Prospective Comparison of Adriamycin, Vinblastine, And

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1988 Prospective comparison of adriamycin, vinblastine, and mitomycin C (AVM) versus adriamycin alone in the treatment of metastatic breast cancer Cristina Bengoa-Becerra Yale University

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PROSPECTIVE COMPARISON

ADRIAMYCIN, VINBLASTINE, AND MITOMYCIN C (AVM) VERSUS

ADRIAMYCIN ALONE IN THE TREATMENT OF

METASTATIC BREAST CANCER

A Thesis Submitted to the Yale University

School of Medicine in Partial Fulfillment

of the Requirements for the Degree of

Doctor of Medicine

Cristina Bengoa-Becerra i 1 / 1988

ABSTRACT

PROSPECTIVE COMPARISON

ADRIAMYCIN, VINBLASTINE, AND MITOMYCIN C (AVM) VERSUS

ADR IAMYCIN ALONE IN THE TREATMENT OF

METASTATIC BREAST CANCER

Cristina Bengoa-Becerra

1988

Fifty-four patients with metastatic breast carcinoma refractory to conventional chemotherapy entered this prospective and randomized study.

One group was treated with Adriamycin 60 mg/m^ IV every 3 weeks. The other group received Adriamycin 30 mg/m^ IV and Vinblastine 6 mg/m^ IV every 4 weeks and 10 mg/m^ IV Mitomycin C every 8 weeks (AVM). Drug dosages were modified if hematologic toxicity occurred. Responses occurred in 15% (4/26) of the Adriamycin patients and 29% (8/29) of the

AVM patients (p>.2). The median time to disease progression was 3.8 and

5.9 months respectively (p = .03). Median survival time was 7.9 and 9.0 months respectively (p = .35). Toxicity was acceptable in both groups and primarily hematologic. No cardiac toxicity was seen. This combination of Adriamycin, Vinblastine, and Mitomycin C appears to be an acceptable alternative to Adriamycin alone for second-line chemotherapy of metastatic breast cancer.

ACKNOWLEDGEMENTS

I would like to thank the following people without whom this thesis could not have been completed:

Dr. Carol S. Portlock was the perfect thesis advisor. She allowed me to learn from my mistakes but was always there with a big smile to get me out of trouble;

Burdeen Caamp, CCOP data manager, and Philip Johnson PH.D. who helped with the data collection and statistical analysis, respectively;

Drs. Samuel Bobrow and Leonard Farber who cared for most of the patients in this study;

Mr. Michael E. Mahig who loaned me his computer during the initial stages of this thesis;

Mr. Andres F. Rodriguez who proofread and helped me put this lengthy manuscript into its final form; and all my friends who I dragged on multiple occasions, though without much resistance, to Archie Moore's. Had it not been for the chicken wings and the many hours spent complaining about how much work we had left to finish our research, this thesis would probably have been finished much sooner.

Finally, but most important, I would like to dedicate this thesis in memory of my father in appreciation of all that he taught me in the few years he was with me and to my mother for her unconditional love and support.

LIST OF ABREVIATIONS

A - Adriamycin (doxorubicin)

AG - aminoglutethimide BUN - blood urea nitrogen C - cyclophosphamide CBC - complete blood count CEA - carcinoembryonic antigen CHF - congestive heart failure

CNS - central nervous system CT - computerized tomography

DES - diethylstilbest rol DFI - disease-free interval DFS - disease-free survival ECOG - Eastern Cooperative Oncology Group ee2 - ethinyl estradiol ER - estrogen receptors L-Pam - phenylalanine mustard

M - methot rexate OS - overall survival

P - predn i sone PR - progesterone receptors [PR] - concentration of progesterone receptors SGOT - serum glutamic-oxaloacetic transaminase

TAD - tamoxifen, aminoglutethimide, and danazol WBC - white blood count U/S - ultrasound V - vinbl ast i ne/vincri st i ne

Vb - vinblastine Vc - vincri stine Vd - vi ndesi ne

TABLE OF CONTENTS

ABSTRACT i

ACKNOWLEDGEMENTS ii

LIST OF ABREVIATIONS iii

PART ONE: CHARACTERISTICS 1

Introduction 1 Sites of recurrence 1 Prognostic factors 3

PART TWO: ENDOCRINE THERAPY 10

Endocrine ablative procedures 10 Tamoxifen 13 Progestins 17 Newer agents: Danazol 18 Combination versus sequential treatment 19 Summary 22

PART THREE: CHEMOTHERAPY 23

Combination Chemotherapy 23 Dose Intensity 25 Adriamycin 26 "CMF" versus Adriamycin 28 Second-line Treatment 29 Closing Remarks 31

PART FOUR: STUDY 33

Methods 33 Patients and Results 37 Discussion 47

REFERENCES 55

TABLES 66

FIGURES 87

PART ONE: CHARACTERISTICS

INTRODUCTION

The breast is the most common site of cancer among U.S. women. It has been estimated that the probability of developing breast carcinoma is

9.1%; that is, 1 in every 11 women will develop cancer of the breast during their lifetime*. Currently, the overall incidence is 72 in

100,000 women^.

In general, the natural history of the disease is extremely variable. A few patients will have a rapid fulminating illness; while others will have a slower more indolent course.

SITES OF RECURRENCE

The current treatment for primary breast cancer is surgery with modified radical mastectomy being the most cornnon. In addition to surgery, a number of patients also receive adjuvant treatment with radiation therapy, chemotherapy and/or hormonal therapy. Many patients with early-stage breast cancer are being treated with lumpectomy, lymph node disection and adjuvant radiation therapy as an alternative to radical surgery**.

Unfortunately, these procedures do not offer a definite cure for all patients. More than 50% of patients have recurrence of their disease in local and/or distant sites. Most of these patients relapse within 18-24 months after their mastectomy-*. The fact that patients might be disease- free at 5-10 years after their initial treatment does not imply cure.

Some patients have been found to develop metastatic disease more than 20 years post-mastectomy^.

Local Recurrence

The incidence of 1ocal/regional recurrence is approximately 10-

20%3>4. Most recurrences occur within two years of initial surgery^.

Local recurrence has been defined as recurrence in the skin or subcutaneous tissues of the chest wall within the boundaries of a previous lumpectomy/mastectomy. Regional recurrence is defined as lesions in lymph node-containing areas of the internal mammary chain, the axilla, and the supraclavicular area. Both local and regional recurrence present serious problems because, if left untreated, they tend to grow, ulcerate, and spread^.

The prognosis of 1 oca 1 / reg i on a 1 disease is not very good.

Approximately 50% of patients have distant metastases simultaneously with local recurrence^. Even of those patients with disease initially limited to local/regional sites, 80-90% relapse at distant sites within the chest wall. Those patients with recurrence in the axilla tend to do better^.

Distant Metastasis

The most common sites of distant metastasis are bone, lung

(including pleura), brain, and liver. Approximately 85% of patients who die of metastatic breast cancer have bone metastases. These usually present with pain and are best diagnosed by x-ray and bone scans 1.

Metastasis to the lung may present with cough, hemoptysis and/or dyspnea. The latter is usually due to obstruction and atelectasis caused by endobronchial lesions. They can occur as discrete coin lesions which are easily diagnosed by x-ray or may be adjacent to the hilum or mediastinum, often associated with infection or pneumothorax. The latter are easily missed by chest x-ray and are best diagnosed by CT scan.

Bronchoscopy is also employed to evaluate obstruction. In addition,

pleural effusions are many times the initial manifestation of

intrathoracic metastatic disease^*^.

The central nervous system (CNS) is also a frequent site of

disseminated disease. Ten percent of stage IV breast cancer patients

have CNS metastases which include lesions to the brain and/or meninges.

These occur more frequently in patients with large primary tumors and/or

axillary node metastasis. They are also more comnon in patients younger than 60 years and/or less than five years postmenopausal^. Brain metastates, which may be detected by CT scan, are usually multiple and

occur in the distribution of the middle cerebral artery. The parietal

lobe is most commonly affected. Usually they present with headache, motor dysfunction, and impaired mentation"7.

Finally, another common site of visceral metastases is the liver.

Hepatic metastases can present with pain, tenderness to palpation,

hepatomegaly and/or hepatic failure. Unfortunately up to 60% of livers

containing metastases are not palpable; and so, they are best evaluated

by technetium liver scan and liver function tests. Nonspecific

abnormalities detected by liver scan are then further evaluated by

ultrasound (U/S) or CT^.IO.

PROGNOSTIC FACTORS

A number of clinical, pathological, and biochemical variables have

been identified as having prognostic significance in both the likelihood

of first recurrence and the subsequent course of metastatic disease. The

following prognostic factors have been shown to determine the likelihood

4 of initial recurrence and survival: tumor size and location, number and level of axillary nodes involved, histologic type and grade, and biochemical parametters such as estrogen receptors (ER) and to a lesser extent, progesterone receptors (PR)^. Another variable which has been shown to favorably affect prognosis is adjuvant therapy^. Once the patient presents with metastatic disease, the indicators of prognostic value have been found to be: disease free interval (DF1), types and number of metastatic sites, and response to initial therapy^,14.

Prognostic Indicators of Disease Recurrence

In terms of tumor size, it has generally been determined that the larger the tumor, the worse the prognosis1^*16. However the number of axillary nodes involved with tumor appears to be more important. For example, in 1.0-1.9 cm tumors, the 5 year recurrence rate with negative vs. positive nodes has been quoted as 13% and 53% respectively, whereas in 3.0-3.9 cm tumors the numbers are 28% and 64%^. Location of the tumor within the breast area also appears to be associated with response to therapy. Nemoto, et al^ reported that tumors in the medial half of the breast had slightly higher "cure" rates than those in the lateral half.

One of the most important clinical factors in determining prognosis, as already mentioned above, is the number of positive axillary nodes^* 15,16. With zero positive nodes, the 5 year recurrence rate is

18-21%3,15,16^ ancj the 5 year survival is 72-76%15,16. With one to three positive nodes the 5 year recurrence rate is approximately 50%3>15, anc) the 5 year survival is 62%15. Unfortunately, these numbers drastically plummet with four or more positive nodes, such that the five year

5 recurrence rate is 81% and the 5 year survival is 31%^. Robbins*' divides prognosis into three groups based on the location of involved axillary nodes: level I nodes - those lateral and inferior to the pectoralis major muscle - are associated with a 10 year survival of 41%;

level II nodes - those behind the pectoralis minor muscle - are associated with a 10 year survival of 30%; and level III nodes - those medial and superior to the pectoralis minor muscle at the apex of the axilla - are associated with a 10 year survival rate of 15%.

Pathologic factors have also been identified as prognostic indicators . The two most important ones appear to be histologic type and grade of tumor. Though of lesser significance, other histogic tumor features, such as lymphatic and blood vessel invasion and presence of tumor necrosis, have been associated with a worse prognosis.

The most coimon histologic type of breast cancer is infiltrating ductal, which represents 70%^a of all infiltrating carcinomas. The prognosis is variable and depends on grade which will be discussed later.

Medullary carcinoma has been said to account for 6%*^ of all invasive carcinomas. The prognosis depends on the amount of lymphoid infiltrate. The variant called medullary carcinoma with lymphoid infiltration has an incidence of 5%*^. It is said to have a better prognosis than infiltrating ductal carcinoma even in the presence of axillary metastases. The 10 year survival for this variant is 84%^.

The colloid or mucinous type tends to occur in older women and grows slowly over the course of many years. It represents approximately 3%*^ of all invasive breast cancers. Its prognosis is much better than

infiltrating ductal or mucinous combined with other types. Lymph node

6 metastases are infrequent^.

Infiltrating lobular accounts for 5-14%*d of all infiltrating breast carcinoma. It tends to occur bilaterally approximately 20% of the time and also has a high incidence of multicenticity. Prognosis is similar to that of infiltrating ductal with 5 and 10 year survival rates of 70% and

57%, respectively, versus 73% and 46% for infiltrating ductal^*.

The tubular type represents 7% of all invasive carcinomas and carries an excellent prognosis**.

Histologic grade, which depends on degree of tubule formation, size of cells, nuclear pleomorphism, degree of hyperchromatism, and number of mitotic figures is another variable of prognostic significance**. For the most part. Grade III (high grade) tumors are associated with earlier more frequent recurrence and lower 5 year survival than Grade I (low grade) tumors. However, the stage of the tumor also determines survival; such that, a high grade stage I tumor has a higher ID year survival rate

(62%) than a low grade Stage III tumor (53%) (Table 1)^.

Biochemical markers, such as the concentration of estrogen* *»23-24 and progesterone^^ receptors in the tumor, are also said to be prognostic indicators of recurrence. ER positive tumors (concentration

>10 pmol g"*) are associated with a longer disease-free interval and a lower recurrence rate than ER negative tumors **» ^*^4. PR positive tumors (concentration >10 pmol g-*) are also associated with a favorable prognosis, longer disease free interval**, and lower probability of distant metastasi s7 »25. Pichon and coworkers*^ reported that patients with PR positive tumors were 3.6 times less probable to develop distant metastasis than patients with PR negative tumors. They also demonstrated

7 that there was an inverse relationship between PR, concentration ([PR]), and the frequency of metastasis. However, the incidence of local recurrence does not appear to be affected by [PR].

