Send Orders for Reprin ts to [email protected] 3 Pharmaceutical Nanotechnology, 2019, 7, 3-23 REVIEW ARTICLE
ISSN: 2211-7385 eISSN: 2211-7393
Drug Combinations in Breast Cancer Therapy
BENTHAM SCIENCE
Funmilola A. Fisusia,b and Emmanuel O. Akalaa,*
aCenter for Drug Research and Development, Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC, USA; bDrug Research and Production Unit, Fac- ulty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
Abstract: Breast cancer therapy involves a multidisciplinary approach comprising surgery, radiotherapy, neoadjuvant and adjuvant therapy. Effective therapy of breast cancer requires maximum therapeutic efficacy, with minimal undesirable ef-
A R T I C L E H I S T O R Y fects to ensure a good quality of life for patients. The carefully selected combina- tion of therapeutic interventions provides patients with the opportunity to derive Received: July 10, 2018 maximum benefit from therapy while minimizing or eliminating recurrence, re- Revised: December 27, 2018 Accepted: January 15, 2019 sistance and toxic effects, as well as ensuring that patients have a good quality of
DOI: life. This review discusses therapeutic options for breast cancer treatments and 10.2174/2211738507666190122111224 various combinations that had been previously exploited. The review will also give an insight into the potential application of the nanotechnology platform for co- delivery of therapeutics in breast cancer therapy. Keywords: Breast cancer, chemotherapy, combination therapy, early breast cancer, metastatic breast can- cer, nanotechnology, radiotherapy, surgery.
1. INTRODUCTION Breast cancer (BC) is the most commonly oc- curring cancer in women and represents the lead- ing cause of death associated with cancer among females globally [1, 2]. Like most cancers, BC is a heterogeneous disease with different molecular subtypes. The major subclasses identified by ge- netic profiling are: Basal-like, Luminal-A, Lu- minal-B, human epidermal growth factor 2 (HER2)- positive/HER2-enriched/HER2-overexpressing BC and normal-like tumors [3-7] (Fig. 1). However, there would be subpopulations of tumors within Fig. (1). Classification of breast cancer according to the main subtypes expressing molecular features molecular subclasses. of another subtype. This molecular classification Key: BL = Basal-like; LA = Luminal-A; LB = Lu- of BC closely resembles the clinical classifications minal-B; HER2+ = Human epidermal growth factor 2 of BC which are based on proliferation markers, (HER2)-positive/HER2-enriched/HER2-overexpressing BC; NL = Normal-like tumors. *Address correspondence to this author at the Center for histological grade, estrogen and progesterone re- Drug Research and Development, Department of Pharma- ceptors expression (ER and PgR respectively), as ceutical Sciences, College of Pharmacy, Howard University, well as the overexpression of HER2 [8]. The Lu- Washington, DC, USA; Tel: 2002-806-5896; E-mail: [email protected] minal (A and B) subtypes are typically hormone
2211-7393/19 $58.00+.00 © 2019 Bentham Science Publishers Pharmaceutical Nanotechnology 4 Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 Fisusi and Akala receptor positive and form the majority (90-95%) tion of the nanotechnology platform for co- of hormone receptor (HR) positive (ER or PgR delivery of therapeutics in breast cancer therapy. receptor positive), HER2-negative tumors [4, 7]. However, it is not intended to be an exhaustive Molecular subtype of BC may impact prognosis review on the subject. and may influence decision making in the thera- peutic management of BC [4, 9, 10]. The prognos- 2. BREAST CANCER THERAPY tic importance of the intrinsic subtypes was evalu- Therapy of breast cancer involves a multimodal ated in a large group (1730) of patients from the strategy with a combination of neoadjuvant chem- UK and Canada who had received different adju- otherapy, surgery of operable tumors, radiotherapy vant treatments except for trastuzumab. and adjuvant chemotherapy and/ or endocrine The results obtained showed that intrinsic sub- therapy [15, 16] (Fig. 2). In locally advanced and type of BC is an independent prognostic variable, inoperable BC, the conventional therapeutic ap- irrespective of tumor size and nodal status. More- proach is the use of neoadjuvant therapy. Systemic over, HER2-positive/Luminal A tumors showed a neoadjuvant therapy may help in shrinking tumors similar outcome to HER2-negative/Luminal A tu- and make otherwise inoperable tumors operable mors [11]. Amongst the molecular subtypes of BC, [17, 18]. HER2-positive and basal-like subtypes are associ- ated with aggressive disease and poor outcomes [6, 7, 12] and Luminal B tumors show remarkably worse prognosis than Luminal A tumors, which have frequently shown better outcomes than the other subtypes [4, 6]. Also, in spite of Basal-like disease showing