Journal of Cancer Research and Therapeutics, Vol. 5, No. 2, April-June, 2009, pp. 116-120
Resource-sparing and cost-effective strategies in current management of breast cancer
Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai
Code Number: cr09029
Breast cancer is the leading cause of death in women throughout the world. There have been significant advances in the practice of breast oncology over the past few years. However, most of these advances have an associated price tag or are resource intensive. The present article discusses means to achieve cost-effectiveness in the treatment of breast cancer, while retaining the benefits of the modern anticancer approaches.
Keywords: Breast cancer, resource sparing, cost effective
Advances in oncology practice related to breast cancer have gathered significant momentum over the last decade. Research centers across the globe are actively involved in basic and translational approaches in developing new molecules or discovering new targets.  Similarly, advances in radiotherapy (RT) techniques and delivery mechanisms are resulting in more precise dose delivery and increased sparing of normal structures. 
Most of the newer advances are expensive and resource intensive,  and while scientific advances need to be encouraged and propagated, pragmatic cost-sparing methods applicable to these innovations need to develop in a parallel fashion wherever possible. Though especially important for developing countries, the economic aspects of these advances are significant even for developed nations. ,,
Unfortunately, for various reasons, cost-effective strategies get less prominence in scientific publications and in oncology conferences. In this article we present a few examples of such measures, which can be applied without losing the therapeutic benefits of the modern approaches in breast cancer patients.
Tamoxifen has saved millions of lives throughout the world ever since its introduction in the 1970s. Its value has been repeatedly proven in randomized trials and meta-analyses.  However, recent trials have shown the clinical superiority of aromatase inhibitors (AI) over tamoxifen in terms of improved disease-free survival and reduction in complications. , Trials such as the Arimidex-Nolvadex study in postmenopausal women (ARNO-95) and the Intergroup Exemestane Study (IES) have even shown a borderline overall survival benefit of AI over tamoxifen. ,
Interesting pharmacogenomic data about the therapeutic risk/benefit ratio for the AI vs tamoxifen has appeared recently. Tamoxifen needs to be converted to its active metabolite endoxifen to exert its therapeutic effect and this step needs the active form of cytochrome P450 CYP2D6 [Figure - 1]. It has been suggested that patients on tamoxifen with an active CYP2D6 pathway can have equivalent or better relapse-free rates than patients on AI.  This makes a case for the use of genetic testing to determine the optimal treatment strategy. ,,[ 13] The CYP2D6 A, B, C, D, E, and T alleles can be assessed at a cost of less than $90 per sample by judicious selection of conditions and procedures.  At present, the cost of a month of therapy with AIs varies between $7.5 to $170 per month as compared to $2.5-41.3 per month with tamoxifen. ,, Thus a one-time test of CYP2D6 has the potential to make the patient eligible for 5 years of savings by allowing the use of tamoxifen instead of the AIs.
Nearly 25-30% of breast cancer patients have overexpression of HER2. Patients with breast cancer and HER2 amplification or overexpression are likely to have associated poor prognostic features such as positive axillary lymph nodes, decreased expression of ER/PR receptors, and poorly differentiated tumors.  Trastuzumab is a monoclonal antibody targeting the extracellular domain of the HER2 protein. In 2001, a phase III randomized trial showed a survival benefit with trastuzumab in metastatic breast disease.  Following this, the National Cancer Institute (NCI) sponsored two trials of adjuvant treatment with trastuzumab, which were led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG).  Another trial, the Adjuvant Trastuzumab (HERA) Trial, was also reported at the same time. All of these trials showed benefit in terms of disease-free and overall survival in breast cancer [Table - 1]. In a Finnish studywomen with tumors that overexpressed HER2/ neu were assigned to receive concomitant treatment with trastuzumab or no such treatment.  One thousand and ten women with axillary node-positive or high-risk node-negative cancers were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better 3-year recurrence-free survival than those who did not receive the antibody (89% vs 78%; hazard ratio for recurrence or death: 0.42; 95% CI: 0.21 to 0.83; P = 0.01).
The hazard ratios in this study were nearly the same as that found with strategies employing trastuzumab for 1 year or more [Table - 1]. In effect, this study showed that a short course of trastuzumab administered concomitantly with docetaxel or vinorelbine was effective in women with breast cancer who have an amplified HER2/neu gene. The proposed rationale for the mechanism was the agonist action of trastuzumab with the anthracyclines that were given earlier, leading to potentiation of anthracycline activity.