Finally, adjuvant therapy has been shown to improve prognosis, particularly disease-free (DFS) and overall survival (OS)^. A review by

Bonadonna and Valagussa^, which included 2,213 patients, revealed a significant increase in overall survival for patients treated with adjuvant chemotherapy regimens versus control (no systemic therapy). It appears that this difference is mostly seen in premenopausal patients with one to three positive axillary nodes. In this subset, adjuvant chemotherapy has been shown to prolong both disease-free and overall survival. In the past, data for postmenopausal patients have failed to demonstrate a clear advantage of adjuvant chemotherapy over control.

However, the 5 year results of a recent study by Brambilla and coworkers^ employing sequential CMFP and AV in 140 postmenopausal patients showed prolonged disease-free and overall survival for a subset of patients with one to three positive lymph nodes over control (i.e., OS

- 87% versus 73% and DFS - 76% versus 60% for treated and control groups, respectively).

Adjuvant endocrine therapy has not proven to be as successful as chemotherapy^. In premenopausal patients, most studies have failed to demonstrate an increase in disease-free and/or overall survival with oophorectomy in treated patients versus control. Adjuvant tamoxifen has been shown to increase disease-free survival in a subset of post¬ menopausal patients with positive estrogen receptors and positive axi 1 lary nodes^ .

Prognostic Indicators for Course of Metastatic Disease

With respect to prognosis after the first relapse has occurred, 3 sets of variables have been identified: Disease-free Interval (D F1), types and number of metastatic sites, and response to therapy ,14.

Overall, the shorter the DPI (time from initial diagnosis to first relapse) the shorter the survival.

Cutler et al^ evaluated yu patients and divided them into 4 groups depending on their DPI: 1 year, 1-2 years, 2-b years, and >b years.

They found the median survival to be 7 months, 12 months, lb months, and

2b months, respectively.

Pei and associates^ studied median survival in 40b patients with respect to types of metastatic sites. Patients were divided into four categories. Category A consisted of patients with pure local/regional , local type with pleural involvement, and pure osseous metastases. These patients had the better prognosis with a median survival of bU-b8 months after diagnosis and 27 months after first relapse. Category B was made up of those patients with pure visceral metastasis. Median survival, in this group was 40 months after diagnosis and 23 months after first relapse. Category C consisted of patients with mixed sites of metastasis. The median survival, for these patients, was 33-43 months after diagnosis and 17 months after first relapse. Patients with the worse prognosis were those with locally inoperable disease (Category D).

Their median survival was 19 months after diagnosis. Survival with respect to number of metastatic sites was evaluated by Cutler et al. .

They found that median survival ranged from 18-24 months with only one site involved, 9-12 months with two to three sites involved, and 6-10

9 months with four or more sites involved. Overall, bony metastases are found to progress little, if any; visceral metastases, particularly those with mainly lung involvement, have a limited tendency to spread; and local/regional metastases have a progressive course^.

The other parameter said to influence survival in patients with metastatic disease is response to treatment. Fei and associates^ reported that those patients who have a complete response or a partial response greater than 501 had a longer median survival than those with a partial response less than 50%, no change, or disease progression.

PART TWO: ENDOCRINE THERAPY

The initial treatment of patients with metastatic breast carcinoma usually consists of endocrine therapy. The following have been employed with varying degrees of success: endocrine ablative procedures

(medical/surgical ), tamoxifen, progestins, and recently danazol .

Furthermore, the use of these agents in combination versus sequentially has also been evaluated.

ENDOCRINE ABLATIVE PROCEDURES

In the past, endocrine ablative procedures have been extensively employed in the treatment of patients with metastatic breast cancer.

Adrenalectomy (medical/surgical) and hypophysectomy have been utilized in postmenopausal patients and oophorectomy has been the preferred treatment

for premenopausal pati ents^,29.

The response rates obtained in postmenopausal patients with such surgical approaches ranges from 25-57%^0-33^ Forest^ reported pooled

data from four studies including 615 patients who underwent hypophysectomy. Response rates ranged from 22-35%. Pearson and associates^ studied the results of hypophysectomy in 218 patients with metastatic breast cancer using transfrontal craniotomies. They reported

results in 109 patients with response rate of 50%, 35% of these lasting up to 6 months or longer. However, they found the procedure to be

associated with serious morbidity: serious visual loss (2 patients),

visual field defects (7 patients), neurological involvement (3 patients),

and pathological fracture of the femur (1 patient). Edelsyn and

coworkers^ examined the benefits in patients treated with hypophysectomy

11 plus an Yttrium implant. They reported a response rate of 57% versus 24% when patients were treated with surgery alone. With respect to surgical adrenalectomy, Daincoff and coworkers22, in a study with 415 patients, had a response rate of 28% with a 5 year survival rate of 12.5%. They also found that patients with metastases at skeletal, cutaneous, pleural, and pulmonary sites had a longer survival than those with metastases in brain or liver.

Bilateral oophorectomy has been employed in premenopausal patients with response rates of approximately 30%. Patients with metastases at skeletal, soft tissue or pleural sites are more likely to respond than those with metastases in brain or liver. Side effects associated with this procedure are mainly menopausal symptoms which are quite acceptable for those patients who respond28.

Medical adrenalectomy with the agent aminoglutethimide (AG) given with steroid replacement is used as an alternative to surgical procedures in postmenopausal patients with metastatic breast cancer28.

Wells and associates2^ used a regimen of AG 1,000 mg per day and either Dexamethasone 2-3 mg per day, or Hydrocortisone 40-60 mg per day

in 50 patients with advanced breast cancer. They obtained a response

rate of 38% with a median duration of response of 18.05 months.

Furthermore, it has been shown that ER status is a useful predictor of response to therapy with ami nog 1utethimide28»28. Santen and coworkers28 studied 69 patients, all of which were ER positive or ER unknown. They employed a regimen of AG 250 mg twice a day for the first two weeks and 250 mg four times a day therafter. They reported a 53%

remission rate in 40 patients treated with aminoglutethimide. Lawrence

12 and associates33 reported a 50% remission rate in 38 patients with ER positive tumors versus 14% in 7 patients with ER negative tumors.

Toxicities associated with AG therapy are varied. One study with 50 patients found the main side effects to be: lethargy (41.5%) and skin rash (36%). No chronic toxicities were encountered3^. Another study with 69 patients found both acute and chronic toxicities. Acute toxicities which developed during the first six weeks of treatment were: lethargy (48%), drug rash (33%), orthostatic dizziness (20%), ataxia

(10%), and drug fever (2.5%). Chronic toxicities which appeared or continued beyond six weeks of therapy were: lethargy (10%), orthostatic dizziness (12%), depression (10%), hypothyroidism (5%), ataxia (2.5%), blurred vision (2.5%), and nausea/vomiting (2.5%)33.

With respect to more severe toxicities, Santen and coworkers33 report that episodes of leukopenia, thrombocytopenia, or pancytopenia occured in 4% of the 639 patients reported in Ciba-Geigy records.

Furthermore, one episode of pancytopenia complicated by bleeding and gram negative septicemia which resolved promptly after stopping AG therapy has been reported3'7.

Medical adrenalectomy with AG has been compared to surgical endocrine ablative procedures by various groups of investigators. Harvey and associates33, in a randomized clinical trial with 35 patients, compared medical adrenalectomy with AG to transfenoidal hypophysectomy.

They obtained remissions in 10 of 21 patients (47%) with a median duration of 11.5 months in the AG treatment group. In the hypophysectomized group only 3 of 14 patients (21%) showed remission.

The median duration for these patients was 4-6 months. Santen and

13 coworkers^ reported a response rate of 53% with AG versus 45% with surgical adrenalectomy.

In view of these reports and the decreased toxicity of AG as com¬ pared to the morbidity and mortality associated with surgical procedures, it appears that AG is a preferable alternative to surgery in endocrine suppression and treatment for postmenopausal patients with advanced breast cancer.

TAMOXIFEN

The introduction of the antiestrogen tamoxifen (Nolvadex) is one of the most important recent advances in the treatment of advanced breast cancer. Many clinical trials have been done in order to try to establish the efficacy of this agent^. Morridsen and associates^ reviewed pooled data from 19 studies involving 1122 patients. Reported response rates vary from 16-52%; the overall rate was calculated as 32%. The median duration of response ranged from 6.7-17.5 months. They also found the incidence of side effects to be low. With respect to menopausal states, response rates were found to be similar in premenopausal and postmenopausal patients; i.e., 31% and 32%. However, those patients which were within five years of menopause (perimenopausal) had a lower response rate (23%).

Three clinical studies address the efficacy of tamoxifen in a group of premenopausal patients. Hoogstraten et al.41 obtained responses in 14 of 138 patients (37%) using a dose of 10 mg twice a day. Manni and associates^ showed remissions in 5 of 11 patients (45%) with a median duration of 19+ months. They employed a dose of 40-120 mg per day.

Prichard and coworkers1^ demonstrated responses in 13 of 42 patients

(32%) with a median duration of 289+ days using a dose of 20 mg twice a day. Furthermore, they showed that patients with ER positive tumors had a response rate of 44% versus 11% in those patients with ER negative tumors. Thus, ER status appears to be a good predictor of response to tamoxifen.

Morridsen and associates^ also evaluated response according to sites of metastatic disease. They found that soft tissue metastases were more responsive (response rate: 138 of 392 patients - 35%) to tamoxifen treatment than bone (response rate: 60 of 238 patients - 25%) or visceral metastases (response rate: 62 of 214 patients - 29%). Furthermore, ER status was a positive predictor of response. Response rate was 49% in patients with ER positive tumors versus 7% in patients with ER negative tumors.

Side effects associated with tamoxifen therapy have been found to be not 1 i fe-treateni ng and the incidence reported is extremely low. In

Morridsen's review^ of 1122 patients reported side effects were as follows: mild nausea and/or vomiting - 107 patients (1%), hot flashes-

94 patients (0.8%), transient thrombocytopenia - 52 patients (0.5%), increased tumor pain and inflammation - 20 patients (0.2%), and hypercalcemia - 11 patients (0.1%).

The recommended dose of tamoxifen is 20 mg per day^. Various investigators have evaluated the efficacy of employing higher doses (30-

90 mg daily). Ward4^1, in a randomized clinical trial with 68 patients found no difference in employing a dose of 10 mg twice a day versus 20 mg twice a day; response rates were 36% and 40% respectively. Steward and

15 associates4*3 treated 25 patients who had had disease progression on 10 mg twice a day (9 of whom had previously responded) with 20 mg twice a day.

They did not observe any responses. Morridsen and coworkers4^ reported no remissions in 19 patients treated with a dose of 30 mg daily and one partial response after the dose was increased to 90 mg daily. On the basis of these studies, it appears to be of no benefit to employ a dose greater than the conventional one.

The efficacy of tamoxifen has been compared to that of est rogen s4 ^»4^, androgens 4^, and the endocrine ablative procedures

(medi cal 50,51 anc| surgi cal ^2,53).

Tamoxifen has been found to be as efficacious or better than est rogens4^»4^ and androgens4^. Lipton and associates4'7 employed a regimen of diethystibestrol (DES) 5 mg three times a day versus tamoxifen

10 mg two times a day in 143 postmenopausal patients, none of which had had prior hormonal treatment. They showed a response rate of 41% with

DES versus 33% with tamoxifen. This difference was not found to be statistically significant. However, they found tamoxifen to have less side effects and decreased overall toxicity than DES. Another estrogen, ethinyl estradiol (EE2) was compared to tamoxifen in a study by Beryl and associates4^. They evaluated a regimen of EE2 0.3 mg per day given with chlorothiazide, to prevent fluid retention, versus tamoxifen 20 mg twice a day in 59 postmenopausal patients, 12% of which had had prior hormonal therapy. Response rates (EE2 - 31%; tamoxifen - 33%), median duration of response (EE2 - 12 months; tamoxifen - 11 months), and median survival time (EE2 - 31 months, tamoxifen - 25 months) were similar for both groups of patients. Side effects with EE2 were more serious than with

16 tamoxifen. Both groups of investigators concluded that tamoxifen should be a drug of choice over estrogens in the treatment of postmenopausal patients with metastatic breast cancer because it leads to similar percentage of remissions with less toxicity. The latter issue, particularly fluid retention with associated congestive heart failure is of particular concern in elderly patients or those with extensive lung metastases.

Androgens have been found to cause remissions in 10-20% of patients with median survival of 19-23 months for responders. Response rates are higher with increasing age and time elapsed after menopause^.

Westenberg and coworkers^ compared the efficacy of androgens, using f 1 uoxymesterone 10 mg twice a day, to that of tamoxifen, using a 20 mg dose twice a day. They reported remissions in 24 of 37 patients (30%) in the tamoxifen treatment group versus 15 of 42 patients (19%) in the fl uoxymesterone treatment group. Survival and time to disease progression were also significantly longer with the tamoxifen than with the fluoxymesterone group. Furthermore, tamoxifen was not associated with the side effects of androgen therapy: virilization, acne, hirsutism, and hypercal cemi a; and therefore, should be a preferred treatment over androgens for patients with advanced breast cancer.

