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Chennai Breast Centre, Chennai, India
Adjuvant Chemotherapy
Introduction
Breast cancer is the most common cancer in females in Western countries [1]. The most recent Globocan data shows that it is also the most common cancer in women in Indian women [2]. Though it seems to be one disease, it is quite heterogeneous with different subtypes behaving differently to different therapeutic strategies. There has been substantial improvement in the outcome due to adjuvant therapy in breast cancer management over last few decades.
Adjuvant therapy in breast cancer has been shown to increase disease-free survival (DFS) and overall survival (OS). A recently reported meta-analysis showed that effective adjuvant chemotherapy can reduce the mortality rate by 36 % when compared to no chemotherapy [3]. Over the years, multiple questions have been addressed, i.e., benefit of adjuvant chemotherapy, chemotherapy drug used, optimal number of drug used, duration of therapy, role of dose dense therapy, anthracycline and/or taxane based on other regimens. Conventionally, the recommendation of adjuvant chemotherapy was based on anatomic and pathologic factors such as tumor size, tumor grade, and lymph nodes status. According to current recommendations, adjuvant treatment in breast cancer should be based on predicted sensitivity and benefit to the chemotherapy and risk of disease recurrence [4]. To know about tumor biology, guidelines incorporate determination of breast cancer intrinsic phenotype through meticulously performed immunohistochemistry. In patients with low-risk disease with unclear indications of chemotherapy, first-generation multiparameter genomic tests (such as MammaPrint or Oncotype DX) TM are being increasingly resorted to.
Evolution of Adjuvant Chemotherapy in Breast Cancer
Locoregional therapies were the mainstay of therapy before concept of adjuvant chemotherapy came into practice. It was perceived that breast cancer is local disease and so Halsted en bloc radical mastectomy was the standard of care during the nineteenth century [5]. Gradually, the concept of micrometastatic nature of breast cancer became apparent and also came the realization that adjuvant chemotherapy can prevent recurrences by acting on micrometastasis [6]. Fisher et al. at National Surgical Adjuvant Breast and Bowel Project (NSABP) and Bonadonna et al. in Milan, Italy showed benefit of adjuvant polychemotherapy in terms of recurrence-free survival and overall survival in node-positive premenopausal patients [7, 8]. In the 1970s, it was evident that chemotherapy was effective only in premenopausal node-positive women but in the 1980s after a series of randomized trials it was realized that benefit of chemotherapy also extends to postmenopausal and node negative women also [9]. During all these years there was constant search to delineate a subset of patients with good prognosis in which adjuvant chemotherapy is not justified.
National Institutes of Health Consensus subsequently released guidelines in year 2000 stating that adjuvant chemotherapy should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status but in node-negative patients less than 1 cm therapy its use should be individualized [10]. Fisher et al. in a pooled analysis of NSABP trials showed that even in patients with less than 1 cm of tumor adjuvant chemotherapy was beneficial in terms of prolonging survival [11]. So the subset in which adjuvant chemotherapy was futile could not be identified. Further, most recent EBCTCG meta-analysis supports this notion that proportional risk reduction from adjuvant chemotherapy was not dependent upon age, nodal status, tumor diameter, differentiation, and tamoxifen used though information lacked about gene expression profile and quantitative immunohistochemistry [3].
Apart from short-term side effects of chemotherapy, long-term side effects of adjuvant therapies are being realized and thus “chemotherapy for all” concept is diminishing gradually based on molecular classification to spare patients of long-term side effects [12]. So current paradigm that treatment should be decided by tumor biology not staging will spare those patients of long-term devastating side effects who do not need adjuvant treatment.
