Beryl McCormick

Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy

In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

PURPOSE To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer. PATIENTS AND METHODS Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) -positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival (OS). RESULTS Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer-specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. CONCLUSION With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.

Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast.

PURPOSE To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. PATIENTS AND METHODS An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8). RESULTS The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or = .15). CONCLUSION The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.

Irradiation after immediate tissue expander/implant breast reconstruction: Outcomes, complications, aesthetic results, and satisfaction among 156 patients

Chest wall irradiation is becoming increasingly common for mastectomy patients who have opted for immediate breast reconstruction with tissue expanders and implants. The optimal approach for such patients has not yet been defined. This study assesses the outcomes of a reconstruction protocol for patients who require irradiation after tissue expander/implant reconstruction. The charts of all patients who underwent immediate tissue expander/implant reconstruction at Memorial Sloan-Kettering Cancer Center between January of 1995 and June of 2001 and who had not previously undergone irradiation were retrospectively reviewed. A subgroup of patients who required chest wall irradiation after mastectomy and reconstruction was identified. Those patients were treated according to the following treatment algorithm: (1) reconstruction with tissue expander placement at the time of mastectomy, (2) tissue expansion during postoperative chemotherapy, (3) exchange of the tissue expander for a permanent implant approximately 4 weeks after the completion of chemotherapy, and (4) chest wall irradiation beginning 4 weeks after the exchange. All irradiated patients with at least 1 year of follow-up monitoring after the completion of radiotherapy were evaluated with respect to aesthetic outcomes, capsular contracture, and patient satisfaction. A control group of nonirradiated patients was randomly selected from the cohort of patients treated during the study period. During the 5-year study period, a total of 687 patients underwent immediate reconstruction with tissue expanders. Eighty-one patients underwent postoperative irradiation after placement of the final implant. A total of 68 patients who received postoperative chest wall irradiation underwent at least 1 year of follow-up monitoring after the completion of radiotherapy, with a mean follow-up period of 34 months. Seventy-five nonirradiated patients were evaluated as a control group. Overall, 68 percent of the irradiated patients developed capsular contracture, compared with 40 percent in the nonirradiated group (p = 0.025). Eighty percent of the irradiated patients demonstrated acceptable (good to excellent) aesthetic results, compared with 88 percent in the nonirradiated group (p = not significant). Sixty-seven percent of the irradiated patients were satisfied with their reconstructions, compared with 88 percent of the nonirradiated patients (p = 0.004). Seventy-two percent of the irradiated patients stated that they would choose the same form of reconstruction again, compared with 85 percent of the nonirradiated patients. The results of this study suggest that tissue expander/implant reconstruction is an acceptable surgical option even when followed by postoperative radiotherapy and should be considered in the reconstruction algorithm for all patients, particularly those who may not be candidates for autogenous reconstruction.

Fractionation for whole breast irradiation: An American society for radiation oncology (ASTRO) evidence-based guideline

PURPOSE In patients with early-stage breast cancer treated with breast-conserving surgery, randomized trials have found little difference in local control and survival outcomes between patients treated with conventionally fractionated (CF-) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. However, it remains controversial whether these results apply to all subgroups of patients. We therefore developed an evidence-based guideline to provide direction for clinical practice. METHODS AND MATERIALS A task force authorized by the American Society for Radiation Oncology weighed evidence from a systematic literature review and produced the recommendations contained herein. RESULTS The majority of patients in randomized trials were aged 50 years or older, had disease Stage pT1-2 pN0, did not receive chemotherapy, and were treated with a radiation dose homogeneity within ±7% in the central axis plane. Such patients experienced equivalent outcomes with either HF-WBI or CF-WBI. Patients not meeting these criteria were relatively underrepresented, and few of the trials reported subgroup analyses. For patients not receiving a radiation boost, the task force favored a dose schedule of 42.5 Gy in 16 fractions when HF-WBI is planned. The task force also recommended that the heart should be excluded from the primary treatment fields (when HF-WBI is used) due to lingering uncertainty regarding late effects of HF-WBI on cardiac function. The task force could not agree on the appropriateness of a tumor bed boost in patients treated with HF-WBI. CONCLUSION Data were sufficient to support the use of HF-WBI for patients with early-stage breast cancer who met all the aforementioned criteria. For other patients, the task force could not reach agreement either for or against the use of HF-WBI, which nevertheless should not be interpreted as a contraindication to its use.