worse outcome than Luminal B tumors at 5-year follow-up, 10-year follow-up does not reflect this, as survival curves for Basal- like disease and Luminal B disease cross at 10- year follow-up [4]. Regarding therapeutic deci- sions, the molecular subtype of BC would influ- ence decisions such as the choice of adjuvant ther- apy to be employed. Thus, patients with HR- positive BC would be expected to derive the most benefit from adjuvant endocrine therapy. Moreo- ver, endocrine therapy reduced the risk of death in patients with HR-positive BC in contrast to pa- tients with ER or PgR receptor negative BC [13]. Similarly, the advent of immunotherapy with bio- therapeutic agents such as the monoclonal anti- body, trastuzumab, has resulted in profoundly in- Fig. (2). Schematic representation of treatment strate- creased survival with HER2-positive BC, which is gies for breast cancer. otherwise associated with poor prognosis [14]. Ba- sal-like BC on the other hand, which is negative Currently, neoadjuvant chemotherapy is exten- for the HRs (ER or PgR receptors) and HER2 does sively used in early-stage breast cancer (EBC) and not present a therapeutic target and so would not locally advanced BC as it helps to provide greater be expected to derive benefit from endocrine or chances for breast-conserving surgery (BCS) by molecularly targeted therapy [6, 7]. downstaging the disease and to determine tumor response to therapy [19, 20]. BC surgery is This review will discuss the use of combination achieved primarily by lumpectomy followed by therapy in the clinical management of breast can- whole-breast irradiation or mastectomy [15]. Ad- cer and give an insight into the potential applica- juvant therapy for BC may involve local irradia- Drug Combinations in Breast Cancer Therapy Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 5 tion, systemic therapy with cytotoxic agents, mo- treatment of EBC. Systemic adjuvant treatment is lecular targeted agents or any combination of these directed mainly at controlling any remaining de- [15, 16, 21, 22]. posits of disease, reducing recurrence rates, and In EBC where the disease is detectable only in improving long term survival in BC patients [31]. the breast and local lymph nodes (in women with Advances in chemotherapy involve the introduc- lymph node-positive disease), cancer can be re- tion and use of new cytotoxic agents, novel treat- moved by surgery [23, 24]. The disease is poten- ment strategies and neoadjuvant therapy which tially curable in such cases and when it is only lo- have been shown to improve overall treatment cally advanced, with no detectable distant metasta- outcomes such as overall survival and disease-free sis [1]. survival [26, 32]. BCS is recognized as a suitable treatment op- In metastatic breast cancer (MBC), the role of tion for many women with EBC and can eliminate surgery for removal of primary tumor is tradition- all detected macroscopic disease. BCS compares ally seen as that of palliation rather than for sur- favorably to total mastectomy regarding overall vival benefits [33]. Systemic chemotherapy with survival and local recurrence rates, while allowing cytotoxic agents or endocrine therapy had been the patients to keep their breasts without excessive core treatment strategy for metastatic breast cancer disfiguration [25, 26]. BCS is usually followed by for several decades [34] and it remains a crucial whole breast irradiation which may or may not in- component of treatment regimens [35]. Chemo- volve further (boost) treatment to the tumor bed therapeutic agents are appropriate for most pa- [27]. Data from a meta-analysis of individual pa- tients with MBC including those with hormone tient data (over 10,000 women) in 17 randomized receptor-positive (HR+) disease with extensive trials carried out by the Early Breast Cancer Trial- visceral involvement, HR+ disease after failure of ists’ Collaborative Group (EBCTG) have shown hormone-directed therapy, HER2-positive disease that the addition of radiotherapy to BCS improved (systemic chemotherapeutic agents used in combi- both long term overall survival and local regional nation with HER2-directed therapy [trastuzumab ± control, reducing local recurrence [23, 26]. Alt- pertuzumab]), and HR-negative (HR-)/HER2- hough whole breast irradiation is considered to be negative disease (triple-negative disease) [35]. relatively well tolerated [27-29], it has been linked Nevertheless, there is no generally accepted first- to some inevitable acute and delayed toxic effects line chemotherapy protocol or approach for the [28, 29]. Accelerated partial breast irradiation treatment of MBC [36]. Unlike EBC, metastatic (APBI) has been introduced as an alternative to breast cancer is considered largely incurable with whole breast irradiation in certain patients with currently available therapies [1, 37], although favorable EBC [27]. APBI could reduce treatment there are a few long-term survivors who continue duration and exposure of normal tissues by deliv- in complete remission after initial treatment [38, ering hypofractionated doses of radiation to re- 39]. stricted areas. 