Integrating Gemcitabine Into Breast Cancer Therapy
Integrating Gemcitabine Into Breast Cancer Therapy
Gemcitabine (Gemzar) possesses meaningful antitumor activity in the treatment of breast cancer, repeatedly demonstrating superior outcomes without the price of excessive toxicity in most patients. In combination with other agents, it has a potential for nonoverlapping toxicities, a novel mechanism of action, as well as a potential lack of complete cross-resistance. Randomized phase III trials with gemcitabine have yielded response rates that have translated into time to disease progression and survival benefits. Thus, enthusiasm continues for gemcitabine, especially in combination with other cytotoxic agents. The augmentation of efficacy (ie, response rates, time to disease progression, overall survival) by the addition of gemcitabine to paclitaxel has established this regimen as a first-line treatment option for patients who might benefit from combination therapy. Gemcitabine now remains under active investigation for the treatment of early-stage breast cancer, with ongoing trials characterizing its role in the neoadjuvant setting.
As the treatment for breast cancer continues to evolve, a striking decline in breast cancer-related deaths has followed. Although largely reflecting improvements in effective screening techniques and the subsequent inherent early diagnosis of disease, improvements in treatment outcomes also bear some responsibilities for the evident decline in breast cancer mortality. However, for both early stage and metastatic disease, the goals of treatment largely remain the same and include reduction of the tumor burden, prolongation of survival, extension of the time until disease progression, as well as improvement in overall symptoms. All efforts are underscored by the desire to preserve and maintain as excellent a quality of life as possible. With the advent of newer and less toxic therapeutic options, physicians have a better chance to achieve these goals. Although systemic treatment continues to be the mainstay for both early as well as advanced stages of breast cancer, the impact of existing chemotherapy on overall survival in patients with metastatic disease remains negligible. In this population, toxicities of the recommended treatment and the quality of life remain foremost in their minds. Whether these patients may have superior clinical outcomes with combination chemotherapy regimens or sequential single agents remains of great debate. Given the heterogeneity of the disease and the lack of evidence-based guidelines in selecting patients appropriate for either of these choices, each of these treatment preferences remains a valid option. Background on Gemcitabine Gemcitabine (Gemzar) is a novel nucleoside analog that has a broad spectrum of antitumor activity in both preclinical and solid-tumor models. The drug requires intracellular phosphorylation that results in the accumulation of difluoro-deoxycytidine triphosphate (dFdCTP). The dFdCTP competes directly with deoxycytidine triphosphate (dCTP) for incorporation into DNA, acting as a fraudulent base that halts DNA synthesis.[ 2] In addition, gemcitabine reduces intracellular deoxynucleotide triphosphate pools, presumably by inhibiting ribonucleotide reductase, the enzyme essential for both the intracellular synthesis of deoxynucleotide triphosphates and normal DNA production.[ 3] This unique mechanism of action has resulted in its subsequent exciting development as an effective antitumor strategy for multiple solid tumors, including breast cancer. Since its inception, gemcitabine has consistently demonstrated a commitment to overall improvement in quality of life. Evidence of improved survival and clinical benefit in cancer patients has followed. In fact, its initial US Food and Drug Administration (FDA) approval, stemming from early studies of gemcitabine in patients with pancreatic cancer, was predicated on gemcitabine's demonstrable improvement in disease-related symptoms, which was measured by a composite assessment of pain including analgesic consumption, pain intensity, performance status, and weight. Other measures of efficacy accompanying these considerations included response rate, time to disease progression, and overall survival. From this point forward, the magnitude attributed to chemotherapyinduced palliation of disease-related symptoms in cancer patients has continued to evolve and be recognized as an equally important end point. An increasing focus on the quality of life and sustained enhancement of these parameters now accompany the other well-established primary efficacy end points of ongoing trials. Because of gemcitabine's established antitumor efficacy, over and beyond its impact on clinical benefit in cancer patients, its utilization in breast cancer has precipitously increased. Its novel mechanism of action in addition to its nonoverlapping toxicity facilitates its ideal combination with other effective agents for the treatment of advanced breast cancer. Single-Agent Studies of Gemcitabine To develop further effective systemic therapies for patients with breast cancer, gemcitabine has undergone extensive evaluation, initially in the metastatic setting, with single-agent studies reporting a response rate of 15% to 42%.