The Emerging Role of Paclitaxel in Breast Cancer Therapy1

Vol. 1, 247-256, March 1995 Clinical Cancer Research 247

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Andrew D. Seidman2 overexpressing subline of MCF-7 cells appears to result in the Breast and Gynecological Oncology Service, Memorial Sloan- development of 4.4-fold less resistance (6). Furthermore, in Kettering Cancer Center, New York, New York 10021 paclitaxel-resistant cells, the ratio of soluble to polymerized tubulin is greater than that observed in sensitive cells (7). Introduction Ongoing investigation should clarify the relationship between Multiple chemotherapeutic agents and regimens exist with tubulin alterations and resistance to taxanes. documented antitumor activity against breast cancer; however, In parallel with the development of clinical trials of paclitaxel- less than one in five patients with stage IV breast cancer are alive based combination regimens, in vivo and in vitro studies have 5 years from the first detection of distant metastases (1). Although examined combinations for cytotoxicity in several systems. In vitro improved response proportions have been observed, overall sur- studies in human MCF-7 breast carcinoma cells exposed to a LD vival for patients with metastatic breast cancer has not been sig- of paclitaxel for 24 h followed by a 1-h incubation with varying nificantly improved by the progress of the past three decades. Furthermore, despite the proven magnitude of benefit of adjuvant concentrations of doxorubicin showed less than additive cytotoxicity for the combination of paclitaxel and doxorubicin (8). On the systemic therapy in reducing the risk of recurrence (2), a significant fraction of patients with early stage breast cancer still will relapse other hand, when an AlT cell viability assay was used, others have and ultimately die of metastatic disease. Clearly new active agents shown the combination of paclitaxel and doxorubicin to be partly and strategies are needed to improve upon this situation. synergistic in vitro (82). Clonogenic cell survival assays have The development of paclitaxel (Taxol#{174}), the prototype demonstrated maximum cytotoxicity in MCF-7 cells when expo- taxane, as an anticancer agent accelerated after the elucidation sure to alkylating agents precedes paclitaxel (9). In SKBR-3 human of its unique mechanism of action (3) and by the initial dem- breast adenocarcinoma cells, pretreatment with edatrexate, a new onstration of its activity in refractory advanced ovarian carci- dihydrofolate reductase inhibitor, before paclitaxel showed marked noma (4). Multidisciplinary efforts to procure sufficient quan- synergism in inhibiting cell growth, while the reverse schedule tities of this agent have allowed a rapid expansion of clinical showed antagonism (10). Synergy has also been reported in trials. This review will address the development of paclitaxel for MDA-MB 435 human breast cancer cells when gallium nitrate, a use in breast cancer, the clinical results noted thus far in the ribonucleotide reductase inhibitor, preceded paclitaxel (1 1), and treatment of metastatic disease, the design of presently ongoing similarly when tiazofurin, a C-nucleoside, was applied prior to trials, and examine avenues of future investigation. paclitaxel in the same cells (12). Others have reported preliminarily on similar sequence and schedule-dependent effects between pa- Predlinical Activity of Paditaxel against Breast Cancer clitaxel and fluorouracil (77), navelbine (78, 79), and estramustine Paclitaxel was chosen for development in part because of (80). While Phase I clinical trials of cytotoxic combinations are significant activity against the subrenally implanted human often empiric or based on in vitro studies such as those mentioned MX-1 mammary tumor xenograft (5). In this model, following above (76), computerized quantitation of synergism and antago- subrenal implantation in athymic mice, s.c. administration of nism of paclitaxel, topotecan, and cisplatin against human terato- paclitaxel (200 mg/kg) on days 1-10 resulted in mammary carcinoma cells may offer a rational alternative to clinical protocol tumor regression. In vitro studies suggest that phenotypic resis- design (81). This approach uses the combination index-isobolo- tance may relate in part to the duration of paclitaxel exposure (6, gram method and is based on the median effect principle which 27, 83). In in vitro studies using paclitaxel in DMSO, CHO and considers the potencies of each drug and combinations of drugs, as human A2780 cells were more responsive to increased exposure well as the shape of their dose-effect curves (81). time than to increased dose above plateau concentrations of With a greater understanding of autocrine and paracrine 0.8-1.6 sWml and 0.01 jig/ml, respectively. However, in four regulation of breast cancer cell proliferation and growth, novel human ovarian carcinoma cell lines treated with paclitaxel in treatment strategies are emerging (13). Synergistic cytotoxicity Cremophor EL, prolonging the duration of paclitaxel exposure has also been demonstrated for the combination of paclitaxel did not appear to increase cell kill or the fraction of cells in and mAbs directed against the her-2/neu receptor in BT-474 G2-M, suggesting that intracellular binding of paclitaxel to cells (which overexpress this receptor) and with the anti-EGFr3 microtubules is stable (84). In this study, there was a suggestion 528 in MDA-468 cells, which overexpress EGFr (14). that Cremophor EL at high concentrations may contribute to the cytotoxic response. With regard to breast carcinoma, prolonga- tion of paclitaxel exposure from 3 to 24 h in a P-glycoprotein

3 The abbreviations used are: EGFr, epidermal growth factor receptor; MSKCC, Memorial Sloan-Kettering Cancer Center; rhG-CSF, recombinant Received 1 1/14/94; accepted 12/22/94. human granulocyte-colony-stimulating factor; CR, complete response; G- t was supported by the American Society of Clinical Oncology Research CSF, granulocyte-colony-stimulating factor; EORTC, European Organiza- Career Development Award. tion for Research on Treatment of Cancer; ECOG, Eastern Cooperative 2 To whom requests for reprints should be addressed, at Breast and Oncology Group; mdr, multidrug resistant; CMFP, Cyclophosphamide- Gynecologic Oncology Service, Memorial Sloan-Kettering Cancer Cen- methotrexate-5-fluorouradil-prednizone; AFM, Adnamycin-5-fluoroura- ter, 1275 York Avenue, New York, NY 10021. cil-methotrexate.

