PRELIMINARY: PLEASE DO NOT CITE What Does the US Buy and What Does It Get from Its Cancer Chemotherapy Drugs Compared to European Nations? Sean Nicholson, PhD1,2 Claudio Lucarelli, PhD1 David A. Asch, MD, MBA2,3 1 Cornell University and National Bureau of Economic Research 2 Leonard Davis Institute of Health Economics, University of Pennsylvania 3 Center for Health Equity Research and Promotion, Philadelphia Veterans Affairs Medical Center 1 ABSTRACT Context: Cancer chemotherapy costs are substantially higher in the US than in Europe. The reasons for this difference, and their clinical implications, are not known. Objective: To examine treatment differences, pricing differences, and expected outcome differences in the chemotherapy management of metastatic colorectal cancer, metastatic non small cell lung cancer, and non metastatic breast cancer between the US and five European countries: France, Germany, Italy, Spain, and the UK. Design: Population‐based analysis of chemotherapy regimens and chemotherapy drug costs supplemented with modeling of expected clinical outcomes from clinical trials. Main Outcome Measures: Cross‐national variation in chemotherapy regimen, cost of chemotherapy treatment, and expected outcome in quality adjusted life years from chemotherapy treatment. Results: For all three cancers, costs of chemotherapy treatment in the US are two to three times higher than in Europe. These differences are a product of higher prices for non generic drugs in the US, lower prices for generic drugs in the US, and the earlier adoption of more effective and more expensive treatment regimens in the US. Relative to Europe, the US substantially overpays for drugs to treat colorectal cancer. Conclusions: The success of comparative effectiveness research is enhanced by examinations of models of care outside the US. In general, the US adopts more effective chemotherapy treatments faster than Europe, but at a higher cost. Those choices seem worth it for adjuvant chemotherapy for breast cancer but not for chemotherapy management of metastatic colorectal cancer. European approaches to breast cancer might be advanced by adopting 2 practices more similar to those in the US. 3 The US spends more per person on health care than does any other industrialized nation. The US also spends more per person on cancer than any other nation, more per person on cancer drugs than any other nation, and the contribution of cancer drugs to the cost of cancer care in the US is, at approximately 15%, among the highest compared to other nations.1,2 However, across a broad range of health care services—hospitalization, pharmaceuticals, medical technology—usage is lower in the US than in other nations of the Organization for Economic Cooperation and Development (OECD). The higher overall costs faced by the US are largely attributable to higher prices the US pays for the same medical goods and services compared those other nations.3,4 These observations are particularly meaningful given current attention to US health reform, interest in comparative effectiveness research, and curiosity about how other nations use health care services and achieve health benefits. Why does the US spend so much more on chemotherapy drugs than other countries? One possibility is that, just as for other broad categories of health services, prices for the same chemotherapy drugs may be higher in the US. But an additional possibility is that the US uses a more expensive mix of drugs in its chemotherapy regimens. If the US is merely spending more for the same drugs then, at least relative to other nations, the US is overpaying. If the US is using different chemotherapy regimens then we can ask whether those regimens might be providing health benefits to US patients with cancer that are worth the additional costs. To disentangle these alternative possibilities, we examined both chemotherapy pricing, regimen use, and expected health benefits for colorectal cancer, non small cell lung cancer (NSCLC), and breast cancer in the US, France, Germany, Italy, Spain, and the UK from 2002 to 2008. 