3. THERAPEUTIC COMBINATIONS IN Moreover, experimental data have shown that BREAST CANCER most recurrences are located near the lumpectomy bed [30]. However, a sizeable proportion of EBC The practice of combining therapeutics dates cases would eventually relapse [15] as undetected back to many centuries [40, 41] with traditional deposits of disease may remain which over time Chinese medicine practice of using a combination may result into the development of clinically fatal of herbs in their formulations [40, 42]. Combina- disease [15, 23, 31]. Thus, the understanding of tion chemotherapy (or polychemotherapy) for BC EBC as a systemic disease has constituted a major treatment traditionally involved a combination of milestone in the advancement of breast cancer re- an alkylating agent (cyclophosphamide) and anti- search, while also playing a major role in current metabolites (methotrexate and 5-fluorouracil) therapy decision making. Therefore, adjuvant sys- which significantly reduced the risk of recurrence temic chemotherapy is now a mainstay in the [43]. It is generally accepted that polychemothera- 6 Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 Fisusi and Akala py results in higher response rates than single- of preoperative doxorubicin and cyclophospha- agent chemotherapy, although the impact on over- mide resulted in a significant increase in clinical all survival is less well documented [44]. and pathologic response rates for operable breast The use of combination chemotherapy poten- cancer [51]. Also, Earl and co-investigators in the tially provides advantages such as chances for bet- Neo-tAnGo (Phase 3 neoadjuvant trial) study as- ter efficacy and dose reduction while increasing or sessed the advantage of adding gemcitabine to ac- maintaining efficacy, decreased toxicity and re- celerated paclitaxel with epirubicin and cyclo- duced or delayed development of drug resistance phosphamide. They also evaluated the effect of [40, 41]. Due to these advantages, combination sequencing the blocks of epirubicin and cyclo- chemotherapy has now become the conventionally phosphamide and paclitaxel (with or without gem- applied strategy in clinical practice [45]. More re- citabine). Their findings showed that the addition cently, advances in the areas of isolation technolo- of gemcitabine to paclitaxel and epirubicin and gy and chemical synthetic capability, as well as cyclophosphamide chemotherapy does not im- omics and cell biology, have also played an im- prove pathological complete response (pCR). portant role in increasing the application of drug However, sequencing chemotherapy such that tax- combinations in modern medical practice [40, 46]. anes are received prior to anthracyclines could im- prove pCR in standard BC neoadjuvant chemo- Chemotherapy in BC may involve the use of in- therapy [52]. itial neoadjuvant chemotherapy [47-49] before the initiation of adjuvant chemotherapy subsequent to Furthermore, the German Breast Group investi- appropriate surgical therapy and/or radiotherapy gated (according to selected subtypes), the defini- [50]. tion and effect of pCR in over 6,000 patients with primary breast cancer who received anthracycline Neoadjuvant chemotherapy can be applied us- and taxanes based neoadjuvant chemotherapy in ing a combination modality. In phase II neoadju- seven randomized trials [53]. vant trial, a combination of docetaxel and epirubi- Buzdar and colleagues (ACOSOG Z1041 trial) cin was evaluated for activity and toxicity in showed that the value of a taxane-first sequence women with large, operable or locally advanced was not shown in patients with HER2-positive dis- (Stage III) breast carcinoma, as well as patients ease in the neoadjuvant setting. pCR rates obtained with inflammatory breast carcinoma. The results in breast or nodes did not differ between the two of the trial showed an observed response rate of regimens in the analysis of anthracyclines fol- 76.7%. More than 25% of the patients experienced lowed by taxane plus trastuzumab compared with clinically significant diarrhoea and 80% experi- taxanes plus trastuzumab followed by anthracy- enced grade 4 neutropenia with one-third experi- clines plus trastuzumab [54]. In another phase II encing febrile neutropenia. The subsequent use of neoadjuvant trial involving 57 patients (9 with tri- prophylactic hemopoietic growth factor support ple negative BC), the efficacy and toxicity of allowed patients to complete the planned treat- docetaxel and carboplatin combination as neoad- ment. The investigators concluded that neoadju- juvant therapy for stage II or III breast cancer (BC) vant epirubicin plus docetaxel was active and fea- were assessed. In the multicentre trial, patients re- sible for patients with breast carcinoma including ceived docetaxel (75 mg/m2) and carboplatin (area patients with unfavorable disease presentations under the curve (AUC) of 6) intravenously on day such as locally advanced breast carcinoma and in- 1 and pegfilgrastim (6mg) subcutaneously on day flammatory breast carcinoma [16]. 