Paclitaxel in Patients with Minimal Prior progression or relapse within 6 months of prior chemotherapy. Chemotherapy Approximately one-third of patients had received only adjuvant chemotherapy, one-third had been treated with one regimen for Phase II Trials. Two initial Phase II clinical trials demon- metastatic disease only, and another third of patients had received strated the significant antitumor activity of paclitaxel in patients both. With 471 patients entered and 454 evaluable for response, who had received minimal prior chemotherapy. In 1991, Holmes et 29% of patients (65/225) responded at the higher dose level, with a!. (15) at M. D. Anderson Cancer Center reported a 56% (95% a 22% response rate (51/229) at the lower dose level (P = 0.108). confidence interval, 35-76%) response proportion in women re- The median time to progression for patients treated with 175 ceiving 200-250-mg/m2 doses via 24-h i.v. infusion every 3 weeks mg/m2 was 4.2 months versus 3.0 months with 135 mg/m2 (ad- as a second chemotherapy regimen (1 1 patients had prior chemo- justed relative risk, 1.34, P = 0.003, log rank P = 0.02). Treatment therapy for metastatic disease, 14 as adjuvant therapy). The median was well tolerated at both dose levels; with 175 mg/rn2, grade 4 response duration was 9 months, with a median time to progression neutropenia of short duration occurred in 27% of patients. Overall for all patients of 10 months. Granulocytopenia was dose limiting, the safety of 3-h pacitaxel infusions in this dose range was firmly but febrile neutropenia occurred in only 5% of 232 courses. A established in more than 2500 cycles of therapy, with a very low confirmatory trial at MSKCC studied the drug as first chemother- incidence of febrile neutropenia (<5% of patients), and a less than apy for stage IV disease in 28 patients (16, 17). rhG-CSF was 10% incidence of any grade 3-4 nonhematological toxicity. Sub- administered daily at 5 p.gfkg/day s.c. on days 3-10 to ameliorate sequent to this trial, in April 1994 the U.S. Food and Drug Ad- anticipated myelosuppression. Three complete and 13 partial re- ministration approved paclitaxel for use in metastatic breast cancer sponses were noted in 26 evaluable patients (62%; 95% confidence at 175 mg/m2 via 3-h infusion after failure of chemotherapy or interval, 41-80%) who received paclitaxel at 250 mg/m2 via 24-h relapse within 6 months of adjuvant chemotherapy. continuous i.v. infusion every 21 days. Responses were observed in visceral, osseous, and nodal/soft tissue sites of disease, including a Paclitaxel in Patients with Extensive Prior Therapy pathologically documented CR in recurrent disease in a previously After the observation of significant antitumor activity of irradiated chest wall site. Treatment was generally well tolerated, paclitaxel in women with stage IV breast cancer with minimal with only 4% of 178 treatment cycles resulting in febrile neutro- prior therapy, a Phase II investigation of the agent as a 24-h penia in 6 patients. The use of rhG-CSF was associated with a infusion with 200 mg/m2 + G-CSF was performed in patients shorter duration of absolute neutropenia < 500 cells/mm3 (3.5 who had received 2 prior regimens in the management of days) in comparison to pacitaxel administration without growth metastatic disease. In this trial 14% of patients had received factor (7 days; Refs. 15 and 16). In a separate MSKCC Phase II prior high-dose chemotherapy regimens requiring autologous trial of paclitaxel at 250 mg/m2 + G-CSF in women who had marrow or peripheral blood progenitor cell plus hematopoietic received one prior chemotherapy regimen for stage IV disease, 9 growth factor support, and 67% had had prior radiotherapy in partial and 2 complete responses were observed in 25 patients the management of metastatic disease; all patients had received (44%; 95% confidence interval, 24-65%; Ref. 16). In these trials prior anthracycline. Partial objective responses were observed in dose escalation was not possible despite the use of prophylactic 14 of 51 patients (27.5%; 95% confidence interval, 16-42%) colony-stimulating factor. Dose reductions to 175-200 mg/m2 by who had received a median of 3 (range, 2-6) prior chemother- the fourth treatment cycle were not uncommon, most frequently for apeutic regimens for metastatic disease, with a median response neutropenia and its complications. duration of 7 months (17, 18). Not surprisingly, results from We have also evaluated pacitaxel at a 250-mg/m2 dose via MSKCC and other trials of paclitaxel in metastatic breast cancer 3-h infusion every 3 weeks as initial chemotherapy for metastatic show a relationship between the extent of prior chemotherapy breast cancer, noting responses in 32% of patients (95% confidence previously received for stage IV disease and the likelihood of interval, 15-53%), including one complete response. The median antitumor response. response duration was 7 (range, 2-13+) months (20). In this trial, Early results of a Phase II trial of paclitaxel at 135-150 a previously unreported symptom, photopsia, was observed in 6 mg/rn2 via 24-h infusion without G-CSF in patients who had patients at doses of 250-275 mg/m2 (jatients experienced a tran- received 3 prior chemotherapy regimens for metastatic disease sient sensation of “flashing lights” across the visual field). Inde- showed partial responses in 6 of the first 32 evaluable patients pendent observations and investigation of this phenomenon in (18.8%; 95% confidence interval, 7-36%), with patients still on patients receiving 3-h infusions in Milan suggests that this phe- study4 (23). In the initial 113 courses, febrile neutropenia oc- nomenon may represent an optic neuropathy (21). Of potential curred in approximately one-third of patients and in one-fifth of relevance, pharmacokinetic data show a saturable component to treatment cycles. In evaluating a shorter infusion schedule as clearance when paclitaxel is administered via 3-h infusion, with a salvage chemotherapy at MSKCC, 25 patients who have re- plateau at doses of 250-300 mg/m2 (22). Thus, small changes in ceived 2 prior regimens for stage IV disease have received 3-h dose administered in this range via short infusion schedule may paclitaxel infusions of 175 mg/m2 every 21 days. Treatment was result in disproportionate increases in drug exposure and toxicity, well tolerated, and a response proportion of 20.8% (95% con- as the area under the time versus concentration curve and the fidence interval, 7-42%) has thus far been observed (20). The maximum concentration may continue to increase linearly. Phase ifi Randomized Trials. A large multicenter trial conducted in Canada and Europe has compared two doses of paclitaxel in metastatic breast cancer, 135 versus 175 mg/m2, both

