Treatment Options for Patients with Refractory Breast Cancer

ABSTRACT: The treatment of refractory metastatic breastcancer is complex and challenging. Practicing oncologists mustchoose from an array of therapuetic options. Palliation remainsthe primary goal of treatment, and the risks and benefits of eachtherapeutic intervention must be carefully assessed. A numberof new agents appear to be quite effective and may ultimatelylead to improved symptom control, better quality of life, andperhaps even longer survival. As new treatments are evaluatedfor patients with refractory breast cancer, it is important toassess the impact of therapy on quality-of-life issues, as wellas on response and survival. [ONCOLOGY 10(Suppl):16-20,1996]

Introduction

In North America, approximately 182,000 women are diagnosed withbreast cancer each year, and 46,000 women die of the disease [1].As many as 10% of these women present with metastatic diseaseat the time of diagnosis, and a substantial proportion of patientsinitially diagnosed with localized disease will develop metastases.The vast majority of women who develop metastatic disease willultimately die of it, with a median survival of 2 to 3 years [2,3].

The prognosis of patients with advanced breast cancer is highlyvariable; some patients die within a few months of developingmetastatic disease and others survive for 10 years or longer.More treatment options exist for patients with metastatic breastcancer than for most patients with cancer. A wide range of bothhormonal therapies and cytotoxic treatments have been in use overthe past 10 to 20 years, and several new agents have recentlybecome available. Although systemic therapy probably prolongssurvival [4,5], definitive evidence that treatment prolongs lifeis difficult to find. The primary goal of treatment is to improvequality of life by palliating the symptoms related to cancer.The heterogeneity among patients, the wide range of treatmentoptions, and the need to weigh the risks versus the benefits ofavailable therapies pose a challenge for medical oncologists caringfor women with advanced breast cancer.

Initial Treatment of Metastic Disease

For patients with estrogen and/or progesterone receptor-positivetumors, hormonal therapy is often the first-line treatment ofmetastatic disease because of its high degree of efficacy andminimal toxicity. Chemotherapy is usually recommended for patientswith hormone receptor-negative tumors or for patients who havebecome refractory to hormonal therapy.

When chemotherapy is indicated, combination therapy is often administered.Some of the most common first-line regimens are listed in Table1. Response rates for these regimens range from approximately35% to 75%.6 Doxorubicin-containing regimens are usually associatedwith higher response rates than regimens that do not contain thisagent. For this reason, many oncologists opt for doxorubicin-basedregimens as initial chemotherapy for patients with metastaticbreast cancer, particularly for patients with troublesome cancersymptoms. Less toxic regimens (eg, cyclophosphamide [Cytoxan,Neosar], methotrexate, and fluorouracil [CMF] or mitoxantrone[Novantrone]-containing regimens) are often administered to olderpatients, individuals with comorbidities, or patients who haveparticular difficulty tolerating the side effects of chemotherapy.Data from the M. D. Anderson Cancer Center, however, suggest thatage alone is not a reason to avoid an anthracycline-based regimen[7].

For patients with metastatic disease who have received adjuvanttreatment with doxorubicin, a taxane-based regimen, usually single-agentpaclitaxel (Taxol), often is used as first-line treatment in themetastatic setting [8,9]. Gianni et al [10] have reported a responserate in excess of 90% with a combination of paclitaxel and doxorubicinas first-line therapy for metastatic disease. Unfortunately, thisregimen was also associated with higher cardiotoxicity than wouldhave been expected given the total doxorubicin dose. Additionalclinical trials evaluating doxorubicin/paclitaxel regimens mustbe completed before this option can be considered a standard first-lineregimen.

The use of high-dose chemotherapy with autologous bone marrowor peripheral stem cell support has gained great attention inrecent years, but this treatment is usually reserved for youngerpatients who have chemotherapy-responsive disease [11]. Of thetotal population of patients with metastatic breast cancer inNorth America, a relatively small percentage receive this intensivetreatment during the course of their illness.

Regardless of the choice of first-line chemotherapy, virtuallyall patients will develop disease progression, often after aninitial response to treatment or a period of disease stabilization.Most patients with metastatic breast cancer are potential candidatesfor second-line chemotherapy. Although large population- basedstudies of treatment of advanced breast cancer have not been performed,the majority of patients with breast cancer in the United Statesprobably receive two or more chemotherapeutic regimens in themetastatic setting. In the remainder of this article, the term"refractory breast cancer" will be used to describepatients with hormone-refractory metastatic breast cancer whohavedeveloped disease progression following an initial chemotherapeuticregimen.

