No predictive test for response to chemotherapy has been sufficiently validated to use in a standard clinical setting. For patients with MBC not previously treated with chemotherapy, the response rates are 30% to 75%. Predictors of response to chemotherapy include DFI, sites of disease, organ function, and performance status, among others. Different biomarkers have been studied; some correlate with treatment response, but none is sufficiently accurate to help make a decision to treat or withhold therapy (47).
Selection of Agents/Regimen
In deciding which cytotoxic regimen to use in the setting of negative ER/PR and HER2 status or in patients who have progressive disease after endocrine therapy, consideration should be given to the previous therapies, organ function, and comorbid conditions. Typically, chemotherapy within the conventional range of doses is associated with higher response rates than “low-dose chemotherapy.” As in the setting of adjuvant therapy, high-dose chemotherapy with peripheral blood/bone marrow stem cell transplantation has not been found to be of clinical benefit in randomized trials (48).
The choice between sequential single agents and combination chemotherapy is controversial. The principle of nonoverlapping mechanisms of resistance and toxicities has been the basis of combination chemotherapy. Multiple randomized trials involving single-agent versus multiple-agent regimens in MBC have generally demonstrated that combination chemotherapy has improved response rates and TTP, but OS is not improved. Fossati et al (49), in a systematic review that included 31,510 patients, estimated that the proportional reduction in overall mortality for combinations versus single-agent regimens is only 18%, translating to an absolute benefit in survival of 9% at 1 year, 5% at 2 years, and only 3% after 5 years. More toxicity was associated with combination therapy. In two randomized trials of combination versus single-agent therapy in MBC, formal quality-of-life analyses favored the single-agent arms, even though response rates were slightly lower (50,51).
A Cochrane review (52) including 28 trials and 5,707 patients with MBC randomly assigned to receive single-agent or combination chemotherapy found that combination therapy was associated with a higher response rate (odds ratio, 1.28; 95% CI, 1.15-1.42), longer TTP (HR, 0.78; 95% CI, 0.73-0.83), and longer OS (HR, 0.88; 95% CI, 0.83-0.94) than single-agent therapy. Most trials included in the Cochrane review did not specifically investigate the combination versus the sequential use of the single agents, and few studies reported the rate of “crossover” to an additional therapy following progression in the monotherapy arm. Therefore, the studies included evaluated the value of the use of two agents versus a single agent and do not address whether a simultaneous combination or a sequential monotherapy strategy should be pursued.
In the absence of strong evidence to guide the decision, and in agreement with different oncologic societies (53), we believe that use of single-agent therapy is preferable in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom or disease control. Ultimately the choice of the use of sequential versus combination chemotherapy depends on a careful evaluation of risks and benefits for individual patients. The other major indication for combination therapy, as in the adjuvant setting, is the treatment of oligometastases.
The optimal duration of chemotherapy for MBC is controversial. Several studies have compared continuous (maintenance) chemotherapy with intermittent therapy. Several studies found that continuous therapy was associated with a longer time to relapse (54,55,56,57,58) but with worse side effects (57). None of the individual studies comparing continuous and intermittent therapy showed prolongation of life with continuous therapy. However, a recent meta-analysis of these data showed a statistically significant improvement in survival for patients receiving chemotherapy for a longer versus a shorter time (58). Some regimens, such as anthracycline-containing treatments, have inherent dose-limiting toxic effects that prohibit prolonged use. Other agents, such as trastuzumab, capecitabine, and, possibly taxanes given weekly, lend themselves to prolonged continued therapy. In an unplanned interim analysis, the recently presented Italian MANTA trial found no PFS or OS benefits for maintenance treatment with paclitaxel (175 mg/m2 every 3 weeks for eight cycles) after first-line chemotherapy for MBC with an anthracycline/taxane-containing regimen (six to eight cycles) (59). Many trials are designed to treat patients until they have progression of disease or for two to three cycles after maximum benefits. Currently, the optimal treatment duration is unknown. The practice at MDACC is to treat patients with MBC with continuous chemotherapy unless unacceptable toxicity arises, at least until a third-line or fourth-line regimen comes into play and/or Eastern Cooperative Oncology Group (ECOG) performance status is ≥3 in patients with MBC.
