N. Nicolaou

Patients with early stage invasive cancer with close or positive margins treated with conservative surgery and radiation have an increased risk of breast recurrence that is delayed by adjuvant systemic therapy.

PURPOSE The association between a positive resection margin and the risk of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation is controversial. The width of the resection margin that minimizes the risk of IBTR is unknown. While adjuvant systemic therapy may decrease the risk of an IBTR in all patients, its impact on patients with positive or close margins is largely unknown. This study examines the interaction between margin status, margin width, and adjuvant systemic therapy on the 5- and 10-year risk of IBTR after conservative surgery and radiation. METHODS AND MATERIALS A series of 1,262 patients with clinical Stage I or II breast cancer were treated by breast-conserving surgery, axillary node dissection, and radiation between March 1979 and December 1992. The median follow-up was 6.3 years (range 0.1-15.6). The median age was 55 years (range 24-89). Clinical size was T1 in 66% and T2 in 34%. Seventy-three percent of patients were node-negative. Only 5 % of patients had tumors that were EIC-positive. Forty-one percent had a single excision, and 59% had a reexcision. The final margins were negative in 77%, positive in 12%, and close (< or = 2 mm) in 11%. The median total dose to the tumor bed was 60 Gy with negative margins, 64 Gy with close margins, and 66 Gy with positive margins. Chemotherapy +/- tamoxifen was used in 28%, tamoxifen alone in 20%, and no adjuvant systemic therapy in 52%. RESULTS The 5-year cumulative incidence (CI) of IBTR was not significantly different between patients with negative (4%), positive (5%), or close (7%) margins. However, by 10 years, a significant difference in IBTR became apparent (negative 7%, positive 12%, close 14%, p = 0.04). There was no significant difference in IBTR when a close or positive margin was involved by invasive tumor or DCIS. Reexcision diminished the IBTR rate to 7% at 10 years if the final margin was negative; however, the highest risk was observed in patients with persistently positive (13%) or close (21%) (p = 0.02) margins. The median interval to failure was 3.7 years after no adjuvant systemic therapy, 5.0 years after chemotherapy +/- tamoxifen, and 6.7 years after tamoxifen alone. This delay to IBTR was observed in patients with close or positive margins, with little impact on the time to failure in patients with negative margins. The 5-year CI of IBTR in patients with close or positive margins was 1% with adjuvant systemic therapy and 13% with no adjuvant therapy. However, by 10 years, the CI of IBTR was similar (18% vs. 14%) due to more late failures in the patients who received adjuvant systemic therapy. CONCLUSION A negative margin (> 2 mm) identifies patients with a very low risk of IBTR (7% at 10 years) after conservative surgery and radiation. Patients with a close margin (< or = 2 mm) are at an equal or greater risk of IBTR as with a positive margin, especially following a reexcision. A margin involved by DCIS or invasive tumor has the same increased risk of IBTR. A reexcision of an initially close or positive margin that results in a negative final margin reduces the risk of IBTR to that of an initially negative margin. A close or positive margin is associated with an increased risk of IBTR even in patients who are EIC-negative or receiving higher boost doses of radiation. The median time to IBTR is delayed; however, the CI is not significantly decreased by adjuvant systemic therapy in patients with close or positive margins-the 5 year results in these patients underestimate their ultimate risk of recurrence.

Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group trial 98-01

PURPOSE To test the ability of the cytoprotectant, amifostine, to reduce chemoradiotherapy-induced esophagitis and evaluate its influence on quality of life (QOL) and swallowing symptoms. PATIENTS AND METHODS A total of 243 patients with stage II to IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m(2) intravenously (IV) days 1 and 22 and carboplatin area under the curve (AUC) days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m(2) IV) and carboplatin (AUC 2), and hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy bid). Patients were randomly assigned at registration to amifostine (AM) 500 mg IV four times per week or no AM during chemoradiotherapy. Beyond standard toxicity end points, physician dysphagia logs (PDLs), daily patient swallowing diaries, and QOL (EORTC QLQ-C30/LC-13) were also collected. Swallowing AUC analyses were calculated from patient diaries and PDLs. RESULTS A total of 120 patients were randomly assigned to receive AM, and 122, to receive no AM (one patient was ineligible); 72% received AM per protocol or with a minor deviation. AM was associated with higher rates of acute nausea (P = .03), vomiting (P = .007), cardiovascular toxicity (P = .0001), and infection or febrile neutropenia (P = .03). The rate of >/= grade 3 esophagitis was 30% with AM versus 34% without AM (P = .9). Patient diaries demonstrated lower swallowing dysfunction AUC with amifostine (z test P = .025). QOL was not significantly different between the two arms, except for pain, which showed more clinically meaningful improvement and less deterioration at 6 weeks follow-up (v pretreatment) in the AM arm (P = .003). The median survival rates for both arms were comparable (AM, 17.3 v no AM, 17.9 months; P = .87). CONCLUSION AM did not significantly reduce esophagitis >/= grade 3 in patients receiving hyperfractionated radiation and chemotherapy. However, patient self-assessments suggested a possible advantage to AM that is being explored with modified dosing route strategies.

Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer.

Objective:To determine the clinically observed incidence and severity of acute skin toxicity with breast intensity modulated radiation therapy (IMRT), and compare the results with a matched cohort of patients treated by conventional radiation therapy. Our hypothesis is that measures to decrease dose inhomogeneity within the breast and skin with IMRT will improve acute skin toxicity. Materials and Methods:The study population consists of 73 women with early stage breast cancer treated with breast-conserving surgery and IMRT. The IMRT technique involves an iteration method for optimization to generate the IMRT plan, Monte Carlo dose calculation, and a step-and-shoot technique using multileaf collimation for beam delivery. Other aspects of the technique including the clinical definition of the clinical target volume by the physician, patient positioning, tangential beam orientation, dose and field sizes were unchanged compared conventional tangential radiation. These patients were matched one-to-one to a control group of 60 women treated with conventional photon radiation by using their bra size and chest wall separation. The study end point was acute skin toxicity. Results:There were no observed differences in the acute toxicity based upon common terminology criteria for adverse events (CTC) for acute radiation dermatitis. There was no desquamation in 42% of IMRT patients, dry desquamation in 37% and moist desquamation in 21%. The degree of desquamation was greater for conventional patients compared with IMRT patients −52% grade 0, 10% grade 1, and 38% grade 2 (P = 0.001). Subgroup analysis showed desquamation was significantly lower with IMRT for small (P = 0.038) and large breast sizes (P = 0.037), but not medium sizes (P = 0.454). For large breast sizes, the incidence of moist desquamation grade 2 was 48% with IMRT compared with 79% in controls. Significant predictors of moist desquamation on stepwise logistic regression were use of IMRT (P = 0.0011) and breast size (P < 0.0001). Conclusions:IMRT is associated with a decrease in severity of acute desquamation compared with a matched control group treated with conventional radiation therapy. As with conventional radiation, breast size remains the most important prognostic factor for acute skin toxicity. The CTC grading system for acute radiation dermatitis is not sensitive when applied to modern breast cancer treatment because of its dependence of subjective rating of erythema and inability to gauge variations in desquamation. Further study of patient symptoms, quality of life, and cosmesis is needed to evaluate the benefit of IMRT for breast cancer.

Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation †‡

The results of radiation on the local control of triple receptor‐negative breast cancer (negative estrogen [ER], progesterone [PR], and HER‐2/neu receptors) was studied.

Second cancers after conservative surgery and radiation for stages I-II breast cancer : Identifying a subset of women at increased risk

PURPOSE To assess the risk and patterns of second malignancy in a group of women treated with conservative surgery and radiation in a relatively contemporary manner for early-stage invasive breast cancer, and to identify a subgroup of these women at increased risk for a second cancer. METHODS AND MATERIALS From 1978 to 1994, 1,253 women with unilateral Stage I-II breast cancer underwent wide excision, axillary dissection, and radiation. The median follow-up was 8.9 years, with 446 patients followed for >or= 10 years. The median age was 55 years. Sixty-eight percent had T1 tumors and 74% were axillary-node negative. Radiation was directed to the breast only in 78%. Adjuvant therapy consisted of chemotherapy in 19%, tamoxifen in 19%, and both in 8%. Factors analyzed for their association with the cumulative incidence of all second malignancies, contralateral breast cancer, and non-breast cancer malignancy were: age, menopausal status, race, family history, obesity, smoking, tumor size, location, histology, pathologic nodal status, region(s) treated with radiation, and the use and type of adjuvant therapy. RESULTS One hundred seventy-six women developed a second malignancy (87 contralateral breast cancers at a median interval of 5.8 years, and 98 non-breast cancer malignancies at a median interval of 7.2 years). Nine women had both a contralateral breast cancer and non-breast cancer second malignancy. The 5- and 10-year cumulative incidences of a second malignancy were 5% and 16% for all cancers, 3% and 7% for contralateral breast cancer, 3% and 8%, for all second non-breast cancer malignancies, and 1% and 5%, respectively, for second non-breast cancer malignancies, excluding skin cancers. Patient age was a significant factor for contralateral breast cancer and non-breast cancer second malignancy. Young age was associated with an increased risk of contralateral breast cancer, while older age was associated with an increased the risk of a second non-breast cancer second malignancy. A positive family history increased the risk of contralateral breast cancer, but not non-breast cancer malignancies. The risk of a contralateral breast cancer increased as the number of affected relatives increased. Tamoxifen resulted in a nonsignificant decrease in contralateral breast cancer and an increase in non-breast cancer second malignancies. The 5-and 10-year cumulative incidences for leukemia and lung cancer were 0.08% and 0.2%, and 0.8% and 1%, respectively. There was no significant effect of chemotherapy or the regions treated with radiation on contralateral breast cancer or non-breast cancer second malignancy. The most common types of second non-breast cancer malignancies were skin cancers, followed by gynecologic malignancies (endometrial), and gastrointestinal malignancies (colorectal and pancreas). CONCLUSION The 10-years cumulative incidence of a second cancer in this study was 16%. Young age and family history predicted for an increased risk of contralateral breast cancer, and older age predicted for an increased risk of non-breast cancer malignancy. The majority of patients treated with conservative surgery and radiation with or without adjuvant systemic therapy will not develop a second cancer. Long-term follow-up is important to document the risk and patterns of second cancer, and knowledge of this risk and the patterns will influence surveillance and prevention strategies.

Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer

PURPOSE To compare outcome for ipsilateral breast tumor recurrence (IBTR), or regional node recurrence, initial and subsequent distant metastases, and overall and cause-specific survival in women treated with conservative surgery and radiation based on whether or not radiation was targeted to the internal mammary nodes (IMN). METHODS AND MATERIALS From 1979-1994, 1383 women with Stage I-II breast cancer underwent wide excision, axillary node dissection with >/=10 nodes removed, and radiation. Median follow-up was 6 years; median age was 55 years. A total of 114 women had radiation targeted to the IMN with deep tangents and 1269 did not. Women who received IMN treatment were more often axillary node-positive (40% vs. 25%, p = 0. 002), had central or inner quadrant tumors (61% vs. 40%, p = 0.001), and had T2 tumors (47% vs. 31%, p = 0.001). All axillary node-positive women received adjuvant chemotherapy and/or tamoxifen. For axillary node-negative women, 13% of the IMN treatment group received adjuvant systemic therapy compared to 37% of the no treatment group (p = 0.001). Radiation was directed to the breast only in 97% of the axillary node-negative women who had IMN treatment and 99% of the no IMN treatment group. For axillary node-positive women, 98% of the IMN-treated group had radiation to the breast and supraclavicular nodes +/- a posterior axillary field compared to 77% of the no IMN treatment group (p = 0.001). There were no significant differences between the two groups for median age, menopausal status, histology, final surgical margin, estrogen and progesterone receptor status, or the number of positive nodes. RESULTS There were no significant differences in the 5- and 10-year cumulative incidence of an IBTR, regional node recurrence, initial or total distant metastases for the two groups. Similarly 5- and 10-year actuarial overall and cause-specific survival were not significantly different. However, subset analysis revealed a statistically significant increase in initial (29% vs. 15% at 10 yr, p = 0.002) and total (30% vs. 17% at 10 yr, p = 0.01) distant metastases and a significant decrease in cause-specific survival (76% vs. 89% at 10 yr, p = 0.02) for postmenopausal women who received IMN treatment. These findings could not be attributed to differences in the use of systemic therapy or the number of positive nodes. Axillary node-positive patients did not experience a significant decrease in initial (36% vs. 22% at 10 yr, p = 0.21) or total distant metastases (37% vs. 28% at 10 yr, p = 0.62) or a significant improvement in cause-specific survival (72% vs. 76% at 10 yr, p = 0.76) with IMN treatment regardless of whether the tumor was lateral or medial/central in location. IMN treatment was not associated with an increase in non-breast cancer deaths during this period of observation. CONCLUSIONS This retrospective series was unable to identify a significant benefit for IMN irradiation in terms of distant metastases or cause-specific survival for the entire patient population, and in particular, for patients with positive axillary nodes and medially located lesions. The results of the proposed or ongoing prospective randomized trials will further address this controversial issue.

Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non–Small-Cell Lung Cancer: An Analysis of RTOG 9801

