LA VERDAD ACERCA DE LA INDUSTRIA FARMACÉUTICA (Cómo nos engañan y qué hacer al respecto)

Resumen del libro "La verdad acerca de la industria farmacéutica. Cómo nos engañan y qué hacer al respecto", de Marcia Angell

INTRODUCCIÓN:

LOS MEDICAMENTOS SON DIFERENTES.

En la publicidad de los medicamentos se transmiten las siguientes ideas:

1.         Si los medicamentos son caros, es porque son valiosos para la salud.

2.         Si los medicamentos son caros, es porque las compañías invierten mucho dinero en investigación y desarrollo.

3.         La investigación de las compañías farmacéuticas produce medicamentos innovadores que alargan la vida, mejoran la calidad de vida y evitan que la atención médica sea más costosa.

4.         Todo esto es posible gracias al sistema de libre empresa bajo el que operan las compañías farmacéuticas.

LA BOLSA O LA VIDA.

Los estadounidenses gastan $200.000 millones al año (cifras 2006)

La cifra crece al 12% por año (en 1.999 creció al 18%)

Los medicamentos es el rubro que más sube en la asistencia sanitaria.

Esto revela que:

1.         La gente consume más medicamentos que antes.

2.         Los medicamentos que se consumen son los nuevos y más caros en lugar de los viejos más baratos.

3.         Los precios de los que más se recetan se ven sometidos a alzas rutinarias varias veces por año.

RETÓRICA VERSUS REALIDAD.

1.         La investigación y desarrollo es una parte relativamente pequeña de los presupuestos de las grandes compañías farmacéuticas: 1) La I&D es mucho menos que lo que gastan en  comercialización y administración y mucho menos que sus ganancias. 2) Durante dos décadas seguidas, la industria farmacéutica fue la más lucrativa de EEUU. Sólo en 2003 quedó en tercer lugar, detrás de “minería, petróleo crudo y banca comercial”. 3) Los precios que cobran las compañías farmacéuticas no guardan relación con los costos de fabricación y podrían rebajarse dramáticamente sin poner en peligro la I&D

2.         La industria farmacéutica no es innovadora: 1) Sólo unas pocas drogas importantes han aparecido en el mercado en años recientes y estas provenían en su mayoría de investigaciones realizadas en instituciones académicas, pequeñas compañías biotécnicas o Institutos Nacionales de Salud y fueron costeadas con fondos públicos. 2) La gran mayoría de nuevas drogas no son nuevas, sino simples variantes de viejas drogas y presentes en el mercado o lo que se conoce como medicamentos “yo también” (Me too drugs). Por ejemplo las 6 estatinas para bajar el colesterol (Mevacor, Lipitor, Zocor, Pravachol, Lescol y Crestor) y todas son variantes del primero. En palabras de la Dra. Sharon Levine (Directora Ejecutiva Asociada del Grupo Médico Permanente Kaiser) “Si soy una fabricante y puedo cambiar una molécula, obtener otros veinte años de derechos de patente y convencer a los médicos de que prescriban y a los consumidores de que exijan la nueva presentación de Prilosec o del Prozac semanal en lugar del Prozac diario, justo cuando vence mi patente, ¿entonces por qué voy a gastar dinero en investigaciones menos seguras, como la búsqueda de nuevas drogas?”

3.         La industria farmacéutica no funciona bajo esquemas de libre empresa: 1) Es libre para decidir qué drogas va a desarrollar (me too drugs en lugar de innovadores, p.ej) y es libre para fijar los precios más altos que le permita el comercio, pero en realidad depende absolutamente de los monopolios otorgados por el gobierno, tales como patentes y derechos exclusivos de comercialización.

 si quiere ver el resto

  todo el libro en pdf

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.

Abstract

BACKGROUND:

Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis.

METHODS:

Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥ 4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m(2) intravenously over 2 h and fluorouracil bolus 400 mg/m(2) intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m(2) repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m(2) intravenously over 2 h and oral capecitabine 1000 mg/m(2) twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m(2) intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m(2) every 2 weeks with regimen one and three or a loading dose of 400 mg/m(2) followed by a weekly infusion of 250 mg/m(2) with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367.