2. Treatment cycles were repeated every 14 days The effects of adding sequential preoperative for a total of 4 cycles (unless there was progres- docetaxel to preoperative doxorubicin and cyclo- sion at any time), prior to definitive breast surgery. phosphamide were reported in the National Surgi- A high rate of clinical responses was reported for cal Adjuvant Breast and Bowel Project Protocol B- the regimen. The results showed that 9 of the 57 27. The study reported that the addition of four patients (16%) had pCR, and 4 of the 9 (44%) pa- cycles of preoperative docetaxel after four cycles tients with triple negative BC (TNBC) achieved Drug Combinations in Breast Cancer Therapy Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 7 pCR. The toxicity profile was also similar to other lished by the EBCTCG in 1998, their analysis anthracycline-regimens with thrombocytopenia showed that the CMF regimen with or without being the only grade 4 toxicity reported in 5% of other drugs had been evaluated in as many as 28 the subjects. The study concluded that 4 cycles of trials [56]. Also, the National Surgical Adjuvant 2-weekly neoadjuvant carboplatin and docetaxel Breast and Bowel Project (NSABP) B-20 trial followed by pegfilgrastim is an active regimen for found that the addition of the CMF combination to BC resulting in pCR rates similar to other an- tamoxifen improved 5-year DFS (HR, 0.65; P = thracycline-containing regimens, with an accepta- 0.001) and OS (HR, 0.64; P = 0.03) for patients ble toxicity profile [24]. with ER-positive, lymph node-negative disease at Therapeutic combinations in adjuvant therapy lower risk for recurrence [57]. of BC (Fig. 3) may take the form of combinations Doxorubicin containing chemotherapy combi- comprising only chemotherapeutic agents (that is nations have also been tested in clinical trials. An at least two chemotherapeutic agents) or combina- example of the initial trials to assess doxorubicin tions of chemotherapeutic agents with hormonal was the NSABP B-11 trial which evaluated mel- therapy or immunotherapy. phalan and 5-fluorouracil with or without doxoru- Reports from the Istituto Nazionale Tumori in bicin in 697 (non-tamoxifen responsive) patients, Milan, Italy, showed improved outcomes (signifi- and found an improved 5-year DFS (HR, 0.65; P = cant reduction in risk of recurrence) with the 0.007) as well as a trend for improved OS (HR, addition of an alkylating agent (cyclophospha- 0.74; P = 0.08) for patients that received doxorubi- mide) and antimetabolites (methotrexate and 5- cin [58]. fluorouracil) to BC therapy [43]. Subsequently, a Early chemotherapy combinations also included National Institute of Health consensus panel in the cyclophosphamide. For instance, in the NSABP B- US in 2001 recommended the use of multiple 15 trial, patients (2,194) with node-positive dis- agents rather than single agents in most women ease were randomized to doxorubicin (60 mg/m2) with local breast cancer, irrespective of lymph and cyclophosphamide (600 mg/m2) (AC; every 3 node, menopausal, or hormone receptor status. weeks for four cycles) given over 12 weeks versus This recommendation was made based on the ex- the conventional CMF regimen for six cycles over istence of sufficient evidence in favor of poly- 24 weeks [59]. Other drug combinations that were chemotherapy [55]. employed in the earlier chemotherapy combina- The first combination adjuvant chemotherapy tions include: 5-FU, adriamycin (doxorubicin) and cyclophosphamide (FAC) [60]; 5-FU 500 mg/m2, regimen tested in a prospective clinical trial com- 2 prised cyclophosphamide, methotrexate and 5- epirubicin 50 mg/m , cyclophosphamide 500 mg/m2 (FEC50) [61]; 5-FU 500 mg/m2, epirubicin fuorouracil (5-FU) (CMF regimen). The trial was 2 2 initiated by the Istituto Nazionale Tumori in Mi- 100 mg/m , cyclophosphamide 500 mg/m lan, Italy, in 1973. The trial randomized node- (FEC100) [62]. Combination regimens involving positive patients after radical mastectomy to 12 the use of platinum-based drugs such as cisplatin cycles of CMF (cyclophosphamide: 100 mg/m2 were also evaluated. Cisplatin has been evaluated orally on days 1-14; methotrexate: 40 mg/m2 IV in combination with Adriamycin (doxorubicin) on days 1 and 8; and 5-fluorouracil: 600 mg/m2 IV and cyclophosphamide [63], 5-FU and etoposide on days 1 and 8) administered every 28 days ver- [64], and other agents such as vinblastine [65], sus no additional treatment. The 342-month fol- epirubicin [66], methotrexate, cyclophosphamide, low-up updated report showed an improved dis- mitomycin C and vincristine [67]. ease-free survival (DFS; hazard ratio (HR), 0.71; P The taxanes form an important class of cytotox- = 0.005) and overall survival (OS; HR, 0.79; P = ic agents commonly used in chemotherapy combi- 0.04) for CMF compared with the control (no ad- nations for the treatment of BC. They have ditional treatment) population [43]. emerged as some of the most active chemothera- In an overview of randomized trials of adjuvant peutic agents introduced in the treatment of breast polychemotherapy among women with EBC pub- cancer in the 1990s [68]. 