Paclitaxel and Carboplatin for Advanced Breast Cancer

Edith A. Perez and Lynn C. Hartmann

This report evaluates the activity of paclitaxel alone (Taxol; Bristol-Mye rs Squibb Company, Princeton, NJ), carboplatin alone, and their combination in the treat­m ent of patients with advanced breast cancer. The pre­liminary safety information of this c~mbination in other ~umor types also is discussed. Finally, the overall ratio­nale for ongoing study of the efficacy of paclitaxel and carboplatin, along with appropriate translational stud­ies, as first-line che motherapy in patients with meta­static. breast cancer is examined. Both paclltaxel and c~boplatin have w ell-established single-agent activity in the treatment of women with breast cancer. The tolerability of this combination, using the sequence paclitaxel followed by carboplatin infusion, already has been established In patients with lung cancer and ovar­ian cancer. In addition, this therapy has the novel attri· bute of a relative platelet-sparing effect. A phase II trial evaluating the efficacy of the paclltaxelfcarboplatin combination, along with an evaluation of thrombopoie­t in levels and quality of life, has been initiated recently through the North Central Cancer Treatment Group. In this trial, intrave nous paclitaxel 200 mg/m1 infused over 3 hours is followed by c.arboplatin at a calculated area under the concentration-time curve dose of 6, with cycles repeated every 21 days. Results from this trial will help document the role of the paclitaxel/car­boplatin combination in the treatment of women with breast cancer. Copyright © 1996 by W.B. Saunden Company

M ET AST A TIC breast cancer is rarely curable with standard chemotherapy. Standard

chemotherapy combinations like cyclophospha­mide/doxorubicin or cyclophosphamide/metho­trexate/5-fluorouracil result in objective responses in approximately 30% to 50% of such patients. 1

Since a significant portion of patients with opera­ble breast cancer are candidates for adjuvant che­motherapy with cyclophosphamide/methotrexate/ 5-fluorouracil or cyclophosphamide/doxorubicin/ 5-fluorouracil (or similar regimens), many patients . with advanced breast cancer will already have been exposed to the drugs most commonly used to treat advanced d.isease, rendering them less likely to re­spond to such treatment a second time. 1 The iden­tification of active new drugs or drug combina­tions, therefore, is urgently needed.

PACLITAXEL IN ADVANCED BREAST CANCER

Paclitaxel (Taxol; Bristol-Myers Squibb Com­pany, Princeton, NJ) is a promising new agent in

Semina11 in Oncology, Vol 23. No S. Suppl 1 I (October). 1996: pp 4 1--45

the treatment of women with advanced breast can­cer. Its use Leads to objective responses in approxi­mately 50% to 60% of such patients when used as initial therapy. 2•3 Paclitaxel also produces objective responses in approximately 20% to 25% of patients with advanced disease who are resistant to other chemotherapy.Ho Clinical trials have investigated the administration of paclicaxel every 3 weeks at

,varying doses (135 to 250 mg/m2) and schedules

( 1- to 96-hour infusions). Weekly administration of paclitaxel is also being investigated, as is pro­longed continuous infusion. Paclitaxel's optimal dose and administration schedule, whether used as a single agent or in a combination regimen, are a matter of extensive ongoing research. The dose­limiting toxicity of paclitaxel, a deep but brief neu­tropenia, is both dose and schedule dependent. A variety of combination chemotherapy trials with paclitaxel and other agents have been reported recently, demonstrating the potentially important role of this agent in combination treatment. Phase l/ll studies by Gianni and colleagues1

1.12 and Gehl

et al13 evaluated paclitaxel and doxorubicin in pa­tients with metastatic breast cancer. Preliminary data are consistent with previous trials and show overall response rates greater than 85% and com­plete response rates between 30% and 40%; how­ever, further follow-up will be necessary to evalu­ate the impact of this combination on median length of survival. The concurrent use of these rwo agents is associated with a somewhat greater than expected degree of cardiac toxicity, thereby lim­iting the total cumulative dose of doxorubicin to no greater than 360 mg/m2

• Recent phase II studies evaluating paclitaxel 200 mg/m1 plus doxorubicin 60 mg/m1 intravenously (IV) every 3 weeks, with and without hematopoietic growth factors, have

·been initiated through the Eastern Cooperative Oncology Group and the Southwest Oncology Group.

From the Division of Hematology/Oncology Mayo Clinic and Mayo Foundation, Jacksonville, FL; and <he Mayo Clinic Roches­ter, MN.

Address reprint requests tO Edich A. Peret, MD, Division of Hemacology/Onco!ogy, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224.