Treatment Options for Refractory BreastCancer

A number of chemotherapeutic agents and regimens are availablefor patients with refractory breast cancer. As with first-linetherapy, the primary goal of treatment is the palliation of cancer-relatedsymptoms. If there is any survival advantage as a result of treatmentof refractory disease, it is almost certainly of a very smallmagnitude. In this setting, the potential for treatment-inducedtoxicity must be considered carefully before any therapy is initiated.Unfortunately, only a limited number of patients who receive treatmentof refractory breast cancer will have an objective (or even subjective)response to treatment, but all patients (whether or not they derivebenefit from treatment) are at risk for developing minor sideeffects and/or debilitating complications. For patients with fewcancer symptoms, the option to withhold further chemotherapy untilsymptoms worsen is always worthy of consideration. Many physicianshave difficulty with this "watchful waiting" approach,particularly for younger patients, for whom they may hope thata response to treatment could offer some prolongation of life.Many patients are also more comfortable receiving active treatment.In these situations, especially when patients are entirely asymptomatic,treatment regimens without serious toxicity should be stronglyconsidered. Although continuing active treatment may facilitatea sense of hopefulness, it is difficult to know how much thisenhanced hopefulness is counterbalanced by the side effects, risks,and inconvenience that result from chemotherapy.

Historical Perspective

As we consider new treatments for refractory breast cancer, itis helpful to view these treatment programs from a historicalperspective. Between 1975 and 1991, 1,756 patients underwent treatmentof metastatic breast cancer at Guy's Hospital in London [12].A total of 758 (43%) received first-line chemotherapy for metastases.More than half of these patients received an anthracycline-containingregimen as initial treatment, with most of the remaining patientsreceiving CMF. The overall response rate in patients receivingfirst-line therapy was 35%, and the median time to progressionin responding patients was 7.8 months. As expected, a longer disease-freeinterval and the absence of metastases were both predictive ofa response to therapy.

Of patients who underwent first-line treatment, approximatelyone-third received a second-line chemotherapeutic regimen. Theoverall response rate to second-line therapy was only 16%; patientswho had responded to first-line treatment had a significantlyhigher chance of responding to treatment in the refractory settingthan did patients who had not responded to first-line treatment.Of interest, the response rate seen in 58 patients who receivedthird-line therapy was similar to that seen in the second-lineexperience, including a small number of responses in patientswho had failed to respond to either of the first two regimens.

Investigators from Finland [13] have described the outcome oftreatments administered for refractory disease in a group of patientswho had participated in a study evaluating two different first-lineanthracycline-based chemotherapeutic schedules. Although responseto therapy could only be determined in approximately half of thetreatment courses, the results echoed those of the Guy's Hospitalexperience. Where data were available, the response rates to second-and third-line chemotherapy were 20% and 12%, respectively. Itis important to note that these results, like those from Guy'sHospital, do not reflect the availability of some of the newercytotoxic agents, such as paclitaxel and docetaxel (Taxotere).Nevertheless, such findings indicate the need to evaluate criticallythe risks and benefits of treatment programs in this population.Of interest, occasional responses were seen with third-line chemotherapyin both the Guy's Hospital and Finnish series. This finding suggeststhat the use of chemotherapy cannot be arbitrarily discontinuedafter a patient has received two regimens.

Combination Regimens

A wide range of combination regimens have been evaluated overthe past 5 to 10 years; a partial list of these regimens appearsin Table 2 [14-23]. Response rates vary but rarely exceed the30% to 40% range and are often much lower. The median durationof response in responders is consistently in the range of 5 to7 months. Because most regimens have been evaluated in the settingof single-institution phase II trials, it is very difficult tocompare one regimen with another. It remains unclear whether thereis any advantage to combination therapy compared with single agents.Clearly, there is no combination regimen that could be consideredthe gold standard for patients with refractory disease.