8 Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 Fisusi and Akala
The first of the class to be introduced was sponse rate (59%, with 10% complete response, paclitaxel which entered clinical trials in the early 49% partial response) in patients that received AT 1980s [69]. Another member of the class, docet- was significantly greater (P = 0.009) than for those axel was later developed and introduced due to that received AC (47%, with 7% complete re- initial scarcity and difficulty in paclitaxel produc- sponse, 39% partial response). The toxicity profile tion [45]. Evaluation of paclitaxel in combination was similar in both groups as Grade 3/4 neutro- with other cytotoxic agents for MBC treatments penia was frequent in both groups. However, fe- began with phase I clinical trials of paclitax- brile neutropenia and infections were more fre- el/doxorubicin combinations with The University quent for patients that received AT than for those of Texas M. D. Anderson Cancer Center and the that received AC (33% v 10%, P < 0.001; 8% v Medicine Branch of the National Cancer Institute 2%, P = 0.01 respectively). Time to progression (USA) simultaneously initiating phase trials of this (TTP; primary endpoint of the study) and time to combination [70]. The combination was also as- treatment failure were found to be significantly sessed in Italy by researchers at the Istituto Na- longer with AT than AC (median TTP, 37.3 v 31.9 zionale Tumori in Milan, Italy. Their combination weeks; log-rank P = 0.014; median TTF, 25.6 v was based on a bolus dose of doxorubicin with an 23.7 weeks; log-rank P = 0.048). The investigators infusion of paclitaxel over 3 hours. In the trial, concluded from the results that AT significantly doses up to 200 mg/m² of doxorubicin and 60 improves time to progression and overall response mg/m² of paclitaxel could be given [71]. rate compared with AC in patients with MBC. However, there was no difference in OS. Thus, AT Combinations of paclitaxel with cisplatin, an represents a valid option for the treatment of MBC agent with less myelosuppressive effects than [75]. A phase II trial of this combination was con- many other cytotoxic agents used for the treatment ducted by the NSABP (NSABP B - 57 trial) at 12 of MBC had been employed in clinical practice. A institutions (89 patients) using doxorubicin (60 preliminary study showed an overall response rate mg/m2) plus docetaxel (60 mg/m2), given every 21 of 85% with an 11% complete response rate and days. The result of the trial showed that amongst there was an acceptable tolerance of the therapy the evaluable patients, there was an overall re- [70]. The paclitaxel/cisplatin combination has also sponse rate of 65.7% with 20.9% complete remis- been assessed by other investigators at different sion, 44.8% partial response and median response dose combinations [72, 73]. Combinations of duration of 25.9 months. The investigators inferred paclitaxel with other agents such as cyclophos- that AT is an active combination and the admin- phamide, 5-FU and mitoxantrone have also been istration is feasible with primary ciprofloxacin and used in the treatment of MBC [70]. secondary colony-stimulating factor prophylaxis Docetaxel has been used in combination with [76]. agents like doxorubicin and this combination is Also, a combination of docetaxel with epirubi- considered to be very effective in the treatment of cin was assessed in phase I/II program by the In- locally advanced and MBC [74]. In phase III mul- ternational Breast Cancer Study Group. In the pro- ticentre study, the docetaxel and doxorubicin com- gram, 70 patients with advanced breast cancer re- bination (AT) was compared with a combination ceived up to eight courses of docetaxel (75 mg/m2) of doxorubicin and cyclophosphamide (AC) as in combination with epirubicin (90 mg/m2) every 3 first-line chemotherapy for MBC. The study in- weeks. From their study, they did not find it neces- volved 429 patients randomly assigned to receive sary to administer G-CSF to patients routinely, one of either the AT or AC regimen. 