Current Status of Salvage Chemotherapy for Refractory Advanced Breast Cancer

ABSTRACT: The definition of refractory advanced breast cancer remains elusive. Because of different definitions of objective response, frequent lack of precision in defining the number of prior chemotherapies, and differing interpretations of "anthracycline resistance," the literature remains confusing. What does seem clear, however, is that clinically meaningful responses can be achieved with third-line (or higher level) chemotherapy, with response rates and survival durations similar to those seen with first-line chemotherapy for metastatic colon cancer and for non-small-cell lung cancer. Given the broad array of potential chemotherapeutic options, both with commercially available combinations and new, exciting investigational agents, more data from prospective trials and more detailed retrospective analyses of large series are needed before patients and health-care administrators can be advised as to when it would be more prudent to abandon cytotoxic palliative therapies in favor of supportive care options, such as hospice care. [ONCOLOGY 10(Suppl):7-15, 1996]

Introduction

In this era of cost containment, the benefits of all therapiesare under intense scrutiny. In breast cancer management, the definitionsof refractory advanced breast cancer and of its management arecontroversial. For the purpose of this article, refractory advancedbreast cancer is partially and arbitrarily defined as primaryor acquired resistance to hormonal therapies, anthracycline resistance,and failure of some otherwise undefined number of prior cytotoxicchemotherapeutic regimens. Attempting to determine the numberof prior chemotherapeutic regimens that help to define refractoryadvanced breast cancer is both an interesting and often frustratingexercise in literature review.

To establish a frame of reference, what is known about the mediansurvival from first relapse (MSFR) of patients with breast cancermust be explored. In a recent review of this topic in the contextof presenting statistics from the University of Miami [1] (inwhich the overall MSFR of 26 months was similar to that in mostreports in the literature), the most striking finding was thevariability in MSFR, which depended on patient characteristics(Table 1). By combining these characteristics into prognosticcategories, patient subgroups with a MSFR ranging from 15 to morethan 90 months were defined (Table 2). Thus, when reviewing theliterature on survival after any therapeutic intervention, itmust be considered that such survival statistics are dependenton the heterogeneity of the population in question.

Difficulties With Response Rates

Other problems inherent in this literature review stemmed froman overreliance on response rates, which may be a relatively poorsurrogate for clinical benefit. A significant percentage of womenwith metastatic breast cancer do not have bidimensionally measurabledisease, and a large number of women have bony metastases thatare difficult to evaluate. This frequently leads to defining "response"in populations of patients with lung, soft-tissue, and liver metastases,with the overall conclusion being that bony metastases "respond"poorly to treatment. Many medical oncologists believe that timefrom initiation of treatment to time of clear-cut tumor progression,or the "time to treatment failure" from any cause, mightbe a better end point than response rate. Howell et al [2] andRobertson et a l[3] have suggested that disease stability lastinglonger than 5 or 6 months should be considered similar to an objectiveresponse.

Different definitions of response have been applied to differentclinical trials, with resultant discordant "response rates"for similar regimens in similar clinical circumstances. A recentphase II trial of medroxyprogesterone for metastatic breast cancerreported an objective response rate of 38.6% [4]. In contrast,two major, randomized, phase III trials of megestrol acetate vsthe new aromatase inhibitor, anastrozole (Arimidex), yielded responserates of approximately 10% for both agents [5]. In the lattertrials, the stringent International Union Against Cancer (UICC)response criteria were used. In these trials, adding patientswith stable disease for longer than 24 weeks to the "responders"probably provided a more realistic assessment of clinical benefit,approximating the 30% rate expected from second-line hormonaltreatment. As the definition of antitumor response becomes morestringent for quantitative purposes, it is important not to losesight of the major goals of treatment: palliation, clinical benefit,and survival.

Similar problems exist with other tumor types. In lung cancer,the Eastern Cooperative Oncology Group conducted a study demonstratingthat carboplatin (Paraplatin) resulted in the lowest responserate and the longest median survival among several different regimenstested [6] In pancreatic cancer, a new term, "clinical benefitresponse"[7] ,as well as an analysis according to that definition,has gained Food and Drug Administration (FDA) approval for gemcitabine(Gemzar), even in the face of low objective response rates. Perhaps,this encouraging precedent will lead to acceptance of alternativeend points that more realistically reflect clinical benefit.