Various investigators have compared tamoxifen with endocrine ablative procedures. Kiang et al. -jn a randomized clinical trial with a crossover phase compared tamoxifen using a dose of 20 mg per day versus hypophysectomy using a transphenoidal approach. They reported response rates of 71% (tamoxifen group) versus 67% (hypophysectomy group) with median duration of response of 12.5 months, and 13.0 months respectively.

Nemoto and associates33 obtained response rates of 52% with adrenalectomy

versus 35% for tamoxifen, but this difference was not statistically

si gnificant.

Two studies39*3^ compare medical adrenalectomy with

aminoglutethimide versus tamoxifen. Smith and associates38 employed a

regimen of tamoxifen 10 mg twice a day for the first 2 weeks then four

times a day with hydrocortisone 20 mg per day in 117 patients. They

obtained a response rate of 30% for both treatment groups. Also, no

significant difference in survival (15 months for both groups) or

duration of response was found. Ami nogl utethimide, however, had a

significantly greater remission rate in bone metastases (35%) than

tamoxifen (17%). Of note, 7 of 97 patients in the AG treatment group had

to discontinue therapy because of toxicity, whereas none of the 95

patients receiving tamoxifen had to do so. Upton et al.^1 employed the

same regimen except for a higher hydrocortisone dose of 100 mg per day in

divided doses during the first two weeks, then 40 mg per day in divided

doses thereafter. They also found similar response rates for both

groups: 38% for the tamoxifen group and 36% for the AG group.

Furthermore, they too found higher response rates in bony metastases but these were not statistically significant. It appears that because of its

reduced toxicity, tamoxifen would be the treatment of choice; however, AG

should be considered in patients with heavy burden of bone metastasis28.

PR0GESTINS

Progestins have also been employed in the treatment of metastatic

breast cancer patients28*39. In clinical studies with mostly

18 postmenopausal patients reported response rates range from 10-20%. These numbers are substantially lower than those obtained with other endocrine agents^. A review by Lober and coworkers55 reports an average response rate of 32% with a median duration of response of 14-52 weeks. Higher remission rates were seen in soft tissue and bone metastases (48% and

46%, respectively) versus visceral metastases (17%). Side effects were all found to be mild, not requiring dose modification.

Rubens and coworkers56 found a 25% remission rate with a median duration of response of 3.5 months using norethindrone acetate 20 mg three times a day. They obtained best responses in cutaneous metastases.

Visceral metastases were found to be resistant, for the most part.

Edelsyn et al5^ showed a higher response rate (41%) with a lower dose (10 mg four times a day) of the same agent. Again, metastases in soft tissue were found to have a higher remission rate than bone or visceral metastases. Another progestin, megestrol acetate was employed by

Alexi va-Figush and associates 5^ in a clinical trial involving 160 patients. They obtained a response rate of 29%. Soft tissue metastases were found to be the most responsive lessions with a remission rate of

35%; whereas visceral metastases were the least responsive with a remission rate of 25%. Using medroxyprogesterone acetate response rates of 40% have been reported with doses of 500-1000 mg per day IM. These doses are markedly higher than the previous conventional dose of 40-400 mg per day IM which produce a response rate of 17%5^.

NEWER AGENTS: DANAZ0L

Other endocrine agents have been studied in the treatment of

19 patients with advanced breast cancer without much success. One such agent, danazol, which is employed in the treatment of benign breast disease, was studied by Coombes and coworkers6*"1. They used a regimen of

100 mg three times a day later increased to 200 mg three times a day in most patients. Thirty-seven of the 41 patients in the study were postmenopausal. Response rates obtained for these patients were low

(7 of 37 patients - 18%) and side effects were seen in 22% of the patients, mainly at higher doses (600 mg per day). The 4 premenopausal patients also included in the study showed no objective responses.

COMBINATION VERSUS SEQUENTIAL TREATMENT

Combination endocrine treatment has not been studied as extensively as combination chemotherapy22*39,61. Staquet6! cites a review of

Macaulay and Smith6-*- of 13 randomized trials comparing combination endocrine treatment with single agent endocrine therapy. All of the studies failed to demonstrate a higher response rate or survival of combination over single agent.

Four randomized clinical studies showed combination regimens including tamoxifen to be therapeutically superior to tamoxifen as a single agent. A study by Powles and associates62 included 222 patients randomized to a combination of tamoxifen 10 mg twice a day, danazol 100 mg three times a day, and aminoglutethimide 250 mg three times a day

(TAD) versus tamoxifen as a single agent using a dose of 10 mg twice a day. The combination TAD had a higher response rate (43%) than tamoxifen alone (31%). Torrney and coworkers62 compared a combination of tamoxifen

(2-100 mg/m2 twice a day) and f1uoxymesterone (7 mg/m2 twice a day)

20 versus tamoxifen alone (2-100 mg/m^ twice a day) in 108 postmenopausal patients. They obtained remission rates of 38% with a time to treatment failure of 180 days for the combination which were significantly higher than those obtained with tamoxifen alone (response rate: 15% with a time to treatment failure of 64 days). Survival, however, was not statistically significantly higher. Stewart et al64 showed statistically significantly higher response rates with a combination of tamoxifen 10 mg twice a day and prednisone 5 mg twice a day (36% with a median survival of 21 months) than with tamoxifen 10 mg twice a day as a single agent

(13% with a median survival of 12 months) in a study with 145 postmenopausal patients. Lipton and coworkers5! studied a combination of tamoxifen 10 mg twice a day and aminoglutethimide 125 mg four times a day with hydrocortisone 100 mg per day in divided doses for the first two weeks, and then ami nogl utethi mi de 250 mg four times a day with hydrocortisone 40 mg per day in divided doses, versus tamoxifen 10 mg twice a day as a single agent. Response rates obtained in the 55 postmenopausal patients were higher with the combination regimen (37%) than with tamoxifen alone (26%).

In addition to treatment with combination endocrine regimens the use of these agents sequentially has also been evaluated. It appears that the sequential use of endocrine agents increases the chances of second- line responses. Not only may it produce responses in those patients who have responded and subsequently progressed on a previous treatment, but also it may induce remissions in patients who have failed initial treatment.

Kiang and associates5^ showed the sequence hypophysectomy-tamoxifen

21 to have a higher response rate (57%) versus tamoxi fen-hypophy sectomy

(22%). Smith and coworkers^ found AG to be effective in 4 of 6 patients

(67%) who have relapsed on tamoxifen and on 5 of 34 patients (15%) who have failed to respond. However, the sequence AG-tamoxifen failed to induce responses in any of the 4 patients who had previously responded and induced only 2 responses in 31 patients who had previously failed.

The sequence tamoxi fen-AG had a markedly higher overall response rate

(9 of 40 patients - 23%) than the sequence AG-tamoxifen (2 of 35 patients

- 6%). The authors suggested that the lack of complete cross-resistance between these two drugs may be related to their different mechanisms of action.

In premenopausal patients, the sequence tamoxifen-oophorectomy with continuing tamoxifen therapy has been studied by three groups of investigators with conflicting results. Pritchard et al.^3 had 6 responses in 8 patients who had previously responded to tamoxifen and subsequently progressed but no responses in any of the 13 patients who had failed tamoxifen treatment. Their overall response rate was 29%.

Manni and associates^ with a smaller number of patients had 1 response in 2 patients who had previously responded, but no responses in any of the 3 patients who had failed. Their overall response rate was 20%.

Results obtained by Hoogstraten et al are completely different. None of the previous 14 patients who had responded to tamoxifen treatment had remission with oophorectomy plus tamoxifen; whereas 5 of the 22 patients who had previously failed tamoxifen achieved remissions. Their overall response rate was lower than in the previous two studies (14%). The authors hypothesized that the initial dose of tamoxifen might have been too low to block all of the estrogen receptors given that these patients

22 are still premenopausal. Furthermore, ovarian castration by eliminating the main source of estrogen will allow the antiestrogen source of tamoxifen to be more efficacious.

SUMMARY

In summary, the initial treatment of postmenopausal patients with metastatic breast cancer should consist of tamoxifen. Those patients who have mainly bone metastases and those who relapse on tamoxifen could benefit from aminoglutethimide. Premenopausal patients could be treated with bilateral oophorectomy with or without tamoxifen. However, those patients with ER negative tumors and/or younger age are best treated initially with cytotoxic chemotherapy.

PART THREE: CHEMOTHERAPY

A large number of chemotherapeutic drugs are employed in the treatment of metastatic breast cancer. They fall in the following classes: alkylating agents (cyclophosphamide, melphalan); antibiotic antitumor agents (doxorubicin, mitomycin C); antimetabolites

(methotrexate, 5-F1uorouraci 1); and vinca alkaloids (vincristine and vinblastine)*^ all of these agents have been tested as single agents with response rates ranging from 14% for vincristine to 22-2 7% for cyclophosphamide and 31-38% for adriamycin (doxorubicin)*^.

COMBINATION CHEMOTHERAPY

The first reports of the therapeutic efficacy of combination chemotherapy for metastatic breast cancer were by Greenspan*^ in 1963 and

Cooper*^ in 1966. The latter was more widely accepted. The regimen consisted of: cyclophosphamide 2.5 mg/kg p.o. daily; methotrexate 25-50 mg IV weekly; 5 Fluorouracil 12 mg/kg IV daily for 4 days, then 500 mg IV weekly; vincristine 35 ug/kg IV weekly; and prednisone 0.75 mg/kg p.o. daily, then taper (CMFVP). The length of this cycle was 8 weeks. Cooper reported "complete remissions" in 8 of 9 patients with lung metastases,

19 of 22 patients with liver metastases, 14 of 16 patients with bone metastases, 7 of 8 patients with brain metastases, and 5 of 5 patients with massive skin involvement. "Complete remissions" lasted an average of 10 months. Many groups of i nvesti gators*^-73 have usecj modifications of this regimen with response rates of 53-68% (Table 2). Other reviewers report average response rates of 4 7% 66 and 50-60%66.

Various clinical studies^* ^ examine the question of whether the

24 addition of vincristine is of vital importance in modifications of the

Cooper regimen. Broader and associates^ compared a combination using

CMFP plus or minus vincristine in 100 patients. Response rates were similar for both groups (CMFP - 28%, CMFVP - 30%). Ahmann et al.^6 studied the combination CMP plus or minus vincristine and found lower response rate (46%), median duration of response (8.8 months) and survival (7.0 months) with the regimen containing vincristine (CMFVP) than with the combination without vincristine (CMP), (response rates-

59%, median duration of response - 9.8 months, and survival - 9.0 months). In general, there is no increase in response rates, response duration, or survival with vincristine containing modifications of "CMF" regimen than with the regimens without vincristine. In addition, the incidence of side effects particularly neurotoxicity and myelosuppression

was higher with the vincristine containing combinations^,75#

On the other hand, the addition of prednisone appears to be beneficial as shown by two studies (Table 2). Tormey and associates^* found higher response rates (63%), median duration of response (8.4 months), and survival (16.4 months) with the CMFP regimen than with the

CMF combination without prednisone (response rate - 57%, response duration - 4.5 months, and survival 14.5 months). A second group of investigators, Ramirez and coworkers^ had similar results in remission rates (CMFVP - 62.5%, CMFV - 44.2%) but found no significant difference in survival. They suggest that one possible explanation for the benefits of adding prednisone to CMF regimens could be that prednisone, by increasing the number of circulating leukocytes, allows larger doses of

CMF to be tolerated613’ ^.

The question of modification in schedule has been examined by

Hoogstraten and associates^. They studied a weekly (continuous) schedule using CMFVP versus the same combination using an intermittent schedule. Response rates were higher (59%) with the continuous regimen versus the intermittent schedule (40%). The median duration of response was similar for both groups (continuous regimen - 8.0 months, intermittent schedule - 10.0 months; difference not statistica 1 ly significant). Thus, they suggested that a continuous schedule is a more effective regiment in the treatment of metastatic breast cancer.

Lastly, combination chemotherapy has been compared to single agents

(Table 3)69,76-79. All of these studies show that combination regimens produce higher response rates with longer response duration and median survival than single agents.

DOSE INTENSITY

One issue which has recently gained increasing importance is the question of dose intensity. Hryniuk and Bush8(\ in a review article which addresses this question, stated that given the numerous manipulations of dose, schedules, and combinations, there should be a standardized method for comparing results obtained with the various chemotherapeutic regimens. They introduced the term dose intensity which they defined as mg/m^/wk. Taking Cooper's modification of his original schedule as the standard, the relative dose intensities of the various modifications of the Cooper regimen previously studied were calculated.

They were able to show a positive relationship between the therapeutic outcome (response rate) and the average dose intensity. This

26 relationship is even more apparent when the actual amount of dose received after reductions made because of toxicities was employed.