214 patients although individual patients may require the sup- 2 received doxorubicin (50 mg/m ) plus docetaxel port. They also pointed out the need for weekly 2 (75 mg/m ) while 215 patients received doxorubi- monitoring of patients and dose modification when 2 cin (60 mg/m ) plus cyclophosphamide (600 necessary, to avoid complications [77]. Another 2 mg/m ) on day 1, every 3 weeks for up to eight phase I/II nonrandomized trial of epirubicin and cycles. The results showed that although there was docetaxel in locally advanced breast cancer evalu- no difference in overall survival, the overall re- ated the combination in 2 weekly or 3 weekly Drug Combinations in Breast Cancer Therapy Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 9 schedules (National Cancer Institute of Canada epirubicin (ET) with 5-fluorouracil plus epirubicin (NCIC) Clinical Trials Group (CTG) - NCIC CTG and cyclophosphamide (FEC) as first-line chemo- MA.22). This trial was conducted to determine therapy for metastatic breast cancer. The patients optimal dosing regimens for docetaxel/epirubicin were randomized to receive either docetaxel (75 combination chemotherapy in women with locally mg/m2) plus epirubicin (75 mg/m2) or 5-FU (500 advanced breast cancer. In the study, escalating mg/m2) plus epirubicin (75 mg/m2) and cyclo- doses of epirubicin and docetaxel were adminis- phosphamide (500 mg/m2) intravenously once eve- tered to patients in either a standard 3-weekly ry 3 weeks for up to eight cycles. Granulocyte- (Schedule A - docetaxel: 75 mg/m2 IV and epiru- colony-stimulating factor (G-CSF) was given bicin: 75, 90, 105, or 120 mg/m2 IV; with pegfil- prophylactically after the first cycle when required grastim 6 mg primary prophylaxis subcutaneously and dose reduction, delay and withdrawal were per cycle on day 2) or dose-dense 2-weekly applied when necessary. The intent-to-treat popu- (Schedule B - docetaxel and epirubicin both ad- lation (n = 142) showed an overall response rate of ministered at doses of 50, 60, and 70 mg/m2 IV; 59% (95% CI, 47-70%) for ET and 32% (95% CI, with pegfilgrastim support) regimen. Phase I was 21-43%) for FEC after a median seven and six cy- used for dose finding for phase II for each dosing cles, respectively. Also, per-protocol analysis (n = schedule. The investigators concluded from their 132) revealed an overall response rate of 63.1% findings that the epirubicin/docetaxel combination (95% CI = 50-78%) and 34.3% (95% CI = 23- chemotherapy can be administered in locally ad- 47%) for ET and FEC after a median seven and six vanced BC patients with acceptable toxicity. Also, cycles, respectively. The median time to progres- the regimen can induce strong reductions in tumor sion (ITT) was 7.8 months (95% CI, 5.8-9.6 RNA integrity in some patients and these are asso- months) for ET and 5.9 months (95% CI, 4.6-7.8 ciated with posttreatment pCRs [78]. months) for FEC. Median survival (ITT) for ET Furthermore, the combination of docetaxel with and FEC were 34 and 28 months respectively, af- cisplatin was reported to be effective in patients ter a median follow-up of 23.8 months. Hemato- with anthracycline-resistant MBC. This combina- logic toxicity was more common with ET and fe- tion was assessed in a phase II trial in 39 patients brile neutropenia (13 patients; 18.6%) as well as with MBC resistant to previous anthracycline two (possibly study treatment-related) deaths were treatment. Patients received docetaxel (75 mg/m2) reported in the ET group. On the other hand, non- followed by cisplatin (60 mg/m2) every 3 weeks hematologic grade 3-4 toxicities were infrequent for a maximum of 6 cycles or until disease pro- in both arms. The investigators concluded that gression. The investigators reported that all 39 pa- both ET and FEC were associated with acceptable tients in the trial were evaluable for safety while toxicity and ET is a highly active first-line therapy 36 were evaluable for efficacy. They found an ob- for MBC [68]. jective response rate of 31% with 3 complete re- Mitomycin combinations have also been used sponses, the median time to disease progression in the treatment of BC. Mitomycins have been in was 7 months, and the median overall survival was clinical use since the 1960s and have demonstrated 23 months (median follow-up of 41 months). The potency against a broad range of cancers [80]. A most frequently observed severe hematologic tox- study reported the efficacy of low-dose mitomycin icity during the study was neutropenia which oc- and low-dose weekly doxorubicin in MBC patients curred in 39% of the patients. The most common previously treated with CMF. Forty-six biopsy- nonhematologic toxicities were asthenia and nau- proven BC patients previously treated with CMF sea and no treatment-related death was observed. were entered in the study. Patients received a In this study, the docetaxel and cisplatin combina- chemotherapy regimen consisting of doxorubicin tion was found to be active and safe in patients (20 mg/m2 IV weekly starting