via 3-h infusion (19). Patients were stratified on the basis of 4 F. Holmes, personal communication.

Table I Randomized trials of paclitaxel in metastatic breast cancer 3-h infusion schedule with doses of 250-300 mg/m2 has been evaluated in patients with anthracycline-resistant disease de- addressing dose and schedule of administration fined more stringently as having progressed on doxorubicin or Study group Dose (mg/rn2) Schedule (h) epirubicin for metastatic disease within a maximum 12-week Canadian/European (048) 175 versus 135 3 interval before starting paclitaxel. In a preliminary report, Ver- CALGB5 9342 175 versus 210 vs. 250 3 morken (Ref. 74; for the European Cancer Center, Amsterdam, Canadian/European (071) 175-sMTD 3 versus 24 the Netherlands) noted responses in 6 of 36 evaluable patients NSABP B-26 250 3 versus 24 MDACC/MSKCC/BCCNSTI 250 versus 140 3 versus 96 (16.7%; 95% confidence interval, 6-33%). a CALGB, Cancer and Leukemia Group B; NSABP, National Motivated by the activity noted in the aforementioned Surgical Adjuvant Breast and Bowel Program; MTh, maximum toler- single-institution trials, the National Cancer Institute developed ated dose; MDACC, M. D. Anderson Cancer Center; BCCA, British a Treatment Referral Center program (TRC-9202) for the corn- Columbia Cancer Agency; 511, Swedish Tumor Institute (Seattle). passionate use of paclitaxel as salvage chemotherapy. Two hundred fifty-six patients who had received at least two prior activity is also being evaluated in a trial of a 14-day continuous regimens for metastatic disease were treated with 175 mg/rn2 via infusion schedule at the NCI Medicine Branch. 24-h infusion (135 mg/rn2 for “high-risk” patients defined by extent of prior radiotherapy or mitomycin C), with accrual Randomized Trials completed early in 1993. A response proportion of 23% was Trials Addressing Optimal Dose and Infusion Duration. noted among the first 156 evaluable patients, with a median Several ongoing randomized trials are presently addressing the response duration of 5 + months (24). Among these heavily important issues of optimal dose and duration of drug infusion pretreated patients, 46% experienced febrile neutropenia, sug- for paclitaxel in the treatment of breast cancer (Table 1). The gesting the potential need for frequent dose reduction or pro- Canadian (National Cancer Institute of Canada)/European phylactic growth factor support in this category of patient re- (EORTC) trial randomizing patients to two dose levels of pacli- ceiving these doses via this schedule. Other nonhematological taxel, both via 3-h infusion, has been addressed (19). Another toxicities were rarely of grade 3-4 severity. Canadian/European trial randomizing patients to receive pacli- It is important to note that quality of life end points are being taxel at 175 mg/m2 via 3 versus 24-h infusion schedules, with addressed in many single-institution and multicenter studies eval- the opportunity for intrapatient dose escalation to the maximally uating paclitaxel and other agents for metastatic breast cancer. tolerated dose, has completed accrual of over 500 patients. At Prospective evaluation of pain, tumor-related symptoms, and the time of this report, results have not yet been available from global quality of life parameters suggests the palliative potential of this important trial. The Cancer and Leukemia Group B is paclitaxel in responding patients treated in a “salvage” setting comparing the high-dose arm of the Canadian/European ran- (25). An intergroup randomized trial led by the Eastern Coopera- domized trial (175 mg/m2 via 3-h infusion) with paclitaxel at tive Oncology Group of paclitaxel versus doxorubicin versus the higher doses of 210 and 250 mg/rn2 via 3-h infusion (rhG-CSF combination with rhG-CSF incorporates the recently validated in- support as needed at 250 mg/rn2). Accrual to this important trial strument ‘ ‘Functional Assessment of Cancer Treatment-B’ ‘ (26) to is expected to be completed in 1996. In another randomized assess the impact of these three treatment arms as initial chemo- trial, the National Surgical Adjuvant Breast and Bowel Project therapy for metastatic breast cancer. Such analyses should allow a may evaluate paclitaxel at its maximally tolerated dose of more enlightened understanding of the impact of these therapeutic 250 mg/rn2 with rhG-CSF, randomizing patients to receive 3-h options for patients with metastatic breast cancer. versus 24-h infusions. In perhaps a more definitive test of the Motivated by in vitro data supporting a role for prolonged question of the importance of infusion duration, a multicenter exposure to paclitaxel in breast cancer cells (6, 27, 83), a 96-h trial involving the M. D. Anderson Cancer Center, MSKCC, continuous infusion schedule was evaluated in patients with an- British Columbia Cancer Agency (Vancouver, British Colum- thracycline-resistant metastatic breast cancer (28). In this Phase I-Il bia), and Swedish Tumor Institute (Seattle, WA) is comparing study, doses of 120-140 mg/rn2 were found to be tolerated over a 3-h and 96-h infusion schedules in patients with refractory 4-day administration period; antiallergic premedication was not metastatic breast cancer. The results of these trials, when avail- administered and no serious hypersensitivity reactions occurred. able, should clarify the significance of dose and duration of Considerable activity was noted, with 16 of 33 patients responding infusion. (48%; 95% confidence interval, 31-66%). In three patients in Trials Addressing Comparative Safety and Efficacy whom pretreatment and posttreatment biopsies were assessed for with Other Agents and Regimens. Other ongoing random- mdr-1 expression, no relationship between expression and response ized clinical trials will allow an estimation of the comparative to paclitaxel was noted. Notably, low levels of mdr-1 expression efficacy and tolerability of paclitaxel with other standard agents were seen in these tissues previously exposed to doxorubicin, and regimens in the management of stage IV breast cancer suggesting that non-rndr-mediated mechanisms of anthracycline (Table 2). The Eastern Cooperative Oncology Group, in collab- resistance were operative. oration with the Southwest Oncology Group and the North At MSKCC we have evaluated the potential efficacy of a Central Cancer Treatment Group, is rapidly accruing patients to 96-h paclitaxel infusion administered shortly after demonstrated a randomized trial of paclitaxel at 175 mg/m2 (24-h infusion) disease progression on prior 3-h paclitaxel (or 1-h docetaxel) infusion (29). Preliminary results show responses in 7 of 25 patients (28%; 95% confidence interval, 12-49%), with 7 patients still on study. The observation of schedule-dependent 5 E. Winer, personal communication.

