Rationale for Trials Studying Pegylated Liposomal Doxorubicin in Metastatic Breast Cancer

October 1, 1997

Breast cancer is second only to lung cancer as a leading cause of cancer mortality in women. In women with metastatic, hence, essentially incurable disease, we strive to find effective chemotherapeutic regimens that offer a

ABSTRACT: Breast cancer is second only to lung cancer as a leading cause of cancer mortality in women. In women with metastatic, hence, essentially incurable disease, we strive to find effective chemotherapeutic regimens that offer a higher quality of life free of the many toxicities associated with standard therapies. We have treated a small group of patients who were heavily pretreated for metastatic breast cancer with pegylated liposomal doxorubicin (PEG-LD) (Doxil) and demonstrated clinical benefit without the usual concomitant toxicity of traditional doxorubicin (Adriamycin). We have initiated trials of combination chemotherapy with PEG-LD with agents designed to improve clinical efficacy, while maintaining or improving patients’ quality of life. We believe that optimal schedules for use of PEG-LD, and its combination with other agents, will provide promising options for treating patients with metastatic breast cancer. [ONCOLOGY 11(Suppl 11):45-53, 1997]

Introduction

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.[3]

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.[4]

Treatment of Metastatic Breast Cancer

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.[5] This group of women could also benefit from the use of effective yet gentle therapy.

Systemic Chemotherapy

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 these—doxorubicin (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.[11] 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.[12]

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 patient’s quality of life, investigators have sought treatment regimens which may offer a good likelihood of response or survival advantage, but with minimal toxicity.

Rationale for Use of Liposomal Encapsulated Doxorubicin

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.[32] PEG-LD was also effective in vivo when used to treat non-Hodgkins lymphoma in dogs that failed on doxorubicin.[32] 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 Kaposi’s sarcoma, even in patients who failed doxorubicin.[35]

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.[36] 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.[37] 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.[38] 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.

PEG-LD

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.[39] 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.[35] 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.

Our Experience with PEG-LD

With the known efficacy of doxorubicin in many tumor types and a favorable toxicity profile of PEG-LD, it was appealing to offer it to patients with advanced cancer refractory to standard chemotherapy, or for which no standard therapy existed, or those who could benefit from doxorubicin but were unwilling or unable to withstand the toxicity of the native drug. Patients were required to have adequate bone marrow, hepatic and renal reserves, and a Karnofsky performance status greater than or equal to 70%.

Patient Population

Twenty-eight patients were enrolled in our study between January 1996 and February 1997. Most of the patients had a diagnosis of breast cancer (N = 16), with the other diagnoses including ovarian (N = 2), lung (N = 2), prostate (N = 3), mesothelioma (N = 1), endometrial (N = 1), hepatocellular (N = 1), pancreatic (N = 1) and colon (N = 1) cancers (Table 3).

Characteristics of the 16 breast cancer patients are described in Table 4. The median age of the patients was 66 years, with six having received at least four prior chemotherapeutic regimens. Most of these patients had, in addition, received three or four levels of hormonal therapy, making this their seventh or eighth level of therapy. Four patients had received doxorubicin previously. In addition, ten of the patients had visceral metastases and only two patients had soft tissue-only metastases.

Activity

Baseline and follow-up studies are listed in Table 5. Patients were begun on PEG-LD 40 mg/m2 by intravenous infusion every 4 weeks. Those who did well at this dose were escalated to 45 mg/m2 and then to 50 mg/m2. The median dose was 45 mg/m2. To date, 12 of the 16 women are evaluable for response; the four other patients have only received one cycle of chemotherapy. Of these 12 evaluable patients, two had a partial response, three patients did not meet the criteria for partial response but clearly benefited from treatment, three had stable disease durations, and four progressed (Table 6).

Toxicity

The toxicity data are compiled from all 24 patients. The hematologic toxicities from 73 evaluable cycles are listed in Table 7. We observed no grade 4 hematologic toxicity and very little grade 3 hematologic toxicity; platelets were not affected at all. Notably, the median time to nadir was 3 weeks, much later than the usual time to nadir in patients on standard chemotherapy, who often experience a nadir between day 10 and 15.

The incidence of nonhematologic toxicity is listed in Table 8. We documented palmar-plantar erythrodysesthesia in only 10% of the cycles, and no patients experienced grade 3 or 4 toxicity. In only two patients was treatment delayed for grade 1 toxicity and that was for only 1 week. No patients experienced alopecia. Other infrequent adverse events, which may or may not be related to chemotherapy, are listed in Table 9.