FINDINGS:

128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21.1 months (95% CI 12.6-33.8) in the chemotherapy alone group and 19.8 months (12.2-28.7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20.7 months (95% CI 17.9-25.6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14.1 months [95% CI 11.8-15.9] vs 20.5 months [95% CI 16.8-26.7], hazard ratio 1.48, 95% CI 1.04-2.12, p=0.030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related.

INTERPRETATION:

Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.

Otras opiniones:

Opinión 1

Opinión 2

FOLFOX/Cetuximab Prolonged Survival in Mutation-Free Colorectal Cancer

Se presentó en ESMO World Congress on Gastrointestinal Cancer 2015, un trabajo de cetuximab mas FOLFOX en el cual se seleccionan los pacientes para no tener ninguna mutación RAS. El ENORME BENEFICIO ES DE 1.9 MESES. Por favor no engañar más a los médicos desprevenidos.

Combination treatment with FOLFOX plus cetuximab resulted in improved progression-free survival compared with FOLFOX alone in patients with metastatic colorectal cancer with “all-RAS” wild-type tumors who had progressed after first-line FOLFIRI plus cetuximab.

However, patients who had tumors with a mutation in KRAS, NRAS, BRAF, and/or PIK3CA genes had a detrimental effect from the combination of FOLFOX plus cetuximab, according to the results of the CAPRI-GOIM study (abstract LBA-09) presented at the European Society for Medical Oncology (ESMO) 17th World Congress on Gastrointestinal Cancer in Barcelona.

“A word of caution: these results generate a very important signal that deserves to be further explored in a larger, randomized, phase III study, that continuing anti-EGFR treatment while switching the chemotherapy backbone in second line is feasible past progression and by identifying patients whose tumor is EGFR-dependent; that by identifying wild-type status for KRAS, NRAS, BRAF, and PIK3CA genes, also identifies patients responsive to this treatment,” said Fortunato Ciardiello, MD, PhD, from Seconda Università degli Studi di Napoli in Naples Italy, in a prepared statement.

The phase II trial included 340 patients with metastatic colorectal cancer and KRAS exon 2 wild-type tumors treated with first-line FOLFIRI plus cetuximab until disease progression or unacceptable toxicity. After progression, these patients were randomly assigned to treatment with FOLFOX plus cetuximab (n = 74) or FOLFOX alone (n = 79). The primary endpoint was progression-free survival.

According to the study results, the median progression-free survival of the intention-to-treat population was 6.4 months for FOLFOX plus cetuximab compared with 4.5 months for FOLFOX alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI], 0.58–1.12; P = .19).

The researchers performed next-generation sequencing in about 75% of cases; 66 patients had “all-RAS” wild-type tumors with no mutations in KRAS, NRAS, BRAF, or PIK3CA genes and 51 patients had tumors harboring a mutation in at least one of these genes.

The median progression-free survival for patients identified as all-RAS wild-type was 6.8 months with combination treatment compared with 5.5 months for FOLFOX alone (HR = 0.80; 95% CI, 0.50–1.29; P = .36). Median progression-free survival in the RAS-mutated population was 2.7 months for FOLFOX plus cetuximab compared with 4.1 months for FOLFOX alone (HR = 1.53; 95% CI, 0.79–2.96; P = .2).

When the researchers looked at those patients considered to be quadruple wild-type, the median progression-free survival was 6.9 months for combination therapy compared with 5.3 months for FOLFOX alone, a significant difference (HR = 0.56; 95% CI, 0.33–0.94; P = .025). In contrast, for patients with any mutation in KRAS, NRAS, BRAF, or PIK3CA, the median progression-free survival was longer for FOLFOX alone compared with combination treatment (4.4 months vs 2.7 months; HR = 1.70; 95% CI, 0.94–3.05; P = .07).

ESMO spokesperson Andrés Cervantes, of University Hospital Valencia in Spain, who was not involved in the study, commented in a press release: “This is a new understanding of how to treat a select group of patients that are wild-type for the KRAS, NRAS, BRAF, and PIK3CA genes who can be treated with the same anti-EGFR antibody and a change in chemotherapy following progression. In the intent-to-treat analysis there is no benefit from this treatment, however, the patients showing no mutation do benefit from this approach.”

