PII S0360-3016(98)00015-7

● Clinical Investigation

LONG-TERM FOLLOW-UP OF A RANDOMIZED TRIAL ON ADJUVANTCHEMOTHERAPY AND HORMONAL THERAPY IN LOCALLY

ADVANCED BREAST CANCER

CARO KONING, M.D., PH.D.* AND GUUS HART, M.SC.†

*Radiotherapy Department, Westeinde Hospital, Lijnbaan, The Hague, The Netherlands;†The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Purpose: To study the effects on survival, disease-free survival, and locoregional control of adjuvant hormonaland chemotherapy in patients with locally advanced breast cancer after a minimal follow-up period of 14 years.Methods and Materials: A total of 118 patients were randomized between radiotherapy alone (arm I); radio-therapy, 12 courses of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and tamoxifen (arm II);adriamycine, vincristine (AV) alternated with CMF, then radiotherapy, followed by four cycles of chemotherapy(AV/CMF); and tamoxifen during the entire treatment period (arm III).Results: No improvement in survival, disease-free survival, or locoregional control was observed. After 6 yearsof follow-up, the overall survival curves grew apart, resulting in differences in 10-year survival rates: 15%(confidence interval—3%, 33%) between arms III and I.Conclusion: Owing to the relatively small numbers of patients involved, the relative value of the three treatmentmodalities cannot be established completely. © 1998 Elsevier Science Inc.

Locally advanced breast cancer, Adjuvant therapy, Long-term follow-up.

INTRODUCTION

Patients with locally advanced breast cancer T4,N0-2,M0 orT1–3,M0 in whom biopsy of the infraclavicular lymph nodeshows tumor (1) have a poor prognosis.

Locally advanced breast cancer is composed of the fol-lowing situations: diffuse carcinoma of the breast, extensiveskin infiltration, edema of the skin involving more than onethird of the breast surface, fixed axillary lymph nodes, or theidentification of tumor cells in the biopsy specimen of theinfraclavicular lymph nodes.

Two aspects are extremely important during the course ofthe disease:

1. The clinical manifestation of distant metastasis. Metas-tases are present subclinically in a large majority ofpatients at diagnosis of breast cancer. The prognosisdepends mainly on these metastases.

2. The need to achieve locoregional tumorcontrol duringthe rest of the patient’s life. If tumor control cannot beeffected, it is important to strive for a situation in whichthe local tumor burden causes as few problems as pos-sible.

Both of these aspects have been the subject of extensiveresearch which has not led to substantial progress.

In 1977, in The Netherlands Cancer Institute (NKI), aprospective randomized trial was started to assess the ef-

fects of adjuvant chemotherapy and hormonal therapy onsurvival, disease-free survival, and locoregional recurrencerate in patients with inoperable locoregional breast cancerwithout clinical signs of distant metastases at the moment ofdiagnosis and staging. After a minimal follow-up period of14 years, the most important findings in this study werereanalyzed and are presented here, 10 years after the firstresults were published (2).

Especially in breast cancer, long-term follow-up is re-quired for clinical trials to detect changes in treatmentoutcome, as many events occur later than 5 years after theintervention. A recent update of European Organization forResearch and Treatment of Cancer (EORTC) Trial 10792revealed that adjuvant hormonal therapy improved survivalin postmenopausal patients with locally advanced breastcancer (3).

The aim of the current study was to find out if the recentdata would yield new conclusions about possible gain insurvival due to the adjuvant strategies.

METHODS AND MATERIALS

From July 1977 to December 1980, 118 patients under 65years of age with histologically or cytologically confirmedlocally advanced carcinoma of the breast, without signs ofdistant disease, were entered into the trial. Originally, a

Reprint requests to: Dr. C. Koning, Radiotherapy Department,Westeinde Hospital, Lijnbaan 32, 2501 CK The Hague, The Neth-

erlands.Accepted for publication 31 December 1997.

Int. J. Radiation Oncology Biol. Phys., Vol. 41, No. 2, pp. 397–400, 1998Copyright © 1998 Elsevier Science Inc.Printed in the USA. All rights reserved

0360-3016/98 $19.001 .00

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patient intake of 120 patients was planned. As the EORTCadopted the basic philosophy of the NKI study in 1979, wedecided to close our study and take part in EORTC trial10792 as soon as possible.

