Concurrent CMF and radiation therapy for early stage breast cancer: results of a pilot study

PURPOSE: The optimal sequencing of chemotherapy (CT) and radiotherapy (RT) for patients with early-stage breast cancer treated with breast-conserving therapy is unresolved. Given the concerns arising from delaying either CT or RT, we conducted a pilot study of a concurrent CT-RT regimen in the hope that this would reduce side effects without decreasing efficacy. METHODS AND MATERIALS: From 1992-1994, 112 patients with 0-3 positive nodes received 6 monthly cycles of classic oral chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF). On day 15 of cycle 1, patients started tangential field RT (39.6 Gy in 22 fractions), followed by a 16 Gy boost in 8 fractions. Median follow-up time for surviving patients was 53 months. RESULTS: Moist desquamation developed during or shortly after RT in 50% of patients, but only 5 patients required treatment breaks. Grade 4 neutropenia during RT occurred in 16 patients, but only 1 required hospitalization. One patient developed Grade 2 radiation pneumonitis. Ninety-three percent of patients received at least 85% of prescribed drug doses. Cosmetic scores of 51 evaluable patients approximately 2 years after the end of chemotherapy were 47% excellent, 43% good, and 10% fair. We have observed 4 local failures and 20 distant failures. CONCLUSIONS: This concurrent CT-RT scheme had acceptable toxicity and outcome. Further comparison of this approach allowing prompt initiation of both CT and RT to alternative sequences is warranted.     

Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer

PURPOSE: Evidence supports the inclusion of the taxanes in the treatment of breast cancer. A recent randomized trial has shown a survival advantage to the addition of paclitaxel in the adjuvant treatment of node-positive patients. Several studies have suggested diminished local control if adjuvant radiation is delayed, while in vitro and in vivo studies have demonstrated a benefit of concurrent administration of taxanes with radiation. For these reasons, we began in 1995 to administer radiation therapy concurrently with the taxanes in advanced breast cancer. This retrospective review examines the feasibility of such treatment. METHODS AND MATERIALS: Forty-four patients were treated with concurrent radiation and either paclitaxel (29 patients) or docetaxel (15 patients). One patient received both paclitaxel and docetaxel. Eighteen patients were treated for recurrent disease, 9 had received prior radiation. Toxicity was assessed by the RTOG scale for acute and late effects. RESULTS: Concurrent radiation and taxane chemotherapy was well tolerated. Nine patients (20%) experienced Grade 3 acute skin toxicity. This was more likely with docetaxel than paclitaxel (p = 0. 04). Among patients undergoing breast conservation, there were no Grade 3 toxicities. With a median follow-up of 11 months, 1 patient has developed breast fibrosis. CONCLUSION: Concurrent administration of both paclitaxel and docetaxel with radiation resulted in acceptable toxicity. Overall, the acute skin toxicity seen with docetaxel was more pronounced. However, among patients undergoing breast conservation the taxanes were both well tolerated. Further study is necessary to assess the impact of concurrent treatment on long-term outcome.     

The sequencing of radiation therapy and chemotherapy after mastectomy in premenopausal women with breast cancer