[5-16] Closer examination of these trials revealed that the highest response rates occurred in minimally pretreated patients, with overall regression of bidimensional tumor measurements determining objective responses. Survival for these breast cancer patients receiving gemcitabine monotherapy ranged from 3.5 to 18 months. In addition, significant activity was evident for single-agent gemcitabine following pretreatment with both anthracyclines and the taxanes, generating subsequent enthusiasm to evaluate gemcitabine in combination with these (and other) agents. The findings of these trials are of paramount importance, as there remains considerable debate as to whether the often lesser toxicity associated with single-agent chemotherapy might outweigh the benefits of combination chemotherapy. This has perhaps been most clearly delineated with the evolution of the taxanes in metastatic breast cancer and their subsequent extended exploration in combination with the anthracyclines, at the time considered the single most effective first-line agent for metastatic breast cancer. Eastern Cooperative Oncology Group (ECOG) 1193, a trial assessing the role of combination and single- agent chemotherapy in metastatic breast cancer, has raised the question of the long-term benefits of combination therapy . In this prospective, randomized phase III trial, investigators compared single-agent doxorubicin vs single-agent paclitaxel vs their combination. As expected, the combination arm demonstrated a statistically superior response rate, albeit at the price of increased hematologic toxicity; disappointingly, neither overall survival nor quality of life varied among the three arms. However, time to disease progression, a parameter that truly reflects the administered therapy and is not influenced by subsequent posttherapy treatments, was significantly in favor of the combination arm statistically, despite a mandated, built-in single-agent sequential crossover for the respective single agents. Consequently, given the enthusiasm imparted by the addition of the taxanes docetaxel and paclitaxel to the treatment of metastatic breast cancer, further exploration of these compounds, as either single agents or in combination with other agents, in the metastatic, adjuvant, and neoadjuvant settings has eagerly followed. Rationale for Combining Gemcitabine and the Taxanes The rationale for combining gemcitabine with the taxanes paclitaxel and docetaxel (Taxotere) is based on the fact that the spindle toxins were two of the most active agents in the treatment of breast cancer. In addition, the taxanes remain active in anthracycline failures, including both anthracycline-resistant and -refractory disease, and increasingly have become utilized in early-stage disease. Gemcitabine, which is effective following pretreatment with both anthracyclines and taxanes, has been evaluated with both taxanes in a variety of phase II metastatic breast cancer trials. Since both of these beta-tubulin-binding drugs have demonstrated single-agent activity in metastatic breast cancer, their union with gemcitabine was inherent, supported by their differing cellular mechanisms of action and their largely nonoverlapping toxicity. Although empiricism often invokes the design of combination regimens in the absence of provocative in vivo preclinical data, a suggestion of clinical synergism between these agents prompted the further evaluation of this doublet as an ideal and promising treatment strategy.[18,19] One of the first phase II trials evaluating gemcitabine and the taxanes was that of Murad et al who evaluated 29 patients treated with gemcitabine and paclitaxel as second- or third-line therapy in metastatic breast cancer.[ 20] Visceral involvement was evident in the majority of patients, with all patients having received prior chemotherapy for metastatic disease. A remarkable 55% overall response rate was noted with nearly 20% of the patients achieving a complete remission. Although the initial schedule administered gemcitabine at 1,000 mg/m2 on days 1, 8, and 15, the day- 15 dose was subsequently deleted due to hematologic toxicity in these heavily pretreated patients. Utilizing docetaxel, Fountzilas et al evaluated the identical gemcitabine dose and day 1 and 8 schedule reported by Murad and colleagues in 40 anthracycline-resistant metastatic breast cancer patients. The study population consisted of a more elderly (median age, 60) and poorer prognosis patient population, with 75% of the patients exhibiting visceral metastases, and yielded a 36% overall response rate with three patients exhibiting complete remission. Median survival was consistent with that reported by Murad et al, at approximately 12 months, with a median duration of response at 10.3 months. More hematologic toxicity was noted for the docetaxel/gemcitabine doublet, reflecting docetaxel's schedule-dependent noncumulative myelosuppression, with 49% of the patients demonstrating grade 3/4 neutropenia. The