The introduction of anthracyclines (doxorubicin and epirubicin) in the 1970s represented a significant advance in the treatment of advanced breast cancer. In patients with MBC, response rates to single-agent doxorubicin (25-75 mg/m2 every 3 weeks) ranged from 25% to 60% and were heavily influenced by patient characteristics such as prior chemotherapy exposure, performance status, and extent and sites of disease (60,61,62,63,64). At MDACC, doxorubicin-containing regimens have historically been the initial treatment of choice for MBC treated previously with non–anthracycline-containing chemotherapy. Patients who received anthracyclines and had a prolonged DFI before the development of metastatic disease occasionally benefit from repeat administration of doxorubicin. However, given the increasing number of active agents available to treat MBC, repeat management with anthracyclines should be reserved for patients in whom other treatments have failed, given the potential risk of heart failure.
Epirubicin is a doxorubicin analog that has been shown to have similar efficacy and somewhat less toxicity than doxorubicin at equimolar doses. Although not designed to perform a head-to-head comparison, results from a randomized trial suggested that epirubicin might be as efficacious as doxorubicin. A formal comparison of two different anthracyclines in combination (5-fluorouracil, doxorubicin, and cyclophosphamide [FAC] vs 5-fluorouracil, epirubicin, and cyclophosphamide [FEC]) at equimolar doses found both regimens to be equally effective in terms of response rate, TTP, and survival. The FEC regimen was associated with less gastrointestinal, hematologic, and cardiac toxicity (65).
Efforts to improve the safety profile of doxorubicin while preserving efficacy have resulted in liposomal formulations of doxorubicin. Response rates with these products appear comparable to those seen in other multicenter trials using conventional single-agent doxorubicin. In a phase III clinical trial, O’Brien et al compared the efficacy and safety of pegylated liposomal doxorubicin with those of conventional doxorubicin as first-line therapy in patients with MBC (66). A total of 509 women received a 1-hour infusion of pegylated liposomal doxorubicin (50 mg/m2 once every 4 weeks) or conventional doxorubicin (60 mg/m2 once every 3 weeks). The median PFS and OS were similar in both treatment groups (6.9 vs 7.8 months and 20.1 vs 22.0 months, respectively). The rates of alopecia, myelosuppression, nausea, and vomiting were lower with pegylated liposomal doxorubicin than with conventional doxorubicin. Perhaps most notably, pegylated liposomal doxorubicin was associated with a significantly lower incidence of cardiotoxicity, even at higher cumulative doses (P < .001) (66). The most important dose-limiting toxicity of pegylated liposomal doxorubicin is palmar-plantar erythrodysesthesia, which is both dose and duration related. The polyethylene glycol coating results in preferential concentration of the drug in the skin; this explains why small amounts of the drug can leak from capillaries in the palms and soles, resulting in redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. As with all liposomal drug delivery systems, there is a low incidence of hypersensitivity reactions.
Taxanes (paclitaxel, docetaxel, and the nanoparticle albumin-bound [nab]-paclitaxel) are among of the most active classes of cytotoxic drugs available today for the treatment of breast cancer. They rival the anthracyclines in terms of response rates and positive impact on TTP. Taxanes are frequently used as first-line chemotherapy for treatment-naive MBC and also in MBC treated with anthracyclines or if anthracyclines are contraindicated. Response rates with paclitaxel range from 21% to 62%; in anthracycline-resistant breast cancer, response rates are 40%.
Two trials have directly compared doxorubicin and paclitaxel, using different dosing and administration schedules. In the Intergroup E1193 study (67), similar response rates and TTP were demonstrated with doxorubicin administered at 60 mg/m2 and paclitaxel at 175 mg/m2 over 24 hours. Thus, paclitaxel may be as effective as doxorubicin when administered as a single agent. The dose and administration schedule may influence the response to paclitaxel. The use of weekly paclitaxel has recently become very popular due to the improvement in the toxicity profile and the ability to deliver a more dose-intensive regimen. At MDACC, the most popular taxane regimen is weekly paclitaxel 80 mg/m2, commonly in a “3 weeks on, 1 week off” or “2 weeks on, 1 week off” schedule.