Decision-Making Factors for Adjuvant Chemotherapy
Classic factors that used to govern prognosis of disease are tumor size and node status. Tumor size more than 1 cm in lymph node-positive patients as a criteria for chemotherapy is now controversial [13]. Also size as independent prognostic factor in all subtype of breast cancer is also a matter of debate [14]. The pathologic characteristics of the tumor also have prognostic significance. Tumor subtypes such as tubular, mucinous, and medullary have a more favorable prognosis than unspecified breast cancer. In an attempt to improve interobserver variability, multiple grading systems have been proposed, with the most commonly used being the Scarff-Bloom-Richardson (SBR) classification.
Value of estrogen receptor (ER) and progesterone receptor (PR) quantitative measurement is more for predictive marker than prognostic marker. Patients with ER/PR-positive tumors have improved disease-free survival at 5 years than ER/PR-negative similar staged tumors but this difference becomes less apparent at 10 years due to tendency for late relapse. HER-2 can be assessed by quantification by IHC or by measuring the number of HER-2 gene copies by fluorescent in situ hybridization. Her-2 overexpression or amplification confers a poor prognosis and is associated with hormone receptor negativity and increased tumor proliferation. Retrospective studies suggest that Her-2 is also predictive for response to anthracyclines though in current era of trastuzumab it might not be certain [15]. Also it is not certain that benefit of anthracyclines in HER-2 disease is due to TOP2A or Ch17CEP duplication but it is increasingly being realized that it is not due to HER-2 per se [16, 17].
Tumor characteristics like proliferation index and lymphovascular invasion are other prognostic factors but they are often used in conjunction with other factors only. Recent guidelines include Ki-67 in treatment decisions now especially for luminal subtypes but standardization of this test and practical utility remains a concern [4, 18].
Further clinical features like age, tumor stage, ER expression, and histological grade have been incorporated into scoring systems that allow a relatively accurate estimation of probability of recurrence and death from breast cancer include Adjuvant! Online, Nottingham Prognostic index, or PREDICT score.
Gene expression profiling has further identified gene expression patterns in breast tumors with distinct molecular profiles, pathologic features, and clinical outcomes. Four subtypes have been defined through gene expression profiling are Luminal A and B (estrogen receptor positive), HER-2 gene-amplified tumors and basal-like tumors. Genetic profiling is not widely available, standardized, and difficult to do in daily practice so St Gallen consensus guidelines 2013 recommends the use of immunohistochemistry (IHC) for ER, PR and HER-2 receptors as a surrogate to gene expression profiling. Luminal A tumors are classified by positive ER/PR and negative HER-2 and low Ki-67 while luminal B has similar characteristics but high Ki-67 or those with ER/PR positive as well as HER-2 positive. Most luminal A tumors except those with increased risk of relapse (extensive nodal involvement) do not require chemotherapy whereas in HER-2 negative subset of luminal B tumors decisions should be individualized according to tumor grade, proliferative markers, lack of PR receptor. In case of any confusion regarding chemotherapy decision especially in node-negative luminal subset, gene expression assay such as MammaPrint or Oncotype DX may be used where available. They help in determining individual recurrence risk and prediction of benefit of chemotherapy [19]. In most of the HER-2 positive breast cancer and triple negative breast cancers, adjuvant therapy should be given unless specific contraindication exists. For neoadjuvant chemotherapy, response to chemotherapy remains an important prognostic factor as it gives an idea about disease biology and in vivo assessment of disease responsiveness to chemotherapy.
Decision-Making Factors for Adjuvant Chemotherapy: Host Factors
Before giving chemotherapy, patients should be evaluated for their fitness of chemotherapy. Careful assessment should be done for comorbidities like cardiovascular comorbidities, diabetes and its complications including neuropathy, renal, hepatic dysfunction, and elderly population. Diabetic neuropathy might predispose patients for severe paclitaxel-induced neuropathy, so either paclitaxel should be replaced with some other taxane or should be used with caution in this patient population [20]. A baseline cardiac evaluation with a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Since most of the trials in breast cancer are focused on younger patients and elderly patients have higher chemotherapy-related complications and mortality from treatment, they should be assessed carefully and considered for chemotherapy dose reduction, use of prophylactic Granulocyte colony stimulating factor, etc.
