Cancer Treatment Reviews (1983) 10 (Sup$ement B), 41-46

Mitoxantrone versus doxorubicin in advanced breast cancer: A randomized cross-over trial

James A. Neidhart,*t Diane Gochnour, * Ralph W. Roach,*@ Jay A. SteinbergS and Donn Young*

*Comprehensive Cancer Center and tDivision of Hematology and Oncology, The Ohio State University, Columbus, Ohio and $ The American Cyanamid Company, Newark, X.3., U.S.A.

Introduction

The need for new therapeutic alternatives in breast cancer is evident. Aggressive therapeutic approaches developed over the last twenty years for breast cancer have failed to produce important therapeutic results for most patients with macrometastatic disease. Systemic chemotherapy will produce tumor regression in the majority of patients, but on average, survival is not improved (2,6, 10). Patients who have tumor regression may live somewhat longer than those who do not, but it is not clear whether the longer survivals are the result of therapy or merely a selection process (10). Responses may offer palliation to symptomatic patients for 8-12 months. Responses to secondary treatment regimens are even less frequent and of shorter duration (5). More enthusiastic reports of successful primary or secondary therapy have been published, but need to be verified (5,7). Certainly presently available therapeutic approaches offer no chance of cure for patients with macrometastatic breast cancer (4,8). One can argue the details, but the state of the art is not acceptable to either patients or their physicians and new agents and approaches are needed.

Mitoxantrone is one ofseveral bis-substituted anthraquinones presently in clinical trials. This agent demonstrated antitumor effect in heavily pretreated patients with breast cancer during early Phase I and Phase II trials (9, 12). On this basis, we initiated a randomized trial comparing the most active single agent, doxorubicin (6, 1 l), with mitoxantrone in minimally pretreated patients. This report updates the results of this study which continues to accrue patients.

Patients and methods

Patients

Women of any age with histologically proven breast cancer and macrometastatic disease were eligible. They had not received more than one prior therapeutic regimen for macrometastatic disease, and had documented failure on prior regimens; they did not have

§Dr Roach is presently at Saint Anthony’s Hospital, Columbus, Ohio, U.S.A.

0305-7372/83/10B0041+06 $03.00/O 0 1983 Academic Press Inc. (London) Limited

41

42 J. A. NEIDHART ET AI,.

any therapy for the four weeks prior to entering the study. They had not received prior therapy with either study drug. They were ambulatory at least half the day (Zubrod performance status O-2) or had a life expectancy of three months. Patients who were bed or chair bound solely due to bone pain were accepted if they otherwise qualified. Patients had disease evaluable for response. Bone pain requiring analgesics was acceptable as evaluable disease (3).

Study design and treatment

Patients were randomized to receive either doxorubicin at 60 mg/m2 or mitoxan- trone at 12 mg/m2. Patients with compromised bone marrow (< 3000 WBC/mm3) received a 25% reduction of the initial dose. Treatments were repeated every three weeks if hematologic recovery had occurred. Doses were increased or decreased by 25% to achieve a nadir of leukopenia of approximately 2500/mm 3. Patients with progression after two courses, failure to achieve a partial response after four full courses of therapy, or progression after an initial response were crossed over to receive the alternate agent. A complete response meant complete disappearance of all disease for one full course. Partial response was a greater than 50% decrease of tumor lasting at least one full course. Stable disease was failure to show response or progression for at least three months. Progressive disease was at least 25% increase in tumor mass or any lesion. Radionuclide scans and bone pain clearly attributable to cancer were considered evaluable, but non-measureable disease. Relief of bone pain was considered a partial response only if pain completely disappeared for one full course and analgesics were no longer needed. Effusions, inflammatory skin lesions, sclerotic bone lesions and laboratory values were not acceptable as measureable or evaluable disease.

Results

Patient characteristics are presented in Table 1. Fifty-nine patients have been entered since 1980. Twenty-seven have been randomized to initial doxorubicin and 32 to initial mitoxantrone. Performance was near normal (Zubrod O-1) in 75% of the patients. Prior chemotherapy was usually cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without tamoxifen. One patient on each arm had refused standard therapy and had no prior therapy.

Response

Table 2 summarizes responses. Ten of 25 patients (40%) randomized to initial doxorubicin and 7 of 26 (27%) receiving mitoxantrone as initial therapy achieved a partial response. Responses lasted about three months for both agents. Doxorubicin and mitoxantrone do not appear to be cross-resistant. Patients failing or progressing after a response on the one may yet respond to the other after cross over. Two of 12 patients receiving doxorubicin and 2 of 15 receiving mitoxantrone as secondary therapy achieved partial response. Median time to progression was 134.2 + 18.7 and 103 + 5.4 days for doxorubicin and mitoxantrone respectively. None of these differences are significant. Sites of response were similar for the two agents (Table 3).

MITOXANTRONE V. DOXORUBICIN IN BREAST CANCER 43

Table 1. Patient characteristics

Number of patients Age: median (range) Zubrod performance status:

0 I

2 3

PriOO;F

Chemotherapy (CMF k tam&fen) Chemotherapy and radiation

Initial therapy

Doxoruhicin 4%)

27 61.0 (33-79)

11 (41) 9 (33) 5 (19) 2 (7)

1 (4) 11 (41) 15 (55)

Mitoxantrone n (%)

32 55.5 (35 77)

10 (31) 15 (44)

5 (16) 2 (6)

1 (3) 17 (53) 14 (44)

Table 2. Response

Initial therapy only Total evaluable Partial response Stable disease Progressive disease

Secondary therapy ,Total evaluable Partial rcsponsc Stable disease Progressive disease

Overall Total evaluahle Partial response Stable disease Progressive disease

Doxoruhicin

Response duration

n (x3) median (days)

Mitoxantrone

Response duration

n (%) median (days)

25 10 (40) 12 (48)

3 (12)

12 2 (17) 6 (50) 4 (33)

37 12 (32) 18 (49)

7 (19)

26 84 7 (27) 96

128 14 (54) 102 5 (19)

15 48 2 (‘3) 96

122 7 (47) 105 6 (40)

41 84 9 (22) 96

127 21 (51) 104 11 (27)

Table 3. Sites of response

Doxorubicin Mitoxantrone .~.