OBJECTIVE: The purpose of this study was to evaluate the prognostic importance of the sequencing of radiation therapy and chemotherapy after mastectomy in high-risk premenopausal women with breast cancer in addition to other known prognostic factors in the literature. METHODS: In this retrospective study, 176 premenopausal women with breast cancer were evaluated. The median age at referral was 39 years (range, 28-59 years); 106 patients had stage II and 70 had stage III disease. All were subjected to mastectomy. The median number of lymph nodes removed was 19. The influence of age, histological grade, number of nodes removed, number of positive nodes, tumor size, estrogen receptor status, lymphovascular invasion and sequencing of radiotherapy and chemotherapy on 5-year locoregional disease-free survival, 5-year systemic disease-free survival, 5-year disease-free survival and 5-year cancer-specific survival were studied. RESULTS: The 5-year locoregional disease-free survival was 94% for the entire patient population. Because of the small number of locoregional recurrences, none of the evaluated factors was prognostically significant for locoregional recurrence. The 5-year systemic disease-free, disease-free and cancer-specific survival rates were 72, 70 and 77%, respectively. On multivariate analysis of host, tumor and treatment-related factors, the number of positive nodes [RR 1.9 (95% CI: 1.36-2.63), RR 2 (1.46-2.84 ) and RR 1.8 (1.3-2.71), respectively], histopathological grade [RR 1.8 (95% CI: 1.24-2.65), RR 1.9 (1.34-2.88), RR 2.5 (1.65-4.07), respectively], estrogen receptor status [RR 3.5 (95% CI: 1.5-8.6), RR 3.9 (1.64-9.41), RR 2.5 (1.05-6.24), respectively] and the sequencing of radiotherapy and chemotherapy [RR 1.6 (95% CI: 1.17-2.39), RR 1.7 (1.25-2.54), RR 1.6 (1.14-2.43), respectively] were all significant independent predictors of outcome. CONCLUSIONS: Our results show that in addition to traditional prognostic factors, the sequencing of radiation therapy and chemotherapy also predict for increased risk of any type of recurrence or further tumor death.     

Concurrent radiotherapy does not affect adjuvant CMF delivery but is associated with increased toxicity in women with early breast cancer

We evaluated whether concurrent radiotherapy (RT) affected delivery and toxicity of adjuvant intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in women with operable breast cancer. The medical charts of 321 consecutive breast cancer patients who received CMF either alone for 6 cycles, or for 4 cycles following of an anthracycline (A-CMF) were reviewed. One hundred forty-four women underwent radiotherapy concurrently with CMF. Optimal CMF delivery (success as opposite to failure) was defined as the combined achievement of an average relative dose intensity (aRDI) > or = 85% and an average percent of the total dose (aPTD) > or = 90% for the three drugs in the CMF regimen. Multivariate logistic regression analysis showed that concurrent-RT did not affect CMF delivery (OR for success 1.391 p=0.230). The sequential A-CMF regimen (OR for success 0.208, 95% C.I. 0.120-0.360, p<0.001) and age > or = 56 (OR for success 0.351, 95% C.I. 0.200-0.161, p<0.001) were independently associated with suboptimal CMF delivery. Moreover, concurrent RT was independently associated with increased leukopenia, thrombocytopenia, upper abdominal pain, mucositis and fatigue. Our retrospective analysis suggests that concurrent-RT has no impact on optimal CMF delivery, but it increases the burden of CMF-related toxicity.     

Concurrent chemotherapy and radiation therapy in primary cancer of the cervix

Radiation therapy has been the most active agent for the treatment of patients with locally advanced cervical cancer for many years. Chemotherapy has shown some activity, but data has been lacking to support its routine use. Recently, data from five prospective, randomized trials evaluating this difficult population have matured. Reports from these trials are startlingly similar, leading to the common conclusion that concurrent cisplatin chemotherapy and radiation therapy substantially decrease the risk of relapse and increase the overall survival. These results are compelling evidence for the inclusion of cisplatin with irradiation as a new standard of care for patients with locally advanced cervical cancer.     

Concurrent chemotherapy and radiation therapy in advanced head and neck cancer

A combination of radiation therapy and cis-platinum (25 mg/m2 i.v.) day 1, vincristine (1 mg i.v.) day 2, and bleomycin (15 U i.v.) day 4 was given concomitantly to 14 patients with advanced inoperable head and neck cancer and one patient with local recurrence. Radiation therapy consisted of 70 Gy to the involved areas and 50 Gy to adjacent uninvolved areas at 1.8 Gy per fraction. The overall response rate was 100%. Nine patients (60%) achieved a complete response, and six patients achieved a partial response. One patient appeared to have increasing disease, but biopsies have shown only fibrosis. The survival is 8 of 15 (53%), with a median follow-up time of 24 months. Most significant toxicity was anorexia and weight loss. Other toxicity consisted of peripheral neuropathy (1 patient), mild transient elevation of creatinine (1 patient), hypothyroidism (1 patient), and mild pulmonary toxicity (2 patients). Mucositis occurred in all patients, requiring interruption of therapy (2-14 days).     