Patients with inflammatory breast cancer were includedin the study as long as radiotherapy was not limited bytechnical factors, such as too-large field sizes.

In our institute, a medial axillary apex biopsy is per-formed on all patients who present with operable disease(4). A lymph node metastasis in this infraclavicular regionis considered to be a sign of locoregional advanced disease,and therefore an indication for radiotherapy rather thansurgery. For this patient group, 5- and 10-year survival rateswere found to be similar to the rates of the T3b-4 patients.A recent analysis confirmed this strong prognostic factor,independent of clinical node and tumor status (5). Patientswith supraclavicular metastases were excluded from thestudy. Prerandomization screening consisted of routine he-matological and biochemical blood tests, bilateral mam-mography, a chest X ray, and bone scintigraphy. Any sus-picion of metastases was investigated more precisely. Inparticular, hot spots on the bone scintigraphy were exam-ined by X ray, and if possible, histology or cytology wasobtained.

To date, the follow-up period for all patients is at least 14years. Four patients were ineligible because of either adifferent histology after review, clinical evidence of lesionsin the stomach that could not be proven histologically to bemalignant at the time of randomization, heterolateral breastcancer, or a tumor-positive supraclavicular lymph node. Thefour ineligible patients were included in the analysis. Thepatients were randomized according to a simple randomiza-tion procedure without stratification to one of the followingthree treatment schedules:

1. Arm I, RT: megavoltage radiotherapy. The breast wasirradiated by two opposing tangential fields with com-pensating wedges. The 40-Gy tumor dose was calculatedon the 90% isodose line and was given in 20 fractionsover 4 weeks, 5 fractions/week. The retrosternal nodeswere treated with one anterior field and the axilla andsupraclavicular nodes with a laterally angled anteriorfield; the dose was calculated at a depth of 2 cm, whereasa small posterior field was applied to effectuate an ade-quate midline dose in the axilla. Bolused fields were usedduring the second week, and in case of inflammatorydisease, during the fourth week as well. A booster doseof 14–20 Gy, 2 Gy/fraction, to the originally palpabletumor masses followed.

2. Arm II, RT 1 CT: Radiotherapy as in arm I, followed by12 4-weekly courses of CMF: cyclophosphamide 100mg/m2, orally, days 1–14; methotrexate 40 mg/m2, in-travenously (i.v.), days 1 and 8; 5-fluorouracil 600 mg/m2, i.v., days 1 and 8; and tamoxifen 30 mg daily duringthe treatment period.

3. Arm III, CT 1 RT 1 CT: Two cycles at 4-week intervalsof adriamycin 60 mg/m2, i.v., day 1; vincristin 1.4 mg/m2, i.v., day 1 (AV), alternating with two cycles of CMF

at 4-week intervals. Then RT as under arm I, total dose40 Gy, no booster and without bolus, followed by an-other four cycles of AV, alternating with four cycles ofCMF; and 30 mg tamoxifen daily during the entiretreatment period.

During the first year, patients were examined monthly,and thereafter at intervals of 3 months.

Forty-five patients were randomized in arm I, 34 patientsin arm II, and 39 in arm III. Thirty-five patients had a T4tumor, 12 in arm I, 11 in arm II, and 12 in arm III; 10 ofthem had a tumor-positive apex biopsy, although this wasnot routinely performed on T4 patients. The other 82 pa-tients had a T1–3 tumor with a tumor-positive infraclavic-ular lymph node biopsy. There were eight T1 patients, 35T2 patients, and 32 T3 and 7 Tx patients equally dividedover the three treatment arms, with the exception of six ofthe eight T1 patients who were treated according to arm I.(One patient had a tumor-positive supraclavicular lymphnode.)

A total of 58 patients were premenopausal: 17 in arm I,17 in arm II, and 24 in arm III; 55 patients were postmeno-pausal: 26 in arm I, 15 in arm II, and 14 in arm III; and fivepatients were uncertain.