Table 2 Randomized trials addressing comparative safety and other active agents. Doxorubicin was the obvious first choice efficacy with other agents and regimens due to its high level of antitumor activity. The National Cancer Trial design Institute (Bethesda, MD) and M. D. Anderson Cancer Center Study group (mg/rn2) designed parallel trials combining paclitaxel and doxorubicin as

ECOG , Paclitaxel, 175 (24 h) initial therapy for metastatic disease. The National Cancer In- 4 Doxorubicin, 60 (bolus) stitute trial delivered both agents by simultaneous 72-h infusion Paclitaxel, 150 + doxorubicin 50 + G-CSF with concurrent prophylactic G-CSF at 10 p.g/kg/day. Two US NCI Paclitaxel, 175 (3 h) every 3 wk maximum tolerated doses were defined for paclitaxel/doxorubi- TRC 93-01 .L. Vinblastine, 5.5 every wk cm: 160/75 and 180/60 mg/rn2 (31). Unexpectedly, at higher Institut Curie, Paclitaxel, 175 (3 h) every 3 wk dose levels, two patients presented with cecal inflammation or et al. Mitomycin C, 12 every 6 wk typhlitis (32). Anemia and thrombocytopenia were common and Australia/ Paclitaxel, 175 (3 h) every 3 wk cumulative; 47% of cycles required hospitalization for neutro- New Zealand CMFP penia fever. Objective responses were observed in 62% (95% EORTC ,, Paclitaxel, 200 (3 h) every 3 wk confidence interval, 36-83%) of 18 evaluable patients, includ- L.> Doxorubicin, 75 every 3 wk ing 1 CR, in this Phase I trial (31). The M. D. Anderson group evaluated a sequential approach to the combination, administering paclitaxel via 24-h infusion versus bolus doxorubicin at 60 mg/rn2 versus the combination of on day 1 followed by doxorubicin via 48-h infusion on days 2 paclitaxel plus doxorubicin at 150 mg/rn2 and 50 mg/m2, re- and 3, with G-CSF 5 pg/kg/day prophylactically (33). Dose- spectively, as first chemotherapy of metastatic breast cancer limiting stomatitis and febrile neutropenia were experienced at (rhG-CSF prophylactically in the combination arm). Patients paclitaxel/doxorubicin doses of 125/60 (mg/rn2), requiring dose receiving either paclitaxel or doxorubicin will crossover to the reduction. When the reverse sequence iteration was tested, the opposite single-agent arm upon disease progression, thus allow- maximum tolerated dose for these agents was 150/60, respec- ing more accurate assessment of the extent of clinical cross- tively. Pharmacokinetic studies revealed the maximimum con- resistance between these two important agents. In another direct centration (Cmax) and area under the time versus concentration comparison of these drugs, the EORTC is conducting a trial curve for doxorubicin to be significantly increased when pacli- comparing paclitaxel via 3-h infusion at 200 mg/m2 versus bolus taxel is administered before doxorubicin with these infusion doxorubicin at 75 mg/m2 every 3 weeks, also with an opportu- schedules, suggesting that paclitaxel might impair the hepatic nity for crossover at the time of disease progression. metabolism of subsequent doxorubicin (34). The U.S. National Cancer Institute’s Treatment Referral Cen- In preparation for a Phase III trial, the ECOG conducted ter protocol 93-01 compares paclitaxel at 175 mg/rn2 via 3-h in- two pilot studies evaluating paclitaxel/doxorubicin combina- fusion every 3 weeks versus weekly vinblastine at 5.5 mg/rn2 in tions. In the first, paclitaxel and doxorubicin were given singly patients who have received prior chemotherapy for metastatic dis- in alternation every 3 weeks at doses of 200 mg/rn2 and 75 ease, and who have anthracycline-refractory disease; crossover to mg/rn2, respectively. At these doses, paclitaxel cycles resulted in the alternate single agent at disease progression will also provide more granulocytopenia and less thrombocytopenia than doxo- for assessment of cross-resistance. This trial will compare the activ- rubicin cycles; objective responses were