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Yo creo que un tratamiento que provee menos de 2 meses en cuanto a período libre de enfermedad y supervivencia es realmente inútil. Si a ello le agregamos que es tóxico y caro, ya es un forma de actuar del laboratorio muy poco ética y extremadamente comercial. Es una pena ver a personas que tienen un nombre en la oncología, prestarse, dinero de por medio a esta farsa.
Opine por usted mismo

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Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial

Una mejoría en el tiempo medio a la progresión de menos de un mes en pocos pacientes en segunda línea después de descartar todos los tipos de Ras mutados realmente es una vergüenza. Se leyó y se publica.

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Anti-EGFR Therapy Worsens Survival in Patients With RAS Mutations

There might now be a better way to predict clinical response to panitumumab (Vectibix), according to a new study.

In patients with metastatic colorectal cancer, KRAS mutations have been established as a predictive biomarker of resistance to antiepidermal growth-factor receptor (EGFR) therapy, but other RAS mutations are also predictive.

In fact, the data suggest that patients with other RAS mutations have worse survival when panitumumab is added to a standard chemotherapy regimen.

Patients with nonmutated wild-type KRAS exon 2 who harbored other RAS mutations had inferior progression-free and overall survival when treated with panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) than when treated with FOLFOX4 alone.

This is consistent with findings in patients with KRAS mutations in exon 2, report Jean-Yves Douillard, MD, PhD, from the Institut de Cancérologie de l'Ouest in Nantes, France, and colleagues. In other words, when a patient has a KRAS mutation in exon 2 or other RAS mutations, they will not benefit from panitumumab.

Conversely, for those without RAS mutations, progression-free and overall survival were better with panitumumab plus FOLFOX4 than with FOLFOX4 alone.

Results from the Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) were published in the September 12 issue of the New England Journal of Medicine.

Detrimental Effect

In PRIME, the researchers looked at the effect of RAS (KRAS or NRAS) or BRAF mutations on the efficacy and safety of panitumumab plus FOLFOX4 and FOLFOX4 alone.

For patients with no RAS mutations, progression-free survival was better when panitumumab was added to FOLFOX4 (10.1 vs 7.9 months; hazard ratio [HR] for progression or death, 0.72; P = .004). Overall survival was also better with panitumumab (25.8 vs 20.2 months; HR for death, 0.78; P = .04).

However, panitumumab did not improve survival in patients with RAS mutations; it actually had a detrimental effect.

For patients with no KRAS mutation in exon 2 who had other RAS mutations, progression-free survival was worse when panitumumab was added to FOLFOX4 (7.3 vs 8.0 months). Overall survival was also worse (17.1 vs 17.8 months).

Clinical Implications

So what does this mean clinically?

In an accompanying editorial, Jordan Berlin, MD, from the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, notes that the benefit of excluding patients with RAS mutations from anti-EGFR antibody therapy is "logical and expected," but the harm was not anticipated.

Even though data from this study are "not definitive enough to require a change from the limited KRASexon 2 testing currently performed" to broadly assess RAS status, "presuming other analyses support these results, it would be difficult to justify taking a long time to change practices," writes Dr. Berlin.

He adds that because the PRIME results show that panitumumab plus FOLFOX4 is less effective than FOLFOX4 alone in the presence of other RAS mutations, the need to quickly confirm or refute these data is "even greater."

"The PRIME study aroused concern that a subgroup of patients may be harmed by the combination of an anti-EGFR therapy with FOLFOX4," he continues. "Thus, it will be difficult to recommend incorporation of these regimens into first-line therapy in metastatic colorectal cancer."

These data might also complicate the integration of forthcoming results from head-to-head comparison trials of bevacizumab and anti-EGFR therapy into daily clinical practice, Dr. Berlin points out.

"Therefore, the reanalysis of the PRIME study is the next important step in the development of a biomarker for the efficacy of anti-EGFR antibody therapy in colorectal cancer," he concludes.