Docetaxel is a semisynthetic taxane with several preclinical, pharmacokinetic, biological, and clinical differences in comparison to paclitaxel. It has demonstrated a 37% to 57% response rate in patients with anthracycline-resistant tumors and was initially FDA approved for this indication at a dose of 60 to 100 mg/m2 every 3 weeks. At this dose, hematologic toxicity is the greatest and the rates of neutropenia are similar to those seen when paclitaxel is given every 3 weeks. In a large clinical trial, 527 patients were randomized to receive docetaxel 60, 75, or 100 mg/m2 every 3 weeks. A relationship between increasing dose of docetaxel and increased tumor response was observed, but toxicities were also related to increasing doses (68). Docetaxel every 3 weeks at doses between 75 and 100 mg/m2 are appropriate choices as first-line therapy for MBC; in most cases at MDACC, we use 75 mg/m2. Compared to every-3-week paclitaxel, docetaxel 100 mg/m2 was associated with longer TTP (HR, 1.64; 95% CI, 1.33-2.02) and improved OS (HR, 1.64; 95% CI, 1.33-2.02), but also greater incidence of treatment-related toxicities (69). To place these data in context, it is important to remember that paclitaxel has greater activity when given on a weekly schedule, yet it is not clear whether docetaxel or paclitaxel provides superior outcomes when each agent is administered at its optimal dose and schedule. In patients who had received paclitaxel previously, docetaxel administration was associated with response rates of 18% to 21%, demonstrating a lack of cross-resistance between the two agents (70).
Moderate nail changes and fatigue are commonly seen with weekly paclitaxel and docetaxel; excessive tearing due to partial or complete canalicular stenosis is seen with weekly docetaxel. Diarrhea, stomatitis, and neutropenia and its complications are uncommon with weekly taxane administration. Fluid retention is seen in patients who receive a docetaxel cumulative dose greater than 300 mg/m2. Premedication with steroids greatly reduces the magnitude of fluid retention; the optimal doses and schedules for steroid administration are not well established. At MDACC, we routinely prescribe dexamethasone 4 mg PO twice a day for 3 days beginning the day before chemotherapy administration.
Nab-paclitaxel is a nanoparticle albumin-bound paclitaxel (Abraxane) that has been investigated in the treatment of MBC. In different comparisons, it has proven to be better, or at least as effective, as the other taxanes (71,72), with the advantage that it does not require Cremophor for solubility and therefore is associated with less hypersensitivity reactions. In a phase III study, 454 patients were randomly assigned to 3-week cycles of nab-paclitaxel 260 mg/m2 or paclitaxel 175 mg/m2. Nab-paclitaxel demonstrated significantly higher response rates compared with paclitaxel (33% vs 19%, P = .001) and longer TTP (23.0 vs 16.9 weeks, P = .006). Grade 3 sensory neuropathy was more common with nab-paclitaxel, the incidence of grade 4 neutropenia was significantly lower with nab-paclitaxel, but the rate of febrile neutropenia was similar in both groups. A phase II four-arm study compared nab-paclitaxel (300 mg/m2 every 3 weeks, 100 mg/m2 weekly, or 150 mg/m2 weekly) and docetaxel (100 mg/m2 every 3 weeks). The weekly dose of 150 mg/m2 of nab-paclitaxel demonstrated longer PFS than docetaxel (12.9 vs 7.5 months, P = .006), but no differences in PFS or response rates were seen when comparing docetaxel and the 3-week schedule of nab-paclitaxel. Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms, but the frequency and grade of peripheral neuropathy were similar in all groups (71). At MDACC, nab-paclitaxel is frequently used as first- or second-line therapy administered in a weekly schedule, and it is preferred to paclitaxel for patients with contraindications to steroid use.