Copyright It> l996 lry W .B. Saunders Company @3-7754/96/2305-l I 10$05.0010

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The combination of paclitaxel/cisplatin has been studied by several groups using biweekly schedules for the treatment of breast cancer. Re­sponse rates are reported to be between 44% and 94%, depending on the extent of prior therapy.14•

18

Cumulative neurotoxicity appears co be signifi­cant, with 9.1 % of patients ·in one study presenting with some degree of neuropathy by the fifth course of treatment and 50% of patients in another study

·having co be withdrawn from treatment.14•19

Data from trials of paclitaxel combined with other agents, including ifosfamide, also have been reported recently. Murad et al, for example, evalu­ated paclitaxel 175 mg/m2 IV over 3 hours on day 1, plus ifosfamide at a dose of 1.8 g/m2 on days 2 to 4, along with mesna in 22 patients receiving third- or fourth-line chemotherapy for metastatic breast cancer, with cycles repeated every 21 days.20

Preliminary data are consistent with a response rate of 50% and only moderate toxicity, with one case of grade 3 neuropathy and three cases of tran­

sient grade 4 neutropenia. Further combination trials of paclitaxel and other chemotherapy agents are warranted.

Carboplatin in Advanced Breast Cancer

Like paclitaxel, carboplatin also has substantial activity when used as a single agent in the treat­ment of advanced breast cancer, yielding objective responses in approximately 25% to 37% of patients who have not received chemotherapy for advanced disease. zo.22 Carboplatin is a less reactive derivative of cisplatin, but both drugs are activated co the same aquated metabolites. The major difference between carboplatin and cisplatin is that car­boplatin has a lower toxicity profile. The renal, neurologic, ototoxic, and emetic toxicities of car­boplatin are reduced substantially compared with those seen with cisplatin, making carboplatin a better-tolerated form of the parent compound. Fur­thermore, carboplatin can be administered on an outpatient basis. The most prominent toxic effect of carboplatin is myelosuppression with prominent thrombocytopenia. Several published formulas, such as the Calvert formula,23 can now successfully predict for a particular level of carboplatin-induced thrombocytopenia. This is based on dosage indi­vidualization based on the glomerular filtration rate (GFR) and target arf!a under the concentra· tion-time curve (AUC), with die total dose of carboplatin (mg) = AUC X (GFR + 25).

PEREZ AND HARTMANN

Paclicaxel Plus Carboplatin

To our knowledge, the combination of pacli­taxel/carbopl.atin has not been studied in the treat­ment of patients with metastatic breast cancer. Phase I and 11 dose escalation studies of this combi­nation, however, have sought an effective, well­tolerated dose for the treatment of patients with non-small cell lung cancer.24

'29 Cumulative severe

neurotoxicity was not found to be a significant problem when paclitaxel was infused over 3 hours and then followed by carboplatin. In a recent dose escalation study of paclitaxel and carboplatin in previously untreated patients with non-small cell lung cancer, the investigators established that the maximum tolerated dose was paclitaxel 250 mg/ m2 with carboplatin at an AUC of 6 given every 3 weeks.24 The dose-limiting toxicity consisted pri­marily of grade 3 osteo/arthralgias or sensory neu­ropathy. Paclitaxel 225 mg/m2 given over 3 hours and followed immediately by carboplatin at an AUC of 6 was established as the optimal dose. Grade 3 or 4 thrombocycopenia was not seen, but 10% of patients demonstrated grade 3 sensory neu­ropachy after the third treatment cycle. Prelimi­nary data of chis combination for advanced non­small ceLJ lung cancer are consistent with response rates between 50% and 65% and median lengths of survival in excess of 1 year.

Based on this background information, we initi· ated through the North Central Cancer T reatmem Group a phase !I study of patients receiving first· line chemotherapy for advanced or metastatic breast cancer. Paclitaxel 200 mg/m2, IV was admin­istered over 3 hours followed by carboplatin at an AUC of 6, based on the Calvert formula, with cycles repeated every 21 days. In addition to evalu­ating the efficacy and toxicity of this combination, this trial includes two corollary studies, one to de­termine its effec.t on thrombopoietin (TPO) levels and the ocher to evaluate effect of treatment on quality of life using the Functional Assessment of Cancer Therapy-Breast (FACf-B) scale.30

Our primary objective is to determine the re­sponse rate achieved by paclitaxel/carboplatin in the treatment of women with advanced breast can­cer; the secondary objectives are to determine its time-to-progression and toxicity and to evaluate its effect on patients' quality of life and serum TPO levels. The study is being conducted in women who are at least 18 years of age who have histologi·

