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Prospective Exploratory Analysis of the Association Between Tumor Response, Quality of Life, and Expenditures Among Patients Receiving Paclitaxel Monotherapy for Refractory Metastatic Breast Cancer

From the Breast Cancer Medicine Service, Departments of Biostatistics and Epidemiology, Finance, and Radiology, and Hospital Administration, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Andrew Seidman, MD, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: seidmana{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To prospectively evaluate the association between tumor response, change in quality of life (QoL), and hospital expenditures in patients with metastatic breast cancer (MBC) receiving single-agent paclitaxel.

PATIENTS AND METHODS: Eligible patients had bidimensionally measurable MBC and any number of previous therapies, excluding taxane chemotherapy. Paclitaxel was administered by various different infusion schedules. QoL measures were evaluated for each patient at baseline and serially using the Memorial Symptom Assessment Scale (MSAS)-Global Distress Index (GDI) and Functional Assessment of Cancer Therapy–Breast (FACT-B) instruments. Patients were assessed for early (first 6 weeks) and ever changes in QoL parameters. Charges were monitored through the hospital’s centralized computer billing system and converted to cost ratios for the analysis. Correlations between response and improvement in QoL were assessed by Fisher’s exact test statistic. Associations between improvements in QoL with cost ratios were assessed by logistic regression and likewise between response and cost ratios.

RESULTS: Of the 59 patients treated, 50 had sufficient data for comparative analyses. The overall response rate was 24% (all partial responses). Minor responses were observed in 17% of patients, 25% had stable disease, and 29% had progression. Responding patients had significant improvement in QoL as assessed by MSAS-GDI (P = .004) and FACT-B (P = .028). The mean total cost/month ratios for patients experiencing improved GDI QoL scores was 1.31 versus 1.56 for those without QoL benefit (P = .52) and 1.05 versus 1.76 for responders versus nonresponders, respectively (P = .07).

CONCLUSION: Patients with evidence of tumor response on paclitaxel had a QoL benefit not observed in nonresponders, and this response was associated with a trend for lower overall costs.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
WITH CURRENTLY available chemotherapy, approximately 50% to 70% of patients with metastatic breast cancer (MBC) have responses to first line regimens.¹ Despite this, improvements in survival have been modest, and the major impact of these treatments is palliative in nature. Unfortunately, little is known about the balance between the palliative benefits that might be derived via a reduction in tumor volume and the toxic effects of the treatments themselves. Furthermore, the utility of these therapeutic regimens when the costs of care are considered remains an area that requires examination as this information is important not only for medical professionals and their patients, but also for health administrators and economists in health care planning and policy making.

Increasingly, studies evaluating the outcome of treatments and interventions are including some measurement of quality of life (QoL). This usually takes the form of an assessment of symptoms and physical functioning, measurement of psychologic well-being, life satisfaction, or coping and adjustment. Numerous scales of psychologic health, physical health status, and physical functioning have been developed for use in the assessment of health outcomes, and a wide range of general, cancer-specific, and cancer diagnosis-specific instruments for measurement of health-related QoL are available.