Capecitabine (Xeloda) is an oral fluoropyrimidine approved by the FDA in April 1998 as single-agent therapy for the treatment of MBC resistant to anthracyclines and taxanes. In September 2001, capecitabine was approved for use in combination with docetaxel in MBC previously treated with an anthracycline. The first phase II study of capecitabine in breast cancer involved 162 patients previously treated with paclitaxel for MBC (73). The majority of patients had also received previous anthracycline therapy. Capecitabine was administered at 2,500 mg/m2/d in two divided doses for 14 days, followed by 1 week of rest. Twenty-seven (20%) of 135 women with measurable disease demonstrated complete or partial responses. The median duration of response was 8.1 months, and the median survival was 12.8 months. In a phase II trial, O’Shaughnessy et al randomized patients to receive cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or capecitabine in the frontline setting (74). The overall response rate was 30% for capecitabine and 16% for CMF; no differences in TTP were seen. Similar levels of nausea, vomiting, and stomatitis were observed in both groups. More cases of grade 3 or 4 diarrhea (8%), fatigue (5%), and hand-foot syndrome (15%) were noted with capecitabine.
Capecitabine is active in the treatment of MBC, and significant response rates can be achieved in women previously treated with an anthracycline and a taxane. However, patients with triple-negative tumors do not benefit from it. The FDA-approved dose and schedule are 2,500 mg/m2/d given orally in two divided doses for 14 days, followed by 1 week of rest. Retrospective studies suggest that a lower starting dose (2,000 mg/m2/d) is better tolerated, with preserved efficacy. Capecitabine as first-line therapy for MBC results in response rates of 30% to 58%, and it is a reasonable option for some patients. At MDACC, it is often used as first-line therapy for patients who have been previously treated with anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting.
Gemcitabine (Gemzar), a nucleoside analog, was approved by the FDA in April 2004 for the first-line treatment of MBC in the United States. In patients with MBC, single-agent response rates have ranged from 14% to 37% (75,76,77). These were small trials, and the disparate results may be due to dosing differences. Generally, chemotherapy-naive patients tolerate doses of 1,000 to 1,250 mg/m2/wk on days 1, 8, and 15 every 28 days. Omitting the day 15 dose or reducing the dose in subsequent cycles of chemotherapy may improve the patient’s ability to tolerate therapy beyond the initial cycles. Pretreated patients may require dose reductions in order to decrease the risk of thrombocytopenia. Gemcitabine has been investigated in many different doublet and triplet combinations; it is a promising agent for its efficacy as a single drug, but also due to its ability to readily combine with paclitaxel, vinorelbine, docetaxel, or cisplatin/carboplatin as first- or second-line therapy. At present, gemcitabine is appropriate treatment for patients with MBC after treatment failure with standard regimens.
Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid that interferes with microtubule assembly and is an important active agent in the treatment of MBC. Phase II trials investigating its efficacy in pretreated MBC have demonstrated response rates ranging from 25% to 47% (78,79,80). The primary side effects are neutropenia, pain with infusion, flu-like symptoms, and gastrointestinal symptoms such as nausea or constipation. Vinorelbine is appropriate third-line (or later) therapy for patients with MBC. At MDACC, it is usually given at a dose of 25 mg/m2 on days 1, 8, and 15 of 21-day cycles.
Ixabepilone (Ixempra) is an epothilone B analog that binds to microtubules and causes microtubule stabilization and mitotic arrest. It was approved by the FDA in October 2007 (alone or in combination with capecitabine) for the treatment of patients with MBC resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. As a single agent, it is also indicated for patients with tumors resistant or refractory to capecitabine.