These tumor and patient characteristics did not differsignificantly over the three treatment modalities (x2 test).

Tumor response was assessed with palpation according toWorld Health Organization criteria on day 1 of each che-motherapy cycle, before and monthly after radiotherapy,and at 3-month intervals after the first year. During the first5 years of follow-up, mammography and chest X ray wereperformed once a year; bone scans were done only yearlyfor the first 3 years, and thereafter if indicated.

In general, patients in arm I who relapsed received thesame systemic hormonal and cytotoxic therapies as patientsin arms II and III. At further progression, all patients wereconsidered for further palliative treatment such as otherendocrine therapy or other chemotherapy—for example,mitomycin C and vindesine.

Local recurrence, defined as tumor in the irradiated areas,was—if possible—treated with surgery and/or systemictreatment.

For statistical analysis of contingency tables, the chi-square test and a trend test were used. For analysis ofsurvival curves, the Kaplan–Meier method was used; the logrank test was performed to test differences between thecurves, and a trend test when the categories of the variablesunder study had a natural order.

It should be realized that the study design was quiterevolutionary at the time of perception and that single-center study requirements were less sophisticated than theyare currently.

RESULTS

Survival curves were almost identical for the first 6 years.Thereafter, they showed some differences: The 5- and 10-year survival rates were, respectively, 38% and 13% for arm

398 I. J. Radiation Oncology● Biology ● Physics Volume 41, Number 2, 1998

I, 35% and 21% for arm II, and 41% and 28% for arm III(Fig. 1). Differences for the 10-year survival data were 8%(confidence interval (CI)29%, 25%) between arms I and II,and 15% (CI23%, 33%) for arms I and III. Thep value ofthe log rank test comparing the curves over the entire timeinterval was 0.38.

The 5- and 10-year disease-free survival rates were,respectively, 11% and 4% for arm I, 21% and 15% forarm II, and 23% and 15% for arm III (Fig. 2). Thedifferences between these curves for the 10-year disease-free survival percentages were 12% (CI21%, 25%)between arms I and II and 12% (CI21.4%, 25.4%)between arms I and III. Thep value of the log rank testcomparing the entire curves was 0.26.

Local recurrence was observed in 19 of the 45 patients inarm I (42%), 15 of the 34 patients in arm II (45%), and 19of the 39 patients in arm III (49%).

Distant disease was seen in 42 of the 45 patients (93%)treated with radiotherapy only (arm I), in 28 of the 34patients (82%) who were adjuvantly treated with CMF andtamoxifen (arm II), and in 29 of the 39 patients (75%)treated adjuvantly with cyclic alternating chemotherapy andtamoxifen (arm III).

The first sign of recurrent disease in patients in arm I waslocal in 12 patients, 22 patients had distant metastases, andin nine patients local and distant recurrence occurred within3 months of each other.

For arm II, 10 patients had locoregional tumor as the firstsign of treatment failure; 13 patients had distant disease; and

in seven, both local and distant disease occurred within 3months of each other. For arm III, these figures were 14, 10,and 9 patients, respectively. Regarding the type of firstrecurrence, there were no statistically significant differencesbetween the armsp 5 0.4 (x2 test).

At the time of the current analysis, of all 118 patients, 14were alive, 10 without any signs of tumor activity. Fourpatients experienced locoregional recurrence and/or distantmetastases, but not all had symptoms or active disease atlast follow-up.

DISCUSSION

The present study was the first Phase III trial to evaluatethe effects of adjuvant chemotherapy and hormonal therapyon survival and disease-free and locoregional recurrence-free survival in patients with inoperable, clinically not-metastasized breast cancer. Three strategies of systemicadjuvant treatment were included in the study: tamoxifen,conventional adjuvant chemotherapy, and the use of alter-nating chemotherapy to overcome multidrug resistance. De-spite these adjuvant treatments, the final results at 14 yearsconfirmed the earlier findings at 4 years: There were nostatistically significant differences in the overall survivalrates. However, the large confidence intervals do not ex-clude a clinically relevant advantage for adjuvant therapy at10 years.