As one example, they analyzed results obtained by Hoogstraten and associates^ with a weekly (continuous) versus intermittent CMFVP combination regimen. Hryniuk and Bush‘d showed that the "low dose" weekly (continuous) combination, which was therapeutically superior to the intermittent combination, was actually the regimen with the higher dose intensity.

Hryniuk and Bush^ also reviewed CAF containing combination regimens. Using the regimen employed by Bull and coworkers^, they demonstrated an even steeper linear relationship between dose intensity

(dose actually delivered) and response rate than the one obtained with

"CMP" regimens

In a recent paper, Hryniuk^ states that dose intensity is not the only variable which affects response to treatment. In addition, the optimum duration of treatment needs to be taken into account since it has been said to determine the duration of remission. Overall, the dose intensity, upon which induction of remission depends, times the optimum duration of treatment determines the outcome of chemotherapy.

ADRIAMYCIN

Adriamycin (doxorubicin) has been shown to be the single most active agent in the treatment of advanced breast cancer. Reported response rates vary between 30-40%66 and 60%03. The dosage conventionally employed is 60 mg/m^ IV every three to six weeks^.

Many investigators have studied the therapeutic effectiveness of

Adriamycin containing combination regimens. One review88 reports

response rates of 60-80% in previously untreated patients. However, it appears that this higher response rate is not translated into increased

survival. Our review of the literature found response rates varying from

25-73% (Table 4)85-88.

One of the major problems associated with the use of Adriamycin in advanced breast cancer is its toxicity. Not only does it cause nausea and vomiting, bone marrow suppression, alopecia and mucositis like many other cytotoxic agents, but its use is also associated with dose- dependent chronic cardiotoxicity82. Due to the latter, the cumulative dose limit should not exceed 450 mg/m2 84.

The incidence of symptomatic congestive heart failure (CHF) has been estimated as 3-4% after a cumulative dose of 450 mg/m2 and 6-10% after a cumulative dose of 550 mg/m2. With doses exceeding 550 mg/m2, the

incidence of CHF rises to 30%89,90. jn addition it has been shown that many patients experience cardiotoxicity at doses lower than the maximum cumulative dose of 450 mg/m2 9!>92. jn one Sj-ucjy by forti and associates9! 13% of the patients developed CHF. The median cumulative dose had been 405 mg/m2.

With the advent of cardiac monitoring with noninvasive techniques and endomyocardial biopsy, it is possible to document subclinical cardiac

injury at lower doses84’92. One study by Jain and associates92 examines the efficacy of epirubicin (4, epi Adriamycin) versus that of Adriamycin.

Epirubicin is a doxorubicin (Adriamycin) analog which retains its

therapeutic effects but has decreased potential for cardiotoxicity. It

was shown that the response rate with epirubicin, using a dosage of 85

28 mg/rn^ IV every three weeks, was the same to that obtained with Adriamycin using the conventional dose of 60 mg/m^ IV every three weeks (i.e. 25%).

Median duration of response was longer with epirubicin (11.9 months) than with Adriamycin (7.1 months). In addition, the median dose to development of cardiotoxicity was higher with epirubicin (935 mg/m^) than with Adriamycin (468 mg/m^). Ten patients developed CHF (epirubicin-4,

Adriamycin-6). When the cumulative doses of these patients were looked at, it was found that those patients who received epirubicin developed

CHF at a substantially higher dose (1134 mg/m^) than those who received

Adriamycin (492 mg/m^). In addition, epirubicin was found to induce bone marrow suppression (on a molar basis) and GI toxicity less often than

Adriamycin. It thus appears that epirubicin could be an alternative to

Adriamycin alone or in combination for the treatment of patients with advanced breast cancer.

"CMF" VERSUS ADRIAMYCIN

Many clinical studies compare "CMF" combinations to Adriamycin as a single agent or Adriamycin containing combinations (Table 5)76,32,93-97.

Most of these studies show that the response rates obtained with

Adriamycin containing combinations was similar or higher than those obtained with modifications of the Cooper regimens. However, except for the study by Smalley et al.^^, comparing CAF versus CMFVP, this difference was not statistically significant. There was, however, one study by Hoogstraten and associates^ where the combination CMFP, given in a continuous schedule had statistically significantly longer response rate (59%) than Adriamycin as a single agent (39%). With respect to

29 median duration of response and survival, again, the Adriamycin containing combinations had similar or longer results than "CMF" combinations. This difference was only statistically significant in the study by Smalley et al.^.

Two studies show "CMF" combinations with statistically longer median duration of response and/or median survival time. In the study by

Hoogstraten et al.^, both CMFVP combinations had statistically significant longer median duration of response (10.3 months and 9.0 months) and longer median survival times, though these were not statistically significant (15.3 months each), than Adriamycin alone

(median duration of response - 4.0 months, median survival - 11.8 months). Also, in the study by Carbone and associates^ the combination

CMFP had a longer median duration of response (8.4 months) and statistically significant longer median survival (16.4 months) than

Adriamycin as a single agent (median duration of response - 7.7 months, median survival - 13.7 months).

It thus seems that the therapeutic efficacy of CMF(VP) regimens is probably similar to that of Adriamycin as a single agent and Adriamycin containing regimens. However, in view of the chronic dose-dependent cardiotoxicity, it seems wise to reserve Adriamycin for a second-line agent in those patients who have failed "CMF" combination treatment.

SECOND-LINE TREATMENT

Even though combination chemotherapy regimens can produce remission in over 50% of the patients*^, these responses are mostly partial and most patients end up with progression of their disease. Most patients

30 relapse within 10-13 months of starting treatment^*98. These patients can then be treated with other drug regimens: single agent or combinations. Unfortunately, second-line chemotherapy for the most part, has a lower response rate with shorter duration of response or time to disease progression and shorter survival. Oster^ comments on the fact that most patients with metastatic disease tend to die within one year of relapsing on their first-line chemotherapy.

Various drugs have been evaluated in the treatment of patients with metastatic disease who have relapsed on their first chemotherapeutic and/or hormonal treatment. Adriamycin has turned out to be the most effective single agent with response rates ranging between 23-38% (Table

5)92,100-102# These numbers are substantially lower than the response rate obtained with previously untreated patients (over 50%)^. Duration of response ranges from 3-12 months.

Mitomycin C has also been studied by multiple groups of investigators as an alternative to Adriamycin in second-line treatment of metastatic breast cancer (Table 7)103-106^ Unfortunately, response rates are much lower (18-26%). In addition, one group^ obtained no responses in 43 patients evaluated.

The next step in second-line chemotherapy has been the evaluation of combinations containing Adriamycin, mitomycin C, and vinca alkaloids

(vinbl asti ne-Vb , vincristine-Vc, and vindensine-Vb) (Table 8)107-113^

Response rates with two drug combinations range from 7-40%^7-liO^ Other studies include the alkylating agent di bromoducitol ^ ^ and the investigational drug ICRF-113 in combination with Adriamycin and mitomycin C or vincristine. Response rates obtained were 27-43% for the

31 combination AM plus di bromoducitol H1-H2 anci 16% for AV plus dibromoducitol and ICRF-159113>

In view of the fact that combinations containing Adriamycin and mitomycin C or vinca alkaloids have response rates around the 30% range, various groups of investigators have studied combinations of these three agents (Table 9)99*114-116 response rates range from 31-73%.

This study was designed as a randomized clinical trial to compare the current standard for second-line chemotherapy in metastatic breast cancer - Adriamycin with a combination using a low dose of Adriamycin with vinblastine and mitomycin C.

CLOSING REMARKS

It should be kept in mind, that breast cancer, particularly after the first or second relapse, is not a curable disease^ and thus, palliation and prolonged survival become the goal of therapy. In conclusion, the current recommended initial treatment for metastatic breast cancer is endocrine therapy. For those patients who fail such treatment or who have recurrence of their disease, chemotherapy is the next step. The one exception appears to be those patients with rapidly progressive disease and/or extensive visceral metastases who seem to do better with chemotherapy as their initial treatment^. For the rest, endocrine therapy is said to be associated with better quality of life and longer survival28,44o

With respect to chemotherapeutic regimens, combination chemotherapy with "CMF" type regimens appears to be the therapy of choice over single

32 agents, the best of which is Adriamycin. However, although combination therapy is associated with increased response rate and prolonged survival, the increased toxicity associated with a larger number of drugs is an important consideration particularly in the elderly and very sick patients. It is important to know that these regimens do not appear to be cross-resistant; and therefore, failing to respond to or progressing on one does not preclude response to the other.

Since a large number of patients do have progression of their disease on first-line chemotherapy, second-line chemotherapy has become a very important area of investigation. Single agent chemotherapy with

Adriamycin is the current recommended treatment with response rates of

23-38%92,10U-1U2. Recent studies^^*^^ show that combination chemotherapy with Adriamycin, vinblastine and mitomycin C also appears to yield similar results. The next step will be to compare the two treatment regimens.

PART FOUR: THE STUDY

METHODS

All women seen in the Yale-New Haven Hospital and affiliated clinics during the period of March, 1981 to September, 1985 who had histologically confirmed adenocarcinoma of the breast with measurable recurrent or distant metastatic disease and had failed prior treatment with CMF or its combinations were eligible for the study. All patients had previously received chemotherapy either as adjuvant or as treatment for metastatic disease with or without hormone therapy and had relapsed.

Estrogen receptor levels were obtained, when available, both for the primary tumor and recurrence. Those patients with a positive ER status had to have been unsuccessfully treated with hormonal therapy prior to entering this study.

Criteria for exclusion included: (1) having received prior treatment with Adriamycin, mitomycin C and/or vinblastine; (2) being more than 75 years of age; (3) having evidence of cardiac disease (measured by a ventricular ejection fraction of <50%); and/or (4) having an expected survival time of less than 30 days.

In order to begin treatment, patients had to not have received any therapy in the last 4 weeks and had to have given appropriate informed consent.

Pretreatment evaluation included a complete history and physical exam with measurement of all lesions and assessment of all disease sites.

Baseline studies included: complete blood count (CBC), platelet count, calcium, blood urea nitrogen (BUN), creatinine, carcinoembryonic antigen

(CEA), and liver function tests (bilirubin - tota 1/indi rect), serum glutamic-oxalocetic transaminase (SGOT), and alkaline phosphatase; chest x-ray, bone and liver scans, and left ventricular ejection fraction.

Performance status of the patients at initiation of therapy was assessed according to the guidelines of the ECOG performance scale:

0. ambulatory, assymptomatic and able to carry out their normal daily activities; 1. ambulatory, but experiencing symptoms from disease and restricted in their daily activities; 2. bedridden <50% of the time;

3. bedridden >50% of the time; and 4. bedridden all the time.

Follow-up studies were performed on all the patients in order to monitor the extent of disease progression and response to therapy. A history and physical exam was done every 4 weeks. Blood counts (CBC and platelet) were obtained every 4 weeks. Other blood studies, including

BUN, creatinine, calcium, and liver function tests (same as above) were performed every 6 weeks. Chest x-rays were obtained every 3 months if the patient's previous studies were normal, or every 8 weeks if such studies indicated metastatic disease. Ventricular ejection fraction tests, to monitor Adriamycin's potential cardiac toxicity, were repeated after the patient had received a cumulative dose of 300 mg/m^.

Patients were randomized into 2 treatment groups: Adriamycin as a single agent (Adriamycin), or Adriamycin in combination with vinblastine and mitomycin C (AVM) • The Adriamycin group received 60 mg/m^ of

Adriamycin IV on day 1 every 3 weeks. The AVM group received 30 mg/m^ of

Adriamycin IV on day 1 every 4 weeks, 6 mg/m^ of vinblastine IV on day 1 every 4 weeks, and 10 mg/m^ of mitomycin C IV on day 1 every 8 weeks.

Drug dosages of AVM and Adriamycin were started at 50% if the

35 patients had experienced cytopenias prior to entering the study (measured by a hematocrit >30%, a white blood count (WBC) <2000/ul, and/or a platelet count <100,000/ul. If on day 1 of the treatment cycle the WBC was >3500/ul and the platelet count was >100,000/ul the dose was increased by 25%.

If bone marrow depression occured during treatment, drug dosages were reduced by 50% if the patient had a WBC of 2500-3499/u 1 and a platelet count of 75,000-99,000/u 1. Treatment was held if the patient had a WBC <2500/ul and a platelet count <75,000/ul.

Adriamycin dose was held if the patient had a ventricular ejection fraction <45%. At this point the patient was taken out of the study due to cardiotoxicity and other treatment options were explored. Adriamycin dose was reduced by 50% if the patient had a total bilirubin of 1.5-3.0 mg% or by 75% if the patient had a total bilirubin >3.0 mg%.

Complete response was defined as a disappearance of all known and measurable disease, as confirmed with x-rays, bone and liver scans. The response should last at least 4 weeks.

Partial response was defined as regression of 50% or more of the sum of the cross-perpendicular dimensions of the largest diameter of all measurable lesions. The response should last at least 4 weeks.

Stabilization was defined as a reduction of <50% or a progression of

<25% of the original measured lesions (size parameters measured as above). No new lesions could have appeared in this time period.