Soft tissue 3 4

Bone Pain 5 3 Scan 1 1 X-rays 3 2

Lung .2 0

Liver 1 1

44 J. A. NEIDHART E7- AL.

Table 4. Hematologic toxicity for first treatment

Number of Evaluable Initial treatment patients courses

WBC x 103/mm3 Platelets x 103/mm3 nadir (range) nadir (range)

Doxorubicin 24 109 2.8 (O.&l 1.1) 169 (16-408)

Mitoxantrone 31 116 2.0 (0.5-10.7) 160 (3G413)

Toxicity

Hematologic toxicity is shown in Table 4. Three patients receiving doxorubicin and one receiving mitoxantrone did not obtain two interim blood counts and are not evaluable for hematologic toxicity. Leukopenia was more marked than thrombocytopenia although an occasional patient developed a clinically significant fall in platelets. Myelosuppression was similar for the two agents. The median day of nadir was day 15 and recovery was rarely delayed beyond day 2 1. Dose modifications were required in about 50% of patients (Table 5) with more patients requiring an increase in dose of mitoxantrone to achieve desired myelosuppression.

Non-hematologic toxicity is shown in Table 6. Nausea and vomiting were more frequent (88% versus 46%) and more severe (median grade 2-3 versus 1-2) with doxorubicin than with mitoxantrone. Alopecia was rare and minimal with mitoxantrone but frequent and usually cosmetically important with doxorubicin. Fatigue and other side effects were similar for the two agents. Six patients showed definite evidence ofcardiotoxicity (Table 7). All patients developing congestive heart failure had received doxorubicin and three had received chest wall radiation. The total dose ofmitoxantrone in patients with cardiotoxicity ranged from O-166 mg/m2.

Discussion

There is no significant difference at this time in response between doxorubicin and mitox- antrone as therapy of patients with minimally pretreated breast cancer. Response rates (40% versus 27%) and response durations (84 versus 96 days) are similar. This study is scheduled to accrue 50 patients on each arm before final analysis. Interpretation of results at this time is, therefore, tentative and premature. The ability of mitoxantrone to induce tumor regression after failure on doxorubicin and vice versa suggests the two agents do, indeed, differ in clinical efficacy. This is consistent with preclinical efficacy data showing mitoxantrone active against a Psss leukemia line refractory to doxorubicin (P,,,/adria).

Table 5. Dose modification required to achieve desired myelosuppression

Change Doxorubicin Mitoxantrone

None 19 20 Increased 5 11 Decreased 14 14

MITOXANTRONE V. DOXORUBICIN IN BREAST CANCER 45

Table 6. Percent and median grade of more common toxicities

Doxorubicin Mitoxantrone

Nausea and vomiting Alopecia Fatigue Diarrhea Anorexia Stomatitis

88% (2-3) 46% (l-2) 79% (3) 20% (1) 36% (1) 24% (1) 10% (1) 2% (1) 8% (1) 2% (1) 2% (1) 10% (l-2)

Table 7. Cardiotoxicity

Chest Doxorubicin Mitoxantrone Evidence for Patient irradiation total mg/m* total mg/m’ cardiotoxicity - ~.~

1 No 270 45 ST1 11 No 394 86 STI; MUGA; CHF 14 Yes 491 76 STI; CHF 22 Yes 489 0 CHF 25 Yes 401 166 STI; MUGA; CHF 29 No 458 55 STI; MUGA, CHF

CHF, congestive heart failure; MUGA, multigated acquisition; STI, ST inversion.

Doxorubicin was more active against L, si,, leukemia and the human colon xenograft, colon 26 (1).

Yap also reported activity of mitoxantrone in breast cancer using a daily x 5 schedule (2). Responses were seen in patients previously refractory to doxorubicin.

Mitoxantrone is a well tolerated agent. Nausea or vomiting is relatively infrequent and usually mild. Other subjective toxicities are minimal. Hematologic toxicity is the most serious side effect. This drug may be a little less predictable than doxorubicin. Using a starting dose of 12 mg/m’, approximately 25% of patients required dose reductions and a similar number required dose escalation to achieve desired myelosuppression. Only 5 of 38 patients receiving doxorubicin required dose escalation to achieve desirable levels of myelosuppression. Weekly blood counts should be obtained with the first several courses of therapy and dose adjusted accordingly. Cardiotoxicity of mitoxantrone has not been proven or quantitated yet. We believe, however, this agent has cardiotoxicity (13) and suggest caution if it is used in patients heavily pretreated with doxorubicin or radiation. Recommendations regarding total safe cumulative doses seem premature at present.

Mitoxantrone is an important new agent for breast cancer. Further studies using combination therapy and maximal doses are ongoing in several institutions and its ultimate usefulness remains to be determined. It is particularly interesting since it represents a new class of anticancer agents differing chemically and in spectrum of activity from existing agents.

Acknowledgements

We thank Joan Loomis for excellent secretarial assistance and the Oncology Research Nurses for caring and helping. This work was supported largely by a grant from the American Cyanamid Company.

46 J. A. NEIDHART ET AL.

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