The National Cancer Institute has estimated that one in eight American women will develop breast cancer in her lifetime, making this disease the most common cancer in females and second only to lung cancer as a leading cause of cancer-related deaths among women in the United States.[1-3] The American Cancer Society projected a total of 181,600 new cases of breast cancer and 44,190 deaths from this disease in 1997.
The single most important risk factor for the development of breast cancer is age, with women 80 to 85 years old being 15 times more likely to develop breast cancer than women 30 to 35 years of age. Other risk factors include age at menarche of younger than 12 years; age at menopause of older than 55 years; first child after age 30 or nulliparity; history of any benign breast disease, proliferative disease or atypical hyperplasia; and a family history of breast cancer, ie, mother or other first-degree relatives affected.
The treatment of metastatic breast cancer, at present, is largely decided by the hormone receptor status of the tumor, with hormonal therapy being the first-line treatment in patients with positive hormone receptors because of its favorable therapeutic index. These women are mostly older, have relatively longer disease-free intervals after primary therapy, and may have already received adjuvant hormonal treatment. Eventually many of these women will be treated with chemotherapy after progressing through several levels of hormonal treatment. However, because their treatment is palliative not curative, it may be preferable to use relatively milder regimens.
Systemic chemotherapy is generally offered as initial treatment to women who may have one or more of the following characteristics: women who are younger, ie, less than 50 years, who have estrogen/progesterone receptor-negative disease; who have a short disease-free interval after their initial treatment; who demonstrate visceral involvement with relatively rapid progession; or who have demonstrated resistance to hormone therapy. Although many young women are now offered bone marrow transplantation as an initial alternative, only 4% of those women in the United States are treated on a randomized protocol comparing it with standard chemotherapy. Thus, there is a paucity of evaluable data on its efficacy. This group of women could also benefit from the use of effective yet gentle therapy.
Recently several new agents have been added to the armamentarium of cytotoxic treatments available for the past 10 to 20 years. Many of these therapies are effective, produce objective reductions in disease burden, and lessen patient suffering, but survival for most patients with metastatic breast cancer is only marginally improved with the currently available therapies.
The response rates for a variety of antineoplastic agents used as monotherapy in breast cancer are listed in Table 1. Breast cancer has the advantage of being responsive to a variety of different drugs, and four of thesedoxorubicin (Adriamycin), docetaxel (Taxotere), paclitaxel (Taxol), and vinorelbine (Navelbine)have yielded response rates of 40% or greater as single-agents for first-line therapy (Table 1). Even when used as second-line treatment, their response rates are comparable to active combination chemotherapy.
Although combination therapy generally produces higher response rates than single-agent treatment, few, if any, randomized trials show improved overall survival or quality of life for combination therapy. The standard first-line chemotherapeutic regimens in recent years in the United States for patients with metastatic disease have included either cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (5-FU) (CMF) or cyclophosphamide and Adriamycin, with or without fluorouracil (CAF, AC) (Table 2). Several randomized trials show that response rates for CAF are consistently higher than those for CMF, but time to disease progression and overall survival are either the same or only slightly prolonged.[6-11] Because CAF has substantially higher toxicity, CMF is generally used as first-line therapy in the average patient with newly diagnosed metastatic disease. Other regimens have been found to be effective in second- or third-line therapy (Table 2), but none have consistently shown superior efficacy or lesser toxicity than any other regimen.
Anthracyclines, such as doxorubicin, are among the most active single agents used in the treatment of advanced breast cancer. Treatment with anthracycline-containing regimens results in a greater number of objective responses, and, in the experience of some investigators, can result in a longer time to disease progression, and an improved survival duration (18 vs 14 months) in patients with untreated metastatic breast cancer when compared with treatment without an anthracycline. However, treatment with anthracyclines is limited by their associated toxicities, including nausea and vomiting, alopecia, mucositis, cardiotoxicity, injection-site reactions, and bone marrow suppression. At dose intensities needed to achieve a meaningful response, neutropenia is frequently seen; severe neutropenia can lead to febrile episodes and occasionally to life-threatening septic infections. The anthracyclines can potentially cause irreversible cardiac damage as cumulative doses exceed 550 mg/m².
