Improved survival with combined modality treatment for stage IV breast cancer

0360-3016/79/081317-05$02.00/O

In?. J. Rudiution Oncology Eiol. Phjx,, Vol. 5, pp. 1317-1321 o Pergamon Press Ltd., 1979. Printed m the U.S.A.

??Adriamycin

IMPROVED

SURVIVAL

CARLO FRANCESCO

Department

WITH COMBINED MODALITY STAGE IV BREAST CANCbR

NERVI

M.D., t

CONCOLINO

of Oncology,

GIORGIO

M.D.,

ARCANGELI

MASSIMO

Istituto Medico Scientifico,

TREATMENT

FOR

M.D.,

CORTESE

M.D.

Roma 00191, Italy

Between November 1974 and March 1977, 85 patients with breast cancer at first postmastectomy relapse were irradiated (Radiation 3500-6000 rad-3/S weeks) to all clinically evident lesions. Radiation fields were properly shaped to include a maximum 40% active bone marrow. After 3-4 weeks rest, chemotherapy was started as adjuvant therapy for residual or subclinical disease (ADR 30 mg/M’ Day 1 and 8, 5-FU 408 mg/M’ Day 1 and 8, CY 100 mg/M* Day 1 through 14: repeated after 14 days). ADR was discontinued at 500/M’ and substituted by MTX 30 mg/M2 Day 1 and 8 for a total of 2 years. Irradiated sites were chest wall in 35, supraclavicular and internal mammary nodes in 22, bone in 56, single lung lesions in 12, brain in 24. Controls were 52 comparable but non-randomized patients treated with chemotherapy only. Forty days after x-irradiation 68 patients (80%) were free of disease (NED) while in 17 cases (20%) some residual was still present (RED). In 28 of 68 cases (41%) NED after x-irradiation and 13 of 17 (76%) in RED group developed second relapse after a median interval of 26 and 20 mos, respectively. Four of 52 patients (8%) in the control group had complete regression with a median interval to second relapse of 7 mos. Median survival was 30 mos., 24 mos. and 13 mos., respectively, for NED, RED and chemotherapy only. Eighteen patients (26%) are free of disease after 36-48 mos. in the combined modality group; none in the chemotherapy group. Combined treatment cases did not show untolerable mylodepression: in 41 patients (60%) the average chemotherapy dose had to be reduced during the first 4-5 cycles because of marrow depression. In 10 long-surviving patients a marked subcutaneous and skin fibrosis developed because of drug additive .effect. Stage IV breast cancers rendered clinically free of disease with x-irradiation and subsequently treated with chemotherapy survive significantly longer than with chemotherapy alone. Advanced breast cancer, Combined irradiation Chemotherapy-radiotherapy interactions

and chemotherapy,

INTRODUCTION

Late skin effects,

using irradiation to treat all clinically recognizable diseases, and administering chemotherapy thereafter, with the aim of controlling micrometastases. Chemotherapy is therefore conceived as an adjuvant treatment to control subclinical disease.” The aim of the study was to determine whether: (1) there would be a difference in the duration of response in patients where tumor cell burden was reduced by means of irradiation; (2) the toxicity of such a regimen would be acceptable; (3) chemotherapy could be used adjuvantly even in patients with metastatic breast cancer.

The

use of combined chemotherapy in advanced breast cancer has shown that, despite the fact that tumor shrinkage can be achieved in 50-70% of cases, complete regression is rarely seen and survival prolongation is short-the response median duration between 5 and 9 months.” The reason the limited efficacy of chemotherapy may be due to particular anatomical involvement and/or tumor volume. For example, while a 50-70% regression can be obtained in soft tissues and visceral metastases, the response averages 3&40% when bone, brain, or liver are involved.z Furthermore, regression after chemotherapy is probably a function of tumor cell numbers; and resistance occurs more frequently in large bulky tumors, as tested in the animal mode1.4 On these premises, a multimodality treatment program was started on Stage IV breast carcinoma,

METHODS AND MATERIALS Between November 1974 and March 1977, 137 women with clinical and/or biopsy proven evidence of first post-mastectomy relapse were admitted to the study. Eligibility criteria included: no prior expo-

tReprint requests to: Carlo Nervi M. D., Head Dept. of Oncology, Istituto Medico Scientifico, Clinica Villa Flaminia, Via Bodio 58 - 00191 Rome, Italy 1317