Study Details

Dr. Douillard and colleagues conducted a prospective–retrospective biomarker analysis of 1183 patients with metastatic colorectal cancer.

Of the 1060 patients (90%) with RAS status available, 512 (48%) had tumors with nonmutated RAS and 548 (52%) had tumors with mutated RAS (any KRAS or NRAS mutation in exon 2, 3, or 4). In addition, 108 of the patients who had no KRAS mutations in exon 2 had other RAS mutations.

RAS and BRAF status was ascertained in 1047 of the 1183 patients (89%). Of the 619 patients with noKRAS mutation in exon 2 who were evaluated for BRAF, 53 (9%) had V600E mutations.

For patients with no RAS or BRAF mutation, the improvement in progression-free survival was 1.6 months when panitumumab was added to FOLFOX4, and the improvement in overall survival was 7.4 months.

The researchers note that there were "minor differences" in the 2 treatment groups for patients withBRAF mutations but no RAS mutations, but these were not significant.

In patients treated with panitumumab plus FOLFOX4, adverse events were similar in patients with noRAS mutations and in those with no KRAS mutations in exon 2 (from a previous analysis reported in J Clin Oncol. 2010;28:4697-4705). Similarly, the safety profile was similar in patients with RAS mutations and in those with KRAS mutations in exon 2.

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Editorial

Adjuvant Chemotherapy for Locally Advanced Rectal Cancer: Is It a Given?

Se analiza y se recomienda el uso de la quimioterapia en el cáncer de recto avanzado T 3 o ganglios positivos, ya que es de utilidad, pero no siempre se utiliza en la práctica.

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Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study

No todos los trabajos muestran utilidad del Cetuximab en cáncer colorrectal avanzado.

Abstract

Purpose The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated.

Patients and Methods Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points.

Results Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients withKRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated.

Conclusion Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

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El costo de las drogas debe ser parte del tratamiento

En una presentación de ASCO 2015 se analiza bevacizumab vs.cetuximab y los importantes costos que conlleva en el tratamiento del cáncer colorrectal, así como la toxicidad inducida.
Esto debería ser tenido en cuenta ya que el agregado de estas drogas a la quimioterapia,si bien es estadísticamente significativa en cuan a progresión libre de enfermedad o supervivencia, no es clínicamente muy relevante

Cost of Cancer Drugs Should Be Part of Treatment Decisions

JUNE 1, 2015

Treatment decisions are based on a hierarchy of factors. Drug effectiveness is considered to be the most important, followed by toxicity, and, lastly, cost. Yet, during the Saturday, May 30, Health Services Research and Quality of Care Oral Abstract Session, discussant Peter B. Bach, MD, of Memorial Sloan Kettering Cancer Center, asked, “Why treat prices as immutable? Would we really pay an infinite amount for a microscopic benefit?” A discussion of how cost does not necessarily reflect drug value, efforts to consider cost as part of the treatment decision, and methods to set new cancer drug prices based on value were the focus of the session.

Since 1965 when Medicare was created, the introductory cost of new cancer drugs has increased 100-fold to approximately $10,000 a month (adjusted to 2014 dollars). Older drugs also contribute to soaring costs; the price of imatinib has risen from less than $100 per day in 2004 to more than $200 in 2014. Meanwhile, the Centers for Medicare & Medicaid Services (CMS) began applying a value-based payment modifier for physician groups in 2015, under which payments will be determined by the quality of patient care balanced against the cost of care.

Balancing Cost with Efficacy, Toxicity

The CALGB/SWOG 80405 trial, begun in 2005, aimed to determine if the addition of cetuximab to leucovorin/fluorouracil/irinotecan (FOLFIRI) or leucovorin/fluorouracil/oxaliplatin (FOLFOX) chemotherapy prolongs survival compared to FOLFIRI or FOLFOX with bevacizumab in patients with metastatic colorectal cancer. From the outset, the trial included an economic companion study of bevacizumab and cetuximab.