Mitoxantrone (Novantrone) may be as active or slightly less active than single-agent doxorubicin in breast cancer,[13,14] and its combination with fluorouracil and leucovorin may produce response rates comparable with those of CMF or CAF but with less toxicity.[15,16]
Paclitaxel treatment has resulted in response rates between 30% and 50% in previously untreated patients with metastatic breast cancer,[17-20] and a related compound, docetaxel, may be even more active with first-line response rates of 48% to 68% and significant activity in anthracycline-resistant patients (response rate, 53% to 57%).[21-25] These agents belong to the taxane group of drugs and produce toxicities such as alopecia, nausea and vomiting, and bone marrow suppression, particularly granulocytopenia. In addition, paclitaxel is associated with a small risk of hypersensitivity reactions and peripheral neuropathy, whereas docetaxel has produced cumulative dose-dependent peripheral edema, pleural effusions and ascites, which can be ameliorated with prophylactic steroid use.[26,27]
Vinorelbine, a vinca alkaloid related to vinblastine (Oncovin), has produced response rates up to 50% when used as a first-line agent and is also active in patients with previously treated metastatic breast cancer.[28-31]
The choice of one systemic therapy over another should be individualized for every patient and depends on treatment goals and the risk-benefit ratio.
Treatment strategies for breast cancer vary geographically and among treatment centers. In addition, the goals of systemic chemotherapy range from palliation to an intent to cure. Many oncologists believe that improved survival may not be a realistic objective of systemic chemotherapy in patients presenting with a high disease burden and/or multiple visceral metastatic sites or those with poor performance status. They believe that the marginal survival benefit, if any, offered by more toxic antitumor agents, such as doxorubicin, does not outweigh the risks and, therefore, offer supportive care to palliate the signs and symptoms of disease. Because of the greater awareness of the importance of the patients quality of life, investigators have sought treatment regimens which may offer a good likelihood of response or survival advantage, but with minimal toxicity.
Encapsulating potentially cytotoxic agents into liposomal membranes allows them to be delivered to their targeted tumor site while minimizing their toxic effect on other tissues. The mechanism of action of liposomally delivered drugs is discussed elsewhere in this supplement.
Pegylated liposomal encapsulated doxorubicin (PEG-LD) (Doxil) has the advantage of delivering this active anthracyline directly to the tumor site while exposing the patient to a lesser degree of doxorubicin-associated toxicities. The increased activity and greater drug delivery which result in a mitigation of toxicity are in keeping with the philosophy of a gentler approach to chemotherapy, where palliation and quality-of-life issues are important. Yet encapsulation of doxorubicin in pegylated (Stealth) liposomes should theoretically maintain the efficacy of the drug. In addition, PEG-LD has been shown to be active in the treatment of breast cancer patients who previously progressed on anthracycline-based therapy.
Preclinical studies have shown PEG-LD to be effective in some tumor models which are generally resistant to doxorubicin. For example, the C26 colon carcinoma cell line is unresponsive to doxorubicin in vivo but responds to PEG-LD. PEG-LD was also effective in vivo when used to treat non-Hodgkins lymphoma in dogs that failed on doxorubicin. In clinical trials, PEG-LD has been shown to be active in refractory ovarian cancer[33,34] (see also the paper by Muggia et al in this supplement) and Kaposis sarcoma, even in patients who failed doxorubicin.
The activity of PEG-LD in patients pretreated with conventional anthracyclines may be due to the altered pharmacokinetics of this liposomal encapsulated preparation. While conventional doxorubicin clears rapidly from the circulation, PEG-LD circulates for a longer period and concentrates in areas of increased vascularity with loose capillary junctions, such as tumor tissue. The use of indium-labeled pegylated liposomes has confirmed that the drug localizes to various tumors, including breast. The ability of liposomal encapsulation to concentrate drug into the tumor for a longer period of time may be responsible for the activity of PEG-LD in cases where free doxorubicin has failed.