4 Methods Chemotherapy Regimens. We used data from IntrinsiQ to determine the proportion of US patients with colorectal cancer, NSCLC, and breast cancer treated with each of several alternative chemotherapeutic regimens. InstrinsiQ provides information systems to help oncologists determine chemotherapy dosing and collects information on 19,500 patients per month (about 3.5% of US chemotherapy patients) from 585 oncologists, in 111 practices, in 36 states. The geographic distribution of oncologists providing data to IntrinsiQ closely matches that of oncologists in the AMA physician Masterfile. Fifty‐six percent of the IntrinsiQ oncologists are in private practice, 32% practice at a community hospital or clinic, 11% at an academic medical center, and 1% in the VA or military system. IntrinsiQ estimates the proportion of US patients receiving each regimen by projecting across three dimensions in its sample: physician specialty (medical oncologist, hematologist‐oncologist, hematologist, gynecological oncologist, pediatric hematologist oncologist), tumor grouping (solid, hematological, gynecological, and myelodysplastic syndrome), and geographic area. Although chemotherapy regimen information is available in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data set, and that set has a larger sample, that sample is restricted to patients over 65 years of age, contains incomplete information on oral components of regimens, and is more delayed in its reporting. We obtained information about the proportion of chemotherapy patients treated with each chemotherapy regimen, separately for each type of cancer and for each quarter between January 2002 and June 2008. For colorectal cancer and NSCLC, we restricted our main market share measurement to those 5 patients with metastatic disease because most of drugs approved to treat these cancers were tested on and approved only for those patients. We also performed secondary analyses using all patients with colorectal cancer and NSCLC, regardless of disease stage. For breast cancer we restricted the sample to patients without metastases because the majority of metastatic breast cancer patients (60.6% of US patients in August 2008 according to IntrinsiQ) receive off‐label chemotherapy regimens for which we do not observe clinical trials efficacy and side effect measures. We re‐scaled the market shares to sum to 100% after omitting regimens approved for second‐line metastatic treatment for colorectal cancer or NSCLC, metastatic treatment for breast cancer, and regimens that have not been approved by the Food and Drug Administration (FDA) for these three cancers and so are being used off‐label. For metastatic colorectal cancer, 23.1% and 15.4% of US patients received off‐label and second‐line regimens, respectively, in the second quarter of 2008, whereas in European countries off‐label use (by FDA standards) ranged from 6.2% to 17.6%, and second line regimen use ranged from 5.7% to 12.8%. For metastatic NSCLC, 20.0% and 44.6% of US patients received off‐label and second‐line regimens, respectively, in the second quarter of 2008, whereas the European countries ranged from 3.1% to 10.4% off‐label use, and from 32.0% to 55.2% for use of second‐line regimens. We omit off‐
label regimens because there often are no clinical trial data demonstrating their value for these cancers. We omit second‐line treatments because outcomes from these trials are generally worse than for first‐line trials, which could bias comparisons between countries that differ in their use of second‐line therapies. 6 Chemotherapy regimens from France, Germany, Italy, Spain, and the UK were determined the same way, using data from Synovate. Like IntrinsiQ, Synovate collects treatment information on about 2‐3% of each country’s chemotherapy patients from about 760 oncologists. From the Synovate data, we estimated the proportion of the same groups of colorectal, NSCLC, and breast cancer patients using each chemotherapy regimen, for each quarter from October 2005 through June 2008, and for each country. Chemotherapy Costs. IMS Health collects information on sales in dollars and the quantity of pharmaceutical products purchased by US‐based physician practices from wholesalers. Rather than the published average wholesale price (AWP), which often differs substantially from the amount physicians actually pay, IMS Health reports the invoice amount that wholesalers charge physician practices. Since wholesalers in the US usually receive a small discount from manufacturers for paying promptly and then charge a small mark‐up when selling the drugs to customers, the prices we observe should be very close to the manufacturer prices. Prices and quantities are reported separately by National Drug Classification (NDC) code, which are unique for each firm‐product‐strength/dosage‐package size. We calculated the weighted average price paid per milligram of active ingredient across the different NDC codes for a particular drug. We converted all prices to 2008 dollars using the consumer price index. IMS Health also reports the sales and quantities of pharmaceutical products purchased by wholesalers in each of the five European countries of interest. Sales were converted from the 7 local currency into US dollars using the average exchange rate during the fourth quarter of 2008. Many chemotherapy regimens consist