1318

sure therapy

Radiation Oncology 0 Biology 0 Physics

to

chemotherapy, radiotherapy (surgical or medical) in the

or hormone previous four

weeks. The diagnostic evaluation consisted of a history, physical examination; CBC; urinalysis; EKG; blood chemistry profile; a complete bone radiological survey; liver, brain and bone scan; and, more recently, computerized axial tomography. Bone marrow examinations were performed in the posterior iliac crest in all cases where blood cell counts were abnormal. In 85 cases, radiation therapy was administered to all clinically evident metastases by means of a Cobalt 60 unit. (Of these 85 patients, 67 were randomly assigned to the combined therapy group. When the effectiveness of combined therapy was recognized, the remaining 18 were included.) The treatment field was limited to the measurable disease and was properly ‘shaped in order to include a maximum 40% normal bone marrow as calculated following Woodward and Holodny.7 The total tumor dose ranged from 3500 to 6000 rad, at 200-250 rad daily dose, 1000-1250 rad per week. The maximum skin dose never exceeded 5500 rad in 5 weeks. In cases with single or multiple cerebra1 metastases, the whole brain was treated with two opposite fields, with a midplane daily dose of 200 rad, to a total 4600 rad/4-5 weeks. Lung metastases were treated separately or, when possible, in couples. Pleural metastases were not considered suitable for x-irradiation. Three to four weeks later, a second complete diagnostic survey to evaluate the response was carried out, and chemotherapy was started. Each course consisted of a cyclical monthly therapy (CAF) with an intravenous bolus of Adriamycin (ADR) 30 followed by an intravenous mg/M2, immediately bolus of 5-fluorouracil (5-FU) 400 mg/M2 on Days 1 and 8, and cyclophosphamide (CY) 100 mg/M2 P.O. from Day 1 through 14. The courses were repeated every 28 days, but provisions were made for a delay up to 2-3 weeks between cycles for low WBC (<2000/mm3) or platelet counts (<7000/mm3) at the end of 4 weeks. The doses of CAF were reduced by 30% if: (1) there was bone marrow involvement as proven by the presence of clumps or clusters of malignant cells in the marrow material; (2) the prechemotherapy WCB counts were between 3000 and 4500/mm3 and platelet counts were between 75.000 and 130.000/mm3; (3) patients had a serum bilirubin concentration greater than 12 mg/ml due to hepatic disease. Total dose of ADR was limited to 500 mgim’ when patients were switched to methotrexate (MTX) 30 mg/m2 given intravenously (CMF). The total duration of CAF + CMF was 2 years. Fifty-two other cases admitted during the same period (with the same eligibility criteria) were treated with CAF

August 1979, Volume 5, Number 8

Table

I. Combined

treatment of stage IV breast cancer Patient characteristics X-irradiation+CAFt

No. of patients Age (range) Premenopausal Postmenopausal Disease free interval (months) tCAF=cyclical

Table

CAF

85 52 years (28-71) 30% 70%

52 51 years (30-72) 33% 67%

16 (o-130)

15 (O-l 10)

monthly therapy

2. Combined treatment of stage IV breast Metastatic sites and response to treatment

Sites

X-irradiation+CAFi No. patients (%) %CR

Skin Soft tissues Lymph nodes Bone Lung Pleura Liver Brain tCAF=cyclical

35 (41) 100 lO(11) 90 22 (25) 100 56 (66) 90 12 (14) 75 9 (10) 3 (3) 24 (28) 75

cancer

CAF No. patients (%) %CR 18 (35) 22 9 (18) 11 10 (20) 10 39 (75) 5 12 (23) 16 5 (10) 40 6 (12) 10 (20) -

monthly therapy.

and/or CMF regimen only. Duration of remission was calculated initiation of irradiation for the combined group, and of chemotherapy for the other the time of relapse or 31 March 1977 when was completed.

from the modality cases, to the study

RESULTS Pre-treatment characteristics (Table 1) and distribution of metastases were comparable in both groups of patients (Table 2). Four weeks after x-irradiation , 68185 (80%) submitted to combined treatment had a complete regression of the irradiated lesion (NED), while in 17 cases only partial regression was obtained (RED). The duration of remission is shown in Fig. 1 (43/68 patients in the NED group have relapsed with a median duration of 26 mos.; 15117 of the RED group have relapsed with a median duration of 20 mos.) In 32 of 52 patients (62%) treated with CAF only, a regression of disease was observed. In 8% (4 patients) complete and in 54% (28 patients) partial response was noted. The median time to PR and CR was 2, 5 and 4 months, respectively.

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Combined Modality Treatment 0 NERVI et al.

52

pts

MONTHS

FIG. 1. Duration of remission in patients with Stage IV breast cancer treated with irradiation (XRT) followed by chemotherapy and with chemotherapy alone. CAF is cyclical monthly therapy: RED, partial remission; NED, no evidence of disease.