In a previously conducted pilot trial, we demonstrated the palliative potential of paclitaxel in responding patients receiving the agent as salvage therapy for MBC.² The improved symptoms and other QoL parameters, as measured by the validated Functional Living Index-Cancer, Memorial Symptom Assessment Scale (MSAS)-Global Distress Index (GDI), and the Rand General Well-Being Instruments, in patients with partial tumor response suggested an acceptable balance between the antitumor effect and drug-related morbidity. Consistent with this was the near uniform and rapid deterioration in QoL noted for the patients with progressive disease (PD). In a retrospective analysis, Geels et al³ have found a similar association between improvements in several disease-related symptoms and objective tumor regression in patients with MBC treated with doxorubicin with or without vinorelbine as part of the National Cancer Institute of Canada-Cancer Treatment Group MA-8 trial. However, in comparison with this important study where specific symptoms were monitored, there has been limited prospective examination to assess the interaction of response with more global QoL measures where symptoms of the disease and the side effects of therapy are both monitored. In addition, there has been even less association between traditional clinical outcome measures and health care expenditures. Given the wide range of agents with activity in breast cancer, there is a compelling rationale to examine the cost-effectiveness of treatments to assist in decisions regarding optimal choice of medical intervention. Whereas the current emphasis is on conducting economic evaluations in the setting of randomized phase III trials, the collection of complete data on all costs associated with treatment, short-term toxic effects, long-term toxic effects, and treatment of recurrent disease, as well as tracking the complex clinical course of patients over many years of follow-up, is an enormous undertaking.⁴ Alternatively, evaluating these end points in the setting of phase II trials may allow meaningful preliminary assessments during the clinical development of specific agents of interest. To date, there are only a few published trials that have incorporated cost analyses alongside phase II studies, nevertheless revealing these to be practical methods of economic assessment.^2,5 In the current communication, we have conducted the first prospective analysis evaluating and correlating the clinical end points of QoL and tumor response with health care expenditures in patients receiving single-agent paclitaxel therapy for MBC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
This companion study prospectively captured data on QoL, tumor response, and hospital/institution-related charges as end points in women with taxane-naïve MBC entering on therapy with single-agent paclitaxel given either on other phase II trials or off protocol. Accrual occurred at Memorial Sloan-Kettering Cancer Center (MSKCC) over a 3-year period from 1994 to 1997. Patients with histologically confirmed breast cancer by the Department of Pathology at MSKCC were eligible for this trial if they had clinical evidence of bidimensionally measurable metastatic disease. Patients may have received any number of previous chemotherapy, hormonal therapy, immunotherapy, and or radiotherapy regimens for stage IV disease and/or as adjuvant therapy; however, they were required to have recovered from the acute toxic effects of any previous therapies before the start of this study. Simultaneous treatment with other hormonal therapy, chemotherapy, immunotherapy, or radiotherapy was not permissible. Minimum age for entry onto the study was 18 years, and all patients had to have a Karnofsky performance status of 50% or more and an anticipated survival of 12 weeks or longer.

Patients were deemed ineligible for participation if they had severe medical illnesses (including severe infection or malnutrition), major psychiatric disorders, or encephalopathy sufficient to compromise QoL data collection.

Paclitaxel was intravenously administered with one of several dose and infusion schedules. Patients received 3, 24, or 96-hour infusions at doses ranging from 135 to 250 mg/m² given at 3-week intervals. Randomized studies have demonstrated similar survival rates with all of these infusion schedules and dose levels.^6-8 A small number of patients, accrued later in the time course of the study, were treated with 1-hour weekly infusions of paclitaxel at doses of 80 to 90 mg/m².⁹ The heterogeneity of paclitaxel schedules reflects the developmental research in the pharmacokinetics and optimization of paclitaxel delivery that was occurring during the conduct of the trial. All patients were eligible to receive recombinant human granulocyte colony-stimulating factor (Neupogen; Amgen, Inc, Thousand Oaks, CA) at the discretion of the treating physician for treatment-related neutropenia. All patients received premedication with dexamethasone, cimetidine, and diphenhydramine hydrochloride to minimize the risk of hypersensitivity reactions. The institutional review board of MSKCC approved the study, and all patients provided written informed consent before participation.

QoL Measures
To evaluate QoL measures, the patients completed the MSAS-GDI and the Functional Assessment of Cancer Therapy–Breast (FACT-B). Both are validated questionnaires.