of a combination of drugs. In order to calculate the price per treatment, we determined the recommended amount of each drug in each regimen from the National Comprehensive Cancer Network (NCCN) supplemented, where necessary, with information from drug package inserts or journal articles. Regimen prices for colorectal and NSCLC were estimated for a representative patient who has 1.7 meters squared of surface area and weighs 80 kilograms; for breast cancer the representative patient has 1.7 meters squared of surface area and weighs 66.8 kilograms .5 Treatment lengths for colorectal cancer are 24 weeks, whereas they vary from 16 to 27 weeks across NSCLC regimens, and vary from 12 to 64 weeks across breast cancer regimens. Prices are therefore expressed on a per‐patient basis assuming the patient completes recommended treatment, but do not incorporate additional regimens a patient may receive if the cancer progresses. Analysis of US‐European Spending Differences. We decomposed the difference in per‐
treatment chemotherapy spending between the United States and the five European countries into a component reflecting different prices for the same chemotherapy regimens, and a component reflecting different treatment regimens.6 To do so, we projected what the US per‐
treatment spending would have been using observed US treatments, but at a price reflecting the average price across the 5 European countries. The difference between that amount and what the US actually spends reflects the component attributable to different prices alone. The 8 difference between the cost of US treatments at European prices and European treatments at European prices reflects the spending difference attributable to different treatment regimens. We performed the same analysis for each cancer and each quarter of data. Health Outcomes. Different chemotherapy regimens yield different clinical outcomes as well as different costs. We estimated a cancer patient’s expected clinical outcome given a particular chemotherapy regimen based on how well that regimen performed in clinical trials. We collected information on metastatic trials for colorectal and NSCLC, and adjuvant trials for breast cancer. Specific health outcomes include the median number of months metastatic colorectal and NSCLC patients survived, and expected quality‐adjusted life years (QALYs) for all three cancer types. We estimated each regimen’s effectiveness and side effects from the FDA‐
approved package inserts that accompany each drug, journal publications of clinical trials referenced by the 2008 NCCN Clinical Practice Guidelines in Oncology publications, and journal articles and conference abstracts identified by searching in PubMed and Google Scholar for the name of each drug in a regimen with at least one percent market share, the type of trial (i.e., first‐line metastatic or adjuvant), and type of cancer. When multiple trials were conducted for a regimen, we calculated the mean performance by weighting each trial equally.
For colorectal cancer and NSCLC, a patient’s expected QALYs associated with a regimen was calculated by determining the average length of time clinical trial patients spent in five health states, and applying previously‐published adjustments for quality‐of‐life associated with each of these states7,8,9: [1] stable metastatic disease without experiencing a side effect from 9 chemotherapy; [2] tumor is responding to treatment (partial or complete response rate) with no side effects; [3] responding to treatment with a side effect; [4] not responding to treatment with a side effect; and [5] the disease has progressed to a more advanced state. For breast cancer, we estimated the proportion of patients who would be alive each year for the 15 years following each adjuvant chemotherapy treatment, and the proportion of those patients who would experience a recurrence of breast cancer. Survival and recurrence rates for the first five years come from the clinical trials. For one trastuzumab‐based adjuvant breast cancer regimen we observe outcomes only for the first four years and base the fifth year on the experience of the other trastuzumab‐based regimen in its fifth year. Women who survived for 15 years were assigned the life expectancy of a 76‐year old based on life tables and the assumption that they were 61 years old at diagnosis (National Cancer Institute, SEER data). Adjustments for quality of life (well versus experiencing a recurrence of cancer) are taken from Kurian.10 QALYs are discounted at 3% per year. Analysis of US‐European Incremental Cost‐Effectiveness. For the three cancer types, we estimated what US chemotherapy spending and expected QALYs would have been if US patients received the mix of chemotherapy regimens that were used by the five European countries between October 2005 and June 2008, weighting each country equally. We used the same approach to estimate European spending and expected QALYs if European patients received the mix of chemotherapy regimens that were used in the US during the same time period. 