Although some combination regimens are well tolerated, the toxicityof most multiagent regimens tends to be higher than that of singleagents. Mitomycin (Mutamycin), which is often combined with oneof the vinca alkaloids or other agents, is active in refractorydisease. Unfortunately, it is highly myelosuppressive and canlimit options for subsequent treatment regimens because of itsprofound effect on bone marrow reserve. With the availabilityof new agents, the use of mitomycin has probably declined in recentyears. Cisplatin (Platinol), another agent often found in combinationtherapy, is active in patients with no prior exposure to chemotherapyin the metastatic setting [24]. As a single agent, it has limitedefficacy in patients with refractory disease, and combinationscontaining cisplatin tend to be quite toxic. For these reasons,cisplatin has no established role in the treatment of refractorybreast cancer. Another platinum analog, carboplatin (Paraplatin),has no definitive role in the treatment of refractory metastaticdisease [17,18].

Single Agents

All the agents used in the combinations previously discussed,as well as several other cytotoxic agents, have been evaluatedas single agents for patients with refractory breast cancer. Inparticular, fluorouracil (5-FU) is quite active in patients withrefractory disease, especially when it is administered as a continuousinfusion or in combination with leucovorin [25-27]. Toxicity withcontinuous infusion 5-FU is usually quite modest; when administeredas a low-dose infusion over a number of weeks, it causes minimalmyelosuppression and few serious toxicities. Although 5-FU hasbeen deleted from some adjuvant regimens in recent years, it remainsan effective agent in patients with refractory disease.

Table 3 includes trials with single-agent paclitaxel, docetaxel,and vinorelbine (Navelbine) [9,28-33]. Each agent is active inpatients with refractory breast cancer. In many centers, paclitaxelhas become the standard second-line regimen, based on promisingresults from initial phase II trials [9,28] and subsequent approvalby the Food and Drug Administration (FDA). A number of questionsconcerning the optimal use of paclitaxel in the treatment of breastcancer remain. Ongoing studies are addressing several of thesequestions, including the importance of dose intensity and therole of different infusion durations.

Docetaxel (Taxotere) has been found to have remarkable activityin patients with anthracycline-resistant refractory breast cancer[30,31]. Unfortunately, significant fluid retention with cumulativedoses of docetaxel has slowed the development of this agent, butpremedication with steroids has decreased the severity of thisproblem. It will be important to see whether the promising earlyresults are sustained with additional clinical trials. [Docetaxelwas recently appproved by the FDA for treatment of patients withlocally advanced or metastatic breast cancer that has progressedduring anthracycline-based therapy or has relapsed during anthracycline-basedadjuvant therapy.--Ed.]

Finally, vinorelbine has also been demonstrated to be active inpatients with refractory disease [32,33], including patients withanthracycline-refractory and both anthracycline- and taxane-refractorybreast cancer [34]. Although response rates with single-agentvinorelbine have been somewhat lower than those seen in some ofthe taxane trials, the toxicity of vinorelbine is quite mild.Vinorelbine has yet to gain FDA approval for use in patients withbreast cancer, but this agent ultimately may play an importantrole in the treatment of patients who cannot tolerate side effectsfrom therapy or patients who have had severe toxic effects withprior treatment regimens.

Other promising agents in early clinical development include gemcitabine(Gemzar), trimetrexate, and losoxantrone.

Is there an ideal single agent for patients with refractory breastcancer? The single agents previously discussed have yet to becompared with one another or with combination regimens in randomizedclinical trials, although some studies are underway. Until furtherinformation is available, the decision to treat patients witheither a single agent or a combination regimen must be based onindividual symptoms, comorbid illnesses, response to prior chemotherapy,ability to tolerate different types of toxicities, and eagernessto proceed with treatment. Whenever possible, patients shouldbe encouraged to participate in clinical trials that address unresolvedquestions about the use of current therapies or that seek to identifynew treatments for refractory breast cancer.

Physicians' Attitudes About Treatment

Little research has addressed physicians' attitudes about thetreatment of patients with refractory breast cancer. In a studyconducted several years ago, Benner and colleagues [35] surveyedoncologists in Maryland to characterize their knowledge and attitudesabout the use of chemotherapy for hormone-unresponsive metastaticbreast cancer. A total of 71% of oncologists cited palliationas the primary goal of treatment. Although they were enthusiasticabout recommending first-line chemotherapy to their patients,they were less likely to encourage patients to consider second-linetreatments. Of interest, however, is the fact that 47% of physiciansindicated that they would not reduce the dose of second-line therapy,even if a patient had experienced febrile neutropenia. Whetherphysicians' attitudes vary in different geographic regions isunknown. It is also unclear as to what extent the availabilityof new agents such as the taxanes has affected practice patterns.Further research in this area will provide a fuller understandingof physicians' attitudes and expectations with regard to the treatmentof refractory breast cancer.

