Many physicians are reluctant to delay the start of chemotherapy until after radiotherapy therapy is administered, due to concern that this might impair the effectiveness of chemotherapy and result in an increased rate of distant metastasis. Similarly, delaying the start of radiotherapy might increase the risk of local disease recurrence.

In the current study, which utilizes concurrent radiotherapy and chemotherapy, the 5-year rate of local disease recurrence was only 4%, despite lower doses of radiotherapy than are commonly employed and a large proportion of patients with risk factors associated with an increased risk of local disease recurrence. Rates of distant metastasis also were comparable to rates observed in other studies using adjuvant CMF.

Other groups have also reported the use of concurrent chemotherapy and radiotherapy in patients with early-stage breast carcinoma. The Trans-Tasman Radiation Oncology Group conducted a prospective trial of 268 patients treated at 4 centers in New Zealand and Australia with concurrent radiotherapy and CMF, including 169 patients who received breast-conservation therapy. The whole-breast dose in 166 of these patients was either 44-45 Gy in 22-23 fractions or 50 Gy in 25 fractions. One hundred fifty-three patients received a 10-20-Gy electron boost to the primary site. Both intravenous and oral cyclophosphamide regimens were used, generally for six cycles. To minimize the acute toxicity of concurrent treatment, the intravenous component of chemotherapy was administered on Fridays, and radiotherapy was omitted on that day. The crude 4-year local disease recurrence rate for patients who underwent breast conservation therapy was 6.3%.

The University of Pennsylvania series of 210 patients with Stage I or Stage II breast carcinoma utilized a classic oral CMF regimen similar to that used in the current study. Methotrexate was omitted during the two cycles given concurrently with radiotherapy. Twenty-four percent of patients also received adjuvant tamoxifen. Ninety-nine percent of patients received a total dose of 60 Gy to the lumpectomy site. Thirty-three percent of patients also were treated to a supraclavicular field. With a median follow-up period of 6.4 years, the actuarial local disease recurrence rates at 5 years and 10 years were 5% and 13%, respectively.

The Royal Marsden Hospital group found a 1.9% risk of local disease recurrence in 184 patients treated with radiotherapy concurrently with a regimen of mitozantrone, methotrexate, and tamoxifen (with or without mitomycin C), with a median follow-up of 57 months. Radiotherapy was administered to the breast to a dose of 54 Gy in 2.0-Gy fractions followed by a 10-Gy lumpectomy site boost. The regional lymph nodes were included in patients who presented with palpable axillary disease and in patients who did not undergo axillary lymph node dissection.

Two French randomized trials directly compared concurrent and sequential chemoradiotherapy programs. Calais  recently reported preliminary results from the Institute Curie and collaborating institutions (the Acrosein group). In that study, 706 patients were randomized to receive 5-FU, mitoxantrone, and cyclophosphamide (FNC) for six cycles either concurrently or preceding radiotherapy. At a median of 37 months, the risk of local disease recurrence was 4.3% in the sequential group and 3.5% in the concurrent group. An additional study by a consortium of French national cancer centers (Federation Nationales des Centres de Lutte Contre le Cancer) compared radiotherapy given concurrently with FNC with a sequential regimen of 5-FU, epirubicin, and cyclophosphamide followed by radiotherapy in 650 patients with 1-7 positive lymph nodes. At a median follow-up period of 41 months, no difference in locoregional disease recurrence was observed.

Although multiple retrospective series have shown that patients with close or positive margins treated with breast-conserving surgery have an increased risk of local disease recurrence, the timing of adjuvant radiotherapy and chemotherapy may potentially have an impact on this finding. Two sequential regimens of CMF and radiotherapy were directly compared in a randomized trial of 244 patients. One-half of the patients received radiotherapy first and the other half received chemotherapy first. The updated results, with a median follow-up period of 11.3 years, did not show statistically significant differences in terms of disease-free or overall survival or patterns of first disease recurrence between the 2 arms. However, there were more local disease recurrences in the arm receiving chemotherapy first. This effect of a delay in radiotherapy was more pronounced in the group with close margins. Four percent of patients in the radiotherapy-first arm with close margins experienced a local disease recurrence as a first recurrence compared with 32% in the chemotherapy-first arm. (Corresponding rates of distant and regional disease recurrences occurred in 43% and 37% of patients, respectively.) Patients with positive margins had a high rate of local disease recurrence even with the early administration of radiotherapy (20% and 23% in the 2 arms, respectively).