Other problems in this literature review stemmed from the differentdefinitions of "heavily pretreated" used in variousseries. It was frequently impossible to determine individual responserates for second-, third-, or fourth-line therapies. In addition,information on anthracycline resistance was either impossibleto discern or was complicated by different definitions. Finally,in terms of survival durations, many articles cited medians, whereasothers cited survival rates for responders and nonresponders;in some series, "stable" patients were combined withresponders, and in others, they were grouped with nonresponders.

With these inherent problems in mind, this article will now endeavorto make some sense of the confusing literature on "salvagechemotherapy" for refractory advanced breast cancer.

First- and Second-line ChemotherapeuticRegimens

In the United States, many first- and second-line chemotherapeuticregimens include combinations, such as cyclophosphamide, methotrexate,fluorouracil (CMF) or cyclophosphamide + doxorubicin (Adriamycin)± fluorouracil (CA ± F)[8,9], with paclitaxel (Taxol)used mostly as second-line (or third-line) treatment. In Europeand Canada, other commonly used first-line regimens substituteepirubicin for doxorubicin; in addition, the mitomycin, methotrexate,mitoxantrone (MMM) combination is widely used as an alternativefirst-line regimen.

Commonly accepted "response rates" are in the 50% to60% range for first-line therapy, with low complete response ratesapproximating 10% and response durations (depending on their definitions)approximating 8 months. Standard second-line chemotherapeuticregimens produce reasonably consistent response rates, which varyfrom 35% to 45% for patients in whom first-line, nonanthracycline-containingregimens failed (Table 3) [9-13] to 20% to 27% for patients inwhom an anthracycline-containing regimen (Table 4) failed [14-16].

Among the newer agents, vinorelbine (Navelbine), at 30 mg/m²/wk,has produced an objective response rate of 32% as second-linetherapy in patients in whom nonanthracycline regimens failed inan American trial [13], with higher response rates reported fromEurope. Response rates with paclitaxel have been highly variable(32% to 62%), depending on the dose and schedule employed, evenwhen it was used as first-line treatment of metastatic breastcancer (Table 5) [13,17-22]. In a single pure second-line trialby Seidman et al [23] using 250 mg/m² of paclitaxel givenas 24-hour infusions with granulocyte colony-stimulating factor(G-CSF, filgrastim [Neupogen]) support, the response rate was44%, with little difference between anthracycline- and nonanthracycline-resistantpatients. Lower doses and shorter durations of paclitaxel therapyappear to yield response rates similar to those of vinorelbinetherapy in previously treated patients [20,24,25].

Results for the taxanes (Table 6) [26,27] and vinorelbine (Table7) [28-31] as second-line therapy for patients in whom anthracyclinetreatment has failed currently seem to favor the taxanes, butcontrolled, randomized trials in this subset of patients are neededto clarify this issue definitively. To date, the best resultsseen for the taxanes in anthracycline-resistant patients are with96-hour paclitaxel infusions [26] or 1-hour docetaxel (Taxotere)infusions [27].

The Controversy Surrounding Salvage Chemotherapy

It seems that most clinicians would accept that first-line chemotherapywith response rates of 50% to 60% and survival longer than 1.5years is generally worthwhile for patients with metastatic breastcancer. In addition, the population of patients with responserates of 35% to 45% for second-line therapy in whom nonanthracycline-containingfirst-line regimens failed should also be considered for treatment.

The use of second-line therapy for patients in whom first-line,anthracycline-containing regimens failed is controversial. Perhaps,it was this group that led to pessimism on the part of oncologistsin Maryland; during a survey, these oncologists indicated thatalthough they used second-line chemotherapy 74% of the time, theydid so without much enthusiasm. In their commentary on these results,Benner et al [32] suggested that "standard chemotherapy bestopped after breast cancer fails to stabilize or respond on astandard regimen." They stated that "the frequent utilizationof second-line regimens probably reflects an effort to offer marginalregimens to patients who want them." This conclusion appearsto be supported by Porkka et al [14] in a wellwritten articlefrom Finland. Although 24% of their patients responded to second-linetreatment after first-line anthracycline failure, only 10% ofthese patients had a time to treatment failure of longer than6 months. In addition, they found that no patient treated witha third salvage chemotherapeutic regimen responded. They concludedthat "the value of offering more than two salvage chemotherapyprograms to an unselected group of patients is questionable."