on day 1) and mi- with MBC resistant to anthracyclines [79]. A tomycin (10 mg/m2 IV on day 1). Treatment cycles phase II multicentre randomized study involving were repeated every 28 days or later, pending re- 142 patients with at least one measurable lesion covery of the neutrophil count (≥ 1500/µl) and the compared the efficacy and safety of docetaxel plus platelet count (≥ 100,000/µl) and the doses of sub- 10 Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 Fisusi and Akala sequent cycles were determined by the degree of (range: 2.5-49 months). Also, 1- and 2-year overall myelosuppression. Forty-four of the 46 patients survival rates were 39.4% and 15.7% respectively. entered in the study were evaluable. The results The treatment was reportedly well tolerated revealed an overall response rate of 43% (11% with an acceptable toxicity profile. Grade 3-4 he- complete remission and 32% partial response), matologic and non-hematologic toxicity was re- 11.5 months median duration of survival and me- ported in 8 (20%) and 3 (7.5%) patients, respec- dian duration of response of 8 months for respond- tively. In addition, two cases of fatalities (5%) oc- ers (complete response and partial response). Also, curred with pulmonary toxicity in women heavily toxicity of the regimen was moderate, comprising exposed to mitomycin-C (cumulative doses of ≥ neutropenia (74%), thrombocytopenia (25%), 40 mg/m²) and soon after red blood cell transfu- pneumonitis (11%), and cardiomyopathy (2%). sion. Thus, the need to take the precaution of Thus, the low-dose mitomycin and low-dose avoiding blood transfusion alone with mitomycin- weekly doxorubicin combination chemotherapy C therapy was pointed out. The investigators con- were considered effective for treating patients pre- cluded that chemotherapy with mitomycin-C and viously treated with CMF [81]. Another study vinblastine is active and well-tolerated in heavily published in 1990 reported the efficacy and re- pre-treated BC patients [83]. duced toxicity of a combination of mitomycin C and mitoxantrone in chemotherapy-naive ad- Furthermore, a retrospective review of the med- vanced BC patients. The study involved 33 pa- ical records of 48 patients treated with a combina- tients with predominantly visceral disease. The tion of mitomycin C and methotrexate showed that patients received a median of two cycles of chem- the combination may be effective in MBC patients pre-treated with anthracycline and taxanes. The otherapy with a combination of mitomycin C (10 2 2 patients were given mitomycin C (8 mg/m on day mg/m ) every 6 weeks and mitoxantrone (6 2 mg/m2) every 3 weeks. Thirty-two of the patients 1) and methotrexate (60 mg/m on days 1 and 15) were evaluable and 47% (15 patients) achieved a in a treatment cycle repeated every 4 weeks. The partial response for a median duration of 7 months. results showed that although there was no com- plete response, there was 24% (11) partial re- It was noted that the response rate and duration of sponse and a median time to progression of 4.8 response for the mitomycin C and mitoxantrone months. Grade 3 thrombocytopenia was observed combination might be inferior to those reported for in five patients (10%) and other toxicity was mild CMF or CAF combination chemotherapy to some and manageable [84]. Also, the combination of extent. However, the combination regimen pro- mitomycin C and capecitabine was evaluated in a duced minimal gastrointestinal toxicity and hair phase II study involving 30 patients. The patients loss with acceptable hematological toxicity [82]. were treated with mitomycin C (8 mg/m2 IV bolus Another study reported that a combination of mi- on day 1) and capecitabine (1000 mg/m2 twice- tomycin C and vinblastine is active and well toler- daily, orally on days 1-14) in 3-weekly cycles for a ated in heavily pre-treated BC patients. In the total of 6 cycles or until disease progression. Ther- study, 40 previously treated (median of 3 prior apy with capecitabine alone was continued beyond regimens) women with measurable disease re- six cycles until there was disease progression, un- ceived mitomycin C (10mg/m² IV on day 1) and acceptable toxicity, patient refusal, noncompliance vinblastine (6mg/m² IV on days 1 and 21) in a 42- to the protocol, physician decision to discontinue day cycle. The combination chemotherapy regi- treatment or treatment delay >2 weeks (unless men resulted in 35% partial response (14 patients) there was perceived benefit to the patient). One with additional 10 patients (25%) having stable patient discontinued treatment after the first cycle disease lasting for 4 months or longer, giving a due to prolonged thrombocytopenia, thus 29 pa- total clinical benefit of 60%. The median TTP and tients were evaluable for response. The overall re- overall survival durations were 4 months (range: sponse rate was 65.5% (95% CI, 48.2-82.8%) and 1.5-23) and 11 months (range, 9-13) respectively, an additional 31% of patients had stable disease. for a median follow-up period of 11 months The median TTP was 8.5 months (95% CI, 6.1- Drug Combinations in Breast Cancer Therapy Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 11