The following cases presented are of the two patients with partial responses and the three others with clear benefit from treatment:

Case I

A 76-year-old white female was found to have a left breast lesion on a mammogram in November 1992 and underwent an excisional biopsy which revealed multifocal infiltrating ductal carcinoma with a 0.6 cm area of microscopic focal infiltration. The tumor was poorly differentiated, estrogen and progesterone receptors were positive, and the margins were involved. She underwent a left-modified radical mastectomy in December 1992. All of the 12 sampled lymph nodes were negative, and the margins were clean. No adjuvant therapy was given at that time.

In September 1994 she was found to have a rising CEA (15.3 ng/mL) and a solitary liver lesion, and underwent staging work-up. A full gastrointestinal work-up did not reveal any gastrointestinal primary tumor, but a fine- needle biopsy aspiration of the liver lesion (measuring 1.5 cm) revealed adenocarcinoma consistent with breast primary. She was started on tamoxifen (Nolvadex), which she took from October 1994 to June 1995 when she was found to have progression in bones. She was switched to megestrol acetate (Megace), which she received from August 1995 to September 1995 with continuous elevation of the tumor markers (CEA = 135 ng/mL; CA15-3 = 52 µ/mL). She did not tolerate megestrol acetate, suffering hot flashes and fluid retention, and was switched to exemestane (an aromatase inhibitor) on a protocol which she received from October 1995 to November 1995; her CEA level rose further (to 165 ng/mL) with a concomitant increase in the size of her liver lesion.

At that time, this patient was given two cycles of chemotherapy with CMF. Upon reevaluation at the end of January 1996, she was found to have disease progression with development of new omental lesions. She was placed on paclitaxel in February 1996, but reevaluation with imaging studies after three cycles revealed progression in the liver and interval development of ascites. She was then enrolled in a capecitabine protocol (an oral pro-drug of 5-FU) but after 2 months (May 1996 to June 1996) showed continual progression in her omentum and liver. Her tumor markers in June 1996 were markedly elevated with a CEA of 783 ng/mL and a CA15-3 of 468 µ/mL.

In June 1996, she was placed on PEG-LD and began to show evidence of response after two cycles which continued with subsequent cycles. At the end of six cycles in December 1996, her CEA had decreased to 18.4 ng/mL and her CA15-3 to 28.4 µ/mL. By February 1997 both of these tumor markers were within normal limits. Concomitantly, a CT scan of her abdomen and pelvis revealed complete disappearance of omental disease and shrinkage of the liver lesions to less than one-half of their original size.

Case II

A 48-year-old white female was diagnosed in 1988 with left-sided breast cancer. She underwent a left lumpectomy and axillary dissection. Pathology revealed extensive intraductal carcinoma of comedo type with focal areas of invasion. The area of invasion measured 1 cm. None of the 22 sampled lymph nodes were involved. Estrogen and progesterone receptors were positive by immunohistochemistry. She was given adjuvant radiation to the breast with six cycles of CMF.

In 1992 she had a relapse in the left breast with infiltrating ductal carcinoma and metastases to her bones. She was started on tamoxifen in July 1992 which she received for 2 to 3 months, but was switched to megestrol acetate after developing progression in her bone. She remained stable on megestrol acetate for 13 months, but discontinued it because of excessive weight gain. She was placed on vinorelbine and 5-FU at that time; she received this treatment for about a year, initially remaining stable, but then clinically progressing.

She was then enrolled in a docetaxel study, but did not tolerate this therapy and refused further doses. Between December 1994 and May 1995 she was given mitoxantrone (Novantrone) and mitomycin C and achieved a partial response; the main toxicity was hematologic. She was then given three additional months of therapy with mitoxantrone alone. She was taken off therapy in August 1995 with stable disease because she wanted to maintain remission with hormones only, and was thus placed on aminoglutethimide (Cytadren). She stopped the hormone after 2 months because she developed a rash and reported a poor quality of life. She received diethylstilbestrol (DES) from September 1995 to November 1995, but had progression in her liver. She was placed on anastrozole (Arimidex) in January 1996 and received it for 8 months. She tolerated the therapy well, but eventually progressed in her left breast with an erythematous, warm, skin lesion with peau d’orange. Biopsy was consistent with inflammatory breast cancer. Her bone and liver disease had remained stable.