Two separate complementary phase I studies investigated PEG-LD dose escalation from 20 mg/m2 to 80 mg/m2 every 3 to 4 weeks in 56 patients (total of 281 courses of PEG-LD) with breast, prostate, ovarian, non-small-cell lung, melanoma, mesothelioma, pancreatic, gastrointestinal, uterine, renal cell, sarcoma, head and neck, or colorectal cancers. Palmar-plantar erythrodysesthesia (hand-foot syndrome) and stomatitis were the dose-limiting toxicities at doses of greater than 70 mg/m2. Skin toxicity (mainly palmar-plantar erythrodysesthesia), although dose limiting after repetitive doses, was tolerable at doses of 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Other chemotherapeutic agents, including continuous infusion doxorubicin, have also been associated with palmar-plantar erythrodysesthesia. Phase I studies also showed only mild myelosuppression, a lack of alopecia, and no indication of cardiotoxicity, with an attenuation of acute subjective symptoms. Objective responses or improvement based on tumor markers was seen in patients with breast, ovarian, prostate, and head and neck carcinomas. Of the six patients with metastatic breast disease, two achieved a complete response, with times to treatment failure of 18 and 12 months, respectively, and survival times of 32 and 12 months, respectively; a third patient showed disease improvement based on serum enzyme markers.
In a recently completed open, noncontrolled, nonrandomized multicenter trial, 71 patients with stage IV metastatic breast cancer were studied to determine the safety, tolerability, and efficacy of PEG-LD. Fifty-seven of these patients had received at least one prior hormonal therapy and 28 had been treated with a nonanthracycline-containing regimen, usually CMF. Fifty-two of these patients had multiple metastatic sites; pulmonary and liver metastases were the most predominant, present in 50 patients (70%). All patients had a Karnofsky performance status of 60% to 100%, and a cardiac ejection fraction of greater than 50% by multiple-gated acquisition scan (MUGA) or echocardiographic assessment.
PEG-LD was administered at a dose of 45 to 60 mg/m2 every 3 to 4 weeks, with a maximum of six cycles of therapy permitted. Because of the need for dose and interval modification due to severe toxicities, most notably palmar-plantar erythrodysesthesia, patients were divided into three different treatment cohorts. Based on phase I safety data, the first 13 patients were treated with 60 mg/m2 PEG-LD every 3 weeks (cohort 1). The next 26 patients were administered PEG-LD at a dosage of 45 mg/m2 every 3 weeks (cohort 2). After multiple cycles at this dose, five patients experienced greater than World Health Organization (WHO) grade 3 palmar-plantar erythrodysesthesia, so the dose was adjusted to 45 mg/m2 every 4 weeks for the next 32 patients (cohort 3).
Of the 71 patients studied, 64 received two or more cycles of treatment and were assessable for response. Complete responses were achieved by 4 patients (6%) and partial responses were achieved by 16 patients (25%); 28 patients (31%) had stable disease on therapy and 24 (38%) had disease progression. Of the 22 assessable patients who had received prior chemotherapy, 7 patients (32%) had an objective response to PEG-LD. The median overall survival was 7 months and the time to disease progression was 9 months.
In terms of safety, 27% of patients developed greater than grade 3 neutropenia at some point during therapy; no cumulative myelosuppression was seen with multiple cycles of therapy. Overall, neutropenia greater than grade 2 was observed in 13% of patients; neutropenia less than grade 2 occurred in 87% of cycles. Thrombocytopenia and platelet nadirs were rare. Unlike conventional doxorubicin, nausea and vomiting were rare and thus the routine use of antiemetics was not required in this study. Alopecia was absent in the majority of patients, with only 5 (7%) experiencing greater than grade 1 alopecia overall.
Gabizon et al treated 20 patients with metastatic breast cancer with single-agent PEG-LD at doses between 45 mg/m2 every 3 weeks and 65 mg/m2 every 5 weeks. All patients had failed previous chemotherapy regimens and 15 of these had received doxorubicin before. Of the 16 patients receiving at least two treatment cycles, two achieved a partial response and six achieved clinical improvement. In those 16 patients, the median time to treatment failure was 8+ months (range, 3 to 13+). Two patients who were previously treated with doxorubicin showed significant clinical improvement for 9+ and 12+ months, respectively, as did the four patients who previously failed paclitaxel. Of the patients previously treated with mitoxantrone, two achieved partial responses and the third showed clinical improvement.
1. CDC: Breast and cervical cancer surveillance, United States, 1973-1987. In: CDC surveillance summaries (April). MMWR 41 (no. SS-2): 1-15, 1992.