Our findings are in agreement with the early and lateresults of EORTC study 10792, which investigated breastcancer patients with the same characteristics (6). There weremore patients in the EORTC study; yet, there was noimprovement in overall survival after a minimal follow-upperiod of 3 years. In that study, the adjuvant interventionconsisted of hormonal therapy, CMF chemotherapy, or acombination of the two. Analysis at 8 years showed animprovement in survival for postmenopausal patientstreated with tamoxifen (3, 7). Chemotherapy improved dis-ease-free survival for the treated group, but overall, 5- and10-year survival curves were not altered. Two other studiesfailed to show survival advantage for adjuvant CMF inlocally advanced Stage III breast cancer patients (8, 9).

A Finnish study reported on postoperative radiotherapy,chemotherapy, both modalities, and immunotherapy inStage III breast cancer. The conclusion was that the com-bined modality treatment provided the best survival resultsand that levamisole increased survival rates in all threearms. This study design differed from the present study, asa postoperative local approach was compared against gen-eral adjuvant chemotherapy (10).

The results regarding tamoxifen in the EORTC studycould not be verified in the present study, because patientsin our study always received tamoxifen in combination withchemotherapy (arms II and III). Also, patient numbers pre-clude analysis according to menopausal status in our study.The positive effect of tamoxifen as found in the EORTCstudy for postmenopausal patients accords with the findingsof the meta-analysis of the Early Breast Cancer TrialistsCollaborative Groups (11). Subgroup analysis of the rela-

Fig. 1. Overall survival of arm I (RT), arm II (RT1 CT 1 H), andarm III (CT 1 RT 1 CT 1 H); p log rank test: 0.38.

Fig. 2. Disease-free survival of arm I (RT), arm II (RT1 CT 1 H),and arm III (CT1 RT 1 CT 1 H); p log rank test: 0.26.

399Adjuvant chemotherapy and hormonal therapy in breast cancer● C. KONING AND G. HART

tively small percentage of patients with advanced locore-gional breast cancer in the meta-analysis study was notperformed.

The side effects of adjuvant tamoxifen are considered tobe mild compared to those caused by adjuvant chemother-apy. This favors tamoxifen as first choice adjuvant treatmentin postmenopausal women with T4,N0-2,M0 and T1–3,M0,with tumor-positive infraclavicular lymph node biopsybreast cancer.

The local recurrence rate of the present study varied from42% (arm I) to 49% (arm III), and seemed not to beinfluenced by the adjuvant treatment. Nowadays, the radio-therapy doses for arm III in particular must be consideredtoo low. In 1977, this choice was made owing to theobservation of recall phenomena in the irradiated skin fol-lowed by severe fibrosis after the application of adriamycin-containing chemotherapy during a pilot study which pre-ceded this randomized trial. The local control rate of theentire patient group was the same as the results reported byBorgeret al. (12).

During the period 1985–1995, two studies of adjuvanttreatment with high-dose chemotherapy were conducted inthis patient group (13, 14). These studies looked at the roleof high-dose chemotherapy with peripheral blood stem-cellsupport in patients with chemosensitive, operable breastcancer with a tumor-positive axillary apex biopsy (15).Follow-up was short (median 31 months), but so far there

has been no survival advantage to high-dose treatment. Theside effects of intensive treatment must be weighed againstthe probability of improvement in survival. It is unclearwhere the balance lies for a treatment which may bringadvantages to a few, but toxicity without benefit to themajority of patients who can also receive the chemotherapyonly when they develop disseminated disease.

In this respect, tamoxifen is the optimal adjuvant treat-ment for postmenopausal patients presenting with locallyadvanced disease.

CONCLUSION

After a minimal follow-up of 14 years, improvement insurvival was not observed for adjuvant hormonal and che-motherapy in patients with locally advanced breast cancer.The same conclusion was reached by three other studies, inwhich more patients were enrolled than in the present study,with the exception of hormonal treatment in postmeno-pausal patients. A possible small positive effect for adjuvanttreatment in subgroups cannot be excluded, but has not beenproven owing to the relatively small numbers of patientsinvolved. If there is any advantage to adjuvant therapy, thismust be balanced against the acute and late treatment-related toxicity in the majority of patients who will notprofit at all.

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