noted preliminarily in 7 ity and tolerability of two agents with distinctly different antimi- of 12 patients who had received no more than one prior che- crotubular effects. In parallel with this, as well as the aforemen- motherapy regimen (35). In a second study, doxorubicin and tioned ECOG and EORTC trials, quality of life parameters will be paclitaxel were given in combination, doxorubicin as a bolus evaluated in parallel with standard assessment of tumor response. infusion and paclitaxel as a 24-h infusion. The order of admin- A French trial comparing the single agents paclitaxel at 175 istration was alternated between and within patients to best mg/m2 (3-h) every 3 weeks and mitomycin C at 12 mg/m2 every assess the impact of schedule on toxicity. Based on the experi- 6 weeks in previously treated pateints with metastatic breast ence of this study, the regimen of 50-mg/rn2 doxorubicin fol- cancer showed an early advantage for paclitaxel. With 25 pa- lowed by 150-mg/rn2 paclitaxel, with prophylactic G-CSF at 5 tients evaluable on each arm, 5 responses (20%) were noted for jig/kg/day, was felt to be optimal for future comparison against paclitaxel versus 1 (4%) for mitomycin C (P = 0.08), with a single-agent regimens (36). median time to progression of 13.3 weeks for paclitaxel versus Given the prospective randomized demonstration of less 8 weeks for mitomycin C (30). myelosuppression with 3-h compared with 24-h paclitaxel infu- Finally, in Australia and New Zealand, a trial comparing sions (37) and the aforementioned difficulties combining pacli- paclitaxel at 175 mg/rn2 via 3-h infusion every 3 weeks versus taxel and doxorubicin (31, 33), Gianni et al. (38), at the Instituto CMFP combination therapy has accrued over one-half its target Nazionale Tumori in Milan, investigated the combination of goal of 200 patients. The mature results of all of the above trials bolus doxorubicin and 3-h paclitaxel in a dose and sequence should better define the role of paclitaxel in the management of finding study (38). Paclitaxel and doxorubicin were given in metastatic breast cancer. both sequences again within and between patients, with dose escalation of paclitaxel from 125 mg/rn2 as tolerated. Doxoru- Paclitaxel Combination Trials bicin was fixed at 60 mg/rn2, G-CSF was not utilized prophy- Doxorubicin. A logical next step in the development of lactically, and treatment was planned every 21 days. Paclitaxel paclitaxel for the treatment of metastatic breast cancer was doses of up to 200 mg/rn2 together with doxorubicin at evaluating potentially synergistic combination regimens with 60 mg/rn2 have been tolerated, and sequence-dependent toxicity

Table 3 Clinical trials evaluati ng paclitaxel combination regimens with doxorubicin, cy clophospharnide, and cisplatin

Sequence MTD Trial design G-CSF? dependence? DLV’ (mg/rn2) Reference

Paclitaxel (P) + doxorubicin (D) Simultaneous + na. Neutropenia I#{212}OP/75Dor 31 72-h infusion Thrombocytopenia 180P/60D Typhlitis (GI) Sequences + Yes Mucositis P-D l25P/48D 33 P, 24 h/D, 48 h Neutropenia D-P 150P/#{212}OD 34 Sequences P, 24 h/D, bolus + Yes Mucositis D-P 150/50 36 Neutropenia Sequences

P, 3 h/d, bolus - No Mucositis Either sequence 38 Neutropenia 2()OP/60D ?Cardiomyopathy5

Sequences - No Neutropenia (too early) 88 P, 3 h/D, bolus ?Cardiomyopathy

Paclitaxel (P) + cyclophosphamide (C) Simultaneous + na. Neutropenia 160P/2700C 39 72-h infusion Thrombocytopenia Sequences + Yes Typhlitis (GI) 200P/1600C 40 P, 24 h/C, 1 h Neutropenia Myalgia/malaise P, 3 h-sC, 1 h pm na. Not yet noted Not yet reached 41 175 + (P)/750 + (C)

Paclitaxel (P) + cisplatin (C) P, 24 h day I, + na. Neutropenia 200P/75C 43 C, bolus day 2 Neuropathy Anemia

P, 3 h, then - na. Neutropenia 90P/60C 44 C, 3 h day 1 biweekly

“DLT, dose-limiting toxicities; MTh, maximum tolerated dose; na., not applicable. h See below.