Dr. Deborah Schrag

The direct cost of bevacizumab and cetuximab for one 8-week cycle in an average patient could easily be determined based on the price of the two antibodies: $9,324 and $20,856, respectively (2014 drug cost). However, as Deborah Schrag, MD, FASCO, of the Dana-Farber Cancer Institute, explained, the cost of these treatments could be driven by additional factors, such as differences in adverse events and consequent differences in hospitalization rates (Abstract 6504). Thus, Dr. Schrag and her colleagues looked at measures, such as days in the hospital/intensive care unit and Medicare costs for particular services associated with these drugs, along with overall survival and quality-adjusted survival (based on EQ-5D health questionnaires) to determine cost effectiveness and cost utility, respectively.

Table 1. Mean Cost Differences Based on Rx Arm Stem from Antibody Costs
	Bevacizumab 559 patients	Cetuximab 578 patients	Cost Difference Bev-Cetux (95% CI)
FOLFOX/FOLFIRI	$2,894	$2,616	$277 (163 to 718)
Antibody Rx	$33,500	$71,718	$-38,217 (-41,050 to -31,384)
Hospital/ Acute Care	$28,951	$29,494	$-543 (-2,830 to 1,745)
Estimated Total Costs	$66,075	$105,339	$-39,264

Dr. Schrag explained that there was no difference in the survival outcomes or quality-adjusted life years (QALY) between the two treatment arms. In contrast, the economic study found a large difference in total cost of treatment between the groups: $66,075 in the bevacizumab group compared with $105,339 in the cetuximab group. The cost difference was $39,264 (95% CI). This difference arose largely because of the difference in costs of bevacizumab and cetuximab, whereas the costs of FOLFOX and FOLFIRI and hospital/acute care were similar (Table 1).

“Because survival and quality of life are similar but cost is less, and because patients have significant out-of-pocket costs, I think there’s a good argument to be made that bevacizumab should be the first-line treatment. It’s certainly what I use in my practice,” Dr. Schrag said.

Dr. Bach was critical of the tendency for clinical oncologists to accept the high price of drugs like cetuximab that have similar efficacy and toxicity to less expensive medications. “Why not close the loop?” Dr. Bach said. “Dr. Schrag says no in clinic, but why not say no more generally?”

Dr. Schrag noted that because ASCO is committed to improving quality and value in cancer care, ASCO and CMS could work together to determine preferred treatment regimens, which have been established for other conditions. Although she explained that bevacizumab is a “no-brainer” from a value perspective, cetuximab plus chemotherapy should be available for patients who want to pay for it, and that there could be clinical settings for which it would be preferred. She added that these monoclonal antibody therapies will go off-patent in the next few years, and at that time it will be interesting to see how companies price their biosimilars.

Setting Cost Based on Value

Daniel A. Goldstein, MD, of the Winship Cancer Institute of Emory University, argued for cost-effectiveness analyses prior to drug approval so that these data could help establish the cost of the drug (Abstract 6505). Performing these analyses after approval is “an academic exercise of no meaningful consequence,” he said.

Dr. Goldstein and his colleagues evaluated the cost at which necitumumab could be considered cost-effective. Necitumumab, an EGFR inhibitor, met its endpoint in the phase III SQUIRE trial of patients with advanced squamous non–small cell lung cancer and resulted in a median overall survival benefit of 1.6 months. Dr. Goldstein and colleagues determined cost based on the incremental cost-effectiveness ratios (ICER), or willingness-to-pay values, that are commonly reported for countries such as the United States. Given an estimated ICER range of $50,000/QALY to $200,000/QALY, cost acceptability curves could be modeled that take into account estimated QALY for the drug and variables, such as adverse events, outpatient follow-up, and drug cost. Dr. Goldstein and his colleagues determined that price tags on necitumumab of $563-$1,309 per 3-week cycle would maintain ICERs below $100,000/QALY and $200,000/QALY, respectively.

Setting drug price based on cost/QALY could be important when there are uncertainties about the superiority of one drug over another, such as the small and not statistically significant overall survival benefit of cetuximab compared with bevacizumab in the CALGB/SWOG 80405 trial. “Those small differences can be priced in, and then we can all sleep at night,” Dr. Bach said.