The effect of adjuvant chemotherapy on the cosmetic results after primary radiation treatment for early stage breast cancer

Breast cancer patients treated by primary radiation therapy who have positive axillary lymph nodes now typically receive adjuvant chemotherapy. In order to evaluate the effect of adjuvant chemotherapy on the response of the breast to radiation treatment, we compared the cosmetic results of 49 patients treated with adjuvant chemotherapy and 206 patients not treated with adjuvant chemotherapy. A variety of chemotherapy regimens were employed, most commonly a combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The median follow-up time for all patients was 33 months. Cosmetic results were scored by the physician at each follow-up evaluation as excellent, good, and fair or poor, depending on the presence and extent of radiation-related changes in the treated breast. Patients who received adjuvant chemotherapy were less likely to have an excellent overall cosmetic result than patients who did not receive adjuvant chemotherapy. At 24 months 24% of these patients had an excellent cosmetic result compared with 64% of patients who did not receive adjuvant chemotherapy (p = 0.0002). This difference was due primarily to a shift in chemotherapy-treated patients from an excellent to a good overall cosmetic result. Breast retraction was noted to be the most frequent determinant of a fair or poor cosmetic result and was more common in patients treated with adjuvant chemotherapy. At 24 months, 62% of these patients had evidence of breast retraction compared with 44% of patients who did not receive adjuvant chemotherapy (p = 0.06). We conclude from this preliminary analysis that adjuvant chemotherapy modifies the response of the breast to radiation, most notably by increasing the development of retraction.     

Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy

Purpose

Capecitabine has been studied as a radiosensitizer, and our study seeks to examine the association of concurrent capecitabine/radiation therapy (RT) on event-free- (EFS) and overall survival (OS) in women with breast cancer (BC) with residual disease after neoadjuvant chemotherapy (NAC).

Methods/patients

In a retrospective study of women with BC who received adriamycin/taxane-based NAC from 2004–2016, we identified 21 women administered concurrent capecitabine/RT. To assess differences in survival, we selected a clinical control cohort (n?=?57) based on criteria used to select patients for capecitabine/RT. We also created a matched cohort (2:1), matching on tumor subtype, pathological stage and age (<?50 or 50+ years). Differences in EFS, using STEEP criteria, and OS, using all-cause mortality, between those who received capecitabine/RT and controls were assessed.

Results

Of the 21 women who received capecitabine/RT, median age was 52 years. The majority were pathologic stage III (n?=?15) and hormone receptor-positive/HER2-negative BC (n?=?20). In those receiving capecitabine/RT, there were 9 events, compared with 14 events in clinical and 10 events in matched controls. Capecitabine/RT was associated with worse OS in clinical (HR 3.83 95% CI 1.12–13.11, p?=?0.03) and matched controls (HR 3.71 95% CI 1.04–13.18, p?=?0.04), after adjusting for clinical size, pathological stage and lymphovascular invasion. Capecitabine/RT was also associated with a trend towards worse EFS in clinical (HR 2.41 95% CI 0.86–6.74, p?=?0.09) and matched controls (HR 2.68 95% CI 0.91–7.90, p?=?0.07) after adjustment.

Conclusion

Concurrent capecitabine/RT after NAC is associated with worse survival and should be carefully considered in BC.

