New Value Model Incorporates Long-Term Adverse Effects of Cancer Drugs

February 2017, Vol 7, No 2

A new economic model suggests that overall survival and drug toxicity profiles are insufficient for assessing the value of a drug. According to a study that incorporated late adverse events in advanced Hodgkin lymphoma, a more comprehensive benefit-to-risk ratio of a drug requires an understanding of its long-term health implications, said Ohad Oren, MD, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, at the 2016 American Society of Hematology meeting.

“Late toxicity matters. A broader value system that combines overall survival, acute toxicity, and long-term toxicity generates a different order of superiority than a traditional or standard model. We believe these results should encourage more careful scrutiny of the long-term safety performance of chemotherapeutic regimens when creating value scores,” Dr Oren said.

Value frameworks have emerged as a means to compare different pharmacologic agents and treatment regimens based on patient-related factors such as efficacy, safety, and cost. However, these formulas largely ignore long-term or permanent adverse effects, which are particularly important in the case of curable cancers, such as Hodgkin lymphoma and testicular cancer, said Dr Oren.

The American Society of Clinical Oncology (ASCO) Value Framework deducts 5 points for “unresolved symptomatic treatment-related toxicities at 1 year after completion of treatment”; the National Comprehensive Cancer Network (NCCN) Evidence Blocks detract 1 point for “significant chronic or long-term toxicities”; and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale applies a grade-B signification for “reduced treatment toxicity or improved quality of life.” Other value frameworks do not address late effects at all, according to Dr Oren.

“The rationale for our model was that late effects have a significant impact on survival and quality of life and are underutilized in value estimations,” he said. “Total economic burden is larger than the cost of chemotherapy. The optimal value score should help patients and oncologists make informed decisions looking into the distant future,” he added.

Longitudinal Approach for Assessing Drug Value

Together with David H. Henry, MD, Abramson Cancer Center, University of Pennsylvania, Dr Oren aimed to define the value of cancer drugs by considering patients’ expected clinical outcomes.

Dr Oren and Dr Henry integrated 3 parameters into their value score for a chemotherapy regimen:

  1. Efficacy, defined as 10-year overall survival
  2. Acute toxicity, defined as the incidence of infections and grade 3 neutropenia
  3. Long-term toxicity, defined as a cumulative incidence of heart disease at 5 years and secondary cancers at 10 years.

The researchers chose advanced Hodgkin lymphoma for simulation, using data from high-value prospective clinical trials to compare different chemotherapy regimens, including ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine); BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone); COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin); and Stanford V (doxorubicin, vinblastine, mechlor­ethamine, etoposide, bleomycin, vincristine, and prednisone).

The net value of each regimen was then assessed by adding the score for each of the 3 individual components and comparing it with an alternative value model that integrates only efficacy and acute toxicity.

Different Value Estimations

This longitudinal value framework yielded different estimations of value from the other value frameworks, such as ASCO’s or the NCCN’s. In the new value model, ABVD and Stanford V had the highest scores (26 of 30) versus 24 and 22, respectively, for COPP-EBV-CAD and BEACOPP.

The superiority of the ABVD regimen persisted in this model as did the overall advantage of COPP-EBV-CAD over BEACOPP. However, Stanford V was shown to be more valuable than COPP-EBV-CAD in this analysis compared with the other value assessment models.

Each drug regimen achieved value in different ways; Stanford V had a superior late adverse-effect profile, whereas ABVD had superior overall survival at 10 years, said Dr Oren.

Stanford V reached a better value score than COPP-EBV-CAD, and was equivalent to ABVD, in contrast to a drug value scheme that neglected long-term toxicities, in which Stanford V was inferior to both regimens, Dr Oren said. The superiority of ABVD to COPP-EBV-CAD and BEACOPP persisted in this new value framework, as was the overall advantage of COPP-EBV-CAD over BEACOPP.

“Ideally, my vision is to create a much more granular and comprehensive value framework that synthesizes all of the major morbid conditions that are associated with chemotherapy,” said Dr Oren. “The next step toward consolidating this value framework is to incorporate patient-reported outcomes and include more data on late effects,” he added.

“We decided not to include cost as a factor in this initial equation, given that the entire economic burden of the patient is composed of many more factors than the chemotherapy cost alone, but cost will be included in future models,” said Dr Oren.

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