with this administration schedule was not noted. Of concern, 5 paclitaxel preceded cyclophosphamide, without an apparent phar- patients developed significant decline in cardiac ejection frac- macological explanation (40). At MSKCC, building on our prior tion with clinical congestive heart failure, with a median cumu- experience with sequential high-dose alkylating agents for chemo- lative doxorubicin dose of 420 mg/m2; 3 of these patients had therapy-responsive stage IV disease, we have incorporated pacli- previously received left-sided chest wall/breast radiotherapy. A taxel into a regimen of tandem high-dose cyclophosphamide + very high degree of antitumor activity has been noted, with paclitaxel and high-dose thiotepa + paclitaxel doublets adminis- nearly 90% of patients responding.6 Early results from Herlev tered every 2 weeks, with G-CSF and peripheral blood progenitor Hospital and Rigshospitalet in Denmark confirm both the activ- cell support. This protocol derives from our prior experience in ity and potential for cardiomyopathy with this regimen.7 These ovarian carcinoma where we have previously noted enhanced mo- trials are summarized in Table 3. bilization of CD34 peripheral blood progenitor cells noted with Cyclophosphamide. Combinations of paclitaxel and cy- the high-dose cyclophosphamide + paclitaxel doublet when com- clophosphamide at various doses and schedules are being eval- pared to cyclophosphamide alone (42). uated at the National Cancer Institute Medicine Branch (39), the Cisplatin. Cisplatin has significant antitumor activity in pa- Johns Hopkins Oncology Center (40), in Bellizona, Switzerland tients with minimally treated metastatic breast cancer (43). Trials (41), and at MSKCC (42), and are summarized in Table 3. Clini- reporting combinations of paclitaxel with cisplatin in patients with cally relevant doses of these agents are achievable in patients with advanced breast cancer have been performed at New York Uni- refractory metastatic breast cancer, with the need for prophylactic versity Medical Center (44) and at the British Columbia Cancer colony-stimulating factor support dependent on the dose and sched- Agency in Vancouver (45), where a unique biweekly schedule of ule used. Interestingly, in the Johns Hopkins Oncology Center administration was evaluated (Table 3). Again, hematological tox- experience with 1-h cyclophosphamide and 24-h paclitaxel admin- icity varied according to the dose and infusion duration of pacli- istration, hematological toxicity appeared to be more severe when taxel in these trials; the optimal sequence of administration for these two agents has been well described (46). Other Agents. Investigators at Duke University have

6 L. Gianni, personal communication. demonstrated the feasibility of administering infusional 5-flu- 7 P. Dombernowsky, personal communication. orouracil at 250 mg/m2/day for 6 weeks between courses of

high-dose chemotherapy, both with and without concomitant ity to overcome paclitaxel resistance in vitro with agents (e.g., paclitaxel at 175 mg/m2 via 3-h infusion every 21 days. There calcium channel blockers and cyclosporine and its analogues; was no compromise of 5-fluorouracil dose by paclitaxel with Refs. 55 and 56) and strategies (e.g., prolonged drug exposure; concurrent administration (47). At MSKCC, we have evaluated Refs. 6, 27, and 83) that address mdr. Indeed, even the Cremo- the combination of paclitaxel and edatrexate, a dihydrofolate phor vehicle in which paclitaxel is formulated has the ability to reductase inhibitor that displays preclinical advantages over reverse multidrug resistance in preclinical systems (57, 58). methotrexate and demonstrated single-agent activity against Despite this, of particular relevance to the clinician are re- breast cancer. Preclinical synergy has been noted for the peated observations thus far of at least partial clinical non-cross-

edatrexate -#{247} paclitaxel sequence in vitro in human SKBR-3 resistance for paclitaxel with doxorubicin in the management of human breast adenocarcinoma cells (10), with antagonism advanced breast cancer. In the MSKCC experience, 1 1 (30%) of 37 shown for the reverse iteration; the former sequence was there- patients who had previously responded to doxorubicin in the treat- fore chosen for clinical evaluation. Clinically relevant doses of ment of metastatic disease had a subsequent response to paclitaxel, both agents have been deliverable with acceptable toxicity (48). while objective responses were observed in 10 of 31 patients (32%)

A Phase I-Il investigation of paclitaxel plus mitoxantrone with who lacked a prior response to doxorubicin (i.e. , primary or de G-CSF support has evaluated both 3- and 24-h infusions of novo resistance) in this setting. Of 6 patients deemed anthracycline paclitaxel at a fixed dose of 175 mglm2, with planned dose esca- refractory due to a short disease-free interval ( 12 months) after lation of mitoxantrone from 8 mg/m2 at 2-mg/m2 increments. The completion of doxorubicin-based adjuvant therapy, 2 (33%) sub- maximally tolerated dose of mitoxantrone was 12 mg/m2 with a sequently responded to paclitaxel for advanced disease (18). Sim- 24-h paclitaxel infusion and 14 mg/m2 with a 3-h infusion; ilarly, in the subset of patients in the European/Canadian random- activity was noted with both schedules, and mucositis and ized trial receiving paclitaxel at 175 mg/m2 via 3-h infusion, neutropenia were dose limiting (49). Investigators at the Uni- responses were observed in 29% of anthracycline-sensitive patients versity of Colorado are performing a Phase I trial of paclitaxel (>6 months relapse time after adjuvant anthracycline, or prior CR with fixed doses of cyclophosphamide and cisplatin as an in- or partial response for stage IV disease) and in 30% of anthracy-