remarkable activity of the gemcitabine/ taxane doublet in pretreated breast cancer patients with easily demonstratable, consistent efficacy parameters, in addition to manageable toxicity, resulted in the further evaluation of this combination as first-line treatment in metastatic breast cancer. The principle of clinical synergism, nicely highlighted by two trials, has heralded the further investigation and evaluation of this couplet in metastatic as well as early-stage breast cancer. In the first of these two trials, Mavroudis et al reported the results of gemcitabine and docetaxel in 52 anthracycline-resistant patients, half of which had received treatment with a prior taxane. Visceral disease was present in 75% of the patients, with 50% of the patients receiving this combination as third-line therapy or greater. The overall response rate was 54%, with approximately 15% of the patients achieving complete responses. Surprisingly, in the 25 patients who were both anthracycline resistant and who had received prior taxane therapy, an overall admirable response rate of 44% was noted, clearly higher than expected in such a heavily taxane-pretreated patient population. In a second trial, Alexopoulos et al evaluated 36 metastatic breast cancer patients, all of whom had received a prior anthracycline and taxane. Following four to six cycles of single- agent docetaxel at a dose of 100 mg/m2 at 3-week intervals, the 22 patients with stable disease and 14 patients with progressive disease continued receiving docetaxel, to which gemcitabine (900 mg/m2 on days 1 and 8) was added. An astonishing response rate of 72% (with complete remissions in 12% of patients) was reported. Although previous studies  reported a 25% response rate for docetaxel administered in paclitaxel-resistant advanced breast cancer, the observation that the docetaxel/gemcitabine combination induces significant responses in patients who progress while receiving docetaxel-based front-line chemotherapy, supports the consideration of an in vivo synergistic effect between these two agents. Certainly provocative, the Hellenic Cooperative Group for Breast Cancer's trial further defined the activity of gemcitabine/ docetaxel. This encouraging activity in heavily pretreated patients fostered the evaluation of the gemcitabine/taxane doublet as first-line chemotherapy in metastatic breast cancer. Delfino et al presented data in the first-line treatment setting employing gemcitabine at a dose of 1,200 mg/m2 on days 1 and 8 with paclitaxel at 175 mg/m2 on day 1. An overall response rate of 55% (with 14% complete remissions), and an estimated 1-year survival rate of 65% were reported. Hematologic toxicity was minimal, with only a 14% incidence of grade 3/4 neutropenia. However, the highest response for a gemcitabine/taxane doublet was noted by Laufman et al, who reported a notable intent-to-treat response rate of 79% accompanied by a median survival of just over 2 years. Neutropenia was universal with this days 1, 8, and 15 gemcitabine schedule; however, only six patients developed febrile neutropenia. Prophylactic growth factor use was prohibited. To capitalize on the significant activity noted for this schedule, Palmeri et al evaluated a weekly docetaxel regimen in lieu of the every 21-day standard docetaxel schedule. Preliminary phase II results demonstrated preserved efficacy, with response rates of 75%; however, preliminary toxicities have not yet been reported. Whether hematologic toxicity was minimized by incorporation of a weekly docetaxel schedule is not yet evident. Differing gemcitabine infusion durations have also been evaluated. Given that the phosphorylation of gemcitabine to the monophosphate by deoxycytidine kinase is the rate-limiting step in the subsequent accumulation of the diphosphate and triphosphate metabolites, the ability of mononuclear cells to accumulate triphosphate gemcitabine was optimized using dosing rates of 10 mg/m2/min.[26,27] A comparison between a gemcitabine fixed infusion rate of 10 mg/m2/min vs a 30-minute bolus infusion following a docetaxel 1-hour infusion in metastatic breast cancer patients demonstrated that the 30-minute infusion schedule allowed for higher doses of each drug to be administered with less observed toxicity.[ 28] In a recently reported randomized phase II trial comparing a 30-minute infusion vs a fixed-dose rate infusion in patients with pancreatic cancer, Tempero et al reported a statistically superior overall median survival at 8 months vs 5 months in favor of the fixed-rate infusion schedule, albeit with consistently more hematologic toxicity. Future trials will address whether increases in efficacy are observed with this schedule in breast cancer. In either regard, a Financial Disclosure: Dr. Yardley has received research support from Lilly, Pfizer, Aventis, and Genentech. She has acted as a consultant for Lilly and Aventis. She has served on the speakers' bureaus for Lilly, Aventis, Genentech, and Bristol-Myers Squibb. high response rate and markedly prolonged survival characterize this doublet balanced with easily manageable toxicity, either in the first-line