Quality-of-Life Issues

Although palliation is the primary goal of treatment for patientswith refractory breast cancer, obtaining a clear assessment ofpalliation is often quite difficult. Quality-of-life issues areoften discussed, but incorporating meaningful quality-of-lifemeasurements into clinical trials (and into clinical practice)is an arduous task. A number of validated quality-of-life instrumentshave been developed and are available as a means to assess outcomesin patients with refractory breast cancer. To date, few studieshave successfully incorporated quality-of-life end points. Coatesand colleagues [36] documented improvements in quality of lifeas a result of chemotherapy despite the side effects of treatment.Their study, however, was limited to first-line chemotherapy.In the future, studies of patients with refractory breast cancershould include quality-of-life assessments that can complementthe more traditional end points of response and survival. Quality-of-lifeassessments can capture the subjective improvements often seenin patients who respond to treatment. As the number of treatmentoptions increases for patients with breast cancer, well-designedquality-of-life assessments can help physicians and their patientschoose from among the various alternatives.

References:

1. Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA CancerJ Clin 45:8-30, 1995.

2. Garber JE, Henderson IC: The use of chemotherapy in metastaticbreast cancer. Hematol Oncol Clin North Am 3:807-821, 1989.

3. Sledge GW Jr, Antman KH: Progress in chemotherapy for metastaticbreast cancer. Semin Oncol 19:317-332, 1992.

4. Swenerton KD, Legha SS, Smith TL, et al: Prognostic factorsin metastatic breast cancer treated with combination chemotherapy.Cancer Res 39:1552-1562, 1979.

5. Hortobagyi GN, Smith TL, Legha SS, et al: Multivariate analysisof prognostic factors in metastatic breast cancer. J Clin Oncol1:776-786, 1983.

6. Hayes DF, Henderson IC, Shapiro CL: Treatment of metastaticbreast cancer: Present and future prospects. Semin Oncol 22(suppl5):5-21, 1995.

7. Ibrahim N, Buzdar A, Frye D, et al: Should age be a determiningfactor in treating breast cancer patients with combination chemotherapy?Proc Am Soc Clin Oncol 12:74, 1993. Abstract.

8. Reichman BS, Seidman AD, Crown JPA, et al: Paclitaxel and recombinanthuman granulocyte colony-stimulating factor as initial chemotherapyfor metastatic breast cancer. J Clin Oncol 11(10):1943-1951, 1993.

9. Seidman AD, Tiersten A, Hudis C: Phase II trial of paclitaxelby 3-hour infusion as initial and salvage chemotherapy for metastaticbreast cancer. J Clin Oncol 13(10):2575-2581, 1995.

10. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hourinfusion in combination with bolus doxorubicin in women with untreatedmetastatic breast cancer: High antitumor efficacy and cardiaceffects in a dose-finding and sequence-finding study. J Clin Oncol13(11):2688-2699, 1995.

11. Champlin R: Dose-intensive therapy with autologous bone marrowtransplantation for treatment of breast cancer. Cancer Bull 45:532-537,1993.

12. Gregory WM, Smith P, Richard MA, et al: Chemotherapy of advancedbreast cancer: Outcome and prognostic factors. Br J Cancer 68:988-995, 1993.

13. Porkka K, Blomqvist C, Rissanen P, et al: Salvage therapiesin women who fail to respond to first-line treatment with fluorouracil,epirubicin, and cyclophosphamide for advanced breast cancer. JClin Oncol 12:1639-1647, 1994.

14. Francini G, Petrioli R, Aquino A, et al: Advanced breast cancertreatment with folinic acid, 5-fluorouracil, and mitomycin C.Cancer Chemother Pharmacol 32:359-364, 1993.

15. Agostara B, Gebbia V, Testa A, et al: Mitomycin C and vinorelbineas a second line chemotherapy for metastatic breast carcinoma.Tumori 80:33-36, 1994.

16. Perrone F, De Placido S, Carlomagno C, et al: Chemotherapywith mitomycin C and vinblastine in pretreated metastatic breastcancer. Tumori 79:254-257, 1993.