Ixabepilone monotherapy was evaluated in a single-arm trial in 126 patients who had previously received an anthracycline, a taxane, and capecitabine (81). The objective response rate was 11.5%, the median response duration was 5.7 months, and the median OS was 8.6 months. Grade 3 or 4 neutropenia was seen in 54% of patients, and grade 3 or 4 peripheral neuropathy was seen in 14%. When used as first-line therapy in patients with MBC who received anthracycline-based chemotherapy in the adjuvant setting, the response rates was 41.5%, with a median duration of response of 8.2 months and a median survival of 22 months (82). At MDACC, we frequently use it in patients who have received anthracyclines, taxanes, and capecitabine. Ixabepilone is given at 40 mg/m2, but based on toxicities and tolerance, it is not uncommon to reduce the dose to 32 mg/m2.
Eribulin mesylate is a synthetic analog, a novel microtubule modulator that induces a conformational change that suppresses microtubule growth and sequestration of tubulin into nonfunctional aggregates. In the phase III study that led to its approval, 762 heavily pretreated women with locally or recurrent MBC were randomized to receive eribulin or physicians’ treatment of choice. Patients treated with eribulin had an improvement in OS (13.1 vs 10.6 months; HR, 0.81; 95% CI, 0.66-0.99) (83). Asthenia, fatigue, and neutropenia were the most common side effects associated with eribulin. Peripheral neuropathy led to discontinuation of treatment in 5% of patients. Recently, a phase II study evaluated the efficacy and safety of eribulin in the treatment of HER2-negative MBC in the first-line setting (84). Fifty-six patients were treated, with the majority having received anthracycline- and/or taxane-containing chemotherapy in the adjuvant setting. The objective response rate was 29% (95% CI, 17.3%-42.2%), the clinical benefit rate was 52%, the median response duration was 5.8 months, and the median PFS was 6.8 months.
Anthracycline-Based Combination Regimens
Doxorubicin-containing combinations result in overall response rates ranging from 50% to 80%, with response durations of 8 to 15 months. The median survival with doxorubicin–alkylating agent combinations was 17 to 25 months. Although doxorubicin-containing regimens are more efficacious in the metastatic setting than are non-doxorubicin-containing combinations, anthracycline-based combinations are not commonly used because of the associated side effects.
As was discussed previously, the issue of whether combination chemotherapy is superior to single-agent chemotherapy in the treatment for MBC continues to be debated. For patients with rapidly progressing disease, treatment regimens most likely to produce an objective tumor response are highly desirable; therefore, there is still an important role for the use of combination chemotherapy. For many years, FAC (500/50/500 mg/m2) was the standard regimen for patients with MBC treated at MDACC. Several randomized clinical trials have compared different anthracycline-based chemotherapy regimens in patients with MBC. Nabholtz et al (85,86) compared the use of docetaxel/doxorubicin/cyclophosphamide (TAC; 75/50/500 mg/m2) with FAC as first-line therapy for MBC (n = 484). The objective response rate was 55% with TAC and 44% with FAC (P = .02; HR, 1.5; 95% CI, 1.1-2.2). There was no significant difference in TTP or OS between treatment arms. Febrile neutropenia occurred more frequently with TAC than FAC (29% vs 5%), but similar rates of infection were seen. Carmichael et al reported the results of a trial comparing epirubicin and cyclophosphamide (EC) with epirubicin and paclitaxel (EP) in patients with MBC (87). A total of 705 patients received up to six cycles of therapy. The objective response rate was higher with EP (67%) than with EC (56%). However, the TTP and OS were similar between the treatment arms. Doxorubicin and cyclophosphamide (AC) were compared to doxorubicin and docetaxel (AT) in 429 patients with MBC (88). The AT regimen significantly improved the TTP (37.9 vs 31.9 weeks, P = .014) and overall response rate (59% vs 47%, P = .008) compared with AC, but there was no difference in OS. The AT regimen is a valid option for the treatment of MBC.