For evaluation purposes, patients who were documented as having stable disease were classified as non-responders together with those who had disease progression.

Those patients who were documented as having achieved a response to treatment or disease stabilization continued to receive treatment until there was evidence of disease progression. When a patient was determined to have relapsed, treatment according to this protocol was terminated and other treatment alternatives were explored. At this point all blood studies, chest x-rays, bone and liver scans were repeated.

Response was evaluated in terms of survival and time to disease progression.

Survival was measured from the date of initiation of therapy, in this study, to the date last seen or date of death. The time to disease progression was defined as the time from initiation of treatment to the time when the patient had a documented disease progression.

The difference between the two treatment arms was analyzed using the

Chi Square test.

Survival and time to progression data were calculated according to the actuarial method of Kaplan and Meier ^ and the significance of differences was analyzed using the Mantel-Cox statistical test.

Difference in survival times and time to progression between responders and non-responders was analyzed. Data were also evaluated for differences in the following parameters: number of disease sites at initiation of treatment, performance status, disease-free interval, stage at diagnosis, and menopausal status at initiation of the study. Data for estrogen receptor status were not included in the analysis because the number of patients with information available was too small.

The cost of each drug regimen was calculated based on the cost at

Yale-New Haven Hospital as of July, 1987 (latest figures available at the time of writing this manuscript) (Table 10).

PATIENTS AND RESULTS

Fifty-eight patients were entered in the study. Four patients were considered unevaluable; three had been randomized into the Adriamycin treatment group and one to the AVM treatment group. One of the

Adriamycin patients died after randomization without receiving any treatment. Another patient received ten courses of treatment at 100% dose, but also received taxomifen during eight of the ten treatments.

The third patient died of a respiratory arrest four days following her first treatment at 100% dose. On autopsy, she was documented to have had lymphangitic disease of the lung and metastases in the liver, mediastinal and para-aortic lymph nodes, adrenal glands, pancreas, bone and opposite breast. The patient who was randomized into the AVM treatment group refused any further therapy after the first treatment. She was admitted to the hospital the following day and expired two weeks later. However, this patient had been admitted to the hospital one week prior to the first treatment because of increased shortness of breath, generalized weakness and progression of her disease. Of the remaining 54 evaluable patients, 26 were in the Adriamycin treatment group and 28 were in the

AVM treatment group.

Patient Character!'sties

Patients characteristics are presented in Table II, subdivided by treatment group.

The age median (Adriamycin-52; AVM-54) and range (Adriamycin 35-74;

AVM 29-73 ) was similar for both groups. Most patients were

38 postmenopausal at the time of study [23 (89%) Adriamycin patients; 21

(75%) AVM patients].

With respect to staging of the primary tumor, most patients (54%) fell in the 111-1V category [Adriamycin-16 (62%); AVM-14 (50%)]. The difference may be accounted for by the fact that 5 of the AVM patients versus only 3 of the Adriamycin patients had an unknown status.

Contrary to expected for this group of patients' performance status, a higher percentage were ambulatory with a performance status of 0 or 1

[Adriamycin-20 (77%); AVM-20 (71%)]. Three patients in the Adriamycin group had an unknown status. Within this category there is a difference between treatment arms: 5 of the 20 Adriamycin patients (25%) were asymptomatic versus 11 of the 20 AVM patients (55%). Eleven patients were non-ambulatory with a performance status of 2 or 3. No patient had a performance status of 4. Almost all the patients were bedridden <50% of the time with a performance status of 2 [Adri amycin-6 (100%); AVM-4

(80%)]. Only one patient was bedridden >50% of the time with a performance status of 3.

The disease-free interval (DFI) was defined as the time from initial diagnosis to the time of first recurrence. This interval was approximately the same for both treatment groups (Adriamycin-25.6 months, range 0-72 months; AVM-22.0 months, range 0-72 months). Seven patients

(Adriamyci n-3; AVM-4) presented with metastatic disease and were considered to have a 0FI of 0.

Previous Treatment

Previous treatment received by the patients before entering the study is shown in Table 12. Most patients had had surgery as their

39 primary treatment (Adriamycin-24; AVM-23). Of these 2 Adriamycin patients and 4 AVM patients had had lumpectomies, and the rest had had either a simple or modified radical mastectomy. One patient, in the AVM group, had had a radical mastectomy. Three of the remaining five patients who had not had surgery received primary radiation therapy.

All the patients in this study have been treated with CMF chemotherapy, either adjuvanct [Adriamycin-12 (46%); AVM-13 (46%)] or after recurrence [Adriamycin-15 (58%); AVM-14 (50%)]. Two patients in the Adriamycin group received CMF chemotherapy both adjuvanct and after recurrence and failed both treatments.

One patients in the Adriamycin group had been treated with hormone therapy as primary treatment. Twelve patients [Adriamycin-6 (23%); AVM-6

(21%)] had received hormone therapy adjuvanct. Approximately two-thirds of the patients [Adriamycin-18 (69%); AVM-17 (61%)] had been treated with hormone therapy after recurrence either alone or in combination with CMF chemotherapy.

Three patients in the Adriamycin treatment group and two patients in the AVM treatment group had had an oophorectomy, either surgical or radiation, following their first recurrence.

Sites of Metastatic Disease at Initiation of Therapy

Sites of metastatic disease at initiation of therapy subdivided by treatment arm, showing both number and percentage of patients with metastatic disease and breakdown by site are presented in Tables 13 and

14.

The majority of the patients [Adriamycin-21 (81%); AVM-21 (75%)] presented with metastatic disease at 2 or more sites. Within this group, only 3 (12%) of the Adriamycin patients and 4 (14%) of the AVM patients

40 had widely disseminated disease with involvement of more than 3 sites.

The single most common site of metastatic disease at initiation of study was bone [Adriamycin-19 (31%); AVM-20 (28%)]. Approximately half of the patients [Adriamycin-14 (56%); AVM-13 (46%)] had visceral disease at one site with involvement of the lung or liver. One patient in the

Adriamycin group had both liver and CNS involvement. Three patients in the AVM group had involvement of both the liver and the lungs. One of these patients had involvement of the kidney.

On-Study Time

On-study time was defined as the time elapsed between the date of first treatment to the date last seen or the date of death. The 54 evaluable patients had a mean on-study time of 234 days, range (27-784 days). The 28 AVM patients had a longer on-study time (mean-268 days, range 34-784 days) than the 26 Adriamycin patients (mean-268 days, range

34-784 days) than the 26 Adriamycin patients (mean-198 days, range 27-563 days).

The 54 evaluable patients received a total of 300 treatment courses.

The 26 Adriamycin patients received a total of 117 treatment courses with a mean/patient of 4.5 cycles of treatment whereas the 26 AVM patients received a total of 183 treatment courses with a mean/patient of 6.5 cycles of treatment.

Response to Therapy

Response to therapy, subdivided by treatment arm is shown in Table

15.

Twelve (22%) of the 54 evaluable patients had an objective partial response: 4 (15%) of the Adriamycin patients and 8 (29%) of the AVM patients. No patient had a complete response. This difference was not

41 statistically significant (p>0.2).

Within the non-responders, three-quarters (33 patients) had progressive disease: 16 (73%) of the 22 Adriamycin patients and 17 (85%) of the 20 AVM patients. The remaining 9 non-responders had stable disease.

Survival

Survival time for all patients was analyzed and is presented in

Table 16 and Figures 1-8.

Median survival time for all patients was 8.41 months. When separated into treatment groups, the Adriamycin patients had a median survival time of 7.56 months and the AVM patients had a median survival time of 9.00 months. This difference was not statistically significant

(p=.35).

Patients who were classified as responders had a statistically significant (p =.01) longer median survival time (20.40 months) than the patients who did not respond (7.33 months).

Separating the patients by numbers of sites of disease at the time they entered the study showed no statistically significant difference in median survival times (p=.19) between the patients who had 1 site of disease (9.66 months), 2 or 3 sites of disease (7.59 months) or >3 sites of disease (5.82 months).

The mean survival time of the patients who were ambulatory (9.66 months) was found not to be significantly higher (p=.06) than that of the patients who were non ambulatory (6.87 months).

In order to analyze data for disease-free intervals, all patients were divided into three groups depending on the length of time they had

42 been disease-free prior to their first recurrence: (0-6, 7-18 or >18 months). Statistical tests demonstrated no significant difference

(p=.89) between the median survival times (9.66 months, 8.41 months, and

8.71 months respectively) of the patients in these groups.

Survival data was also analyzed with respect to stage of tumor at initial diagnosis. It was found that patients with Stage III tumors had overall shorter (6.38 months) median survival (9.79 months, 9.33 months, and 9.66 months, respectively) than those with Stage I and II tumors. It is not clear why patients with Stage IV tumors had a longer median survival than those with Stage III tumors. One possibility is that these patients, because they presented with metastatic disease at diagnosis, had not been as heavily pre-treated when they entered this study.

There was no statistically significant difference (p=.12) between the median survival time of the premenopausal (12.85 months), and the postmenopausal (7.56 months) patients.

Time to disease progression

Another parameter used to analyze the data in this study was time to disease progression. Data is presented in Table 17 and Figures 9-16.

The median time to disease progression for all patients was 4.50 months. When separated by treatment groups, the AVM patients had a longer (p=.03) time to disease progression (5.91 months) than the

Adriamycin patients (3.84 months).

Looking at all patients, responders had a significantly longer

(p=0.03) time to disease progression (10.12 months) than non-responders

(3.22 months).

Dividing the patients into three groups depending on the number of disease sites at the time they entered the study, showed no statistical

significant difference (p=.70) between those who had 1 site of disease

(median time to progression - 3.22 months), 2-3 sites of disease (median time to progression - 5.59 months) or >3 sites (median time to progression - 3.83).

There was no statistically significant difference (p =.91) in the time to disease progression in the patients who were ambulatory (3.84 months) and those were non-ambulatory (5.91 months).

In terms of disease free interval there was no statistically significant difference (p=.42) in the time to disease progression of the patients in the three groups (disease free intervals 0-6, 7-18, and >18 months; time to disease progression 3.02, 3.84, and 5.59 months respectively.

Time to disease progression was analyzed with respect to stage of tumor at diagnosis. Overall, patients with Stage I and II tumors had a longer time to disease progression than those with Stage III and IV tumors.

There was no statistically significant difference (p=.99) in the time to disease progression between the patients who were premenopausal

(5.59 months) and those who were postmenopausal (4.50 months) at the time they entered the study.

For 22 patients the study was ended for reasons other than disease progression (Adriamycin-12, AVM-10). Of these, seven patients

(Adriamycin-3, AVM-4) died while receiving treatment without having had documented disease progression. The remaining 15 patients (Adriamycin-9,

AVM-6) were taken out of the study for various reasons. This date was

used as their date of disease progression.

Of the nine Adriamycin patients, five were changed either to weekly

Adriamycin or to AVM after a total dose of 300 mg/m2. None of them had

44 experienced cardiac toxicity. One patient was hospitalized for a small bowel obstruction and was treated with the wrong protocol after

discharge. Another patient was changed to AVM for no apparent reason.

The remaining two patients were lost to follow-up.

Two of the six patients receiving AVM stopped treatment due to shortness of breath. It should be noted that both had a normal

ventricular ejection fraction. The other 4 patients were still receiving treatment at the time this study was ended.

Sites of Metastatic Disease at Progression

Sites of metastatic disease at progression, subdivided by treatment arm showing both number and percentages of patients with metastatic disease and breakdown by site, are presented in Tables 18 and 19.

Most patients had progression of their disease in 3 or fewer sites

[Adriamycin-21 (84%), AVM-21 (84%)]. Of the Adriamycin patients, approximately half [11 (52%)] had disease in 0 or 1 site, and half [10

(48%)] had disease in 2 or 3 sites. Only 4 patients in each group had disease in 4 or more sites. Overall, the majority of the patients had

recurrence at the same sites of metastatic disease prior to initiation of therapy.

The most common site involved at disease progression was bone

[Adriamycin-13 patients (52%), AVM-16 patients (64%)]. Visceral disease with involvement of lung, liver or CNS was documented in 16 (64%)

Adriamycin, and 14 (56%) AVM patients. One of the Adriamycin patients and 2 of the AVM patients had involvement at 2 of these sites.

Toxicities

The most significant toxicities experienced by the patients in this

study are presented in Table 20.

The lowest white blood counts seen in the interval between cycles of

21 (57%) patients, AVM-17 patients of 23 (74%) patients]. Such blood counts were seen in 17 of 53 (32%) evaluable courses in the Adriamycin treatment group and in 30 of 89 (34%) evaluable courses in the AVM treatment group. Only 6 (14%) patients had white blood cell counts >1000 cells/ul^. Five of these were in the Adriamycin treatment group.

Platelet counts of <100,000 cells/ul were seen in 13 of 44 (24%) patients [Adriamycin-5 of 21 (24%) patients, AVM-8 of 23 (34%) patients].