Compared to 1-2 years of weekly trastuzumab in the NSABP or HERA trials, this study employed only 9 weeks of trastuzumab- a strategy that can lead to> 80% reduction in the cost of the total trastuzumab regimen. Although the numbers were small, the cost saving with the use of trastuzumab as per the FINHER regimen can be dramatic. A cost-sparing strategy such as this needs serious consideration in clinical practice.
Lapatinib is an orally active, small-molecule, dual-kinase inhibitor that targets both ErbB1 and ErbB2 receptors. It works inside the cell and directly targets the tyrosine kinase (TK) domain. A landmark trial has established the efficacy of lapatinib plus capecitabine as compared to capecitabine alone in women with HER2-positive advanced breast cancer that progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.  In this trial, lapatinib was used in a dose of 1250 mg per day administered on an empty stomach.
However, it is well established that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal. There is a two-fold mean increase inr the area under the concentration-time curve for lapatinib for high-fat meals. , Further, it has been suggested that strong CYP3A inhibitors, including grapefruit juice, may also increase plasma concentrations of lapatinib.  It follows that just 250 mg of lapatinib, taken together with food, 1-2 teaspoons of butter, and grapefruit juice, would yield plasma concentrations comparable to that obtained with 1250mg taken on an empty stomach; this would result in total cost savings of 80%.  Considering the current cost of lapatinib, this can translate into monumental savings across the globe.
This dose schedule would have another beneficial effect. A common side effect of lapatinib is diarrhea, which has been suggested to be due to unabsorbed drug. It follows that a lower dose, taken along with food, would significantly reduce the amount of unabsorbed drug in the gut and lead to reduced severity of diarrhea as well. 
Chemotherapy vs Ovarian Ablation as Adjuvant Treatment
Cytotoxic chemotherapy has a well-defined place in the management of breast cancer. Six cycles of anthracycline-based chemotherapy are considered a standard in adjuvant treatment of breast cancer. However, there is data to suggest that not all patients will benefit from anthracyclines. In a recent study, patients who were Her2 negative did not gain any added benefit from addition of anthracylines as compared to regimens employing the classical chemotherapy of CMF (cyclophosphamide, methotrexate, and 5-flourouracil).  Furthermore, randomized studies over the past decade have demonstrated equivalence between CMF regimens and ovarian ablation/suppression in receptor-positive premenopausal patients. The best known among these are the Zoladex trial and the Scottish and the International Breast Cancer Study Group trial. ,, All these trials reported that the control rates and survival with ovarian ablation/ovarian suppression were similar to that with chemotherapy, which in most of the trials was a combination of cyclophosphamide, methotrexate, and 5-flourouracil.
In a recent randomized study that included patients with large tumor sizes and nodal positivity, nine cycles of CMF were equivalent to RT-induced ovarian ablation.  The study included 762 women who were premenopausal, were hormonal receptor positive, and were at high risk of relapse (defined as metastasis to at least one lymph node or tumor > 5 cm). The patients were randomized to receive either ovarian ablation by RT or chemotherapy with nine cycles of intravenous CMF. A total of 358 first events were observed: 182 in the ovarian ablation group and 176 in the CMF group. The unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI: 0.81 to 1.22; P = 0.95 by the log rank test). Median disease-free survival time was 130 months in the ovarian ablation group compared with 122 months in the CMF group. After a median follow-up of 10.5 years, the overall survival was similar in the two groups, with a hazard ratio of 1.11 (95% CI: 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. No significant correlation was demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.
Taking these findings together, it appears that the simple technique of ovarian ablation by RT (which can be given when the patient reports for locoregional RT to the breast/chest wall) or surgical ovarian ablation is at least equivalent to CMF. This strategy may be considered in a low-risk, young, premenopausal woman, whose compliance for chemotherapy is doubtful, and who has a strongly hormone-sensitive tumor. The readily apparent gains from this approach are that repeated visits for chemotherapy can be avoided, as also the toxicity of chemotherapy; there is also considerable savings in cost for the patient or the medicare.
Hypofractionated Schedules in Radiotherapy
Conventionally, a dose per fraction per day of 1.8-2 Gy has been used in the treatment of breast cancer. This has been practiced because of the concern that fraction sizes of greater than 2 Gy could possibly increase the likelihood of the late effects on normal tissue toxicity and impair cosmesis in cases undergoing breast-conserving surgery.  Most of the series of breast RT using 1.8-2.0 Gy per fraction have reported good to excellent cosmetic outcome in 60-90% of patients. 