PURPOSE To determine the added value of quality of life (QOL) as a prognostic factor for overall survival (OS) in patients with locally advanced non-small-cell lung cancer (NSCLC) treated on Radiation Therapy Oncology Group RTOG-9801. PATIENTS AND METHODS Two hundred forty-three patients with stage II/IIIAB NSCLC received induction paclitaxel and carboplatin (PC) and then concurrent weekly PC and hyperfractionated radiation (to 69.6 Gy). Patients were randomly assigned to amifostine (AM) or no AM during chemoradiotherapy. The following pretreatment factors were analyzed as prognostic factors for OS: Karnofsky performance status, stage, sex, age, race, marital status, histology, tumor location, hemoglobin, tobacco use, treatment arm (AM v no AM) and QOL scores (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [QLQ-C30] and Lung Cancer 13 [LC-13]). A multivariate (MVA) Cox proportional hazards model was performed using a backwards selection process. RESULTS Of the 239 analyzable patients, 91% had a baseline global QOL score. Median follow-up time was 59 months for patients still alive and 17 months for all patients. Median baseline QLQ-C30 global QOL score was 66.7 on both treatment arms. Whether the global QOL score was treated as a dichotomized variable (based on the median score) or a continuous variable, all other variables fell out of the MVA for OS. Patients with a global QOL score less than 66.7 had an approximately 70% higher rate of death than patients with scores > or = 66.7 (P = .004). A 10-point higher baseline global QOL score corresponded to a decrease in the hazard of death by approximately 10% (P = .004). The other independent QOL predictors for OS were the QLQ-C30 physical functioning (P = .011) and LC-13 dyspnea scores (P = .012). CONCLUSION In this analysis, baseline global QOL score replaced known prognostic factors as the sole predictor of long-term OS for patients with locally advanced NSCLC.

Breast intensity-modulated radiation therapy reduces time spent with acute dermatitis for women of all breast sizes during radiation.

PURPOSE To study the time spent with radiation-induced dermatitis during a course of radiation therapy for breast cancer in women treated with conventional or intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS The study population consisted of 804 consecutive women with early-stage breast cancer treated with breast-conserving surgery and radiation from 2001 to 2006. All patients were treated with whole-breast radiation followed by a boost to the tumor bed. Whole-breast radiation consisted of conventional wedged photon tangents (n = 405) earlier in the study period and mostly of photon IMRT (n = 399) in later years. All patients had acute dermatitis graded each week of treatment. RESULTS The breakdown of the cases of maximum acute dermatitis by grade was as follows: 3%, Grade 0; 34%, Grade 1; 61%, Grade 2; and 2%, Grade 3. The breakdown of cases of maximum toxicity by technique was as follows: 48%, Grade 0/1, and 52%, Grade 2/3, for IMRT; and 25%, Grade 0/1, and 75%, Grade 2/3, for conventional radiation therapy (p < 0.0001). The IMRT patients spent 82% of weeks during treatment with Grade 0/1 dermatitis and 18% with Grade 2/3 dermatitis, compared with 29% and 71% of patients, respectively, treated with conventional radiation (p < 0.0001). Furthermore, the time spent with Grade 2/3 toxicity was decreased in IMRT patients with small (p = 0.0015), medium (p < 0.0001), and large (p < 0.0001) breasts. CONCLUSIONS Breast IMRT is associated with a significant decrease both in the time spent during treatment with Grade 2/3 dermatitis and in the maximum severity of dermatitis compared with that associated with conventional radiation, regardless of breast size.

TOXICITY AND OUTCOME ANALYSIS OF PATIENTS WITH RECURRENT HEAD AND NECK CANCER TREATED WITH HYPERFRACTIONATED SPLIT-COURSE REIRRADIATION AND CONCURRENT CISPLATIN AND PACLITAXEL CHEMOTHERAPY FROM TWO PROSPECTIVE PHASE I AND II STUDIES

Patients with local recurrences or new head and neck primary tumors in previously irradiated tissues have few options for salvage treatment. One option for select patients is to undergo reirradiation with concurrent chemotherapy. The purpose of this study is to report the initial clinical results of the Fox Chase phase I and II prospective reirradiation and chemotherapy studies.

Postmastectomy chest wall radiation to a temporary tissue expander or permanent breast implant--is there a difference in complication rates?

PURPOSE The purpose of this study was to evaluate the likelihood of complications and cosmetic results among breast cancer patients who underwent modified radical mastectomy (MRM) and breast reconstruction followed by radiation therapy (RT) to either a temporary tissue expander (TTE) or permanent breast implant (PI). METHODS AND MATERIALS Records were reviewed of 74 patients with breast cancer who underwent MRM followed by breast reconstruction and RT. Reconstruction consisted of a TTE usually followed by exchange to a PI. RT was delivered to the TTE in 62 patients and to the PI in 12 patients. Dose to the reconstructed chest wall was 50 Gy. Median follow-up was 48 months. The primary end point was the incidence of complications involving the reconstruction. RESULTS There was no significant difference in the rate of major complications in the PI group (0%) vs. 4.8% in the TTE group. No patients lost the reconstruction in the PI group. Three patients lost the reconstruction in the TTE group. There were excellent/good cosmetic scores in 90% of the TTE group and 80% of the PI group (p = 0.22). On multivariate regression models, the type of reconstruction irradiated had no statistically significant impact on complication rates. CONCLUSIONS Patients treated with breast reconstruction and RT can experience low rates of major complications. We demonstrate no significant difference in the overall rate of major or minor complications between the TTE and PI groups. Postmastectomy RT to either the TTE or the PI should be considered as acceptable treatment options in all eligible patients.