A particular advantage of concurrent chemoradiotherapy is that it might overcome the higher risk of disease recurrence observed in patients with close or positive margins in a number of series using sequential treatment programs, even when radiotherapy is given shortly after surgery. Markiewicz  found 2 local disease recurrences in 45 patients (4%) with close (defined as 2 mm) or positive margins and 6 local disease recurrences in 73 patients (8%) with unknown margins treated with concurrent radiotherapy and chemotherapy. Investigators from the Royal Marsden Hospital also analyzed their results by margin status. Local disease recurrence (as a site of first disease recurrence) occurred in 2 of 70 patients (3%) with positive margins (defined as a tumor at or within 1 mm of the inked edge of the specimen). In the current study, crude rates of local disease recurrence were 4%, 6%, and 4%, respectively, in patients with negative, close, and positive margins.

Late toxicity was unusual in the current study. One patient developed AML and an additional patient developed Grade 2 pneumonitis. Other investigators found somewhat different results, most likely because of differences in the details of both the chemotherapy and radiotherapy. The Trans-Tasman Radiation Oncology Group reported the development of AML in 1 patient undergoing concurrent treatment with radiotherapy and CMF 4 years after treatment. Approximately 9% of patients (14 of 157 patients) developed radiation pneumonitis. The severity was not reported. However, no cases of pneumonitis were reported to have occurred in a group of 202 patients treated at the Princess Margaret Hospital in Toronto with concurrent radiotherapy and CMF. Five percent of patients (4 of 87 patients) in a report of the triple M program of the Royal Marsden Hospital developed symptomatic radiation pneumonitis within 6 weeks of completing radiotherapy. The investigators found that the risk of pneumonitis was correlated with having > 3 cm of lung in the tangential radiation field. Similar to the early experience with concurrent paclitaxel and radiotherapy, pneumonitis resulting from concurrent treatment in the Royal Marsden experience presented sooner than the 3-4 months after radiation that is usually obeserved. Finally, in the University of Pennsylvania series, 3 patients (1%) treated with concurrent therapy developed pneumonitis compared with none of 41 patients receiving sequential treatment'

Concurrent administration of chemotherapy and radiotherapy might impair the cosmetic outcome of treatment. This was observed in a retrospective study of patients treated at the Joint Center for Radiation Therapy. However, doses of radiotherapy in that study were higher than those in the current report. Results from different investigators have been mixed. Unfortunately, patients in the current study often were not routinely followed by the treating radiation oncologist, and therefore, cosmetic results were not recorded for all patients in a uniform fashion. Consequently, the cosmetic results of our regimen could not be reliably analyzed.

We acknowledge some of the limitations of the current study, especially the implications for current treatment policies. Central pathology review was not performed, so the current study findings regarding margin status must be considered tentatively. Patients with positive surgical margins are no longer routinely accepted for breast-conservation. However, the improvement in local control observed in high-risk patients receiving concurrent treatment may indicate that even patients with standard risk will have superior results as well. In addition, CMF regimens are no longer commonly used. It remains to be determined whether concurrent regimens containing anthracyclines and/or taxanes can be given safely with radiotherapy.

Concurrent CMF and reduced-dose radiotherapy is a well tolerated regimen with a low risk of long-term toxicity. Despite the inclusion of patients at high risk for local disease recurrence, a low risk of local disease recurrence was observed at 5 years. Whether this regimen is superior to sequential regimens remains to be determined. In addition, it remains to be seen whether novel treatment planning strategies such as intensity-modified radiotherapy, which can improve the homogeneity of radiation delivery, can reduce the toxicity of concurrent regimens. Additional study of concurrent regimens with other chemotherapy agents more commonly employed today is warranted and is currently being considered by our group.