10 Results Tables 1 and 2 report the chemotherapy regimens used in this analysis and the estimated QALYs associated with each. Table 3 reports the mean chemotherapy costs per chemotherapy patient for the US in the fourth quarter of 2002, and for each of the six countries at two different quarters between 2005 and 2008. Across all quarters and across all cancers, chemotherapy spending per patient is considerably higher in the US than in any of the European countries. Spending differences reflect, in part, differences in the price of chemotherapy regimens across countries. These relationships are complex, because while most branded chemotherapy drug prices are considerably higher in the US than in Europe, generic chemotherapy drug prices are typically lower in the US than in Europe. Spending differences also reflect differences across countries in the mix of chemotherapy treatments used. Figures 1A‐C show these differences for the second quarter of 2008, labeled according to the quality‐adjusted life years (QALYs) a patient can expect with that regimen from Tables 1 and 2. Other quarters reveal generally similar dispersions across regimens. Over time all countries show progressive adoption of relatively expensive regimens that yield more QALYs; however, the US generally adopts these regimens earlier. Results were generally similar when chemotherapy used for all stages of colorectal cancer and NSCLC, rather than just metastatic disease, were included. 11 The absolute contributions of price differences and regimen differences to the higher US costs are shown in Figures 2A‐C for the second quarter of 2008. For example, average US spending per chemotherapy patient with metastatic colon cancer was $43,598 compared to European spending (averaged over the five countries) of $14,038. Of that $29,560 difference, $19,008 (64%) was attributable to higher prices for the same regimens, and $10,561 (36%) was attributable to a greater use of relatively expensive regimens. In contrast, most of the difference between US and European chemotherapy spending for metastatic NSCLC and adjuvant breast cancer in the second quarter of 2008 was attributable to greater use of relatively expensive regimens. Figures 3A‐C show the absolute contributions of price differences and drug regimen differences over all periods in the study. For all three cancers, prices explain a higher proportion of the spending difference over time. Until recently, however, US prices for the same regimens were lower than European prices for NSCLC and breast cancer, due to the high use of regimens with generic drugs during those years and the relatively low US prices for generic drugs. If US patients received the mix of chemotherapy regimens reflecting the average used by the five European countries between July 2007 and June 2008, US chemotherapy treatment costs would fall approximately $4 billion per year, but expected clinical outcomes would be worse. By using US treatment regimens rather than European treatment regimens, the US is purchasing additional QALYs at a cost of $257,423, $72,348, and $8,271 for metastatic colorectal, metastatic NSCLC, and adjuvant breast cancer patients, respectively (Table 4). If 12 Europeans used the US treatment mix they could purchase these additional QALYs at a cost of $184,438, $171,945, and $9,868. Discussion The US spends more on chemotherapy drugs for patients with cancer than other countries. This study has two main findings that explain why: First, while chemotherapy prices for patients with NSCLC and breast cancer are generally similar across the US and Europe, chemotherapy prices for colorectal cancer are considerably higher in the US. Second, US chemotherapy patients with these cancers typically receive regimens that would be more expensive even at European prices. These two effects are large, sustained over time, and conspire to increase the cost of cancer chemotherapy treatment in the US compared to Europe. Higher prices for the same drugs are hard to justify, and are likely due to differences across countries in buyers’ negotiating power and development of the generic market. In contrast, greater use of relatively expensive drugs might be worth it, as seems to be the case with the US management of breast cancer which offers additional QALYs over the European approach at a cost of only $8,271 each. All countries might be better off focusing on the single