Undoubtedly, the findings of Benner's [32] and Porkka's [14] groupswill be widely cited by managers of health maintenance organizations,as guidelines are written for the purpose of cost containment.In contrast, this degree of therapeutic nihilism comes at a timewhen a wide variety of potential salvage regimens are available(Table 8) and an unprecedented number of new investigational drugswith proven effectiveness for metastatic breast cancer are underdevelopment (Table 9).

The problem is compounded by the general unavailability of stringentlycontrolled trials to define the value of third-line and fourth-line(or higher level) therapies in patients with metastatic breastcancer. Clinicians are faced with a large number of small, uncontrolledtrials often citing results at variance with the existing biasthat third-line (or higher level) chemotherapy is generally ineffective.

'Standard' Regimens for Refractory AdvancedBreast Cancer

Two major "standard" regimens have been used as third-line(or higher level) chemotherapy for refractory advanced breastcancer. The first of these regimens, mitomycin with a vinca alkaloid,has been used for 2 decades, most commonly in anthracycline-refractorypatients. Table 10 summarizes several series [11,12,16,33-39].In general, response rates have exceeded 20%. In the series byPerrone et al, [38], even though the response rate was low, overallsurvival was reasonably good. In the series by Denefrio et al[39], a dose of only 6 mg/m² of mitomycin was used. In theIngle et al series [11], vincristine, generally considered tobe less effective in breast cancer than some of the other vincaalkaloids, was used.

Another frequently used salvage regimen consists of 5-fluorouracil,either by continuous infusion or modulated with leucovorin. Table11 presents data summarized by Lokich and Anderson.[40,41] Twoadditional review articles on this topic have also been published[42,43]. Again, response rates seem generally favorable and areapproximately 28%, usually for "heavily pretreated patients."

Table 12 summarizes the relatively rare studies devoted to third-linetherapy. Again, except for the previously discussed study by Ingleet al [11], the response rates of 31% to 41% are respectable andraise questions about the conclusions of Benner et al [32] concerningthe value of third-line chemotherapy for the management of metastaticbreast cancer.

The Role of Salvage Therapy

In this era of managed care, many organizations are seeking reasonsto restrict therapy when the expectations of such treatment are"limited." Although Benner's [32] and Porkka's [14]groups would limit salvage chemotherapy for metastatic diseaseto, at most, two forms of chemotherapy, the data previously presentedin Tables 10,11 &12, as well as unpublished personal observationsover 20 years devoted to the practice of breast medical oncology,point to a less nihilistic conclusion about "salvage"therapy for refractory advanced breast cancer. Table 13 providessome intriguing comparisons with other disease entities [46,47].Thus, although few clinicians would challenge the use of first-linechemotherapy for patients with non-small-cell cancer of the lungsor cancer of the colon, the use of third-line chemotherapy forpatients with breast cancer is being questioned, despite similarresults in terms of both response rates and median survivals.With all the available agents and regimens for salvage therapy,well-controlled trials of third-line (and higher level) chemotherapyare now needed. These trials are necessarily more complex becauseof the wide variability of preceding therapies.

Philosophically, my approach to treatment of refractory advancedbreast cancer utilizes regimens that will maximize quality oflife without substituting the toxic side effects of aggressivechemotherapeutic regimens. Even in the advanced stages of thisdisease, many women remain concerned with the problem of nauseaand alopecia; hence, regimens including vinorelbine or fluorouracil(5-FU) alone or in combination are useful. Gemcitabine could wellemerge as an important palliative drug in breast cancer management,and exciting preliminary results using

HER-2/neu antibody therapy could point to new noncytotoxicchemotherapeutic directions. Two other combinations that I haveused effectively with little toxicity have been a mitoxantrone,5-FU, and leucovorin regimen given on a day 1 and 8 schedule [48]and a Memorial Sloan-Kettering Cancer Center salvage regimen.The latter uses moderately high-dose methotrexate on day 1 followedby leucovorin rescue and 5-FU on day 2.