Breast Cancer in Patients Irradiated for Hodgkin's Disease: A Clinical and Pathologic Analysis of 45 Events in 37 Patients

PURPOSE To characterize the clinical and pathologic features of patients who developed breast cancer (BC) after treatment for Hodgkins disease (HD). Recent epidemiologic studies have shown that women who are cured of HD have an increased risk of developing BC. PATIENTS AND METHODS The clinical data, mammograms, and pathologic specimens of 37 women who developed 45 BCs (eight bilateral events), and had a prior history of treatment for HD were analyzed. RESULTS The median age at diagnosis of HD was 27 years (range, 11 to 60). All patients received radiotherapy (RT) to the upper part of their body, and 10 also had chemotherapy for HD. The median interval from the treatment of HD to the diagnosis of BC was 15 years (range, 8 to 34). The median age at diagnosis of BC was 43 years (range, 27 to 75), 41% of patients were 39 years old or younger. Most mammograms (81%) showed abnormal findings of mass and/or microcalcifications. Of the eight patients (22%) with bilateral tumors, four were synchronous and four were metachronous. Involvement of the medial half of the breast occurred more frequently than in patients with primary BC (39% and 21%, respectively; P < .002). But, the histologic types, grades, presence of lymphocytic reaction, and lymphatic invasion were similar to those observed in 935 primary BC patients who were previously analyzed at our center. The 6-year actuarial relapse-free survival (RFS) for node-negative BC after HD was 85%. Node-positive patients had a significantly lower RFS of 33% (P = .002). CONCLUSIONS In comparison to patients with primary BC, patients who develop BC after HD are more likely to be younger, have bilateral disease, and have their tumors more frequently involve the medial half of the breast. Pathologic characteristics, nodal involvement, and prognosis are similar to those of primary BC. BC in women who were treated for HD is becoming an increasing problem, as more patients cured of HD reach a follow-up time of 10 to 15 years. Breast examination and mammography at an early age should be part of the follow-up program for women who are cured of HD.

A Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: Tumor control and survival outcomes of RTOG 95-17

PURPOSE Radiation Therapy Oncology Group 95-17 is a prospective Phase II cooperative group trial of accelerated partial breast irradiation (APBI) alone using multicatheter brachytherapy after lumpectomy in select early-stage breast cancers. Tumor control and survival outcomes are reported. METHODS AND MATERIALS Eligibility criteria included Stage I/II breast carcinoma confirmed to be <3 cm, unifocal, invasive nonlobular histology with zero to three positive axillary nodes without extracapsular extension. APBI treatment was delivered with either low-dose-rate (LDR) (45 Gy in 3.5-5 days) or high-dose-rate (HDR) brachytherapy (34 Gy in 10 twice-daily fractions over 5 days). End points evaluated included in-breast control, regional control, mastectomy-free rate, mastectomy-free survival, disease-free survival, and overall survival. The study was designed to analyze the HDR and LDR groups separately and without comparison. RESULTS Between 1997 and 2000, 100 patients were accrued and 99 were eligible; 66 treated with HDR brachytherapy and 33 treated with LDR brachytherapy. Eighty-seven patients had T1 lesions and 12 had T2 lesions. Seventy-nine were pathologically N0 and 20 were N1. Median follow-up in the HDR group is 6.14 years with the 5-year estimates of in-breast, regional, and contralateral failure rates of 3%, 5%, and 2%, respectively. The LDR group experienced similar results with a median follow-up of 6.22 years. The 5-year estimates of in-breast, regional, and contralateral failure rates of 6%, 0%, and 6%, respectively. CONCLUSION Patients treated with multicatheter partial breast brachytherapy in this trial experienced excellent in-breast control rates and overall outcome that compare with reports from APBI studies with similar extended follow-up.

Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status

PURPOSE This study was performed to determine the long-term outcome for women with mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. METHODS AND MATERIALS An analysis was performed of 422 mammographically detected intraductal breast carcinomas in 418 women from 11 institutions in North America and Europe. All patients were treated with breast-conserving surgery followed by definitive breast irradiation. The median follow-up time was 9.4 years (mean, 9.4 years; range, 0.1-19.8 years). RESULTS The 15-year overall survival rate was 92%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 94%. There were 48 local failures in the treated breast, and the 15-year rate of any local failure was 16%. The median time to local failure was 5.0 years (mean, 5.7 years; range, 1.0-15.2 years). Patient age at the time of treatment and final pathology margin status from the primary tumor excision were both significantly associated with local failure. The 10-year rate of local failure was 31% for patient age < or = 39 years, 13% for age 40-49 years, 8% for age 50-59 years, and 6% for age > or = 60 years (p = 0.0001). The 10-year rate of local failure was 24% when the margins of resection were positive, 9% when the margins of resection were negative, 7% when the margins of resection were close, and 12% when the margins of resection were unknown (p = 0.030). Patient age < or = 39 years and positive margins of resection were both independently associated with an increased risk of local failure (p = 0.0006 and p = 0.023, respectively) in the multivariable Cox regression model. CONCLUSIONS The 15-year results from the present study demonstrated high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of mammographically detected ductal carcinoma in situ of the breast using breast-conserving surgery and definitive breast irradiation. Younger age and positive margins of resection were both independently associated with an increased risk of local failure. The 15-year results in the present study serve as an important benchmark for comparison with other treatment modalities. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of appropriately selected patients with mammographically detected ductal carcinoma in situ of the breast.