tensification regimen after induction ‘ ‘AFM’ ‘-type chemother- chine-resistant patients (6 months disease-free interval after ad- apy in an autologous bone marrow transplantation program (50). juvant anthracycline, or progression through anthracycline for met- While innumerable combinations of paclitaxel and cyto- astatic disease; Ref. 19). Finally, of 33 patients receiving paclitaxel toxic agents will undoubtedly be explored, one promising area after prior anthracycline or anthracene-dione via a prolonged 96-h of investigation derives from a greater understanding of auto- infusion schedule, Wilson et a!. (28) reported that 12 (50%) of 24 crine and paracrine regulation of breast cancer cell growth. patients who previously lacked a response to these agents had a Synergy between chemotherapeutic agents and mAbs directed at subsequent response (partial response) to paclitaxel, while 4 of 9 growth factor receptors in human tumor xenografts has been who had a prior response to them subsequently responded to demonstrated (13). Supraadditive cytotoxicity exists with the paclitaxel. combination of paclitaxel and the 4D5 antibody directed against Since non-mdr-mediated mechanisms of resistance to an- the her-2/neu receptor in BT-474 cells (which overexpress her- thracyclines exist, such as alterations in topoisomerase activity 2/neu), as well as with the anti-EGFr 528 in MDA-468 cells (59), these data do not necessarily imply that the mdr phenotype (which overexpress EGFr; Ref. 14). Such novel strategies may is clinically irrelevant to patients receiving taxanes after anthra- represent viable leads for future clinical exploration. cycline failure, but should serve to allay concerns about their use Paclitaxel as a Radiation Sensitizer. The ability of pa- based on the theoretical issues raised by preclinical data. Indeed, clitaxel to arrest cells in the G2-M interphase has led to studies a number of centers are evaluating paclitaxel in combination evaluating its potential role as a radiation-sensitizing agent (51). with agents and strategies that address mdr, such as calcium A clinical trial combining paclitaxel and radiation therapy in channel blockers (60), quinidine, and cyclosporine. Further in- breast cancer is under way at Columbia Presbyterian Medical vestigations into other potential mechanisms of resistance to this Center in New York for patients with locally advanced disease.8 class of drugs, including alterations in tubulin (61), may even- tually define clinically relevant strategies by which human Issues for Future Investigation breast cancer cells evade the cytotoxicity of this new class of Drug Resistance. Theoretical concerns regarding the po- chemotherapeutic agents. tential clinical efficacy of paclitaxel after anthracyclines have Clinical Considerations in Paclitaxel Administration. been raised largely based on the demonstration of in vitro Due to the negative chronotropic effect of paclitaxel on the cross-resistance with these and other agents to which resistance cardiac conduction system, most clinical trials thus far have is thought to be at least partly mediated via the P-glycoprotein excluded patients thought to be at increased risk of developing pleiotropic mdr phenotype (52). In murine macrophage-like cardiotoxicity. The safety of paclitaxel infusions in patients cells, Roy and Horwitz (53) have described a plasma membrane receiving medication that affects the cardiac conduction system phosphoglycoprotein that correlates with paclitaxel resistance, (e.g., 3-blockers, calcium channel blockers, digitalis), and to and mdr-1 gene expression has been characterized in this system patients with a history of cardiac conduction defects and/or (54). Additionally, several investigators have reported the abil- arrhythmias still requires further clarification.9 With the large

8 P Schiff, personal communication. 9 5. Arbuck, personal communication.

Pilot Studies

Study Study Drugs/Doses Group Design (mg/rn2) -H D=D=doxorubicin6O D J NSABP o I III C = = cydophosphamide 600 (BP-56) p = I = paclitaxel 250 (3h) D 75 CALGB 0 0 0 0 0 #{149}UUU C 2000 (9141) #{149} UU P 175 (3h) G = = GCSF 5 vs. lO(Ig/kgfday D90 MSKCC U 0 0 I II C 3000 (93-23) P 250 (24h) G = 5(tg/kg/day

IIIIIIIII 0 3 6 9 12 15 18 21 24 Fig. 1 Pilot studies and randomized trials of ad- Weeks juvant chemotherapy with paclitaxel. Symbols in

‘‘ Randomized Trials’ ‘ correspond to those in ‘‘ Pi- lot Studies.” Randomized Trials

Study Study Drugs/Doses Group Design (mg/rn2) 11 II 0000UUUU 0 = 90 vs. 75 vs. 60 i/s #{149} . #{149}‘<(nou) C = 600 P = 175 (3h) Intergroup :_. 0 0 0 0 U U U U \ B UUU (nou) 0 000

0=80 C = 3000 MSKCC 0 0 0 :!,f,,!.,,! ______P=200(24h) (94-85) ILLLZ7ZLLii G = 5 pgilcglday