2. Kosary CL, Ries LAG, Miller BA, et al, (eds): SEER cancer statistics review, 1973-1992: tables and graphs. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute; publication no. (NIH) 96-2789, 1995.
3. American Cancer Society. Cancer Facts and Figures, 1997. Atlanta, Georgia: American Cancer Society, publication no. 5008.96, 1997.
4. Harris JR, Lippman ME, Veronesi U, et al: Breast cancer. N Engl J Med 327:319-328, 1992.
5. Antman KH, Rowlings PA, Vaughan WP, et al. High dose chemotherapy with autologous hematopoetic stem cell support for breast cancer in North America. J Clin Oncol 15:1870-1879, 1997.
6. Hayes DF, Henderson IC: CAF in metastatic breast cancer: Standard therapy or another effective regimen. J Clin Oncol 5:1497-1499, 1987.
7. Muss HB, White DR, Richards F III, et al: Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer. Cancer 42:2141-2148, 1978.
8. Tormey DC, Weinberg VE, Leone LA, et al: A comparison of intermittent vs continuous and of Adriamycin vs methotrexate 5-drug chemotherapy for advanced breast cancer. Am J Clin Oncol 7:231-239, 1984.
9. Smalley RV, Lefante J, Bartolucci A, et al: A comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat 3:209-220, 1983.
10. Bull J, Tormey D, Li SH, et al: A randomized comparative trial of Adriamycin versus methotrexate in combination drug therapy. Cancer 41:1649-1657, 1978.
11. AHern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67:801-805, 1993.
12. Von Hoff DD, Maxwell WL, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979.
13. Henderson IC, Allegra JC, Woodcock T, et al: Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 7:560-571, 1989.
14. Neidhart JA, Gochnour D, Roach R, et al: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4:627-677, 1986.
15. Hainsworth JD, Andrews MB, Johnson DH, et al: Mitoxantrone, fluorouracil, and high-dose leucovorin: An effective, well-tolerated regimen for metastatic breast cancer. J Clin Oncol 9:1731-1735, 1991.
16. Jones SE, Mennel RG, Brooks B, et al: Phase II study of mitoxantrone, leucovorin, and infusional fluorouracil for treatment of metastatic breast cancer. J Clin Oncol 9:1736-1739, 1991.
17. Holmes FA, Walters RS, Theriault RL: Phase II trial of Taxol: An active drug in metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991.
18. Seidman A, Crown J, Reichman B, et al: Lack of clinical cross-resistance of Taxol (T) with anthracycline (A) in the treatment of metastatic breast cancer (MBC) (abstract 53). Proc Am Soc Clin Oncol 12:63, 1993.
19. Holmes FA, Valero V, Theriault RL, et al: Phase II trial of Taxol (T) in metastatic breast cancer (MBC) refractory to multiple prior treatments (abstract 178). Proc Am Soc Clin Oncol 12:94, 1993.
20. Fumoleau P, Chevallier B, Kerbrat P, et al: First line chemotherapy with Taxotere (T) in advanced breast cancer (ABC): A phase II study of the EORTC Clinical Screening Group (CSG) (abstract 27). Proc Am Soc Clin Oncol 12:56, 1993.
21. Ten Bokkel Huinink WW, Prove AM, Piccart M, et al: A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: A study of the EORTC Early Clinical Trials Group. Ann Oncol 5:527-532, 1994.
22. Trudeau ME, Eisenhauer E, Lofters W, et al: Phase II study of Taxotere as first line chemotherapy for metastatic breast cancer (MBC). A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study (abstract 59). Proc Am Soc Clin Oncol 12:64, 1993.
23. Valero V, Walters R, Theriault R, et al: Phase II study of docetaxel (Taxotere) in anthracycline-refractory metastatic breast cancer (abstract 1636). Proc Am Soc Clin Oncol 13:470, 1994.
24. Taguchi T, Adachi I, Enomoto K, et al: Docetaxel (RP56976) in advanced or recurrent breast cancer: Early and late phase II clinical studies in Japan (abstract 152). Proc Am Soc Clin Oncol 13:87, 1994.
25. Hortobagyi G: Docetaxel in breast cancer and a rationale for combination therapy. Oncology 11(6):11-15, 1997.
26. Rittenberg CN, Gralla RJ, Cole JT, et al: Preventing docetaxel-induced fluid retention: The efficacy of corticosteroids. Proc Am Soc Clin Oncol 15:531, 1996.
