy or combination chemotherapy and for panitumumab monotherapy were very high (£90,000, £88,000 and £110,000–£150,000 per QALY gained respectively) and therefore these technologies did not represent a cost-effective use of NHS resources.
Current practice Clinical need of patients, including the availability of alternative treatments	The Committee heard from the clinical specialists and patient experts that there are limited treatment options for people with metastatic colorectal cancer that has progressed after treatment with first-line chemotherapy.
	For second-line therapy in people whose disease has progressed despite first-line treatment, NICE technology appraisal guidance 93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.
The technology	The Committee agreed that KRAS testing was an innovation in the treatment of metastatic colorectal cancer. The Committee was not presented with a case, substantiated by data, that the technologies under consideration add demonstrable and distinctive benefits of a substantial nature that have not already been adequately captured in the QALY measure.
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? What is the position of the treatment in the pathway of care for the condition?	The UK marketing authorisation for bevacizumab is in combination with fluoropyrimidine-based chemotherapy for the treatment of patients with metastatic carcinoma of the colon or rectum.
	Cetuximab has a UK marketing authorisation for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with irinotecan-based chemotherapy or FOLFOX (5-FU and folinic acid and oxaliplatin) or as a single agent in patients whose disease has failed to respond to oxaliplatin and irinotecan-based therapy, and who are intolerant to irinotecan.
	Panitumumab has a UK marketing authorisation as a 'monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal cancer with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens'.
	The Committee did not discuss specific issues around the adverse reactions to the technologies appraised but it was aware of the special warnings and precautions for use outlined in the SPCs for bevacizumab, cetuximab and panitumumab.
Adverse reactions
Evidence for clinical effectiveness Availability, nature and quality of evidence	The Committee noted the only evidence identified for the clinical effectiveness of bevacizumab as second-line treatment for metastatic colorectal cancer was one RCT (the E3200 trial) in which bevacizumab was given with oxaliplatin-containing chemotherapy, and two non-randomised observational studies using data from the BRiTE and ARIES patient registries. The Committee agreed that the evidence presented by the manufacturer could not be used to establish the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy as second- or third-line treatment for people with metastatic colorectal cancer that had not responded to first-line or second-line chemotherapy.
	The only evidence for the clinical effectiveness of cetuximab was one RCT (the CO.17 trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. The Committee noted that the people in the CO.17 trial had previously received oxaliplatin- and irinotecan-based therapy, and that the trial had shown a median overall survival of 9.5 months for cetuximab plus best supportive care compared with 4.8 months for best supportive care alone.
	The Committee noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer. The Committee agreed that the results of the mixed treatment comparisons should be interpreted with caution, and concluded that the estimates of overall survival for cetuximab plus irinotecan were subject to a high degree of uncertainty.
	The only evidence for the clinical effectiveness of panitumumab monotherapy came from one RCT (the Amgen trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. However, people in the trial had previously received both oxaliplatin- and irinotecan-based therapy, that is, panitumumab was given as third-line or subsequent therapy. The Committee noted that although a benefit in progression-free survival of 5 weeks was associated with panitumumab monotherapy relative to best supportive care, no statistically significant effect on overall survival was observed and therefore the magnitude of this benefit was uncertain.
	The Committee did not discuss specific issues around the relevance to general clinical practice in the NHS.
Relevance to general clinical practice in the NHS Uncertainties generated by the evidence	The uncertainties were:
	·                             the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy in people with metastatic colorectal cancer who had previously received chemotherapy
	·                             the estimates of overall survival for cetuximab plus irinotecan based on the mixed treatment comparison
	·                             the magnitude of the survival benefit of panitumumab relative to best supportive care.
	None considered.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded that there was sufficient evidence to show that cetuximab plus best supportive care gave greater benefit in terms of both progression-free survival and overall survival than best supportive care alone.
	The Committee concluded that panitumumab provided a survival benefit relative to best supportive care, but that the magnitude of this benefit was uncertain.
Evidence for cost effectiveness	Two economic models were available for this appraisal, one from the manufacturer of cetuximab and one from the Assessment Group.
Availability and nature of evidence Uncertainties around and plausibility of assumptions and inputs in the economic model	The uncertainties were:
	·                             the mean time on cetuximab treatment
	·                             the overall survival estimates used in the economic models for panitumumab and cetuximab in combination with irinotecan, which were based on the mixed treatment comparison.
	The Committee noted that the utility estimates for each of the disease states were not consistent with the expectation that quality of life worsens with progression of disease. The Committee also noted that the utility estimates in the model (for example, 0.81 for progression-free disease for cetuximab plus best supportive care) were similar to those expected for people of the same age without metastatic colorectal cancer. The Committee concluded that the utility values in the manufacturer's model were highly uncertain.
Incorporation of health-related quality-of-life benefits and utility values	None considered.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	None considered.
Are there specific groups of people for whom the technology is particularly cost effective? What are the key drivers of cost effectiveness?	The Committee noted that one of the main factors affecting the cost effectiveness of cetuximab was the assumption about the mean duration of treatment.
	For panitumumab, the estimate of overall survival was the main factor found to substantially change the ICER.
Most likely cost-effectiveness estimate (given as an ICER)	The most plausible ICER for cetuximab plus best supportive care was £90,000 per QALY gained and for cetuximab plus irinotecan plus best supportive care the ICER was £88,000 per QALY gained, both compared with best supportive care.
	It was not possible to specify a precise ICER for panitumumab plus best supportive care compared with best supportive care alone, but this would likely lie between £110,000 and £150,000 per QALY gained.
Additional factors taken into account	N/A
Patient access schemes (PPRS) End-of-life considerations	The Committee agreed that the life expectancy of people with metastatic colorectal cancer treated with best supportive care in the second-line setting was less than 12 months.
	The Committee concluded that bevacizumab plus non-oxaliplatin chemotherapy did not meet all of the criteria for a life-extending, end-of-life treatment. This was because there was no evidence to show by how much bevacizumab plus non-oxaliplatin chemotherapy given as second-line treatment extended survival and bevacizumab has a marketing authorisation for a number of indications and therefore does not fulfil the criterion of being indicated for a small patient group.
	The Committee concluded that cetuximab did not meet all of the criteria for a life-extending, end-of-life treatment because the cumulative population covered by the indications in the marketing authorisation for cetuximab was likely to be over 10,000 patients and was not small.
	The Committee noted that in the near future, panitumumab will be licensed for the treatment of metastatic colorectal cancer in a patient population of similar size to that for cetuximab. The Committee noted that the most plausible ICER for panitumumab monotherapy lies between £110,000 and £150,000 per QALY gained. Therefore, the Committee concluded that, even if all the criteria for a life-extending, end-of-life treatment were met for panitumumab monotherapy, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.
	The Committee heard that people with colorectal cancer in England are becoming increasingly worried about what they perceive to be unequal access to treatment with biological drugs, which are currently only provided to some patients through the Cancer Drugs Fund.
Equalities considerations and social value judgements