The MSAS-GDI is a 32-item patient-rated survey that was developed at MSKCC.¹⁰ Its validity and reliability have been confirmed in patients with solid tumors including advanced breast cancer. The first 26 symptoms are rated in terms of three dimensions (frequency, intensity, and distress) and the other six symptoms in terms of two dimensions (intensity and distress). Each symptom characteristic is scored to reflect frequency (1 = rarely, 2 = occasionally, 3 = frequently, and 4 = almost constantly), intensity (1 = slight, 2 = moderate, 3 = severe, and 4 = very severe), and distress (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much). The GDI is a 10-item subscale reflecting global symptom distress and is calculated as the average of the scores for 10 symptoms: the frequency scores for feeling sad, worrying, feeling irritable, and feeling nervous, and the distress scores for lack of appetite, lack of energy, pain, feeling drowsy, constipation, and dry mouth. The GDI score was used for the comparative analyses with tumor response and charges.

The FACT-B¹¹ survey consists of 28 items that assess physical, functional, social, and emotional well-being, as well as overall QoL, specifically in breast cancer patients. The FACT-B total score was used.

Both instruments were administered to each patient within the 7 days before the administration of the first dose of paclitaxel (and before dexamethasone administration) for baseline determination and then were completed after every two cycles (or every 6 weeks) before receiving the paclitaxel infusion and off study when feasible.

Tumor Response
This study was performed before the publication of the Response Evaluation Criteria for Solid Tumors, and thus, objective tumor response was analyzed by the use of standard World Health Organization parameters in use at the time.¹² Complete response (CR) was defined as the disappearance of all physical and biochemical evidence of disease. Partial response (PR) required a 50% or greater reduction in bidimensionally measurable tumor size without the appearance of new lesions. Stable disease (SD) was defined by a less than 25% decrease in tumor burden and a less than 25% increase in any tumor lesion. Minimal response (MR) was classified as a decrease in bidimensional disease by more than 25% but less than 50% (that is intermediate between a PR and SD). PD was described as a 25% or more increase in tumor size or the appearance of new lesions. Tumor response evaluations were performed every two courses of therapy (or every 6 weeks), and the minimum duration for best response reported was 4 weeks.

Health Care Costs
All resource data was prospectively gathered, and for this report, charges were captured and subsequently converted for presentation into cost ratios to comply with institutional administration policies on the publication of cost data. The expenditures were analyzed from the institutional perspective, and thus, all professional and hospital-related expenditures associated with the delivery of the treatment, management of its attendant complications, and standard follow-up were monitored through MSKCC’s centralized computer billing system. This included physicians’ fees, radiologists’ fees, laboratory, radiology imaging, physical therapy and rehabilitation, operating room, urgent care, pharmacy, blood bank, outpatient care, and hospitalization (room and board) costs. This information was continuously accrued for each patient from the time of initiation of pretreatment testing until completion of treatment with paclitaxel. The patients had 24-hour daily access to hospital and physician resources related to their ongoing cancer care; however, any out-of-facility costs or non–cancer-related treatment costs incurred by the patient were not captured in the study database.

Hospital charges for each patient were collected by service date and department. The corresponding cost was calculated by multiplying the charges by the annual ratio of cost to charges (RCC) for each department. RCCs were derived from the institutional cost report. They are specific for each institution and department and vary from year to year. For study dates spanning 2 years, the RCC for the later year was used. The cost data were then adjusted for inflation to 1999 dollars using the consumer price index (CPI) for medical care of the New York City metropolitan region. An inflationary factor was calculated for each year by dividing the CPI for 1999 by the CPI for each year from 1994 to 1999. The cost was multiplied by the inflationary factor, based on the year of the service date, to yield cost adjusted to 1999. The adjusted costs were then accumulated at the departmental level for each patient and summed to yield a total adjusted cost per patient.

For physician costs, the Medicare reimbursable amount was used as a proxy. Physician billing data (charges and quantity) were collected for each patient by service date and current procedural terminology (CPT) code. Physician cost was calculated by multiplying the quantity by the Medicare reimbursable amount for the CPT code found in the 1999 medicare fee schedule for New York. If a CPT code was divided into professional and technical components, only the fee for the professional component was used.