27. Schrijvers B, Wanders J, Dirix L, et al: Coping with toxicities of docetaxel. Ann Oncol 4:610-611, 1993.
28. Canobbio L, Boccardo F, Pastorino G, et al: Phase II study of Navelbine in advanced breast cancer. Semin Oncol 16:33-36, 1989.
29. Bruno S, Lira-Puerto V, Teixeira L, et al: Phase II trial with vinorelbine, (Navelbine, NVB) in the treatment of advanced breast cancer (ABC). Ann Oncol 3:268(a), 1992 (suppl 1).
30. Romero A, Rabinovich MG, Vallejo CT, et al: Vinorelbine as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 12:336-341, 1994.
31. Garcia-Conde J, Lluch A, Martin M, et al: Phase II trial of weekly IV Navelbine in first-line advanced breast cancer chemotherapy. Ann Oncol 5:854-857, 1994.
32. Data on file, SEQUUS Pharmaceuticals.
33. Muggia FM, Hainsworth JD, Jeffers S, et al. Liposomal doxorubicin (Doxil) is active against refractory ovarian cancer. Proc Am Soc Clin Oncol 15:781,1996.
34. Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal doxorubicin (DOXIL) in epithelial ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15:987-993,1997.
35. Gabizon A, Uziely B, Lotem M, et al: Doxil in patients with pretreated metastatic breast cancer: A dose-schedule finding study with pharmacokinetics (abstract). Proc ASCO 16:516, 1997.
36. Harrington KJ, Mohammadtaghi S, Uster PS, et al. Stealth liposomes: A new targeting modality for solid tumors. In preparation
37. Uziely B, Jeffers S, Isacson R, et al: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13:1777-1785, 1995.
38. Lokich JJ, Moore C: Chemotherapy-associated palmar-plantar erythrodysesthesis syndrome. Ann Intern Med 101:798-800, 1984.
39. Ranson MR, Carmichael J, OByrne K, et al: Treatment of advanced breast cancer with Stealth liposomal doxorubicin (CAELYX): Results of a multicenter phase II trial. J Clin Oncol 15:3185-3191, 1997.
40. Blajman C, Balbiani L, Coppola F, et al: Phase III study: Navelbine plus Adriamycin versus fluorouracil plus Adriamycin plus cyclophosphamide in advanced breast cancer. Proc 21st ESMO (abstract 112P), 1996.
41. Spielmann M, Dorval T, Turpin F, et al: Phase III trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12:1764-1770, 1994.
42. Smalley R, Craig J, Jones S, et al: Navelbine and Adriamycin in combination for advanced breast cancer: Phase I-II evaluation of a new schedule. Proc ASCO 13 (abstract 157), 1994.
43. Hochster H, Vogel C, Blumenreich M, et al: A U.S. multicenter phase II study of Navelbine and doxorubicin as first line chemotherapy of metastatic breast cancer (abstract 258). Breast Cancer Res Treat 32(suppl):93, 1994.
44. Coppola F, Balbiani L, Blajman C, et al: Vinorelbine containing regimens in three different schedules for the treatment of advanced breast cancer (abstract 144). Proc ASCO 13, 1994.
45. Costa MA, Cabral-Filho S, Correa M, et al: Phase II sequential navelbine and doxorubicin for the treatment of metastatic breast cancer: Preliminary results (abstract 65). Proc ASCO 15, 1996.
46. Firat D, Baltall E, Icli F, et al: Navelbine doxorubicin combination in advanced breast carcinoma previously untreated. (abstract 108P) Proc 21st ESMO, 1996.
47. Norris B, Pritchard K, James K, et al: A phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer (abstract 59). Proc ASCO 15, 1996.
48. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
49. Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of Taxotere (docetaxel), doxorubicin (Dx) and cyclophosphamide (CTX) (TAC) in the treatment of metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 16:148a, 1997.
50. Marty M, Extra JM, Dieras V, et al: A review of the antitumor activity of vinorelbine in breast cancer. Drugs 44(suppl 4):29-35, 1992.
51. Hayes DF, Henderson IC, Shapiro CL: Treatment of metastatic breast cancer: Present and future prospects. Semin Oncol 22:5-21, 1995.