Platinum-Based Combination Regimens
As single agents, the platinum salts (primarily cisplatin and carboplatin) have had relatively limited use in the treatment of MBC. Platinum compounds have been reserved for third-line therapy or beyond. Objective responses in this setting are less than 10% (89). In a limited number of trials of cisplatin or carboplatin first-line chemotherapy for MBC, objective responses were up to 50% (89). The availability of many active chemotherapeutic regimens and the significant toxicities associated with platinum compounds resulted in their being largely used in the salvage setting. With the introduction of newer cytotoxic agents and preclinical data demonstrating their synergy with platinum compounds, there is renewed interest in incorporating the platinum compounds into regimens for MBC. The major reason for the revival of interest in platinum compounds is a greater understanding of the sensitivity of cells with homologous recombination deficiency, especially those with BRCA mutations, to platinum. Platinum monotherapy or platinum-based combinations are being widely tested in primary breast cancer and MBC in BRCA mutation carriers. By extrapolation, there is also much interest in testing platinum-based therapies in patients with triple-negative breast cancer and in those with HER+ tumors because in vitro synergy has been shown with anti-HER2 therapy in experimental models.
Phase II trials have been reported with the combination of paclitaxel and cisplatin. As first-line therapy for MBC, overall response rates have ranged from 50% to 90%. Trials evaluating this combination as second- or third-line therapy reported response rates of 30% to 50% (89). These results suggest that the combination of cisplatin and paclitaxel produces response rates higher than those expected with paclitaxel alone. Perez et al reported on the combination of paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC] 6 every 3 weeks) as first-line treatment of MBC (90). In 53 patients, an overall response rate of 62% was observed, including a complete response rate of 16%. The median TTP was 7.3 months, with a 1-year survival rate of 72%. A similar trial combining paclitaxel (175 mg/m2) and carboplatin (AUC 6) administered every 3 weeks (91) reported an objective response rate of 43% (14% complete response rate); the objective response rate was higher among patients who had received prior adjuvant therapy (76% vs 45%). A phase II study examined the combination of a platinum compound and docetaxel (92). Among this previously treated group of patients, the overall response rate was 61%, the median duration of response was 8 months, and the median TTP was 10 months.
The activity of the cisplatin/gemcitabine combination in MBC had been explored with promising results. In one trial, patients previously treated with an anthracycline and/or taxane received cisplatin (30 mg/m2) plus gemcitabine (750 or 1,000 mg/m2) on days 1, 8, and 15 of 21-day cycles. The objective response rate was 50%, with 10% of patients attaining a complete response. The most common toxicities were peripheral neuropathy, nausea/vomiting, and hematologic toxicities (neutropenia, thrombocytopenia, and anemia) (93). In a trial evaluating cisplatin 25 mg/m2 on days 1 through 4 and gemcitabine 1,000 mg/m2 on days 2 and 8 of a 21-day cycle, patients (n = 136) were divided in two cohorts according to prior treatments (heavily pretreated and not heavily pretreated). The response rate for both of the cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively (94).
Platinum agents may prove to have a specific role in the treatment of triple-negative breast cancers, particularly in tumors harboring BRCA dysfunction. In preclinical and clinical studies, mutations in BRCA have greater sensitivity to DNA-damaging chemotherapeutic agents, such as platinum agents. Several studies are evaluating the safety and efficacy of platinum-based chemotherapy in combination with novel agents, particularly poly(ADP-ribose)polymerase (PARP) inhibitors. Given the similarities between triple-negative tumors and tumors harboring BRCA1 mutations, a large phase III study evaluated the combination of gemcitabine and carboplatin versus gemcitabine, carboplatin, and iniparib. The overall response rate for 258 patients treated with gemcitabine plus carboplatin was 33.7%, with a median PFS of 4.1 months and median OS of 11.1 months (95). Unfortunately, iniparib was not an active PARP inhibitor, and the trial did not meet its primary end point. A recent meta-analysis evaluated four studies of platinum-based combination chemotherapy in the metastatic setting (96). The overall response rates were comparable, but patients with triple-negative breast cancer treated with platinum agents had longer PFS. At present, we believe there may be a benefit in the use of platinum-based chemotherapy in all patients with triple-negative breast cancer regardless of BRCA status. Ongoing clinical trials will help clarify whether the majority of the benefit is derived from the efficacy of the platinum agents among BRCA mutation carriers.