Such platelet counts were seen in 5 of 52 (10%) evaluable courses in the

Adriamycin patients and 12 of 89 (14%) evaluable courses in the AVM treatment group. No platelet counts <20,000 cells/ul were seen.

The percent of optimal dose administered per cycle was averaged for each treatment arm. Results are presented on Figure 17-19. It should be noticed that a higher percentage of the ideal dose was able to be administered with the AVM combination than with Adriamycin with the AVM combination than with Adriamycin as a single agent.

Figures 20 and 21 show the relationship of the platelet count

(mean/cycle) and percent of ideal dose (mean/cycle) administered for each treatment group. It may be observed that, for the most part, there was not much variation in terms of the platelet count as the percent of ideal dose was decreased for both groups of patients (Adriamycin: 231,000-

378,000 cells/ul, AVM: 180,000-291,000 cells/ul).

The mean (range) WBC counts per cycle were plotted by course of treatment for each of the treatment groups on Figure 21. Looking at the mean WBC count per cycle again, there is not much variation throughout the different cycles of treatment for both treatment arms. However, in general, the mean WBC count in the AVM treatment group tends to be

46 slightly higher than in the Adriamycin treatment group.

None of the patients experienced symptoms of cardiac toxicity. Two patients, however, were changed to a different regimen because their ejection fraction had significantly declined from 69-60% and 74-50%, respectively, after a cumulative Adriamycin dose of 300 mg/m^. However,

10 patients (Adriamycin-4, AVM-6) received >300 mg/m^, and 11 patients

(Adr i amycin-7 , AVM-4) received between 200-300 mg/m^ of Adriamycin without developing cardiac toxicity.

Two patients deserve special mention. One patient declined further therapy following her complaint of shortness of breath, secondary to

Adriamycin, after a total dose of 161 mg/m^. Her ventricular ejection fraction, however, was 80%. One patient in the AVM group developed bigeminy after a total dose of 300 mg/m^. Her ventricular ejection fraction, however, was 62%. Her Adriamycin was held, she was taken out of the study at this point, and her cardiac problem was controlled with a hi gh dose of Inderal .

None of the patients developed neurotoxicity from vinblastine.

One patient was hospitalized due to severe liver disease and declined further treatment; however, this patient had metastatic disease in her liver at the time she entered the study.

Seven patients developed sufficiently profound thrombocytopenia to require hospitalization (Adriamycin-4, AVM-3). One of these patients also had a fever. Another patient was admitted with GI bleeding.

Some patients experienced nausea and vomiting, stomatitis, tissue irritation, rashes, and alopecia during treatment, but all of these were considered minor toxicities.

Seven patients died during treatment. Five of the deaths were primarily due to progressive disease (Adriamycin -3, AVM -2); the other two (AVM) were of unknown etiology.

Eleven patients were still alive at the date last seen; 6 in the

Adriamycin group, and 5 in the AVM group. None of these patients were disease-free. Four patients had no evidence of disease progression at the date last seen, and were still receiving treatment at the time the study was ended. All of them were in the AVM treatment group, and had experienced a partial response. Three patients, all from the Adriamycin group, had been taken out of the study after a total Adriamycin dose of

300 mg/m^. However, none of them had developed signs of cardiac toxicity. Two of the Adriamycin patients were lost to follow-up. The remaining 2 patients have had documented disease progression and were receiving other treatment.

Cost

Data used to calculate costs was presented in Table 10. Total figures for each treatment group were adjusted for a four week period.

It was found that the cost per month of treatment was suprisingly more expensive for the single drug ($307.29), than for the three drug combination ($263.91).

DISCUSSION

The high rate of recurrence and short duration of response obtained with first-line chemotherapy for advanced breast cancer (usually "CMF" regimens) is well-known. Adriamycin is the current standard of treatment for patients with metastatic breast cancer refractory to conventional chemotherapy. However, as already discussed, this drug is associated

48 with dose-dependent cumulative cardiotoxicity which has limited its use to 450 mg/m^. Usually treatment need to be changed once this dose has

been exceeded. Unfortunately, the number of single agents and combinations shown to be effective for third-line treatment is small and the response is quite poor HO. This study compares one such combination

(Adriamycin, vinblastine, and Mitomycin C) to single agent Adriamycin.

One of the approaches to improve palliation of disease and prolong survival is to employ combination regimens containing Adriamycin as second-line treatment. The idea is that, by giving Adriamycin with two other synergistic, but potentially less toxic drugs, one could achieve equal or greater responses with a lower dose of Adriamycin. Thus, it would permit less drug to be given over a longer period of time. This has been one of the approaches suggested by Jain et al .^2 for reducing cardiac toxicity.

Before analyzing the results, it should be noted that the patients in this study are of a poor prognostic category with respect to the course of metastatic disease. Their disease-free interval was generally less than two years. According to Cutler and associates H this gives them a median survival after relapse of 15 months. In addition, most patients had between two and three sites of metastatic disease at relapse. This places them in category C (mixed sites of metastatic disease) according to Fei and coworkers and therefore, their expected survival after relapse should be approximately 17 months, or 9 to 12 months according to Cutler and associates n0 information was available with respect to response to first-line treatment.

Also of note, this group of patients had been heavily pre-treated

with first-line agents. Approximately, one half of the patients had been

treated with chemotherapy, the other half had received hormone therapy.

Ten percent of the patients had been treated with combination

chemotherapy and endocrine therapy at relapse.

Response rates were higher with the AVM combination regimen (29%) than with Adriamycin as a single agent (15%). All of these responses were partial remissions. This difference, however, was not statistically

significant (p>.2). Most likely this was due to the small number of

patients who responded in both treatment groups (Adriamycin-4, AVM-8).

With respect to response duration, the patients treated with the AVM

combination had a longer time to disease progression (5.91 months) as

compared to the patients treated with Adriamycin alone (3.84 months).

This difference was statistically significant (p<.05). As expected,

responders had a significantly longer time to progression than non¬

responders (i.e., 10.12 versus 3.22, p=.003). However, none of the

parameters evaluated: namely, numbers of sites of metastatic disease at

initiation of study, performance status, disease-free interval, and

menopausal status was of prognostic value in evaluating time to

progressi on of disease. The only factor that appears to make a

difference is stage at diagnosis. Overall, the patients with more

advanced disease at diagnosis (Stages III and IV) had a significantly

shorter time to progression than those with less advanced disease (Stages

I and II).

In terms of survival, the patients in the AVM treatment arm had a

longer, though not statistically significant, median survival (7.56

months) than those in the Adriamycin treatment group (9.00 months). As

50 expected, responders had a significantly longer median survival time

(20.40 months) than non-responders (7.33 months). None of the other parameters, already mentioned, were found to be of prognostic value except for stage at diagnosis. Again, those patients with more advanced disease at diagnosis (Stages III and IV) had a significantly shorter median survival than those with less advanced disease (Stages I and II).

Overall, results obtained with the AVM combination were similar to those reported in previous studies 99,114-116.

Luikart and coworkers using a combination of Adriamycin 30 mg/m^ on day one every eight weeks (the same regimen employed in this study) in previously treated patients, obtained a 33% (nine responders) response rate. Of these nine responders, three were complete responses, and six were partial responses. Median survival for this group of patients was 264 days (approximately 8.7 months) which is comparable to our group of patients in the AVM treatment arm (9.00 months). Time to progression was 116 days (approximately 3.8 months) which is shorter than that observed in this study for the AVM patients (5.91 months). Luikart et al.H6, observed that, in general, patients with one or two sites of metastatic disease tended to have more responses or stabilization of disease than those with three or more sites. This was not true in this study. Of the twelve patients who responded, four in the AVM group, and three in the Adriamycin group had metastatic disease at three or more sites prior to initiating treatment.

Another study by Borowik and colleagues using these same agents in different doses (Adriamycin 45 mg/m^ and vinblastine 4.5 mg/m^ IV every three weeks and mitomycin C 10 mg/m^ IV every six weeks) in

51 previously treated patients reported a response rate of 24.3% with a median duration of 5+ months. Their response rate was much higher (38%) in patients who received over 80% of the calculated dose. They found that those patients who received the combination regimen after failing adjuvant CMF had a higher response rate (45%) compared to those who had failed CMF for advanced disease (20%). In addition, they showed that response rate to the combination regimen was related to disease-free interval. Those patients with a DFI greater than 24 months had a higher response rate (41%) than those with a DFI less than 24 months (10%).

Two other studies 99,115 evaluated a combination containing

Adriamycin, mitomycin C, and vincristine instead of vinblastine. Shipp and associates reported a 31% response rate with a median duration of

5 months with a combination of Adriamycin 40 mg/m^ and vincristine 1.5 mg/m^ on day one and 22 and mitomycin C 10 mg/m^ on day one every six weeks in previously treated patients. Of the 11 responders, one had a complete response, the remaining 10 had partial responses. Median survival for this group of patients was 7.9 months. Like Borovik et al.114, they too found that response rate was significantly higher (53%) for those patients who were treated with the combination regimen after adjuvant CMF, compared to those who had failed CMF for advanced disease

(14%). However, no other pretreatment characteriStic evaluated: age, performance status, number of and dominant sites of metastatic disease,

disease-free interval, and estrogen receptor concentration, was found to be of prognostic value in predicting response.

The other group of investigators Osier and coworkers ^9 obtained a

much higher (73%) response rate with a longer median duration (8.0

52 months) and survival (18 months). Of their 11 patients who responded, three had complete remissions. One possible explanation for this high response rate could be that this was a small sample of patients approximately one-half of which had soft tissue disease. Eight of these responses were in soft tissue. The other four were in visceral sites

(lung or liver). None of the patients had metastatic disease in bone.

Results obtained with Adriamycin as a single agent in this study

(response rate - 15%, time to progression - 3.84 months, and survival

7.56 months) were somewhat lower than those reported by other researchers

(23-38%) 89-91# Jain ancj associates 92} Gotlieb and coworkers and

Fredericksen and colleagues employed dosages of Adriamycin 60 mg/m^

IV 60-75 mg/m^ IV, and 70 mg/m^ IV every three weeks, similar to those used in our study (60 mg/m^ IV every 3 weeks). They reported response rates of 25%, 30%, and 23%, respectively. Median duration of response

ranged from 3+ to 11.9 months. Creech and coworkers 96^ using a lower dose of Adriamycin 20 mg/m^ on day one and eight every 23rd day, obtained a 27% response rate with a median duration of 7 months.

There are a couple of possible reasons which could explain the lower

response rate obtained in this study. First, this was a group of heavily pretreated patients with poor prognostic disease, for many of whom

Adriamycin was a third-line, rather than a second-line, agent. Second,

and probably because of the above mentioned reasons, they only tolerated,

on the average, 75% of the optimal dose of Adriamycin which they were to

receive.

Hematologic toxicity was moderate for both treatment groups.

Leukopenia (WBC count <2000/ul) and thrombocytopenia (platelet count

<100,000/ul) were similar for both treatment groups when analyzed in terms of evaluable courses. Variation in both WBC count and platelet count with respect to percent of optimal dose administered is small and similar for both treatment arms. However, overall, a higher percentage

of the optimal dose was able to be administered with the AVM combination than with Adriamycin as a single agent. This could have been due to the

fact that the combination was given every four weeks, whereas the single drug was given every three weeks.

Cardiac toxicity was not observed in this study. Two patients, both

in the Adriamycin treatment group, had to be changed to a different

regimen due to a fall in ejection fraction, but for neither patient had there been a significant change (74% to 50% and 69% to 60%).

Furthermore, neurotoxicity due to vinblastine was also not seen in any of the patients.

Finally, the question of cost needs to be addressed. It would seem

logical that a single drug would be cheaper and, therefore, preferred over a three drug combination. However, because this combination contains only one-half of the standard Adriamycin dose, and is given every four, instead of every three, weeks, it turns out that the AVM

regimen is actually less expensive ($263.91/month) than Adriamycin as a

single agent ($307.29/month).

In summary, the combination of Adriamycin, vinblastine and mitomycin

C appears to be at least as effective as Adriamycin as a single agent.

The AVM combination had a significantly longer time to disease

progression, and allowed for a higher percentage of the optimal dose to

be administered. It also had a higher response rate and median survival.

54 but these differences were not statistically significant most likely due to the small number of patients involved. Furthermore, the combination was less expensive, on a monthly basis, than single agent Adriamycin.

Since toxicity was similar for both regimens, it appears worthwhile to employ this combination as second-line treatment for patients with metastatic breast cancer.

It has been previously established that epirubicin is as therapeutically efficacious as Adriamycin, but with less potential for cardiac toxicity, thus allowing for a higher cumulative dose to be administered 92. jn the future, it would be important to determine the efficacy of a combination of epirubicin with vinblastine and mitomycin C as second-line chemotherapy in patients with advanced breast cancer.

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86. Jones, S., Durie, B., and Salinon, S.: Combination chemotherapy with Adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36:90-97, 1975.

87. Tranum, B.L., Hoogstraten, B., Kennedy, A., Vaughn, C.B., Sanol, B. , Thighpen, T., Rivkin, S., Smith, F., Palmer, R.L., Constanzi, J., Tucker, L.U.G., Wilson, H., and Maloney, T.R.: Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study. Cancer 41:2078-2083, 1978.