To account for differences in clinical course and treatment duration, the total costs per month were calculated for each patient. These were derived by dividing the total adjusted costs for each patient by the number of months in the study, as defined by days from the start date to off date, divided by 30.

The costs were then converted to adjusted cost ratios by dividing the adjusted costs per month by the median adjusted cost/month. This creates relative value units around the median. For example, if a patient has an adjusted cost ratio of 2.5, then her adjusted cost was 2.5 times higher than the median adjusted cost.

Statistical Analysis
Patients were rendered inassessable if they died from a non–cancer- or non–treatment-related event within 4 weeks of beginning therapy or if there was a major protocol violation by the administration of other simultaneous therapy. They were inassessable for QoL assessments if there was a lack of compliance with more than 20% of requested QoL data items. Participants were removed from study if there was evidence of either progression of disease or withdrawal because of treatment-related toxicity.

The GDI subscale of the MSAS is the average of the scores for 10 symptoms, as previously detailed. Threshold criteria for changes in GDI QoL scores were intentionally set at a modest 10% in magnitude from the baseline score. Specifically, responses were characterized as improved if there was a 10% improvement from baseline score to follow-up and as deteriorated if there was a 10% decrease in scores. Differences of less than 10% were considered unchanged.² The total score was used for the FACT-B. An improvement in QoL by FACT-B was defined as an increase in the FACT-B total score of 0.5 SDs. For these data, this translated into a 9.6 total point increase from baseline. Two binary variables were created for each of the QoL assessments (MSAS-GDI and FACT-B): early improvement was defined as an improvement at the first completed questionnaire from baseline (at 6 weeks), and ever improvement was defined as an improvement at any subsequent completed questionnaire from baseline. Associations between response and early/ever improvements in QoL were assessed by Fisher’s exact test. Associations between early/ever improvements in QoL with cost ratios were assessed by logistic regression and likewise between response and cost ratios.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Of the 62 enrolled participants, three were ineligible. One patient had cardiac arrest before receiving any therapy, and two patients had severe allergic reactions to paclitaxel, despite premedications, and withdrew from the study. Demographic data for the remaining 59 patients are listed in Table 1. The median age of patients on the study was 53 years (range, 26 to 83 years), and the patients had a median Karnofsky performance status score of 80 (range, 60 to 100). The median number of previous chemotherapy regimens was two (range, one to six). The baseline median MSAS-GDI score was 1.24 (range, 0.3 to 3.13), with lower scores corresponding to a higher QoL, and the median FACT-B score was 80 (range, 33 to 112), with higher scores corresponding with a better QoL.

There was baseline MSAS-GDI QoL data on all 59 patients; however, eight patients had insufficient data for longitudinal QoL evaluation, which required at least baseline and one set of follow-up scores. The reasons are as follows: four patients declined questionnaires because of distress (specifically for change in mental status, two refusals to complete forms, and misplaced questionnaires), one patient died, one patient changed health care providers, and two patients developed severe secondary medical conditions (acute leukemia and cardiac disease). One patient who did have serial QoL data was however inassessable for tumor response (as noted above), leaving a total of 50 of 59 patients with complete data for tumor response, expenditures, and serial GDI-QoL analysis. Twelve of these 50 patients received paclitaxel on phase II protocols, and 38 were treated off protocol. For the FACT-B analysis, there was a baseline score for 58 patients because one patient did not complete the form as instructed, and for the same reasons cited above, there was complete longitudinal data for only 49 of 59 patients. Approximately 60% of the patients completed three or fewer serial FACT-B and MSAS questionnaires, and approximately 75% completed four or fewer.