     

Cosmetic results after surgery, chemotherapy, and radiation therapy for early breast cancer

Adjuvant chemotherapy (CT) is increasingly being used in conjunction with radiation therapy (RT) in the treatment of early stage breast cancer. To assess the effect of CT on the cosmetic outcome of the irradiated breast, we retrospectively reviewed the cosmetic results of patients who received either cyclophosphamide-methotrexate-fluorouracil (CMF) or doxorubicin-based chemotherapy in conjunction with breast irradiation between 1968 and 1985. The overall cosmetic results were evaluated by the physician as "excellent," "good," "fair," or "poor" using a standardized scale. The CT group consisted of 170 patients treated with CT and RT administered either concurrently or sequentially (CT before RT, after RT, or both) with a minimum of 24 months of cosmetic follow-up. These were compared to an RT alone control group of 170 patients who did not receive CT and were matched by tumor size, radiation technique, and year of treatment. At 36 months, the cosmetic scores for the CT group compared to RT alone were 47% versus 71% excellent (p less than 0.01), 36% versus 19% good, and 17% versus 9% fair or poor. For the 50 patients treated with concurrent CMF and RT, the scores were 31% excellent, 45% good, and 24% fair/poor, whereas for the 118 patients treated with sequential RT and CT they were 54%, 31%, and 14%, respectively. There was no difference between those patients who received sequential CMF and those treated with doxorubicin. We conclude that adjuvant chemotherapy adversely affects the cosmetic outcome of breast irradiation, but that this effect is not clinically significant unless CMF is administered concurrently with RT. Patients treated with either sequential CMF or doxorubicin-based CT had only a slight decrement in their cosmetic result compared to patients treated without CT.     

Concurrent chemotherapy and thoracic radiation therapy for limited-stage small cell lung cancer

We conducted a phase II study of therapy for limited-stage small cell lung cancer (LD-SCLC). The chemotherapy regimen consisted of a three-week cycle of cisplatin (80 mg/m(2), given intravenously on day 1) and etoposide (100 mg/m(2), given intravenously on days 1, 3 and 5), given three to four times. Fifty Cy thoracic irradiation was administered in standard fractions simultaneously without a treatment break. A total of 19 patients with SCLC were entered into the study, and 18 were eligible. This concurrent treatment produced 39% complete-response and 89% overall-response rates in the eligible patients. The median response duration was 36 weeks, and the median survival time was 67 weeks. A local relapse within the irradiation field was observed in 28% of the eligible patients. Brain metastasis as the first relapse was seen in 33% of the eligible patients. Myelosuppression represented by grade 3 and 4 leukopenia was experienced in 79% of the entered patients. We conclude that the concurrent modality with cisplatin and etoposide (PE) chemotherapy and early thoracic radiation therapy without split is a feasible and beneficial therapy.     

Concurrent chemotherapy and radiation therapy as the standard of care for cervical cancer

From 1999-2000, each of five randomized trials demonstrated improved rates of survival and local control when concurrent cisplatin-based chemotherapy was added to radiation therapy in patients with loco-regionally advanced cervical cancer. These studies demonstrated that addition of chemotherapy to radiation therapy improved the outcome of patients treated with radiation therapy and hysterectomy or radiation therapy alone. Although concurrent chemotherapy increases the severity of acute side effects, it does not appear to increase the risk of late side effects of radiation therapy. A sixth randomized trial, published in 2002, failed to demonstrate improved outcome with concurrent weekly cisplatin over radiation therapy alone; however, the earlier trials demonstrated benefit with this chemoradiation regimen. In addition, three of the earlier randomized trials demonstrated improved outcome with combinations of cisplatin and 5-fluorouracil compared with radiation therapy alone. Although cisplatin-based chemoradiation is the most accepted standard, individual trials have suggested that other drugs, including mitomycin and epirubicin, might be beneficial. Randomized trials that investigated the administration of neoadjuvant chemotherapy before radiation therapy have failed to demonstrate a benefit of this approach. Although the evidence for benefit of concurrent chemotherapy is strong for otherwise healthy patients with newly diagnosed, loco-regionally advanced cervical cancers confined to the pelvis, the relative benefits and risks are not well understood for patients who are infirm or who require larger fields of radiation therapy. In such patients, the theoretical benefits and potential risks should be considered carefully before a treatment plan is prescribed.     