Adjuvant Chemotherapy Regimens
Nontaxanes Regimens
As mentioned above, Bonadonna et al. published results of their landmark trial of adjuvant chemotherapy in breast cancer in 1976 showing 12 months of postoperative chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil decreased risk of recurrence of breast cancer in women with positive axillary lymph nodes [7]. There was no benefit in this study in a subset of post-menopausal women. Though many speculate that benefit of chemotherapy in premenopausal women was due to chemical castration but main reason for no benefit in post-menopausal group in this trial was due to reduced dose intensity of chemotherapy and decreased compliance among post-menopausal women in this trial [21]. Other CMF regimens have been evaluated differing from classic version and all CMF regimens might not have same efficacy. All intravenous CMF regimen was inferior to the classic oral-cyclophosphamide CMF regimen in advanced disease [22]. No randomized trial comparing intravenous versus classic CMF have been done in adjuvant setting. NSABP studies further showed that chemotherapy is beneficial in node-negative patients as well [9]. Since 12 month of adjuvant chemotherapy was of long duration and with considerable toxicity, randomized trials were conducted and subsequently it was proved that 6 months of chemotherapy were equally efficacious as 12 months of chemotherapy [23]. When efficacy of shorter duration chemotherapy was shown more and more, anthracyclines-related trials came up as concerns about anthracyclines cardiotoxicity was alleviated.
First anthracycline-containing regimen that became gold standard in adjuvant therapy was used in NSABP-15, which used adriamycin and cyclophosphamide. National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with node-positive breast cancer nonresponsive to tamoxifen. There was no difference in efficacy advantage of AC over CMF but patients in AC arm had advantage of shorter duration of treatment, less number of hospital visits, and lesser need of antiemetic medications [24]. Similarly NSABP B-23 showed no difference between efficacy of four cycles of AC regimen vs six cycles of CMF regimen in node-negative patients. It was further speculated that four cycles of AC are inadequate as adjuvant chemotherapy and six cycles AC should be the optimal regimen [25]. CALGB 40101 study enrolled women with operable breast cancer and zero to three positive nodes and randomly assigned to either four or six cycles of either AC or T. A total of 3,171 patients were enrolled; 94 % were node-negative and 6 % had one to three positive nodes it found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome. This being unique study as most of the studies have compared same number or different number of cycles of different regimens but none has compared different number of cycles of same regimen. Though conclusion of this study that in patients with one to three lymph nodes four cycles of AC might be sufficient, this population was underrepresented in this study.
In last two decades, several studies have then compared anthracyclines-based combination with CMF like combinations as adjuvant chemotherapy for operable breast cancer. Since many of these trials were not specifically designed to question role of anthracycline versus methotrexate so the results are difficult to interpret. Also individual trials differed in the number of drugs used, schedules, and dose intensities. Another problem with most of these trials was small sample size and most of the trials had inadequate sample size to specifically address this question. Largest trial of CAF versus CMF conducted in 2,691 high-risk node-negative patients showed that CAF was marginally superior to CMF OS but not DFS and had higher toxicities [26].
Latest EBCTCG analysis showed that comparison of CMF and anthracycline-containing regimen versus no chemotherapy confirms a significant reduction not only in breast cancer mortality but also in overall mortality. CMF and anthracycline-based regimens resulted in 20–25 % proportional reduction in breast cancer mortality rate, which in the population studied resulted in absolute reduction in breast cancer mortality of 6.2 and 6.5 %, respectively, at 10 years [3]. Also in this meta-analysis, trials with CMF-treated controls showed that standard 4 AC and standard CMF were equivalent (RR 0.98, 2p = 0.67) but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4 AC (e.g., CAF or CEF) were superior to standard CMF (RR 0.78).