Gemcitabine in Combination With Other Agents
Several phase II trials have investigated salvage therapy with docetaxel/gemcitabine combinations in MBC. Drug doses and schedules varied. Among previously treated patients, the objective response rates ranged from 36% to 79%. In a phase III study, the combination of gemcitabine (1,250 mg/m2 on days 1 and 8) and paclitaxel (175 mg/m2 on day 1) was associated with an improvement in response rate and TTP compared with paclitaxel alone (39.3% vs 25.6% and 5.4 vs 3.5 months, respectively) as first-line therapy for MBC (97). Median OS was also significantly improved with the combination (18.6 vs 15.8 months; HR, 0.77; 95% CI, 0.62-0.95). There was more frequent grade 4 hematologic toxicity with the combination. Of note, most patients randomized to paclitaxel alone did not receive subsequent gemcitabine.
A phase III European trial found no difference between gemcitabine-docetaxel (1,000 mg/m2 on days 1 and 8 and 75 mg/m2 on day 1) and capecitabine-docetaxel (1,250 mg/m2 twice a day on days 1-14 and 75 mg/m2 on day 1) (98). Similar PFS, OS, and response rates were seen. The toxicity profile for the gemcitabine-docetaxel combination was better.
Vinorelbine-Based Combination Regimens
A trial of single-agent doxorubicin compared to doxorubicin plus vinorelbine failed to demonstrate a superior response rate with the combination (99). Vinorelbine has been successfully combined with taxanes. There are no phase III trials to confirm that these combinations are better than either single agent. Phase II studies combining vinorelbine and paclitaxel in MBC have been reported (100). The overall response rates with first-line vinorelbine/paclitaxel are 49% to 60%. The overall response rates for second-line vinorelbine/paclitaxel and vinorelbine/docetaxel are 46% to 56% and 37% to 59%, respectively. Toxicities associated with vinorelbine/taxane combinations were myelosuppression and mild neurotoxicity (100).
In September 2001, the FDA approved capecitabine in combination with docetaxel for patients with MBC previously treated with an anthracycline. This was based on the results of a multinational phase III trial that randomized 511 anthracycline-refractory patients to receive docetaxel 100 mg/m2 or capecitabine 1,250 mg/m2 twice daily for 14 days plus docetaxel 75 mg/m2 intravenously every 3 weeks (101). The response rates for the single-agent and combination regimens were 30% and 42%, respectively (P =.006). The TTP was 4.2 and 6.1 months, respectively (P = .0001). The OS was significantly superior with the combination (HR, 0.775; 95% CI, 0.63-0.94). This is one of the few randomized trials that reported a survival benefit of one treatment over the other, but the design of the trial does not confirm that the combination is better than the sequential administration of single-agent docetaxel followed by capecitabine, or vice versa. Grade 3 treatment-related adverse events were more common with the combination versus docetaxel alone (71% vs 49%, respectively), but overall, the incidence of treatment-related adverse events was similar between the two groups (98% vs 94%, respectively).
Capecitabine in combination with ixabepilone has been approved for the management of resistant MBC or MBC progressing after anthracyclines and taxanes. The trial that led to the approval of this combination randomized 752 patients to ixabepilone (40 mg/m2 intravenously every 3 weeks) plus capecitabine (2,000 mg/m2 on days 1-14 of a 21-day cycle) or capecitabine alone (2,500 mg/m2 on the same day schedule) (102). Patients receiving the combination had a 25% reduction in the estimated risk of disease progression (HR, 0.75; 95% CI, 0.64-0.88). Median PFS (5.8 vs 4.2 months) and response rate (35% vs 14%) were also higher with the combination. Grade 3 or 4 treatment-related sensory neuropathy, fatigue, and neutropenia were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% vs 1%). Patients with liver dysfunction were at higher risk of complications and therefore should not be treated with this regimen. Despite its toxicity, this combination represents a good alternative for patients with resistant disease previously treated with anthracyclines and taxanes and in whom a fast response is needed.