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A Prospective Study of Concurrent Cyclophosphamide/Methotrexate/5- Fluorouracil and Reduced-Dose Radiotherapy in Patients With Early- Stage Breast Carcinoma

Posted on: Friday, 22 October 2004, 03:00 CDT

Objective:

To investigate the efficacy and toxicity of concurrent cyclophosphamide/methotrexate/5-fluorouracil (CMF) and reduced-dose radiotherapy in early stage breast cancer.

Introduction:

Concurrent treatment with chemotherapy and radiation offers potential advantages over sequential treatment scheduling for patients with early stage breast cancer. In addition to shortening treatment time, concurrent systemic therapy may enhance the effects of radiotherapy on tumor control. This paper is the final report of a phase II study testing the efficacy and toxicity of concurrent CMF and breast radiation for breast cancer patients with early stage disease.

Methods:

* Prospective study of 112 women, median follow up of 94 months.

* All patients had pathologic stage I or II disease with primary tumor ≤ 5 cm.

* Number of positive lymph nodes: O (56%), 1-3 (40%).

* Systemic treatments:

* standard dose CMF in all patients;

* tamoxifen in post-menopausal patients with estrogen receptor- positive disease.

* Concurrent radiotherapy:

* 39.6 Gy (1.8 Gy/fraction) to whole breast;

* 16 Gy tumor bed boost (2-Gy/fraction).

* Margin status: positive (22%), negative (63%), close (14%).

* Lymphovascular spacer invasion: yes (51%), no (46%).

Results:

The five year overall survival rate was 94% (95% CI, 89-98%), and the five year rate of freedom from any event: 74% (95% CI, 65-82%).

Crude rates of first events (all patients followed for at least 5 years):

* local: 4%;

* distant: 17%;

* second cancer: breast - 4%, other - 1%.

Recurrence (local or other) according to margin status and positive lymph nodes:

* negative margin - 11%, positive margin - 10%, close margin - 7%;

* negative nodes - 9%, 1-3 positive nodes - 18% (p = 0.02).

There were no other significant influences on local or other disease recurrence rates and long-term toxicity was rare. One patient developed AML and one patient developed pneumonias.

Conclusion:

For patients with early stage breast cancer, concurrent CMF and reduced-dose radiotherapy may be given with a low risk of long-term toxicity and low 5 year risk of local recurrence.

Commentary:

The majority of breast cancer patients with stage I or II breast cancer are recommended to have both chemotherapy and radiation as components of their treatment. Despite this fact, how to optimally sequence chemotherapy and radiotherapy for patients with early stage breast cancer has yet to be clearly defined. An early report from the Harvard group who authored this current paper suggested that delaying the start of radiotherapy to complete chemotherapy increased the risk of local recurrence . Subsequently, this group completed a randomized trial that compared sequencing of chemotherapy and radiation. The initial report of this trial concluded that delaying chemotherapy to give radiation first increased the risk of distant metastases2. However, with longer follow-up3, the differences in outcome according to sequencing schedule were no longer present.

This background set the stage to question whether chemotherapy and radiation could be delivered concurrently, thereby avoiding a delay in the initiation of either treatment. This report indeed demonstrates that CMF and reduced-dose radiotherapy can be given concurrently with acceptable long-term toxicity and low 5 year local recurrence rates. These data are consistent with other reports, including results from two large randomized trials that show comparable LRR rates following concurrent chemotherapy and radiation4,5. Importantly, these studies achieved low 5 year rates of breast recurrences in patients with close or positive surgical margins. This fact, along with the reduced radiation dose used in this study, suggests that concurrent chemotherapy delivery provides a radiosensitizing effect.

Several aspects of this study warrant comment. First, the trial did not prospectively follow breast cosmesis as an end-point and so the aesthetic outcomes associated with the concurrent treatment were not reported. This limitation is an important consideration in that a change in breast aesthetics would likely be the most common form of normal tissue injury with concurrent treatment. secondly, the majority of patients with positive surgical margins currently undergo re-excision and most data suggest that there is no increased risk of breast recurrence with radiation delay in patients with negative margin. Finally, anthracyclines are currently much more commonly used than CMF, for patients with lymph node-negative disease antracyclines permit for a four cycle schedule, vs. a six cycle regimen for patients with lymph node-positive disease, data suggests that a combined anthracycline-taxane regimen improves outcome. The profound normal tissue radiosensitizing properties of anthracyclines limit the enthusiasm for studying concurrent doxorubicin-radiation sequencing schedules in breast cancer.

Additional work will continue to explore whether combining systemic agents with chemotherapy can enhance the therapeutic ratio. This strategy has proven successful in a variety of other disease sites. However, in breast cancer, radiation is very infrequently used to treat gross disease (exceptions are those patients with inoperable disease refractory to neoadjuvant chemotherapy and patients with inoperable locally recurrent disease). Accordingly, the local-regional recurrence risk is very low for most cases of breast cancer treated with radiation, and novel radiosensiziting approaches are not needed.

Bellori JR, Shulman LN, Come SE, Li X, Gelman RS, Silver BJ, Harris JR, Recht A. Cancer 2004;100:1358-64

Selected references:

1. Recht A, Come SE, Gclman RS, et al. Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and outcome. J Clin Oncol 1991;9:1662-7

2. Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 1996;334:1356-61

3. Bellon J, Come S, et al. Sequencing of chemotherapy with radiation therapy in early stage breast cancer: updated results of a prospective randomized trial [abstract]. Int J Rad Oncol Biol Phys 2001;51(Suppl):2-3

4. Rouesse J, Cvitkovic F, et al. Concomitant or sequential chemoradiotherapy (CRT) in operable breast cancer. Final results of a French multicentric phase III study. Breast Cancer Res Treat 2002;76:S160

5. Calais G, Serin D, et al. Randomized study comparing adjuvant radiotherapy with concomitant chemotherapy versus sequential treatment after conservative surgery for patients with stages I and II breast carcinoma. Int J Rad Oncol Biol Phys 2002;54(Suppl):57-8

Further reading:

Buchholz TA, Hortobagyi GN. Sequencing of surgery, systemic treatment, and radiation in the management of breast cancer. Wom Oncol Rev 2001; 1:349-54

Commentary by: Amit K. Garg, MD, and Thomas A. Buchholz, MD, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Copyright CRC Press Jun 2004

Source: Women's Oncology Review

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