10.9). Analysis of the subgroup of patients with mg/m2 on day 1) and methotrexate (60 mg/m2 on prior exposure to (neo) adjuvant chemotherapy day 1 and day 15) by IV administration every 4 (n=18) demonstrated an overall response rate of weeks and 3 treatment cycles were completed as 61.1% and TTP of 7.3 months. Median follow up scheduled. During sequential mitomycin C/metho- of 18.5 months (range 5.7-47) showed that 14 pa- trexate treatment, the progressively increasing lev- tients (46.7%) were still alive and the median els of tumor markers decreased for the first time overall survival was 29.8 months (CI 95%, 18.3- after the disease showed resistance to any chemo- 41.3). Thrombocytopenia, pneumonitis and hemo- therapy. The combination regimen provided dis- lytic uremic syndrome were the main adverse ease control for 7 months without disease progres- events in the study. The data suggest that capecita- sion. Grade 1 hematuria was observed after 3 bine and mitomycin C combination chemotherapy treatment cycles but improved spontaneously has good antitumor activity as first-line treatment without treatment. Grade 2 interstitial pneumonia in MBC. However, the regimen is associated with which necessitated skipping treatment occurred in mitomycin C-specific toxicity [36]. the fourth course. Grades 3 and 4 hematological Another retrospective review of the medical adverse effects were observed after 5 cycles which records of 31 patients with HER2-negative MBC necessitated postponement of treatment. Also, the previously treated with anthracycline, taxane, dose of mitomycin C was reduced by 50% in cy- capecitabine, and vinorelbine showed that a mito- cles 7 and 8 because of hematological toxicity. mycin C and methotrexate chemotherapy combi- The cycles were however completed as scheduled. nation demonstrated the effectiveness of this com- Thus, this case report suggests that mitomycin bination in this group of patients. Each treatment C/methotrexate combination may be an effective cycle comprised mitomycin C (8 mg/m2 on day 1) treatment for MBC patients with progressive dis- and methotrexate (60 mg/m2 on day 1 and day 15) ease following aggressive treatment with multiple by IV administration every 4 weeks. Mitomycin C regimens [37]. was administered till a cumulative dose of 50 Gemcitabine, capecitabine and vinorelbine con- mg/m2 was attained, following which only metho- taining chemotherapy combinations have also been trexate (60 mg/m2 on day 1 and day 15) was re- used in the therapy of BC. A phase II randomized peated until progressive disease or adverse events trial evaluated lapatinib combination with capecit- were noticed. abine, vinorelbine, or gemcitabine in HER2- The study revealed response rate and clinical positive MBC patients with progression after benefit rate of 9.7 and 19.4% respectively and me- treatment with a taxane (Latin American Coopera- dian TTP and times to failure of 3.9 and 3.7 tive Oncology Group (LACOG) 0801 Study). The months respectively. Grade 3 and/or 4 adverse trial enrolled a total of 142 women 18 years and events were observed in 36% patients (grades 3 older, with histologically confirmed locally ad- and 4 thrombocytopenia: 12.9 and 3.2% respec- vanced or metastatic invasive HER2-positive ade- tively; grades 3-4 leucopenia and anemia: 12.9 and nocarcinoma of the breast. The primary endpoint 9.7% respectively) and 7 patients needed dose re- of the trial was an overall response (percentage of ductions due to hematological toxicity. There was patients experiencing a confirmed complete re- no renal toxicity and all toxicities were managea- sponse or partial response) and secondary end- ble. The study indicated that mitomycin C and points included progression-free survival, overall methotrexate combination chemotherapy may be survival, and duration of response. effective and tolerable for heavily pre-treated pa- The patients were randomized to: LC arm, to tients with good performance status [85]. In addi- receive every 3-week cycles of lapatinib (1250 tion, a case study report showed the efficacy of mg; orally once daily continuously) plus capecita- mitomycin C and methotrexate combination in bine (2000 mg/m2/day orally in 2 doses on days 1 MBC which was resistant to eribulin, vinorelbine, to 14); LV arm, to receive lapatinib at the same and bevacizumab with paclitaxel. The patient was dose as LC arm, plus vinorelbine (25 mg/m2/day started on the treatment with mitomycin C (8 IV on days 1 and 8); or LG arm to receive lapatin- 12 Pharmaceutical Nanotechnology, 2019, Vol. 7, No. 1 Fisusi and Akala