Among the wide variety of salvage programs available, platinum-basedchemotherapeutic regimens and docetaxel are seldom used becauseof their toxicity profiles. In contrast, cisplatin and docetaxelshould be intensively studied within first-line metastatic diseaseprotocols and as part of potentially "curative" strategiesin the adjuvant setting.

In clinical situations, it is unusual for patients with refractoryadvanced breast cancer to choose hospice care when there are somany therapeutic options available that hold some hope (albeitmodest) for induction of antitumor response, palliation of symptoms,and prolonged survival. Patients almost always have social landmarks(upcoming weddings, births, graduations) that lead them to optfor attempts at active antitumor palliative care as opposed tohospice care.

Comprehensive Cancer Research Group, Inc.

This South Florida research group provides the research infrastructurefor regional private practicing oncologists interested in havingaccess to clinical trials for their patients. Table 14 providesthe current first-line protocol flow for our Comprehensive CancerResearch Group, Inc. (CCRGI). This first-line program may verywell be unique with the availability of seven first-line chemotherapeuticprograms. Protocol niches have been developed to cover most clinicalsituations. The high-dose Adriamycin/cyclophosphamide program,with or without interleukin-6 (IL-6) for platelet support, isavailable for neoadjuvant therapy.

The first-line Adriamycin/cyclophosphamide ± HER-2/neuantibody trial is for patients desiring standard anthracycline-based,first-line therapy. For the 70% of patients whose tumors do notexpress the HER-2/neu antigen, Adriamycin/cyclophosphamideis randomized against losoxantrone plus cyclophosphamide. Forpatients with no measurable disease, fluorouracil, Adriamycin,cyclophosphamide (FAC), with or without dexrazoxane (Zinecard),is available. In contrast to patients willing to accept aggressiveanthracycline-based, first-line therapies, others would preferexchanging a few percentage points of response for a better quality-of-liferegimen. For such women, single-agent vinorelbine for patientsolder than age 60 and single-agent gemcitabine for patients youngerthan age 60 are available. Each of these single agents inducesresponse rates of 35% to 40%, with 8-month remission durations,but without significant hair loss or other subjective side effectsthat frequently limit the tolerability of the more standard regimens.For women who absolutely refuse any form of cytotoxic chemotherapyand for women who have HER-2/neu antigen-positive tumors,an antibody trial is available.

Second-Line CCRGI Program--CCRGI's second-line programevaluates different schedules of paclitaxel administration. Forthird-line therapy, a phase II trial of the HER/2-neu antibodyfor eligible patients is offered.

CCRGI's program is contrasted with a more conventional treatmentflow, which is depicted in Table 15 [8,9]. Thus, a reasonablycommon sequence of treatments would start with cyclophosphamide,methotrexate, fluorouracil (CMF); move to vinblastine, Adriamycin,thiotepa, Halotestin (VATH) or some other anthracycline-basedregimen; and be followed by paclitaxel (third-line), mitomycinplus vinblastine (fourth-line), and then some form of infusionalor leucovorin-modulated fluorouracil regimen. CCRGI's standardflow would be similar to this one, except that it would startwith an anthracycline.

CCRGI'S Quality-of-Life Protocol--CCRGI's quality-of-lifeprotocol flow would start with vinorelbine or gemcitabine, thenmove to a day 1 and day 8 mitoxantrone, 5-fluorouracil, and leucovorinregimen [48], and be followed by a phase II trial of the HER-2/neuantibody for women who express this antigen or a vinorelbine/fluorouracilregimen (if first-line therapy had been gemcitabine). If vinorelbinehad been used as a first-line agent, either CMF or the MemorialSloan-Kettering Cancer Center salvage regimen (moderately high-dosemethotrexate on day 1 followed by leucovorin rescue and fluorouracilon day 2) is a reasonably well-tolerated alternative third-lineprogram. For fourth- through sixth-line therapy, single agents,such as low-dose weekly infusional doxorubicin, mitomycin, orinfusional or leucovorin-modulated fluorouracil, might be offered.

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