regimen for each cancer that provides an incremental cost effectiveness ratio most consistent with their price point for QALYs. In the US, that price is often quoted around $50,000 ‐ $100,000. The US appears to be exceeding that budget in its chemotherapy management of colorectal cancer compared to the overall 13 approach in Europe. In contrast, if European countries have a price point for QALYs similar to that in the US, these results suggest they would be better off using the approach to adjuvant breast cancer chemotherapy revealed in the US. Varied clinical circumstances may justify flexibility in chemotherapy regimens. Nevertheless, an explicit evaluation of value may improve upon current management. This study has several important limitations. First, we considered only the costs of chemotherapy drugs in the treatment of cancer. Colorectal cancer, NSCLC, and breast cancer are managed with surgery, radiation, hormonal therapy, and/or chemotherapy. At times, these therapies substitute for each other. In addressing chemotherapy drug costs alone, this study does not address the extent of chemotherapy use, nor how that use may offset other treatments or be offset by them. Nevertheless, this study indicates that differences in chemotherapy spending between the US and Europe are a product of prices and regimen mix, and that both are important. Second, our measures of chemotherapy use, prices, and the expected clinical benefits of different regimens reflect broad population distributions derived from samples that are imperfect and studies with varied enrollment and design. Comparing outcomes across such trials is suspect. On the other hand, our estimates reflect best available data, reflect usage in actual practice, and should be preferred to no systematic comparison at all. Each step in our process involves simplifying assumptions and estimates across countries, time, and currency exchange rate. Precision under these circumstances would be hard to define; nevertheless, we believe we have enough precision to establish a picture of how individual drug price and chemotherapy regimen conspire to widen the gap between US and 14 European chemotherapy drug spending. Third, in this study, we evaluate chemotherapy treatments. In most cases, these reflect individual patients, but in some cases patients may not complete treatments and in other cases patients may receive more than one treatment—a clinical practice that may differ across the countries in this study. Indeed, US chemotherapy patients with these cancers are far more likely to be treated with second line and off label agents compared to European patients, suggesting a more aggressive approach in the US compared with Europe. For that reason, our results are likely to be conservative estimates of US‐European differences. Conclusion Despite challenges in making cross‐national comparisons, this study reveals substantial differences in the chemotherapy used to treat three common cancers between the US and 5 European countries. The US pays more for drugs to treat metastatic colorectal cancer than does Europe, but does not seem to overpay as much for adjuvant treatment for breast cancer or treatment for metastatic NSCLC. The US also adopts newer chemotherapy regimens earlier. This early adoption seems to provide value for breast cancer, but not for colorectal cancer. The success of comparative effectiveness research is enhanced by examinations of models of care outside the US. 15 References 1. Johnsson B, Wilking N. The Burden and Cost of Cancer. Ann Oncol. 2007;18(Supplement 3):8‐22. 2. Jönsson B, Wilking N. Market Uptake of New Oncology Drugs. Ann Oncol. 2007;18(Supplement 3):31‐48. 3. Anderson GF, Frogner BK, Reinhardt UE. Health spending in OECD countries in 2004: an update. Health Aff (Millwood). Sep‐Oct 2007;26(5):1481‐1489. 4. Anderson GF, Reinhardt UE, Hussey PS, Petrosyan V. It's the prices, stupid: why the United States is so different from other countries. Health Aff (Millwood). May‐Jun 2003;22(3):89‐105. 5. Jacobson M, O'Malley AJ, Earle CC, Pakes J, Gaccione P, Newhouse JP. Does reimbursement influence chemotherapy treatment for cancer patients? Health Aff (Millwood). Mar‐Apr 2006;25(2):437‐443. 6. Oaxaca R. Male‐Female Wage Differentials in Urban Labor Markets. International Economic Review. 1973;14(3):693‐709. 7. Brown RE, Hutton J. Cost‐utility model comparing docetaxel and paclitaxel in advanced breast cancer patients. Anticancer Drugs. Nov 1998;9(10):899‐907. 8. Brown RE, Hutton J, Burrell A. Cost effectiveness of treatment options in advanced breast cancer in the UK. Pharmacoeconomics. 2001;19(11):1091‐1102. 9. Lloyd A, Nafees B, Narewska J, Dewilde S, Watkins J. Health state utilities for metastatic breast cancer. Br J Cancer. Sep 18 2006;95(6):683‐690. 