During the discussion, an audience member noted that he might not have received the stem cell therapy that has made him cancer free if quality considerations were made, and he urged the presenters to be very specific when they discuss quality and what it means for different patients. In response, Dr. Goldstein said that the “aim is to deliver the best possible care that is valuable to patients, but necitumumab and many drugs have not cured any patients. When drugs are curative, then that changes the ICER significantly.”  

Utilidad del bevacizumab más FOLFIRI como segunda línea en cáncer colorrectal avanzado

Que difícil es sacar conclusiones con las distintas publicaciones en las que se hace el agregado de bevacizumab en cáncer colorrectal (CC) avanzado no pasible de cirugía.   

En un estudio recientemente aparecido en Annals of Oncology se analizan 2 dosis de bevacizumab más FOLFIRI como segunda línea en  CC, observándose que son comparables y que el tiempo a la progresión es de 6.1 y 6.4 meses. Esto me remitió al trabajo original de Christophe Tournigand del año 2004. Publicado en el Jorunal of Clinical Oncology con el título: FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study, el cual se basaba en 2 brazos uno iniciando con FOLFIRI y a la progresión cambiar a FOLFOX6 y el otro a la inversa. Cuando se analiza la segunda progresión (que sería la población estudiada en el primer trabajo) los tiempos son: entre 11.8 y 14.2 meses.    

                                                                                                                                           Si bien no hay ninguna duda que no es correcto comparar 2 trabajos diferentes y SI las conclusiones se deben hacer en estudios aleatorizados, no dejan de sorprender estos datos. Será que las poblaciones de los 100 hospitales japoneses tienen un evolución más desafortunada?                                                                  

Bibliografía:

FOLFIRI Plus Bevacizumab as Second-Line Therapy in Patients With Metastatic Colorectal Cancer                                                                                                                                                                                

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study

                                                                                                             

Estudio radomizado de FOLFOX 4 vs. mas quimioterapia (MIROX) en pacientes con cáncer colorrectal metastático, pasibles de cirugía

Este estudio fracasó en agregar al estándar de FOLFOX 4 para pacientes con cáncer colorrectal metastático FOLFOX7 y FOLFIRI en aumentar el tiempo a la progresión y supervivencia. Es otro ejemplo que no siempre más es mejor.

Abstract

Background Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative.

Patients and methods In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m²) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m²) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m²). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS).

Results A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7–FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7–FOLFIRI.

Conclusions FOLFOX7–FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing.

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Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial

Del presente trabajo se pueden hacer algunas preguntas y comentarios: Si el número de pacientes que los autores creían necesario para tener error α y β adecuados ¿porque se suspendió la incorporación antes? provocando una alteración estadística irreparable. Un tiempo libre a la progresión de 1.8 meses no es para celebrar.

Un aumento de la supervivencia con un HR cuyo IC está por debajo  y por encima 1 no es muy creíble que sea útil.

Es probable que se quiera imponer el bevacizumab en todas las líneas del tratamiento sistémico del cáncer colorrectal, pero en la mayoría de los trabajos el fundamento es muy pobre. De la calidad de vida no se habla y mucho menos de los costos.

G. Masi1, et al

On behalf of the BEBYP Study Investigators

Abstract

Background The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer. We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy.

Patients and Methods In this phase III study patients with metastatic colorectal cancer treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end-point was progression-free survival. To detect an HR for progression of 0.70 with an α and β error of 0.05 and 0.20 respectively, 262 patients were required.

Results In consideration of the results of the ML18147 trial the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, median progression-free survival was 5.0 months in the chemotherapy-group and 6.8 months in the bevacizumab-group (adjusted HR=0.70; 95%CI 0.52-0.95; stratified log-rank p=0.010). Subgroup analyses showed a consistent benefit in all subgroups analysed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR=0.77; 95%CI 0.56-1.06; stratified log-rank p=0.043). Responses (RECIST 1.0) were similar in the chemotherapy- and bevacizumab-groups (17% and 21%; p=0.573). Toxicity profile was consistent with previously reported data.

Conclusions This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of metastatic colorectal cancer.

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