She was placed on PEG-LD in August 1996 and showed obvious improvement in the appearance of her left breast within a month. She received a second cycle of PEG-LD in September 1996 and had dramatic clearance of inflammatory carcinoma of the breast with complete normalization of skin. Her liver and bone disease remained unchanged. Adverse effects were mild mucositis, very mild myelosuppression, and palmar-plantar erythrodysesthesia (in the first cycle but not in the second cycle).

Case III

A 77-year-old white female with breast cancer was originally diagnosed in October 1988 with left breast carcinoma and underwent left modified radical mastectomy. Pathology revealed infiltrating lobular carcinoma measuring 2.3 × 1.6 cm. Five of 41 sampled lymph nodes were involved. Hormone receptors were positive. She received adjuvant hormonal therapy with tamoxifen 10 mg po bid which was stopped in 1993 after she completed 5 years.

In July 1994, she developed left chest wall relapse with multiple skin nodules which were again hormone receptor positive on biopsy. She was placed on megestrol acetate and treated from June 1995 to October 1995 when she progressed with multiple new lesions on her chest wall. She subsequently progressed on tamoxifen rechallenge (October 1995 to December 1995), exemestane, 25 mg/day (December 1995 to February 1996), and anastrozole, 1 mg/day (February 1996 to April 1996). She then received two cycles of CMF chemotherapy but did not tolerate it well.

In June 1996 she was placed on PEG-LD and received six cycles until February 1997. She tolerated this chemotherapy very well, experiencing only mild palmar-plantar erythrodysesthesia (Grade 1) and mild myelosuppression. Her skin lesions responded to PEG-LD therapy with some small lesions disappearing, one lesion on her left upper arm shrinking from 1× 1 cm to 0.7 × 0.7 cm, and two lesions remaining unchanged. She did not meet the clinical criteria for partial response.

Case IV

A 49-year-old premenopausal white female presented in April 1986 with a 2 × 1.5 cm poorly differentiated adenocarcinoma with 4 of 18 sampled lymph nodes positive for tumor involvement. Estrogen receptors and progesterone receptors were positive. She underwent right modified radical mastectomy and received adjuvant CMF followed by tamoxifen for 5 years.

She relapsed in January 1992 with skin, sternal, and omental involvement. She had a periumbilical lymph node that was also palpable. She received two cycles of Adriamycin, methotrexate, and fluorouracil (AMF) followed by high dose thiotepa (Thioplex) and carboplatin (Paraplatin) with peripheral stem cell rescue. She was followed with observation but eventually progressed. In June 1995, she received tamoxifen for 2 months. In August 1995 she was placed on paclitaxel but it was discontinued due to neurotoxicity, pain, shortness-of-breath, night sweats, and weakness.

She was placed on PEG-LD in January 1996. After 3 months with good tolerability and minimal myelosuppression, this patient decided to stop chemotherapy despite a drop in her tumor markers and improvement in her functional status. In April she was placed on anastozole and in July and August 1996 she received weekly vinorelbine. She then opted to re-start on PEG-LD in August 1996 and received four more cycles. Megestrol acetate was added concomitantly as a treatment for anorexia. In October 1996 she reported dramatic improvement in the way she felt. She experienced only mild palmar-plantar erythrodysesthesia and mild mucositis with PEG-LD. Although she did not meet the objective criteria for partial response, she was declared a clinical benefit response because of improvement in her functional status and drop in her tumor markers.

Case V

A 49-year-old white female was diagnosed with right-sided breast cancer in 1983 and underwent a right modified radical mastectomy with immediate reconstruction. Two of the 18 sampled lymph nodes were involved with tumor. Hormone receptors were positive by immunohistochemistry. The patient underwent six cycles of adjuvant chemotherapy with CMF followed by tamoxifen.

The patient did well until February 1990 when she recurred in bone. She was given six additional cycles of CMF for metastatic disease and was then given tamoxifen from June 1990 to May 1991. At that time she progressed in her cervical spine and required radiation therapy. She was given mitomycin, vinblastine, thiotepa, and fluoxymesterone (Halotestin) (an androgen) for two cycles prior to receiving megestrol acetate. In 1992 she underwent cervical spine surgery for stabilization. In March 1994 megestrol acetate was withdrawn because of progressive bony metastases and she was given palliative radiation to the left hip (3,000 rads in 10 fractions) and aminoglutethimide for 5 months. In September 1994 she was rechallenged with tamoxifen and continued that treatment for 2 months.