16 10. Kurian AW, Thompson RN, Gaw AF, Arai S, Ortiz R, Garber AM. A cost‐effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu‐positive breast cancer. J Clin Oncol. Feb 20 2007;25(6):634‐641. 11. Bir A, Tan W, Wilding GE, Lombardo J, Fakih MG. 5‐fluorouracil, leucovorin and oxaliplatin plus bevacizumab in the first‐line treatment of metastatic colorectal cancer: a single‐institute study. Oncology. 2007;72(1‐2):4‐9. 12. Saltz LB, Clarke S, Diaz‐Rubio E, et al. Bevacizumab in combination with oxaliplatin‐based chemotherapy as first‐line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. Apr 20 2008;26(12):2013‐2019. 13. Giantonio B, Catalano P, Meropol NJ, et al. High‐dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Journal of Clinical Oncology. June 1 2005;23(16S). 14. Hochster HS, Hart LL, Ramanathan RK, Hainsworth JD, Hedrick E, Childs BH. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first‐
line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE‐Study Journal of Clinical Oncology. 2006;24(18S). 15. Avastin (bevacizumab). Packet Insert. Vol 2009. 16. Eloxatin. Packet Insert. Vol Laval2009. 17. Welles L, Hochster H, Ramanathan RK, et al. Preliminary results of a randomized study of the safety and tolerability of three oxaliplatin ‐based regimens as first‐line treatment for 17 advanced colorectal cancer (CRC) ("TREE" study). Journal of Clinical Oncology. July 15 2004;22(14S). 18. Camptosar. Packet Insert. Vol Kalamazoo: Pharmicia & Upjohn Company; 1998. 19. FDA Background for Colon Cancer Endpoints Workshops. In: FDA, ed2003. 20. Xeloda (capecitabine). Packet Insert. Vol Nutley: Roche Laboratories, Inc.; 2006. 21. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non‐small‐cell lung cancer. J Clin Oncol. Jun 1 2004;22(11):2184‐2191. 22. Sandler A, Gray R, Perry MC, et al. Paclitaxel‐carboplatin alone or with bevacizumab for non‐small‐cell lung cancer. N Engl J Med. Dec 14 2006;355(24):2542‐2550. 23. Taxotere. Packet Insert. Vol. 24. Kosmidis P, Mylonakis N, Nicolaides C, et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non‐small‐cell lung cancer: a phase III randomized trial. J Clin Oncol. Sep 1 2002;20(17):3578‐3585. 25. Navelbine Injection. Packet Insert. Vol 2009. 26. Gemzar Packet Insert. Vol: Eli Lily and Company; 2009. 27. Alimta (pemetrexed for injection). Packet Insert. Vol Indianapolis: Eli Lily and Company; 2009. 28. Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non‐small‐cell lung cancer. J Clin Oncol. Jan 2000;18(1):122‐130. 18 29. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2‐positive breast cancer. N Engl J Med. Oct 20 2005;353(16):1673‐1684. 30. Robert NJ, Eiermann W, Pieniazek J, et al. BCIRG 006: Docetaxel and trastuzumab‐based regimens improve DFS and OS over AC‐T in node positive and high risk node negative HER2 positive early breast cancer patients: Quality of life (QOL) at 36 months follow‐up. Journal of Clinical Oncology. 2007;25(18S). 31. Jones S, Holmes F, O'Shaughnessy J, et al. Extended follow‐up and analysis by age of the US Oncology Adjuvant Trial 9735: Docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophosphamide and is well tolerated in women 65 or older. Paper presented at: San Antonio Breast Cancer Symposium2007; San Antonio, TX. 32. Roche H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin‐based and docetaxel chemotherapy for node‐positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. Dec 20 2006;24(36):5664‐5671. 33. Joensuu H, Kellokumpu‐Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. Feb 23 2006;354(8):809‐
820. 34. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. Apr 17 2008;358(16):1663‐1671. 35. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node‐positive breast cancer. N Engl J Med. Jun 2 2005;352(22):2302‐2313. 19 36. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node‐positive breast cancer: results from NSABP B‐28. J Clin Oncol. Jun 1 2005;23(16):3686‐3696. 37. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node‐positive primary breast cancer. J Clin Oncol. Mar 15 2003;21(6):976‐983. 38. Assikis V, Buzdar A, Yang Y, et al. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10‐year follow‐up. Cancer. Jun 1 2003;97(11):2716‐2723. 39. Levine MN, Bramwell VH, Pritchard KI, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node‐positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. Aug 1998;16(8):2651‐2658. 40. Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node‐positive breast cancer. J Clin Oncol. Jun 15 2001;19(12):3103‐
3110. 41. Cameron DA, Massie C, Kerr G, Leonard RC. Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Br J Cancer. Nov 17 2003;89(10):1837‐
1842.