Several modifications have been tried with dose intensification of doxorubicin for better efficacy as well as use of epirubicin with the pretext of lesser cardiotoxicity and better efficacy. CALGB 9344 showed that escalating dose of doxorubicin dose in the AC regimen from 60 to 75 mg/m2 or 90 mg/m2 does not improve outcomes.
Regarding epirubicin there is no head-to-head trial comparing the doxorubicin-based regimen to epirubicin-based regimen in adjuvant setting. However, in metastatic setting FAC (doxorubicin = 50 mg/m2) was shown to have equivalent efficacy as compared to FEC50; also tolerance was better in epirubicin arm [27]. So at equimolar doses, the efficacy of epirubicin is equivalent to doxorubicin though epirubicin has lesser hematological toxicities and cardiotoxicities. So in adjuvant setting though epirubicin has not proven to be superior to adriamycin in terms of efficacy or cardiotoxicity, it might have lesser side effects and since higher doses can be given as compared to adriamycin without fear of cardiotoxicity, it might be more efficacious.
Taxanes Regimens
Taxanes were initially used in metastatic breast cancer in the early 1990s and were subsequently introduced in adjuvant therapy [28]. Evidence about 175 mg/m2 dose of paclitaxel comes from the CALGB 9342 trial, 474 women with measurable MBC who had received no more than one prior course of chemotherapy were randomized to receive paclitaxel (175, 210, or 250 mg/m2) via a 3-h infusion every 21 days there were no differences in time to disease progression (TTP) or overall survival (OS) among treatment groups [29]. Toxicity increased with increasing dose of paclitaxel without proportionate increase in efficacy.
Cancer and Leukemia Group B (CALGB) 9344 trial randomized patients with node-positive breast cancer to either four cycles of AC alone, or that treatment followed by four cycles of paclitaxel [30]. The addition of paclitaxel produced superior disease-free and overall survival rates. In the NSABP B-28 trial, 3,060 patients with node-positive operable breast cancer were randomized to receive either AC for four cycles or AC for four cycles followed by paclitaxel (at a dose of 225 mg/m2) every 3 weeks for four cycles [31]. With a median follow-up of 64 months, a significantly higher disease-free survival rate with sequential paclitaxel than with AC alone (76 % versus 72 %; p = 0.008). There was no difference in overall survival between treatment groups (85 % both groups). The adequacy of the control arm in these studies has been the subject of discussion but taxanes became the standard in lymph node-positive patients.
Also it was speculated in indirect comparison of above mentioned studies NSABP-28 higher dose paclitaxel was not superior because due to more neurotoxicity in 225 mg/m2 arm fewer patients completed all four cycles of paclitaxel (76 %) when compared to CALGB study (92 %). Thus 175/m2 paclitaxel remains the standard dose.
Sequential or Concurrent?
Taxanes can be either sequentially with anthracyclines or sequentially after anthracyclines. As paclitaxel cannot be combined with anthracyclines in view of pharmacokinetic interactions and unacceptable high level of cardiotoxicity, most of the publications with adjuvant taxane and anthracycline combination have been done with docetaxel [32]. BCIRG-001 study showed that adjuvant chemotherapy with six cycles of TAC regimen was more effective than six cycles of FAC regimen in axillary node-positive patients [33].
Regarding concurrent versus sequential taxanes BCIRG-005 trial randomized node positive Her-2 nonamplified patients to six cycles of TAC versus four cycles of AC followed by four cycles of taxanes and both the regimens had similar efficacy in terms of disease-free survival but TAC was associated with more febrile neutropenia [32].
If Sequential, Anthracycline First or Taxane First?
Most trials have used anthracycline first and taxane later, so instead of being evidence-based this sequence is more of convention. Randomized trial comparing this sequence do not suggest any harm in giving taxanes first followed by anthracycline and relative drug dose intensity might be higher if we use taxane first with less toxicity in first few cycles [34].
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