setting or as salvage therapy. Nevertheless, findings from several recent phase I studies identifying the biweekly schedule as perhaps one of the most advantageous gemcitabine- administration schedules have challenged this schedule as the besttolerated one. Demonstrating a favorable toxicity profile in the setting of significant activity in previously treated patients with advanced breast cancer, the fortnightly schedule permits easily achieved dose intensification for both agents. Enhanced activity (with surprisingly less hematologic toxicity) characterizes this every-2- week schedule. Accumulated data generated from several phase I trials led to[28,30,31] Colomer et al's evaluation of gemcitabine at 2,500 mg/m2 with paclitaxel at 150 mg/m2 administered every 14 days. They reported a 69% response rate, with one-quarter of the patients demonstrating complete responses. Grade 3/4 neutropenia was minimal, at 17%, with febrile neutropenia evident in only one patient; nonhematologic toxicity was insignificant. The median duration of response was 11 months; mature survival data have not yet been reported. Pelegr and coworkers evaluated the taxane docetaxel at 65 mg/m2 with Colomer et al's gemcitabine regimen, again noting significant activity evident with a 66% response rate and 13% CRs with the biweekly schedule. With docetaxel, the grade 3/4 neutropenia was higher at 46%, with only two cases of febrile neutropenia; additional efficacy parameters were not available at the time of their report. Whether dose intensification of these combinations results either in enhanced progression-free or overall survival cannot be discerned at this time. Nonetheless, it is evident that the biweekly schedule, with the accompanying two- to threefold increase in delivered dose of gemcitabine, produces response rates that are significantly higher without incurring additional toxicity. Perhaps most astounding is that this accelerated or socalled dose-intense program was delivered without the need for growth factor support. This attractive approach offers an active and appealing schedule with significant future development potential. Phase III Data With Gemcitabine in Breast Cancer Based on the significant activity demonstrated for the gemcitabine/taxane doublet, Albain et al subsequently conducted a randomized, prospective phase III trial (JHQG) at 98 centers in 19 countries to characterize specifically and identify the potential benefit of adding gemcitabine to standard-dose paclitaxel compared with standard-dose paclitaxel monotherapy (n = 529 evaluable). Anthracycline- pretreated, locally advanced and metastatic breast cancer patients having received no prior chemotherapy for metastatic breast cancer were enrolled and randomized to receive gemcitabine at 1,250 mg/m2 on days 1 and 8 plus paclitaxel at 175 mg/m2 on day 1 vs paclitaxel alone every 21 days until disease progression. With a median age of 53, patient characteristics and demographics were balanced in both treatment arms. Visceral metastases were noted in 70%, with two or more sites of metastatic disease present in 76%. Unlike most other combinations, including the combination arm of ECOG 1193, full doses of both gemcitabine and paclitaxel were administered in the combination arm, with P P P = .018), with median overall survival also increased in those receiving the couplet (18.5 vs 15.8 months). One-year survival was significantly increased for the gemcitabine plus paclitaxel arm (70.7% vs 60.9%; P = .019). Definitive, protocol-specified overall survival analysis will take place in 2005. Perhaps even more impressive is that this benefit did not come at the cost of excessive toxicity or impaired quality of life, as is often the case when combining two or more antineoplastic agents. In addition, three parameters assessing pain relief (with the Brief Pain Inventory [BPI]), overall patient functioning, and quality of life while receiving the gemcitabine/ paclitaxel combination were also measured in a subset of patients. With regard to pain relief (291 patients completed the BPI questionnaire), patients receiving single-agent paclitaxel manifested unchanged pain scores throughout their treatment, whereas patients receiving the combination couplet demonstrated a trend toward improvement. This result also translated into a 25% decrease in usage (investigator rated) of analgesic medications for those patients treated with the combination (vs 14% for patients receiving paclitaxel alone), based on patients requiring analgesics at baseline.[ 35] Investigators used the Rotterdam System Checklist for overall qualityof- life assessment (370 patients completed the questionnaire), and no significant differences were evident between the single-agent and combination gemcitabine/paclitaxel arm. However, for those patients receiving gemcitabine and paclitaxel, the main quality-of-life scores were significantly improved over baseline scores statistically, notably at cycles 5 and 6 (P = .005 and .0036, respectively) but not for those treated with single-agent paclitaxel. The incidence of grade 3/4 febrile neutropenia (5% vs 2% of patients), anemia (7% vs