20 Dr. Nicholson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Financial support: This work was supported in part by a grant from Pfizer to Drs. Nicholson and Lucarelli. Role of the Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Financial disclosures: None reported.
21 Table 1. Calculated expected outcomes for alternative chemotherapy regimens for metastatic colorectal cancer and metastatic non small cell Lung Cancer QALY weights Metastatic Colorectal Cancer Expected Months in Each Health State Stable metastatic disease without chemotherapy side effects Tumor responding to treatment without chemotherapy side effects Tumor responding to treatment with chemotherapy side effects 0.68 0.82 0.69 0.55 Tumor not responding to treatment with chemotherapy Tumor side effects progression Expected Survival (months) Expected QALYs 0.42 7,8,9
Source bevacizumab, oxaliplatin, fluorouracil, leucovorin 3.77 2.96 1.31 1.66 12.60 22.3 1.01 11‐14
bevacizumab, oxaliplatin, capecitabine 3.77 2.96 1.31 1.66 12.60 22.3 1.01 14
bevacizumab, irinotecan, fluorouracil, leucovorin 2.96 2.42 2.35 2.87 9.70 20.3 0.94 15
oxaliplatin, fluorouracil, leucovorin 2.32 2.04 2.08 2.36 10.90 19.7 0.88 12, 14, 16
oxaliplatin, capecitabine 2.72 1.57 1.39 2.42 11.30 19.4 0.85 14, 17
irinotecan, fluorouracil, leucovorin 1.72 0.94 1.43 2.61 8.90 15.6 0.68 15, 16, 18
irinotecan, capecitabine 1.72 0.94 1.43 2.61 8.90 15.6 0.68 15, 16, 18
capecitabine 1.36 0.36 0.56 2.12 8.70 13.1 0.54 19, 20
0.53 15, 18‐20
fluorouracil, leucovorin 1.93 0.51 0.47 22 1.79 7.80 12.5 Metastatic Non Small Cell Lung Cancer paclitaxel, carboplatin, bevacizumab docetaxel, cisplatin paclitaxel, carboplatin gemcitabine, paclitaxel vinorelbine, cisplatin gemcitabine, cisplatin vinorelbine 3.92 2.11 0.27 0.50 5.50 12.3 0.60 21, 22
2.64 1.22 0.36 0.78 5.90 10.9 0.50 23
0.46 21, 22
0.43 24
0.42 23, 25
0.41 26
0.37 27
3.52 0.62 1.96 1.06 2.46 0.77 1.62 0.68 4.26 0.69 0.04 0.27 0.46 0.83 0.03 0.22 0.51 1.47 1.97 0.16 5.90 6.00 3.85 3.80 2.05 10.3 9.8 9.0 8.9 7.2 etoposide, cisplatin 1.68 0.25 0.19 1.28 3.80 7.2 0.31 cisplatin 2.30 0.24 0.11 1.04 3.20 6.9 0.31 25, 28
23 25, 28
Table 2. Calculated expected outcomes for alternative adjuvant chemotherapy regimens for non metastatic breast cancer. Expected Years in Each Health State Healthy years Disease recurrence years Expected Survival (years) Expected Survival (discounted years) Expected QALYs (discounted years) Source QALY weights 0.87 0.55 doxorubicin, cyclophosphamide, paclitaxel, trastuzumab 20.0 0.7 20.7 14.2 12.2 29, 30
docetaxel, cyclophosphamide 19.1 0.8 19.9 13.7 11.8 31
docetaxel, carboplatin, trastuzumab 19.3 0.7 20.0 13.8 11.8 30
cyclophosphamide, epirubicin, fluorouracil, docetaxel 18.6 0.8 19.4 13.4 11.6 32, 33
docetaxel, doxorubicin, cyclophosphamide 16.8 0.9 17.7 12.3 10.6 34, 35