All 52 patients treated with CAF only relapsed with a median duration of 7 mos. The complete rein this group showed a median remission sponders interval of 10 months. The most important effect of combined treatment was prolongation of survival (Fig. 2). The median survival of patients classificed as NED at the end of radiotherapy has been 30 mos. Fifteen patients are alive with no evidence of disease after 36-48 months from the beginning of treatment. The median survival of the RED group was 24 months (2 patients alive and free of disease after 37 and 41 mos., respectively). In the CAF group, the median survival for all patients was 13 mos., and was dependent upon the response of chemotherapy: only 25 weeks for non-responders, 12 mos. for partial responders,

and 15 mos. for complete responders. The median survival is statistically different (p=
MONTHS

FIG. 2. Survival of patients with Stage IV breast cancer treated ation (XRT) followed by chemotherapy and with chemotherapy is cyclical monthly therapy; RED, partial remission; NED, no disease. With XRT+CAF, 48 of 85 patients are dead after patients are alive and NED after 36-48 mos. With CAF, all 52 dead.

with irradialone. CAF evidence of 30 mos; 18 patients are

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Table

Radiation Oncology 0 Biology 0 Physics

3. Combined

Toxicity

treatment Treatment

of stage IV breast toxicity

X-irradiation+CAFt No. patients (%)

cancer

CAF No. patients (%)

Leukopenia (<25OO/mmc)

35 (41)

15 (29)

Thrombocytopenia (<75OOO/mmc)

12 (14)

4 (8)

Nausea or Vomiting

80 (95)

47 (90)

Diarrhea

6 (7)

3 (5)

Stomatitis

5 (6)

4 (5)

Alopecia

75 (88)

48 (93)

8 (9) 2 (2)

6 (11) -

Clinical sepsis Cardiotoxicity Skin fibrosis Esophagitis tCAF=cyclical

10 (12) 12 (14)

August 1979, Volume 5, Number 8

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FIG. 3. Late skin fibrosis in patient who underwent combined treatment with metastases in the spine. Total skin dose was 5500 rad in five weeks.

monthly therapy.

DISCUSSION An aggressive disease such as metastatic breast cancer may respond temporarily to a number of chemotherapeutic agents. Unfortunately, even in responders, progression of disease occurs after 5-8 months because of the development of resistance. The particular vascularization of the metastatic site (and consequently the low local concentration of the drug) may explain the low regression rate observed in bone or brain metastases, whereas in other visceral areas with sufficient blood supply the regression rate is almost twice as much. The size of the metastatic deposit can also be a cause of resistance. A major advance in cancer chemotherapy is based on the concept of tumor cell fraction killed by each therapy cycle, from which the logic of “reducing” the initial tumor cell number can be derived. This concept has led to the development of adjuvant chemotherapy, in which the treatment is directed to the subclinical disease, i.e., to likely micrometastases in high-risk patients. In breast cancer, the strategy of treating the minimal disease as in post-surgery high-risk cases, has resulted in prolonging the disease-free interval.’ Location and size of metastases are limiting factors even for ionizing radiation. Breast cancer is considered a “radiosensi-

tive” tumor since two-thirds of metastases disappear after a sufficient radiation dose. Unfortunately, the bone marrow is the critical organ sensitive to cytotoxic drugs and irradiation. From other clinical protocols with combined radiotherapy and chemotherapy it can be estimated that irradiation of a maximum 40% bone marrow usually does not promote major complications. For this reason, in our cases, the irradiation fields were shaped in order never to exceed that value. The hematological toxicity observed in the combined therapy group was therefore acceptable (even if slightly higher than in patients treated with chemotherapy alone). An expected side effect of combined therapy was the enhanced subcutaneous radiation fibrosis due to the additive effect of chemotherapy.” Such a complication can be overcome, by employing higher energy radiations or rotation techniques in order to limit skin dose to a maximum of 5500 rad. The strategy of irradiating all clinically recognizable lesions and then treating with chemotherapy the subclinical disease, has caused a significant prolongation in the survival of patients with advanced breast cancer. Eighteen patients are alive and free of disease after a minimum of 3 years. It would seem reasonable to extend this combined therapy to other types of cancer in which sensitivity to cytotoxic drugs is limited in time.

Combined Modality Treatment

0 NERVIet al.

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4. Martin, D. S., Fugmann, R. A., Stolfi, R. L., Haywort, P. E.: Solid tumor animal model therapeutically predictive for human breast cancer. Cancer chemotherapy Rept. 5: W-109, 1975. 5. Phillips, T. L., Fu, K. K.: The interaction of drug and radiation effects on normal tissues. Int. J. Radial. Oncology Biol., Phys. 4: 59-64, 1978. 6. Schabel, F. M.: Rationale for adjuvant chemotherapy. Cancer 39: 2875-2882, 1977. H. A., Holodny, E.: A summary of the 7. Woodward,

data of Mechanik in the distribution of human marrow. Phys. Med. Biol. 5: 57-59, 1960.

bone