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92. Jain, K.K., Casper, E.S., Geller, N.L., Hakes, T.B., Kaufman, R.S., Currie, V., Schwartz, W., Cassidy, C., Petroni, G.R., Young, C. W., and Witles, R.E.: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. Journal of Clinical Oncology 3:818-826, 1985.

93. Brambilia, C., DeLena, M., Rossi, A., Valasusa, P., Bonadonna, G.: Response and survival in advanced breast cancer after two non- cross-resi stant combinations. British Medical Journal 1:801-804, 1976.

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95. Smalley, R.V., Carpenter, J., Bartolucci, A., Vogel, C., and Krauss, S.: A comparison of cyclophosphamide, Adriamycin, and 5- Fluorouraci 1, vincristine, and prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer 40:625-632, 1977.

96. Creech, R.H., Catalano, R.B., Harris, D., Engstrom, N., Grotzinger, P.: Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, Adriamycin, methotrexate, and 5- Fluorouracil (CAMF ) versus sequential cyclophosphamide, methotrexate, and 5-Fluorouracil (CMF) and Adriamycin. Cancer 43:51-55, 1979.

97. Muss, H.B., White, D.R., Richards, F.II, Cooper, M.R., Stuart, J.J., Jackson, D.V., Rhyne, L., and Spurr, C.L.: Adriamycin versus methotrexate in fine-drug combination chemotherapy for advanced breast cancer. A randomized trial. Cancer 42:2141-2148, 1978.

98. Haskel , C.M. (Mod.): Systemic therapy for metastatic breast cancer. Annals of Internal Medicine 86:68-80, 1977.

99. Oster, M.W., and Park, Y.: Vincristine, Adriamycin, and mitomycin C (VAM) therapy for previously treated patients with breast carcinoma: a preliminary report. Cancer 51:203-205, 1983.

100. Frederiksen, P.L., Joergensen, S.T., Roesdahl , K., Thomsen, J., and Morridsen, H.T.: Activity of Adriamycin in metastatic breast cancer resistant to combination regimen with cyclophosphamide, methotrexate, 5-Fluorouraci 1, vincristine, and prednisone. Cancer Treatment Report 62:449-450, 1978.

101. Creech, R.H., Catalano, R.R., Shah, M.K.: An effective low dose Adriamycin regimen as a second-line chemotherapeutic agent for metastatic breast cancer. Cancer:433-437, 1980.

102. Gotlieb, J.A., Rivkin, S.E., Spiegel, S.C., Hoogstraten, B., O'Bryan, R.M., Delaney, F.C., and Si nghakowi nta, A.: Superiority of Adriamycin over oral nitrosoureas in patients with advanced breast cancer. Cancer 33:519-526, 1974.

103. Pasterz, R.B., Byzder, A.V., Hortogagyi, G.N., and Blumerchein, G.R.: Mitomycin C in metastatic breast cancer refractory to hormonal and combination chemotherapy. Cancer 56:2381-2384, 1985.

104. Creech, R.H., Catalano, R.B., Shah, M.K., and Dayal, H.: An effective low dose combination regimen for hormone and chemotherapy refractory patients with metastatic breast cancer. Cancer 51:1034-1040, 1983.

105. Lopez, M., Papaldo, Q., Lauro, L., Barduagni, M., Perno, C.F., and Barduagni, A.: Mitomycin C in patients with metastatic breast cancer refractory to hormone therapy and chemotherapy. Oncology 40:244-247, 1983.

106. DeLena, M., Jirillo, A., Brambilla, C., and Villas, S.: Mitomycin C in metastatic breast cancer resistant to hormone therapy and conventional chemotherapy. Tumori 66:481-484, 1980.

107. Harris, M.A., Byrne, P.S., Smith, F.P., Veno, W., Schlesinger, C., Oishi, S., and Schein, P.S.: Treatment of advanced breast cancer with two doxorubicin containing regimens. American Journal of Clinical Oncology 7:51-58, 1984.

108. Denefrio, J.M., East, D., Tronei, M.B., and Vogel, C.C.: Phase II Study of mitomycin C and Velban in women with advanced breast cancer refractory to standard cytotoxic therapy. Cancer Treatment Reports 62:2113-2115, 1978.

109. Konitz, P.H., Ainer, J., Van Echo, D.A., Lichtenfeld, K., and Wiernik, P.H.: Mitomycin C and Velban in chemotherapy for advanced breast cancer. Cancer 48:1295-1298, 1981.

110. Di Costanzo, F., Gori, S., Tonato, M., Buzzi, F., Crino, L., Grignani, F., and Davia, S.: Vindesine and mitomycin C in chemotherapy refractory advanced breast cancer. Cancer 57:904- 907, 1986.

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TABLE 1: CORRECTED 10 YEAR SURVIVAL (PERCENTAGE) BY STAGE AND GRADE*

Stage Grade I Grade II Grade III

I 73 65 62

II 59 27 17

III 53 23 12

IV 11 3 4

22 *From Bloom, H.J.G. and Field, J.R.

TABLE 2: "CMF" COMBINATION REGIMENS USED IN THE TREATMENT OF METASTATIC BREAST CANCER •r— 2: -O Q 4-> CD 03 C 33 c_ 03 o c Z cl JO -i- >4- CH —' oc 01 4_- oh 0 ■0 •1— --—' •1— +-> ^ 21 00 O CO =3 03 E 4-> CD C_ c CD CL CO CD 0 a cr CD CO c Cl C_ CD 4-> ra CD ai O C/1 4-> (D c: CL XT O C/1 cr -—- C/I CD c 0 i~ CO > CD 03 E 13 xr > 03 OO -a a; <4- Z OH •1— 4-> 4-1 CJ CD O 01 CD C_ 33 >1 0! CD c CD E CD C 03 E c • O CO co CO O O 2Z CL 00 co U_ > r-H O O O O CL £_ CD 1 • CO CT1 CO O 1— 03 1— CT1 CO CO z: U_ LO CO CO 1-1 C\J O 03 CD CO C3 4-1 CD O • • • O 1— 03 1— r-- 0 CD cm cn c_> IE U_ CL co 01 0 r—1 CO + 03 CD C3 4-i CD 0 • co • O 1— 03 1— r-^ 'cr c-H 0 00 0 0 a_ co co 1—1 co O 2: Li_ 03 CD 0 . CO C3 4-1 CD • • 1— CM co O co <13- 00 LO LO CO 0- co t“H r—l LO CO z U- 0 CD C- 4-1 E CD 03 >>r- • • LO CL • i"» CO OH •r— LO CM > ■==t CM 0 z U_ 03 E £_ CD rsi 1 1 • r— 00 > CO CM LO 0 Cl z U_ 4-1 03 CD 1 1 • • 67

TABLE 3: COMPARISON OF SINGLE AGENT VERSUS COMBINATION REGIMENS USED IN THE TREATMENT OF ADVANCED BREAST CANCER •r- — T3 O •r- at O CO4-> -M CO at ro E c o;o L OVI ■o -- GO 4-> at O co at CO =3 ra Cl o cr at TO a> c a> c o > — > 03 =3 xr - ^ OO ■a Cl. OC 4- cc: 4—t -M co at aj c o o 33 >•> at t_ CD at o at at £_ at c IT3 CJ) at cr co r— O r— LO CT> o co cn cor~^ocrtc\jcm H COO'!LO^3- Q. U_ CsJ LO co lo CO _i <_> O') CM O *—H 03 OJ • OO CT) nr LO eC T3 • r- •r— >d-oto -t-> r— o r—H t—H oo o at O +J cn CO TO t_ . TO at c U t_ 03 E d >■ + • > LO O') o 2: Ll_ CL. i—H LO co • > ^3" c_> Cl. •X o OO s: Ll_ * r—H LO • T3 •r— o i— X3 u_ .o -o CM LO LO CO C" co o ■ r— O d CO d d a; u o o-s: o > CO CL. 03 at Cl E r— 4-> a; 03 • > r— LO -M OJt U_ Q- o OJ 03 • CM o U- > Cl. QC X3 O' o r— X3 U_ LO lo LO o X3 • i— -a LO CM CO 33 at c >> o o CL^ O > to CL 03 E at (- 4-> 03 OJ i • *r— ■X +J (J O O CO cr c: 33 33 * -X • r— •i— +j -M -LJ -M c at L_ E at C 68

TABLE 4: ADR IAMYCIN-CONTAINING COMBINATION REGIMENS AS FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED BREAST CANCER TO O •<- -- •l- a> Q to-*-> CD T3 E e oco T3 cz cs a__c: o 2T CL. JO <4- O' CC 4_> - T3 OO 4_> to CD o (/> 3 > "—• OO ■o QC Q_ QC 4-> 4-> +-> CD C_ O) c U CD CD 03 >3 r— o: CM tnCO00 E O T3 O • CD -M C_3 cC Ll- oo to C C_) r—H o o GO ,— O 4-> C (D TO • CD • 1— CD oo o to CO U- Lt_ C e£ to 00 to CO oo coo r-H CM to cm<—• t- 03 C 03 E • 3 i— • • O 1— oo 00 cd 00 r-^ C C_> CO c_ ro C E 3 • r— ^d 4-> r-H• co o Ll_ cC O

TABLE 5: COMPARISON OF ADRIAMYCIN (ADR IAMYCIN-CONTAINING COMBINATIONS) VERSUS "CMF" REGIMENS IN THE TREATMENT OF ADVANCED BREAST CANCER -o o □ W4-> +J CO O) LOW to E d aco 13 CLjd (O r- CD o d -O •<- ZZ Cl cc cc "O CO +J t_ d O co E cd Q_ o c at to '—- fl3 =3 JZ > ■- •p— to T3 4- OC DC Q_ 4-> -f-J 4-> CD >1 CD CD t_ d o cd a> 03 e d a * CD d 1— o 03 O (Ti in c~- t-—( «—IC\Ji—I CO CD • o > s; Lx. CL. ■K r— r— 03 00 C\J OO CO lo co O OO CO CO 0> < S Lx. Ll_ CO LO O LO to- O CO o =3 -|-J t— • CO • I—r— ■- • r- 03 LO CO 2: co oo co LO O CO JO LO ou i—t oo r-- lo TO 4-J E TO C- CD u_ TO" LD CO c_> JO 03 03 to- LO r-'- to-oo CO .3-LO > LO u_ a) 03 • LO oo o a_ u_ CO r— 1— TO 03 LO LO 03 TO" LO CO CO LO LO O CJ < s: Lx. u_ TO" E CD TO 4_) CD r— >1 • I > CL. C_3 -d 03 LO CO 03 —i O 03 o co o u_ CO 03 s: u_ £_ o CD CD r— +-> CD 03 • 03 LO CO O LO < LX. > a. oo to 3 co r— r'- o > s: Lx. Q. a) 03 •

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~~TABLE 10: COST OF EACH DRUG REGIMEN~~

~~ADRIAMYCIN AVM~~

~~Drug(s): Adriamycin~~

~~50 mg vial $144.44 $144.44 10 mg vial $ 31.39 $ 31.39~~

~~Vinblastine~~

~~10 mg vi al $ 22.89~~

~~Mitomycin C~~

~~20 mg vi al $208.88 4 mg vial $ 61.85~~

~~Administration Charges:~~

Cost per drug $ 10.00 $ 20.00/$30.00*

Infusion charge $ 60.00** $ 60.00**

* Amount was calculated as $30.00 in cycles when all three drugs were given (every eight weeks) and as $20.00 in cycles when only two drugs were given (every four weeks).