Recent work on techniques which reduces the treatment time to half (3 weeks instead of the present 6 weeks) is therefore of considerable interest. ,,, This technique, also known as hypofractionation, involves giving large doses per fraction (2.5-2.8 Gy per fraction), thereby reducing the total duration of RT from 6 weeks to 3-4 weeks. The early results have reported equivalent cosmetic and control rates with hypofractionated regimens as compared to conventional fractionation. ,, However, it critical to realize that the late effects produced by RT are strongly related to dose per fraction. Therefore, higher dose per fraction increases the susceptibility of normal tissues to RT. It is for this reason that the data on late lung and cardiac morbidity and survival rates is very important when hypofractionated regimens are employed in breast cancer. The Oxford meta-analysis has reported that RT reduced the annual mortality from breast cancer by 13% but increased the annual mortality rate from other causes by 21%. Also, this increase was due primarily to an excess number of deaths from cardiovascular causes.  By radiobiological rationale, hypofractionation has the potential for worsening cardiovascular side effects. Furthermore, the cardiac side effects take up to 15 years to manifest completely after treatment and persist well beyond this period.  The final benchmark of success of the hypofractionation approach is overall survival, and this has not yet been reported for patients treated with hypofractionated regimens.
This strategy will however be watched with keen interest since it has the potential to drastically reduce treatment times and has important financial implications.
Concomitant Radiotherapy Boost During Breast Radiotherapy
Another approach which is of interest as a resource-sparing strategy is that of giving a boost concurrently during the course of whole-breast RT itself instead of giving it sequentially after whole-breast RT. Besides providing equivalent local control and a decrease in overall treatment time, this strategy can also decrease the cost implications to the patients and the health providers. A study was done at our center to shorten the relatively long duration of treatment by delivering a concomitant boost (CB) to the tumor bed on Saturdays.  Thirty patients with locally advanced breast cancers suitable for breast conservation following neoadjuvant chemotherapy (CAF/CEF) were accrued in the study. Conventional RT (CRT) to the whole breast was delivered 5 days a week to a dose of 50 Gy, using 6-10 MV photons. In addition, an electron boost to the tumor bed was delivered every Saturday (12.5 Gy/5#, weekly fraction on Saturday). With this, the entire RT treatment was completed in 5 weeks instead of the usual 6 weeks. All patients completed RT within the stipulated time with no grade IV skin toxicity in either group. At conclusion of RT, confluent moist desquamation (grade III) developed within the tumor bed region in one patient (3.3%) and outside the tumor bed region in three patients (10%) in the CB group. In the CRT group, three and four patients (9.4% and 12%), respectively, developed moist desquamation within and outside the tumor bed region. CB did not significantly affect the global cosmesis as compared with the CRT group at the end of 3 years ( P = 0.23).
In yet another study, 52 patients with early-stage node- negative breast cancer were enrolled. The RT dose to the whole breast was 40.5 Gy in 2.7 Gy/fraction with a CB of 4.5 Gy in 0.3 Gy/fraction. No acute Clinical toxicity criteria(CTC) grade III or IV and no late soft tissue toxicity were noted. The cosmetic results observed were good to excellent.  These studies demonstrate that giving a CB during whole-breast RT is a viable resource-sparing option and does not lead to any detriment in cosmetic outcome.
Single Fraction in Palliative Bone RT
It has been overwhelmingly demonstrated in several randomized trials that a single fraction of RT is equivalent to fractionated RT for palliation of bone metastasis. Single fraction of RT is a convenient and cost-effective strategy for patients with bone metastasis and should be adopted as the standard of care throughout the world. This can be given on Saturdays in busy oncology centers, while the radical RT cases are treated through the 5 days of the week. With this approach, the treatment of bone metastasis is convenient to patients and machine time can be saved as well. The most recent of the randomized studies is from the Radiation Therapy Oncology Group (RTOG), and this has once again demonstrated that single-dose RT is effective for metastatic bone pain. The overall response rate is this trial was 66%. The complete and partial response rates were 15% and 50%, respectively, in the 8-Gy arm compared with 18% and 48% in the 30-Gy arm. 
Palliative hemibody irradiation in extensive bone metastasis has demonstrated its safety and efficacy. This technique, in which an entire half of the body (upper/lower) is treated with RT, is particularly useful in patients with pain and extensive bone metastasis and should be considered standard treatment in such circumstances. 
In summary, scientific innovations in breast cancer care improve the understanding and management of this disease. However, these advanced techniques need to be pragmatically incorporated into the existing treatment protocols. Economic factors are a major issue with newer oncology techniques and medications. Intelligent use of pharmacological data and knowledge of the biology of the disease can help us exploit new techniques for maximum therapeutic gain with minimal investment of resources; the time saved by the patient and the physician is a bonus.
Copyright 2009 - Journal of Cancer Research and Therapeutics
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