Curability of ewing's sarcoma and considerations for future therapeutic trials

Twenty previously untreated children with primary Ewings sarcoma and 8 children with primary tumor and metastatic disease were treated with surgery or radiation therapy (6,000–7,000 rads) for their primary tumor and T‐2 chemotherapy. Of the 20 children with primary Ewings sarcoma treated with T‐2“adjuvant” chemotherapy, 15 had no evidence of recurrent disease for from 31+−82+ months (median 46+ months) from the start of treatment. The actuarial 5‐year disease‐free survival rate for this group of patients was 75%. Eight patients presenting with metastatic disease had complete responses to T‐2 chemotherapy, but 7/8 with metastatic disease eventually had tumor recurrence. Examination of the treatment failures, both those patients relapsing after adjuvant chemotherapy for primary Ewings sarcoma (5), and those relapsing after having a complete response of metastatic disease (7) to T‐2 chemotherapy, revealed that all relapses occurred at the end of the second year of T‐2 chemotherapy or after chemotherapy was stopped. In addition, of 23 patients receiving “curative” radiation therapy to their primary tumor, 5 had local recurrence (22%) and 6 (26%) had severe functional debility secondary to combined radiation therapy and T‐2 chemotherapy. The conclusions drawn from this experience have led us to consider a new approach to the treatment of Ewings sarcoma, namely: 1) more aggressive initial or “induction” chemotherapy with subsequent T‐2“maintenance” chemotherapy to eradicate more completely all metastatic microfoci of disease presumed to be present in patients with primary tumor at the time of diagnosis, and ostensively present in patients with metastatic disease; 2) the use of surgery alone or in combination with moderate doses of radiation therapy in those patients in whom we can predict a high frequency of local recurrence (pelvic lesions) or a high percentage of “functional failures”(young children with lower extremity lesions). Preliminary results with this latter approach are encouraging with 11/13 patients with primary Ewings sarcoma free of disease at 12+−26+ months. A longer follow‐up of this more aggressive treatment is needed to determine the superiority of this approach for both increased survival and improved late physical rehabilitation.

RTOG 9804: A Prospective Randomized Trial for Good-Risk Ductal Carcinoma In Situ Comparing Radiotherapy With Observation

PURPOSE The Radiation Therapy Oncology Group 9804 study identified good-risk patients with ductal carcinoma in situ (DCIS), a breast cancer diagnosis found frequently in mammographically detected cancers, to test the benefit of radiotherapy (RT) after breast-conserving surgery compared with observation. PATIENTS AND METHODS This prospective randomized trial (1998 to 2006) in women with mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm, compared RT with observation after surgery. The study was designed for 1,790 patients but was closed early because of lower than projected accrual. Six hundred thirty-six patients from the United States and Canada were entered; tamoxifen use (62%) was optional. Ipsilateral local failure (LF) was the primary end point; LF and contralateral failure were estimated using cumulative incidence, and overall and disease-free survival were estimated using the Kaplan-Meier method. RESULTS Median follow-up time was 7.17 years (range, 0.01 to 11.33 years). Two LFs occurred in the RT arm, and 19 occurred in the observation arm. At 7 years, the LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001). Grade 1 to 2 acute toxicities occurred in 30% and 76% of patients in the observation and RT arms, respectively; grade 3 or 4 toxicities occurred in 4.0% and 4.2% of patients, respectively. Late RT toxicity was grade 1 in 30%, grade 2 in 4.6%, and grade 3 in 0.7% of patients. CONCLUSION In this good-risk subset of patients with DCIS, with a median follow-up of 7 years, the LF rate was low with observation but was decreased significantly with the addition of RT. Longer follow-up is planned because the timeline for LF in this setting seems protracted.