II )‘)wrni’’mwls II II 0 3 6 9 12 15 18 21 24 Weeks

number of patients in clinical trials who have received this agent Due to the risk of severe hypersensitivity reactions to after anthracycline, there has been no demonstration that sub- paclitaxel in its Cremophor EL vehicle, routine premedication sequent single-agent paclitaxel causes or exacerbates cardio- with corticosteroids, diphenhydramine, and H, receptor antag- myopathy. onists should be administered (e.g. , 20 mg dexamethasone p.o. The similar concern that prior exposure to Vinca alkaloids approximately 12 h and 6 h before paclitaxel, 50 mg diphenhy- or cisplatin in patients with breast cancer might predispose to dramine i.v., and 300 mg cimetidine or 50 mg ranitidine i.v. more frequent or severe paclitaxel-related neurotoxicity is not 30-60 mm before paclitaxel). Although emerging data from supported by clinical trial data thus far. Strategies utilizing lower several centers with the 96-h infusion schedule suggests that the doses (e.g., 135-150 mg/m2) or dose intensity for patients who may incidence of significant hypersensitivity reactions may be cx- be predisposed to neuropathic complications (alchohol or diabetes) tremely low with this schedule (total dose generally 120-140 are appropriate. Alternation of paclitaxel with non-neurotoxic mg/rn2), this observation requires further confirmation in a agents such as doxorubicin, an approach that has been piloted by controlled clinical trial setting. Sledge et a!. (35) for the ECOG may be a reasonable approach to With greater experience and confidence in safe drug dcliv- perhaps minimize the risk for neuropathy in such patients. Studies cry, investigators have begun to explore the feasibility of out- addressing the potential value of neuroprotective agents (75) in patient administration of paclitaxel via ambulatory infusion de- high-risk patients may be warranted. vices. Paclitaxel must be prepared in non-PVC bags and infused Certain other pretreatment variables such as extent and nature of prior chemotherapy, particularly mitomycin C or high- via non-PVC tubing through an in-line 0.22-p.m filter. Several dose myelosuppressive regimens, extensive radiotherapy to compatible battery-operated infusion pumps are available for marrow-bearing bone, and elevation of hepatic transaminases ambulatory delivery of infusional paclitaxel. The paclitaxel con- reflecting liver dysfunction and the likelihood of delayed pacli- centration in solution should not exceed 1.2 mg/ml. Recent data taxel clearance need to be considered in the choice of initial suggesting that paclitaxel is stable in solution at ambient tem- dose for an individual patient. Any of these factors can predis- peratures in flexible polyolefin containers for up to 48 h makes pose to impaired drug tolerance. this approach more feasible (87). The safety of outpatient infu-

sional paclitaxel will ultimately be clarified by ongoing clinical breast cancer is the focus of active clinical and laboratory trials, as well as by broader experience in the community. research. The incomplete clinical cross-resistance with anthra- Paditaxel in the Adjuvant Therapy of Node-positive cycline observed thus far is particularly gratifying, since treat- Early Stage Breast Cancer. With the demonstration of sig- ment options for patients after anthracycline failure are limited nificant activity for paclitaxel against advanced breast cancer, and often unsatisfactory. Results of ongoing randomized multi- including in the setting of anthracycline-resistant disease, the center trials presently addressing issues of optimal dose level, evaluation of this promising agent as a component of postoper- infusion duration, and comparative efficacy with other standard ative adjuvant chemotherapy was inevitable. Three pilot studies agents will, in coming years, provide concrete guidelines for the have been performed testing the feasibility of the addition of best use of this drug. Emerging data suggest that further studies paclitaxel to doxorubicin-cyclophosphamide chemotherapy, may be warranted in reevaluating even shorter (i.e., 1-h), more each with its own unique approach (Fig. 1). An Intergroup trial frequent paclitaxel infusions (86). Based on the demonstrated is comparing the worth of four-course paclitaxel versus no single-agent activity of paclitaxel in metastatic breast cancer, paclitaxel administered as a 3-h infusion after doxorubicin- Phase I, II, and III trials evaluating paclitaxel combination cyclophosphamide therapy in node-positive patients. In this regimens with doxorubicin, cisplatin, and cyclophosphamide, trial, there is an initial randomization between three dose levels among other agents, are either planned or under way. Pharma- of doxorubicin (60 versus 75 versus 90 mg/m2) every 3 weeks, cokinetic evaluation of paclitaxel as monotherapy and in corn- with a fixed dose of cyclophosphamide (600 mg/m2) every 3 bination should guide optimal and safe drug delivery. Clinical weeks for four cycles. and laboratory studies should ultimately define clinically rele- Demetri et a!. (62) reported on the feasibility of paclitaxel vant mechanisms of resistance to this class of drugs, and thus administration after a dose-intensified regimen of 2 g/m2 cyclo- may guide the development of rational strategies to overcome phosphamide plus 75 mg/rn2 doxorubicin every 3 weeks for five resistance and/or to guide analogue development. courses with G-CSF support followed by paclitaxel. The safety The promise of paclitaxel has motivated its incorporation of delivering paclitaxel at 175 mg/m2 via 3-h infusion every 3 into clinical trials of adjuvant chemotherapy regimens for patients with resectable stage Il-Ill breast cancer. Preliminary weeks for four cycles after dose-escalated cyclophosphamide promising activity demonstrated with the related taxane, do- and doxorubicin was demonstrated, with no advantage noted for cetaxel (Taxotere), in breast cancer clinical trials thus far (68- 10 over 5 p.g/kg/day G-CSF as hematological support of cycles 73) suggests that this new class of agents will secure a promi- of doxorubicin + cyclophosphamide (Fig. 1). nent role in the management of this disease. Their optimal Building on prior experience with sequential administra- integration into treatment strategies for patients with breast tion of doxorubicin and cyclophosphamide (63), in an approach cancer remains an important challenge for this decade. supported by mathematical models of tumor kinetics (64) as well as clinical experience showing the superiority of this ap- References proach (65), Hudis et a!. (66) have shown the feasibility of sequential high-dose adjuvant therapy with these three agents. In 1. 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A D Seidman

Clin Cancer Res 1995;1:247-256.

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