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PACLITAXEL/CARBOPlATIN FOR ADVANCED BREAST CANCER

cally confirmed adenocarcinoma of the breast with manifestations of metastatic cancer and · measur­able disease. All women have an Eastern Coopera­tive Oncology Group performance status of 0, 1, or 2, a life expectancy of 2:3 months, and adequate hematologic, renal, and hepatic functions. · Premedication for paclitaxel is required and consists of dexamethasone 20 mg orally 6 and 12 hours before paclitaxel plus dexamerhasone 20 mg IV in combination with diphenhydramine 50 mg and cimetidine 300 mg IV administered 30 to 60 minutes before paclitaxel. (Omitting the oral dexa­methasone premedication at 6 and 12 hours prior to paclitaxel infusion is permitted.) Paclitaxel is then administered as a 3-hour infusion in 500 mL of D5W. Carboplatin is infused immediately after paclitaxel, over 30 minutes in 250 mL of DSW. The dose of carboplatin administered is calculated by the Calvert formula: carboplatin dose (mg) = target AUC X (GFR + 25). The treatment cycles are repeated every 21 days. Preliminary results from this trial should be available in the next several months.

Paclitaxel, Carboplatin, and Platelets

In addition to the above tolerability and re­sponse data, Keams et al have observed that pacli­taxel has a modulating effect on the thrombocyto­penia caused by carboplatin.31 This effect was measured in two other separate studies as well. Each study demonstrated that platelet nadirs in­creased as the doses of paclitaxel increased.3032

Bolis et al29 reported that as the dose of pacli­taxel increased, while the dose of carboplatin re­mained at 300 mg/m2, both the median platelet nadir. and the median white blood cell nadir in­creased. This finding suggests a modulatory effect

· of paclitaxel on carboplatin-induced myelosup­pression. In addition, significant dose-limiting nonhernatologlc toxicity was not observed using the combination of paclitaxel 150 to 250 mg/m2

administered over 3 hours and carboplatin at 300 mg/m2 in this study.

A study by Siddiqui et al33 demonstrated that the incidence of thrombocytopenia decreased as the dose of paclitaxel increased from 150 to 175 mg/m2 administered over 3 hours in combination with carboplatin. The investigators concluded that paclitaxel has a protective effect on the· thrombo­cytopenia caused by carboplatin. They further con­cluded that the pharmacokinetics of carboplatin

are not altered by concurrent use of paclitaxel. The pathophysiology of this interaction has not been elucidated, but potencial inhibition of platelet mi­crotubules, modulation of cytokines such as TPO, or interference with megakaryocyte ploidy/bleb­bing are hypotheses worthy of exploration.

Platelets are released from long pseudopods ex­tending from megakaryocytes, either directly or from proplacelets, which are fragments of pseudo­pods containing multiple platelet domain. Intra­cellular cytoskeletal proteins, such as tubulin, par­ticipate in pseudopod formation.31 Paclitaxel binds to tubulin subunits and thus may alter platelet re­lease processes. 35

The primary hormone-regulating platelet pro­duction is TP0.34

•36.37 Thrombopoietin, also re­

ferred to as c-Mpl ligand or megakaryocyte growth and development factor, is a mature polypeptide of 332 amino acids. Recombinant TPO stimulates the proliferation and maturation of megakaryo­cytic stem cells and megakaryocytes in vitro.34 ·It also infiuences characteristics of megakaryocytic maturation, such as cell size, ploidy, and the ten­dency to form pseudopods. Thrombopoietin can enhance che recognition of multilineage colonies that have a megakaryocytic component and thus may stimulate multipotential cells to some extent. Thrombopoietin blood levels change reciprocally to the circulating platelet count in both animals and hurnan.5,34•38 but the effect of chemotherapeu­tic drugs on circulating TPO levels or the relation­ship of TPO levels to platelet nadirs seen after the administration of chemotherapy have not been explored.

Jn this ongoing North Central Cancer Treat­ment Group study we propose to test the hypothe­sis that TPO blood levels are higher during periods of thrombocytopenia when paclitaxel is given just · prior to carboplatin, compared with what would be expected with similar levels of chrombocyto­penia in patients with primary bone marrow disor­ders.

CONCLUSION

Both paclitaxel and carboplatin have significant single-agent activity in the treatment of breast cancer. The combination appears to be tolerable, with less hematopoietic toxicity tha.n was expected based on the potential additive toxicities of each agent. The antitumor activity of this combination is being established in a variety of tumor types.

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Our ongoing trial of paclitaxel 200 mg IV over 3 hours followed by ·carboplatin AUC = 6 will help . answer the question of the potentiai role of this combination in the treatment of advanced breast cancer.

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PACLITAXEUCARBOPLATIN FOR. ADVANCED BR.EAST CANCER

patients with metastatic breast cancer. Proc Am Soc Clin On­col 15:1 10, 1996 (abstr) .

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