17. Turrill M, Spicer DV, Kelley AS, et al: Phase II clinicaltrial of carboplatin, ifosfamide, with oral mesna for metastaticbreast carcinoma. Cancer Invest 13:160-164, 1995.

18. Barker LJ, Jones SE, Savin MA, et al: Phase II evaluationof carboplatin and VP-16 for patients with metastatic breast cancerand only one prior chemotherapy regimen. Cancer 72:771-773, 1993.

19. Scheithauer W, Kornek G, Kwasny W, et al: Effective secondline chemotherapy of advanced breast cancer with Navelbine andmitomycin C. Breast Cancer Res Treat 26:49-53, 1993.

20. Alonso MC, Tabernero JM, Ojeda B, et al: A phase III randomizedtrial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF)versus cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF)in patients with metastatic breast cancer. Breast Cancer Res Treat34:15-24, 1995.

21. Perrone F, De Placido S, Carlomagno C, et al: Mitomycin Cand mitoxantrone in anthracycline pretreated advanced breast cancerpatients: A phase II study. Am J Clin Oncol 17:218-222, 1994.

22. Stöger H, Schmid M, Bauernhofer T, et al: A phase IItrial of weekly high-dose folinic acid and 5-fluorouracil in combinationwith epirubicin as salvage chemotherapy in advanced breast cancer.Oncology 51:518-522, 1994.

23. Içli F, Günel N, Dinçol D, et al: Cisplatinplus VP-16 combination chemotherapy in advanced refractory breastcancer. J Surg Oncol 50:251-253, 1992.

24. Sledge GW Jr, Loehrer PJ Sr, Roth BJ, et al: Cisplatin asfirst-line therapy for metastatic breast cancer. J Clin Oncol6(12)1811-1814, 1988.

25. Cameron DA, Gabra H, Leonard RC: Continuous 5-fluorouracilin the treatment of breast cancer. Br J Cancer 70(1):120-124,1994.

26. Doroshow JH, Leong L, Margolin K, et al: Refractory metastaticbreast cancer: Salvage therapy with fluorouracil and high-dosecontinuous infusion leucovorin calcium. J Clin Oncol 7:439-444,1989.

27. Swain SM, Lippman ME, Egan EF: Fluorouracil and high-doseleucovorin in previously treated patients with metastatic breastcancer. J Clin Oncol 7:890-899, 1989.

28. Seidman AD, Reichman BS, Crown JPA, et al: Paclitaxel as secondand subsequent therapy for metastatic breast cancer: Activityindependent of prior anthracycline response. J Clin Oncol 13:1152-1159,1995.

29. Abrams JS, Vena DA, Baltz J, et al: Paclitaxel activity inheavily pretreated breast cancer: A National Cancer InstituteTreatment Referral Center trial. J Clin Oncol 13(8):2056-2065,1995.

30. Ravdin PM, Burris III HA, Cook G, et al: Phase II trial ofdocetaxel in advanced anthracycline-resistant or anthracenedione-resistantbreast cancer. J Clin Oncol 13:2879-2885, 1995.

31. Valero V, Holmes FA, Walters RS, et al: Phase II trial ofdocetaxel: A new, highly effective antineoplastic agent in themanagement of patients with anthracycline-resistant metastaticbreast cancer. J Clin Oncol 13:2886-2894, 1995.

32. Jones S, Winer E, Vogel C, et al: A randomized comparisonof vinorelbine and melphalan in anthracycline-refractory advancedbreast cancer. J Clin Oncol. 13(10):2567-2574, 1995.

33. Weber BL, Vogel C, Jones S, et al: Intravenous vinorelbineas first-line and second-line therapy in advanced breast cancer.J Clin Oncol 13(11):2722-2730, 1995.

34. Livingston RB, Ellis GK, Williams MA: Weekly vinorelbine (Navelbine,NVB) and GCSF in Taxol-refractory metastatic breast cancer (MBC):A phase I-II study. Proc Am Soc Clin Oncol 14:110, 1995. Abstract.

35. Benner SE, Fetting JH, Brenner MH: A stopping rule for standardchemotherapy for metastatic breast cancer: Lessons from a surveyof Maryland medical oncologists. Cancer Invest 12:451-455, 1994.

36. Coates A, Gebski V, Stat M, et al: Improving the quality oflife during chemotherapy for advanced breast cancer. N Engl JMed 317:1490-1495, 1987.