Data from the QoL questionnaires were correlated with tumor responses and are listed in Table 2. Only data from the early QoL analysis are shown because the data for ever QoL changes were similar. Of the responders (patients with either PR or MR), 17 (74%) of 23 had early GDI improvement, whereas fewer nonresponders (patients with either SD or PD) had an appreciable GDI improvement, with only eight (30%) of 27 reporting an increase in QoL after 6 weeks. By the Fisher’s exact test statistic, the relationship between early improvement in QoL and objective tumor shrinkage was statistically significant, with P = .004, and this correlation persisted for ever improvement in QoL and tumor regression as well (P = .01, data not shown).

The comparison of tumor response with hospital cost/month ratios is summarized in Table 3. There was a tendency for decreasing costs with increasing tumor response to paclitaxel. The highest mean cost/month ratios were attributable to the patients with PD at 2.01, gradually decreasing to a mean cost/month ratio of 1.04 for patients with PR (P = .07). Overall, the trend suggested lower costs incurred by the responders versus those with no objective tumor response, despite a longer duration of time on the study. A departmental breakdown of the costs based on tumor response is presented in Fig 1, and the total costs per each category, presented as a cost unit derived by multiplying the total adjusted costs by a constant, are presented in Fig 2.

View larger version (49K): [in this window] [in a new window]   Fig 1. Allocation of costs based on tumor response.

View larger version (23K): [in this window] [in a new window]   Fig 2. Adjusted cost per patient per month based on tumor response. *Adjusted cost unit (vertical axis) was derived by multiplying adjusted cost by a constant.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In our study, we were able to demonstrate a statistically significant correlation between tumor regression and improvement in QoL measures. Of those patients who had an early improvement in QoL scores after two cycles of paclitaxel, the majority (17 of 25, 68% by GDI; 11 of 15, 73% by FACT-B) had demonstrated an objective tumor response (PR or MR), suggesting that indeed effective but potentially toxic palliative therapy can provide more than just a radiographic benefit for patients with incurable disease. Although this was a statistically significant observation, there were a small number of patients who derived symptomatic improvement without a greater than 25% reduction in the sum of the product of the bi-perpendicular diameters of measurable lesions (eight of 27, 28% by GDI; four of 26, 15% by FACT-B), indicating the possibility of an additional palliative effect of chemotherapy independent of tumor response as classically assessed. Thus, tumor response by itself could not be reliably used as a surrogate marker for the palliative benefit of paclitaxel in this setting.

Other investigators have found similar results.^17-21 Poon et al¹⁸ conducted a large randomized trial in metastatic colorectal patients on different 5-fluorouracil chemotherapy regimens and reported a correlation between symptom improvement and objective response rate. In the arm with a 10% response rate, 34% of patients had symptom improvement versus the arm with 43% response rate where 69% of patients had symptom improvement.¹⁸ In a slightly different way, Tannock et al¹⁹ evaluated men with metastatic prostate cancer and compared symptom improvement with an objective decrease in prostate-specific antigen values. They demonstrated that 58% (20 of 58) of men had symptom amelioration versus 12% (seven of 58) if there was a decrease in the prostate-specific antigen of 25% or more from baseline.¹⁹

There have also been studies of this nature in patients with MBC. Geels et al³ reviewed the QoL data collected from 300 patients with advanced breast cancer enrolled onto a randomized trial of doxorubicin versus doxorubicin plus vinorelbine. They extracted the nine most common symptoms and assessed their change from baseline over the course of the study using a validated QoL questionnaire and case report form. The three symptoms of cancer pain, shortness of breath, and abnormal mood showed a significant relationship between improvement and objective tumor response by both measures. In addition, constipation, anorexia, and nausea also showed a significant inverse correlation with tumor response using the QoL questionnaire alone. Their study found that symptom improvement was greatest in patients who had a CR or PR, followed by SD, and those with PD. In another study, Kramer et al²⁰ tested several clinical factors and baseline QoL parameters for their ability to predict a response to chemotherapy and survival in women with advanced breast cancer. In this trial of paclitaxel versus doxorubicin as a first-line chemotherapy for 187 women with MBC, univariate and multivariate analyses determined that a disease-free interval 2 years, multiple sites of visceral disease, and baseline pain were predictors of poor survival; also disease-free interval 2 years, multiple sites of visceral disease, and dyspnea were predictive of poor response to chemotherapy. Their findings suggest that QoL variables may be important predictors of both response to chemotherapy and survival.