Concurrent use of chemotherapy or novel agents in combination with radiation in breast cancer

Treating breast cancer patients concurrently with chemotherapy and radiation is a potentially attractive approach. The goal is to develop strategies that enhance the effects of each modality while minimizing toxicity. Most data evaluating the role of simultaneous therapy have been generated from small phase 1 and 2 trials. As few prospective, randomized controlled trials have been performed in this area, generating definitive conclusions regarding the efficacy and toxicity from combined therapy remains difficult. This article reviews the current literature on the benefits and toxicities of concurrent radiation with cytotoxic chemotherapy, as well as with novel biologic agents such as monoclonal antibodies, tyrosine kinase inhibitors, and heat shock protein antagonists. Because the appropriate use of concurrent radiation with chemotherapy and biologic agents continues to evolve, we also highlight future and ongoing trials evaluating this treatment option.     

早期乳腺癌放射治疗进展

放射治疗在早期乳腺癌的综合治疗中具有重要地位。在早期浸润性乳腺癌乳房保留治疗已成熟的基础上，近年的临床研究着眼于对乳房保留治疗的标准模式的挑战，包括全乳照射后瘤床加量的意义，是否有低危复发患者可以接受单纯手术以及部分乳腺照射的可行性等。对于局部复发高危患者进行乳房切除术后胸壁和区域淋巴结的放射治疗可以降低2／3的局部和区域的复发率，但是目前仍然只有少数研究证实术后放疗提高了生存率，尤其关于中等复发危险的患者术后放疗是否有价值尚存在较多争议。本文将对上述进展和争议作一综述。     

The current status of primary radiation therapy in the treatment of early breast cancer

Summary Primary radiation therapy, usually with limited surgery, is being used increasingly as an alternative to mastectomy in patients with early breast cancer. Results so far appear similar in terms of local control and overall survival. Current questions on patient selection, extent of surgery, radiation therapy technique, possible long-term complications, and the role of axillary dissection and of adjuvant therapy are reviewed. Though many questions remain, it is hoped that this alternative will contribute to improved survival along with breast preservation for improved quality of life. Address for reprints: Dr Nancy Tarbell Leslie, Joint Center for Radiation Therapy, Dept. of Radiation Therapy, Harvard Medical School, 50 Binney Street, Boston, MA 02115, USA.     

Oral contraceptive use has no adverse effect on the prognosis of breast cancer

This study evaluates the possible effect of OC use on the prognosis of established breast cancer. Three hundred forty-seven patients with primary invasive breast carcinoma age 50 and under treated from 1971 to 1981 are included in this study. There were 112 OC Users (U) and 235 Non-Users (NU). Separate retrospective analysis were done for a group of 154 patients (59 U and 95 NU) under age 35 (Group A) and for 193 patients (53 U and 140 NU) age 35 to 50 (Group B), in order to pay particular attention to relationship of duration, recency and latency of OC usage. Both subsets of U and NU presented similar clinical characteristics regarding menstrual, reproductive, family history, histology, receptor status. Users presented with a similar extent of disease as Non-Users. No significant differences were found between U and NU in disease-free interval (Gr A p = .41; Gr B p = .81), metastatic period (Gr A p = .66; Gr B p = .41) or survival (Gr A p = .54; Gr B p = .79), either alone or when adjusted for extent of node involvement. Users of less than two years (78 patients) had a similar survival (Gr A = .54; Gr B p = .36) as those of longer duration (33 patients). Recent OC users within a year of diagnosis had a similar survival as other users who stopped the pills more than one year (Gr A p = .86; Gr B p = .14). No significant differences were noticed in survival between the patients who began the use 10 years or more before diagnosis from those beginning more recently (Gr A p = .82; Gr B p = .69). Our data suggests no adverse effect of OC on the outcome of breast cancer, regardless the duration of use, latency or recency period.