Because of continued progression in bone she was switched to vinorelbine which she received from November 1994 to May 1995, at first remaining stable, but then showing evidence of progression. At that time she was switched to mitoxantrone plus 5-FU plus leucovorin (NFL) which she received from June 1995 to October 1995. She was given a break from NFL and remained stable for about 3 months. NFL was restarted in January 1996 and pamidronate disodium (Aredia) was added. She received this therapy for only 2 months and wanted to be off chemotherapy again. At that time (March 1996) she was placed on anastrozole, which she received for about 2 months before showing signs of progression. She was placed on methotrexate plus 5-FU and leucovorin in May 1996 and received only one cycle. Chemotherapy had to be interrupted because of a need for radiation therapy to the right hip and sacrum; only minimal improvement of symptoms resulted from the radiation.

She was placed on PEG-LD in July 1996 and continued to receive this therapy until February 1997. She achieved significant improvement in her performance status, stopped using her walker and cane, and became almost pain-free. Although it is very difficult to assess bone healing on x-rays, the patient had stopped taking all analgesics at her evaluation in October 1996. Her CEA decreased from a pretreatment level of 54 ng/mL to a level of 17 ng/mL. Her CA15-3 remained stable, between 75 and 81 µ/mL. She did not meet the criteria for partial response, but clearly benefited clinically.

In conclusion, PEG-LD provides a reasonable option in breast cancer patients with metastatic disease where gentler and effective single-agent therapy is desirable because maintenance of quality of life is important, and cure is not likely.

Future Combination Studies

Given the relatively mild myelosuppression seen with PEG-LD, combinations of this drug with other agents active against metastatic breast cancer, such as the taxanes, vinorelbine, and cyclophosphamide, are being performed. It is likely that dose and dosing schedules of such combinations can be optimized to increase response rates with manageable toxicity.

Given the excellent toxicity profile of PEG-LD, it seems logical to combine it with other gentle yet effective agents such as vinorelbine. Vinorelbine has shown excellent activity in breast cancer with single-agent response rates exceeding 40% in some studies and response rates of around 20% in anthracycline-resistant breast cancer. This prompted several phase II trials studying the combination of doxorubicin with vinorelbine.[40-47] Response rates from these studies show impressive activity and good tolerability of the combination. The excellent toxicity profile of vinorelbine, however, was compromised by the usual toxicities of doxorubicin in these trials. With the advent of PEG-LD, we have the option of combining two gentle drugs that do not seem to produce alopecia and hopefully still maintain the efficacy of this combination. It could be an excellent quality of life regimen with great efficacy.

The other approach could be to combine a highly effective taxane, such as docetaxel, with myelosuppression being its main dose-limiting toxicity, with PEG-LD in an endeavor to find an appropriate dose for phase II trials. Indeed, there has been great interest in combinations of doxorubicin with taxanes. Perhaps the most publicized trial is that of Gianni et al from Milan, demonstrating a 90% response rate with a combination of paclitaxel and doxorubicin in a group of 36 previously untreated patients with metastatic breast cancer.[48] There was, however, an unacceptably high (21%) rate of congestive heart failure. Nabholtz et al have piloted a combination of Taxotere, Adriamycin, and Cytoxan (TAC) showing a response rate of 82% in a group of 38 women without cardiotoxicity.[49] This regimen will now be compared with FAC (5-FU, Adriamycin, Cytoxan) in the adjuvant as well as metastatic settings in North America.

Given this background, we have begun two separate Phase I/II dose-escalation studies, one using PEG-LD and docetaxel, and the other with PEG-LD and vinorelbine. The eligibility requirements for both of these studies are listed in Table 10.

Summary

In summary, PEG-LD is active in the treatment of breast cancer, including refractory tumors. Liposomal encapsulation allows the drug to concentrate at the site of the tumor, resulting in increased efficacy and decreased toxicity to other systems. Thus, PEG-LD has a very favorable toxicity profile, with significantly less bone marrow suppression and cardiac toxicity than standard chemotherapy. The efficacy and mild toxicity of PEG-LD make it an ideal agent in metastatic breast cancer where palliation and increased quality of life are desirable goals of therapy. In addition because of its non-overlapping toxicities, it is well-suited for combination therapy in metastatic breast cancer refractory to other treatments. After documentation of its efficacy in the metastatic setting, PEG-LD and its combinations may be tested in the adjuvant setting. New schedules for its use, and its use in combination with established and new agents, will give us a wide spectrum of promising options for treatment of patients with metastatic breast cancer.

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