To our knowledge, our study is the first to capture prospective and concurrent data on treatment costs in association with QoL and tumor response variables. We attempted to find a correlation between the cost of administering paclitaxel chemotherapy with its effectiveness as a treatment for MBC. By prospectively monitoring all hospital-related charges during therapy, we were able to demonstrate that patients with measurable tumor regression had lower mean cost/month ratios versus those who did not. As expected, the greatest proportion of the total expenditures in responders was attributable to pharmacy charges, whereas for nonresponders, the major proportion of total charges was consumed by pharmacy, clinic visits, and hospitalizations. Overall, nonresponders had higher costs per patient for each cost category analyzed as compared with responders. In addition, an exploratory subset comparison revealed that of the patients who did not have an improvement in QoL, the responders had lower mean cost/month ratios compared with the nonresponders (Table 5). We also observed that patients experiencing improved QoL scores had lower overall cost/month ratios, although the difference was not statistically significant. Overall, patients with measurable tumor regression incurred a lower mean cost/month ratio than their counterparts, and patients with improved QoL demonstrated a similar trend.

To date, the only other published economic evaluations of paclitaxel for MBC have focused on determining cost-utility ratios for incremental quality-adjusted life years gained with paclitaxel versus other accepted metastatic chemotherapy regimens, including docetaxel and vinorelbine.^22-26 These studies have produced conflicting conclusions that may be attributable to the methodologic difficulties encountered in conducting these types of evaluations. Underlying this was the lack of a direct clinical comparison between paclitaxel, docetaxel, and vinorelbine that resulted in wide variations in the estimates of drug efficacy between the different studies and may have resulted in the disparate conclusions.

Unfortunately, one of the difficulties encountered with conducting serial QoL analyses in a medically ill population is the potential lack of patient compliance with the completion of questionnaires. In our study, the QoL assessments were administered 6 weeks apart, and because 60% of patients completed three or fewer FACT-B and MSAS forms, the changes in QoL over time reflect at most 3 months of follow-up for 60% of the data. As a result, the significance of the longitudinal analysis may be weaker than that of the early QoL data. In an attempt to minimize this bias, only early QoL data were shown, although the results of the ever (after 6 weeks) changes were statistically concordant with the early data results. Moreover, Coates et al¹⁷ have previously demonstrated that early changes in QoL scores are predictive of subsequent outcomes.

Although our study is limited in the strength of its conclusions by a small sample size and a failure to capture out-of-institution charges, it does generate hypotheses about the possible mechanism of benefit of palliative paclitaxel and the economic feasibility of its use for QoL enhancement. Additionally, it confirms the feasibility of conducting these types of evaluations in a phase II-type setting, as the resources expended by our institution in collecting these data were modest, although we were supported in part by a sponsor-funded study assistant in these efforts. Furthermore, this research reinforces the value of conducting QoL evaluations in conjunction with traditional measures of efficacy to determine the utility of any palliative therapy. As cost containment is becoming an ever-increasing concern in the health care sector, this type of analysis might aid decision-makers who must weigh the information in the context of other competing health care needs. Certainly, in the setting of incurable metastatic cancer where the goal is to prolong and maintain QoL, analyses of tumor response, QoL, and the associated cost of achieving these end points are highly relevant.

	ACKNOWLEDGMENTS

 
Supported in part by research grant no. CA139-056 from Bristol-Myers Squibb, Wallingford, CT.

	REFERENCES

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Submitted August 7, 2001; accepted May 29, 2002.

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