** Cost per cycle (same for both regimens)

~~TABLE 11: GENERAL CHARACTERISTICS OF PATIENTS WITH ADVANCED BREAST CANCER BY TREATMENT ARM~~

~~CHARACTERISTICS TREATMENT GROUPS A AVM~~

~~Number of Patients 28 29~~

~~Number of Evaluable Patients 26 28~~

~~Median Age in Years (Range) 52 ( 35-'74) 54 (29-•73)~~

~~Stage at Diagnosis I 3 1 II 4 8 III 10 5 IV 6 9 Unknown 3 5~~

~~Menopausal Status at Study Premanopausal 3 (12%) 7 (25%) Postmenopausal 23 (89%) 21 (75%)~~

~~Performance Status Ambulatory 0 5 11 20 20 1 15 9~~

~~Non-ambulatory 2 6 4 6 5 3 0 1~~

~~Unknown 0 3~~

~~Median Disease-Free Interval in Months (Range) 25 .6 (0*- 72) 22 (0*-72~~

* Patients presented with metastatic disease

~~TABLE 12: PRIOR TREATMENT OF PATIENTS WITH ADVANCED BREAST CANCER BY TREATMENT ARM~~

~~Treatment Modality Number of Patients A AVM~~

~~Mastectomy 22 19 Lumpectomy 2 4~~

Radiation Therapy Pri ma ry 1 5 Adjuvant 4 1 For Relapse 4 4*

~~Chemotherapy Adjuvant 12 13 For Relapse 15 14~~

~~Hormone Therapy Primary 1 0 Adjuvant 6 6 For Relapse 18 17~~

~~Oophorectomy Surgical 1 1 Radiation 2 1~~

* One patient received radiation therapy both as primary therapy and after relapse

~~TABLE 13: NUMBER OF PATIENTS WITH METASTATIC DISEASE AT INITIATION OF THERAPY (NUMBER OF SITES OF DISEASE)~~

~~Number of Sites of Disease Number of Patients (Percentages ) A AVM~~

~~0 0 0 5 (20) 7 (25) 1 5 7~~

~~2 14 6 18 (69) 17 (61) 3 4 11~~

~~4 0 2~~

~~5 1 3 (12) 1 4 (14)~~

~~6 2~~

~~TABLE 14: NUMBER OF PATIENTS WITH METASTATIC DISEASE AT INITIATION OF THERAPY (SITES INVOLVED)~~

~~Sites of Disease Number of Patients (Percentages) A AVM~~

~~Bone 19 (76) 20 (80)~~

~~Li ver 8 (32) 7 (28)~~

~~Lung 7 (28) 12 (48)~~

~~Nodes 6 (24) 6 (24)~~

~~Ski n 6 (20) 8 (32)~~

~~PIeura 3 (12) 6 (24)~~

~~Breast 3 (12) 4 (16)~~

~~CNS 1 ( 4) 0~~

~~Bone Marrow 1 ( 4) 1 ( 4)~~

~~All others* 8 7~~

~~Sites Include: chest wall, mediastinum, kidney, and subcutaneous mass.~~

~~TABLE 15: RESPONSE TO THERAPY~~

~~Number of Patients (Percentages) A AVM Total~~

~~Patients evaluable for response 26 28 54~~

~~Complete response 0 0 0~~

~~Partial response 4 (15)* 8 (29)* 12 (22)~~

~~No response 22 (85) 20 (71) 42 (78)~~

~~Stable disease 6 (27) 3 (15) 9 (21)~~

~~Progressive disease 16 (73) 17 (85) 33 (79)~~

~~p value based on comparing the difference in groups shown using the Chi Square test~~

~~TABLE 16: SURVIVAL~~

~~Median Survival p value* (months)~~

~~All Patients 8.41~~

~~Treatment groups: Adriamycin 7.56 .35 AVM 9.00~~

~~Response groups: Responders 20.40 .01 Non-responders 7.33~~

~~Disease Sites:** 1 9.66~~

~~2-3 7.59 .19~~

~~>3 5.82~~

~~Performance Status: Ambul atory 9.66 .06 Non-Ambulatory 6.87~~

~~Disease-Free Interval (months) 0-9 9.66~~

~~7-18 8.41 .89~~

~~>18 8.71~~

~~Stage: I 9.79~~

~~II 9.33 .05 III 6.38~~

~~IV 9.66~~

~~Menopausal Status:** Premenopausal 12.85 .12 Postmenopausal 7.56~~

* p value based on the difference comparing groups shown using the Mantel-Cox test ** at initiation of study

~~TABLE 17: TIME TO PROGRESSION~~

~~Median Time to Progression p value* (months)~~

~~All Patients 4.50~~

~~Treatment Groups: Adriamycin 3.84 .03 AVM 5.91~~

~~Response Groups: Responders 10.12 .003 Non-responders 3.22~~

~~Disease Sites:** 1 3.22~~

~~2-3 5.59 .70~~

~~>3 3.83~~

~~Performance Status: Ambulatory 3.84 .91 Non-ambul atory 5.91~~

~~Disease-free interval (months) 0-6 3.02~~

~~7-18 3.84 .42~~

~~>18 5.59~~

~~Stage: I 5.29~~

~~II 7.16 .02 III 2.83~~

~~IV 4.11~~

~~Menopausal Status:** Premenopausal 5.59 .99 Postmenopausal 4.50~~

* p values based on the difference comparing groups shown using the Mantel-Cox test ** at initiation of study

~~TABLE 18: NUMBER OF PATIENTS WITH METASTATIC DISEASE AT PROGRESSION (NUMBER OF SITES OF DISEASE)~~

~~Number of Sites of Disease Number of Patients (Percentages) A AVM~~

~~0 3 11 (44) 3 (6) 1 3~~

~~2 8 6 10 (40) 15 (60) 3 2 9~~

~~4 2~~

~~5 24 (16) 1 4 (16)~~

~~6 1 1~~

~~TABLE 19: NUMBER OF PATIENTS WITH METASTATIC DISEASE AT PROGRESSION (SITES INVOLVED)~~

~~Sites of Disease Number of Patients (Percentages) A AVM~~

~~Bone 13 (52) 16 (64)~~

~~Liver 8 (32) 5 (20)~~

~~Nodes 2 (8) 6 (24)~~

~~Lung 7 (28) 8 (32)~~

~~Skin 2 (8) 8 (32)~~

~~PIeura 3 (12) 6 (24)~~

~~Breast 2 (8) 3 (12)~~

~~CNS 1 (4) 1 (4)~~

~~Bone Marrow 1 (4) 2 (8)~~

~~All others* 6 6~~

~~Sites include: chest wall, mediastinum, node, and subcutaneous mass/nodules.~~

~~TABLE 20: TOXICITY~~

~~Type Adri amyci n Patients AVM Patients Patients Courses Patients Courses No. (%) No. (%) No. (%) No. {%)~~

~~Cardiac 0 0~~

Myelosuppression*

WBC/ul3 0-1000 1 ( 5) 1 ( 2) 5 (22) 11 (12) 1001-2000 11 (52) 16 (30) 12 (52) 29 (33) 2001-3000 6 (29) 22 (42) 3 (13) 33 (37) 3001-4000 2 (10) 6 (11) 1 ( 4) 5 ( 6) >4000 2 ( 5) 8 (15) 2 ( 9) 11 (12) 3 Platelet count/ul <20,000 0 0 0 0 20-50,000 2 (10) 2 ( 4) 1 ( 4) 3 ( 3) 50-75,000 0 0 3 (13) 4 ( 5) 75-100,000 3 (14) 3 ( 6) 4 (17) 5 ( 6) 100-150,000 8 (38) 13 (25) 3 (13) 13 (15) >150,000 8 (38) 34 (65) 12 (52) 64 (72)

* Blood count nadirs

~~1 0~~

~~0 t-1-1-r 10 20 30 40 Months to Last Seen~~

~~1 Survival for all patients after initiation of~~

~~1 0~~

~~0 40 Months to Last Seen~~

~~Survival for all patients according to treatment -Adriamycin; V-AVM).~~

~~Figure 3. Survivalforresponders (R)versus non-responders (N) after initiationoftreatment. Proportion Surviving 83~~

~~1 0~~

~~Months to Last Seen -e . Survival for all patients according to numbers of 3 o metastatic disease at initiation of treatment (L- 1 of disease; M- 2-3 sites of disease; H- > 3 sites of~~

~~00'~~

~~90'~~

~~80'~~

~~70'~~

~~60-~~

~~50-~~

~~40-~~

~~30-~~

~~20-~~

~~io-~~

~~Months to Last Seen are Survival for all patients according to perforaance at initiation of treatment (A-Ambulatory; N-Non-~~

~~t 90 S 4—$ & 80~~

~~55 44 70~~

~~4 i 60~~

~~50 2-~~

~~D 20 C-~~

~~1 0 5—5~~

~~0 T~ 41 0 10 20 30 40 Months to Last Seen Survival for all patients according to stage at s (1-Stage I; 2-Stage II; 3-Stage II; 4-Stage IV).~~

~~Figure 7. Survival for all patients according to disease- free interval at initiation of treatment (L- 0-6 months; M- 7-18 months; H- > 18 months).~~

~~Figure 8.Survival forallpatientsaccordingto menopausal menopausal). status at initiationof treatment (A-Postmenopausal; B-Pre- Proportion Surviving 93~~

~~.20~~

~~.10~~

~~Months to Progression gur 9. Time to disease progression for all patients at of treatment.~~

~~1.00~~

~~c o~~

~~o CL o v_ Q_~~

~~Months to Progression~~

~~Figure 10. Time to disease progression for all patient according to treatment group ( c-o Adriamycin; AVM).~~

~~.10~~

~~0 0 10 15 20~~

~~Months to Progression ur e 11. Time to disease progression for responders (R) non-responders (N).~~

~~Months to Progression~~

~~>ur 12. Time to disease progression for all patients :or to numbers of sites of metastatic disease at Lti of treatment (L- 1 site of disease; M- 2-3 sites ; > 3 sites of disease).~~

~~according toperformance statusatinitiationof treatment Figure 13.Time todiseaseprogressionfor all patients (A-Ambulatory; N-Non-ambulatory). Proportion Surviving Months toProgression 98~~

~~1 00~~

~~60'~~

~~.50'~~

~~40'~~

~~30'~~

~~.20-~~

~~.10'~~

~~Months to Progression sure 14. Time to disease progression for all patients ng to disease-free interval at initiation of (L- 0-6 months; M- 7-18 months; H > 18 months).~~

~~100~~

~~I 00 '1-542~~

~~'LEI 90 4- 2r2 80~~

~~S 4 .70 22~~

~~60 >~~

~~.50~~

~~.40 s 4~~

~~30 X-4 55 2-2~~

~~.20 5'~~

~~.10 5-5~~

~~0 I i_i 0 1 0 1 5 20 Months to Progression ur e 15. Time to disease progression for all patients ng to stage at diagnosis (1- Stage; 2-Stage II; III; 4-Stage IV).~~

~~101~~

~~1 00~~

~~.30~~

~~.10~~

~~Months to Progression Time to disease progression for all patients menopausal status (A-Postmenopausal; B-Pre-~~

~~(28) ^ (19) (15) (27) 3S0Q “U3QIJ2JLN33H3d~~

Figure 17. Comparison of percent optimal dose of Adriamycin (mean/cycle) administered to patients treated with Adraimycin as a single agent (60 mg/m IV day 1 every 3 weeks) or AVM combination (Adriamycin dose- 30 mg/m IV day 1 every 4 weeks). Numbers in parenthesis indicate total number of

~~patients included per course of treatment. 102~~

103 istered to patients treated with the AVM combination (vinblastine dose- Figure 18. Percent of optimal dose vinblastine (mean/ cycle) admin¬ number of patients included per course treatment. 6 mg/m IV on day 1 every 4 weeks). Numbers in parenthesis indicate total

~~(28)~~

Figure 19. Percent of optimal dose of mitomycin C (mean/cycle) admin¬ istered to patients treated with the AVM combination (mitomycin C dose- 10 mg/m IV on day 1 every 8 weeks). Numbers in parenthesis indicate total number of patients included per course of treatment. 104

~~10b~~

~~<4-4 CD O 4_> TO 4-1 CJ C -H O "C u c~~

CD G. C/3 c 4> co CO & Z3 CO ^ G G CD C CD 4-> I W CC .G I Q) E4j EGO <4 ? QJ • CC 4-J G V ^ c g 4> r- (D CD O / OO U y ro / ~ CO 4-1 CD 0) IT) 03 t-H C- f = r-4 CC I CD CD I ^ 4-) -H CD — & CO CC -c /, ♦ w2 1-4 G G. CO i-4 U 44 CJ C CO o ro -h <3' w c cc C -f-4 4-1 O CJ c V 3 CSJ CC >i (D \ w •H E *r4 \ G CO 4-1 ro -h ro 0*0- G. G G. V 3 E XT O ■< <44 o o <4-4 i O G CD 8 8 9 8 (D -G o CC E CN O G 3SOO TH3QI JO lN33*Gd JO *01 X iNHOO 13T31tnd •G C CD G r—4 r—4 g ro ro CC CD 4-1 -h -a o Iju *H 4-J

~~106~~

J-1---I—_J_ -1, ■■■,.I____L___L 8 8 8 9 8 3S0O TU30I & lN33H3d -•<> X 1NH0O JL3T3JUTW ideal dose of Adriamycin, vinblastine, and mitomycin C in AVM combination. three drugs) included per course of treatment. Numbers in parenthesis indicate total number of patients (average for all Figure 21. Comparison of platelet count (.mean/cycle) versus percent

~~107~~

~~+ e~~

4 U I I L L 1-I J—J J-1-i-J L—I-I l-L m o in o *01 X 1NTO3 ODD'S 3IIHM diamonds indicate mean WBC/cycle (day 1); pluses range. Figure 22. Comparison of white blood count (mean/cycle) at administration of adriamycin as a single agent versus AVM combination. Circles and

~~u YALE MEDICAL LIBRARY~~

~~3 9002 01012 9006~~

~~YALE MEDICAL UBSATtfi YALE MEDICAL LIBRARY~~

~~Manuscript Theses~~

Unpublished theses submitted for the Master's and Doctor's degrees and deposited in the Yale Medical. Library are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but passages must not be copied without permission of the authors, and without proper credit being given in subsequent written or published work.

~~This thesis by has been used by the following persons, whose signatures attest their acceptance of the above restrictions.~~

~~NAME AND ADDRESS DATE~~