doxorubicin, cyclophosphamide, paclitaxel 16.2 1.0 17.2 11.9 10.4 29, 34, 36, 37
24 cyclophosphamide, doxorubicin 15.9 1.0 16.9 11.7 10.2 31, 36, 37
fluorouracil, doxorubicin, cyclophosphamide 14.9 1.1 16.0 11.2 9.7 35, 38
cyclophosphamide, epirubicin, fluorouracil 14.7 1.1 15.8 11.0 9.6 32, 39
cyclophosphamide, methotrexate, fluorouracil 12.9 1.3 14.1 10.0 8.7 39‐41
25 Table 3. Spending, expected life years, and expected quality adjusted life years for chemotherapy patients in different countries and years. Year: Quarter 2002:4 2005:4 2008:2 Colorectal Cancer
Spending per Expected Expected patient on Life Years QALYs chemotherapy Non Small Cell Lung Cancer
Spending per Expected Expected patient on Life Years QALYs chemotherapy Breast Cancer
Spending per Expected patient on QALYs chemotherapy US $18,319 1.27 0.66 $14,801 0.78 0.43 $5,433 10.12 US $46,812 1.59 0.85 $13,424 0.82 0.45 $8,872 10.51 France $13,281 1.43 0.75 $9,068 0.75 0.42 $7,034 10.12 Germany $8,389 1.45 0.77 $11,111 0.73 0.41 $3,939 9.91 Italy $9,343 1.48 0.78 $6,758 0.72 0.41 $2,969 9.47 Spain $13,000 1.48 0.78 $7,397 0.77 0.43 $3,629 10.14 UK $7,541 1.32 0.69 $6,622 0.72 0.41 $3,811 9.62 European Mean $10,311 1.43 0.75 $8,191 0.74 0.41 $4,276 9.85 US $43,598 1.60 0.86 $16,356 0.83 0.47 $14,717 11.01 France $21,527 1.54 0.83 $8,293 0.76 0.42 $8,206 10.32 Germany $12,734 1.54 0.83 $7,165 0.72 0.41 $4,634 10.14 Italy $15,062 1.54 0.83 $6,411 0.74 0.41 $4,289 10.01 Spain $15,284 1.55 0.82 $6,910 0.76 0.42 $4,487 10.15 UK $7,841 1.41 0.74 $7,084 0.73 0.41 $4,802 10.03 European Mean $14,489 1.52 0.81 $7,173 0.74 0.41 $5,284 10.13 All dollar figures are 2008 US Dollars. QALYs = Quality adjusted life years. US = United States. UK = United Kingdom 26 Table 4. Effect on US costs and clinical outcomes of using the European chemotherapy mix and effect on European costs and clinical outcomes of using the US chemotherapy mix. Incremental dollar saved per QALY lost if the US used the European chemotherapy mix Incremental dollar cost per QALY gained if Europe used the US chemotherapy mix Metastatic colorectal cancer $257,423 $184,438 Metastatic NSCLC $72,384 $171,945 Stage I‐III breast cancer $8,271 $9,868 NSCLC = Non small cell lung cancer 27 Figure 1. Market share of cancer chemotherapy regimens in six countries in the second quarter of 2008. Panel A: Colorectal Cancer. Panel B: Non Small Cell Lung Cancer. Panel C: Breast Cancer. 1A 28 1B 29 1C 30 Figure 2. Price and treatment mix components of US‐European chemotherapy costs differences in the second quarter of 2008. Panel A: Colorectal Cancer. Panel B: Non Small Cell Lung Cancer. Panel C: Breast Cancer. 2A 31 2B 32 2C 33 Figure 3. Price and treatment mix components of US‐European chemotherapy costs differences 2005‐2008. Panel A: Colorectal Cancer. Panel B: Non Small Cell Lung Cancer. Panel C: Breast Cancer. 3A 34 3B 35 3C 36