Laura A. Vallow

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.

Prognostic factors in Merkel cell carcinoma: Analysis of 240 cases

BACKGROUND Knowledge regarding behavior of and prognostic factors for Merkel cell carcinoma (MCC) is limited. OBJECTIVE We sought to further understand the characteristics, behavior, prognostic factors, and optimal treatment of MCC. METHODS A multicenter, retrospective, consecutive study of patients with known primary MCC was completed. Overall survival and survival free of locoregional recurrence were calculated and statistical analysis of characteristics and outcomes was performed. RESULTS Among the 240 patients, the mean age at diagnosis was 70.1 years, 168 (70.0%) were male, and the majority was Caucasian. The most common location was head and neck (111, 46.3%). Immunosuppressed patients had significantly worse survival, with an overall 3-year survival of 43.4% compared with 68.1% in immunocompetent patients. In our study, patients with stage II disease had improved overall survival versus those with stage I disease, in a statistically significant manner. Patients with stage III disease had significantly worse survival compared with stage I and with stage II. Primary tumor size did not predict nodal involvement. CONCLUSION The data presented represent one of the largest series of primary MCC in the literature and confirm that MCC of all sizes has metastatic potential, supporting sentinel lymph node biopsy for all primary MCC. Because of the unpredictable natural history of MCC, we recommend individualization of care based on the details of each patients tumor and clinical presentation.

Clinical outcomes after a diagnosis of brain metastases in patients with estrogen- and/or human epidermal growth factor receptor 2-positive versus triple-negative breast cancer

BACKGROUND Women with triple-negative (TN) breast cancer are at increased risk of distant metastases and have reduced survival versus other breast cancer patients. Relative survival of women with TN breast cancer who develop brain metastases is unknown. METHODS Patients with breast cancer who developed brain metastases at our institution from 1993 to 2006 were reviewed. Four survival time intervals were compared in patients with TN disease and those with non-TN disease: initial diagnosis to distant metastases, distant metastases to brain metastases, brain metastases to death, and overall diagnosis to death. RESULTS One hundred and eighteen patients were identified. Fifty-one (50%) of 103 were estrogen receptor positive, 26 (39%) of 67 were human epidermal growth factor receptor 2 positive, and 20 (22%) of 91 were TN. Survival times were shorter for TN patients, with overall survival of 26 months in TN patients versus 49 months for non-TN patients. In TN patients, time to development of distant metastases, brain metastases, and death after brain metastases was shorter than in non-TN patients. CONCLUSION Patients with TN disease were more likely to develop distant metastases earlier than non-TN patients, developed brain metastases sooner, and had shorter overall survival.

Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial

BACKGROUND Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy. METHODS The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete. FINDINGS Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group. INTERPRETATION Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ. FUNDING US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

Unknown primary Merkel cell carcinoma: 23 new cases and a review

BACKGROUND Knowledge is limited regarding unknown primary Merkel cell carcinoma (UPMCC). OBJECTIVE We sought to document the characteristics and behavior of UPMCC, and determine the most appropriate treatment. METHODS A multicenter, retrospective, consecutive study reviewing patients given a diagnosis of UPMCC between 1981 and 2008 was completed. In addition, a literature review of cases of UPMCC was performed. RESULTS In all, 23 patients with UPMCC are described and 34 cases from previous reports are compiled. Among the 23 new cases of UPMCC, the average age at diagnosis was 66.0 years; the majority of patients were male (87%) and Caucasian (100% of those reported). One patient was immunosuppressed, and 39% had a history of other cancer. After the initial biopsy, 16 patients had further evaluation of the involved lymph node basin. Half of these had additional positive nodes (8 of 16). The majority of patients had lymph node basin involvement only (78%), whereas 22% had lymph node basin and distant metastasis. The most common lymph node basin involved was inguinal. The median size of the involved lymph node at diagnosis was 5.0 cm. At 2 years, the overall survival of stage IIIB UPMCC was significantly improved versus stage IIIB known primary Merkel cell carcinoma (MCC): 76.9% to 36.4%. LIMITATIONS Limited number of cases and retrospective review are limitations. CONCLUSION Our data demonstrate improved overall survival in patients with stage IIIB UPMCC versus those with stage IIIB known primary MCC. Because of the unpredictable natural history of UPMCC, we recommend individualization of care based on the details of each patients clinical presentation.

Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial

BACKGROUND The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms. METHODS The study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (<60 years vs ≥60 years). Patients and investigators were masked to treatment allocation. Patients completed questionnaires at baseline and every 6 months thereafter for 6 years. The primary outcomes were SF-12 physical and mental health component scale scores, and vasomotor symptoms (as per the BCPT symptom scale). Secondary outcomes were vaginal symptoms and sexual functioning. Exploratory outcomes were musculoskeletal pain, bladder symptoms, gynaecological symptoms, cognitive symptoms, weight problems, vitality, and depression. We did the analyses by intention to treat, including patients who completed questionnaires at baseline and at least once during follow-up. This study is registered with ClinicalTrials.gov, NCT00053898. FINDINGS Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled in the study, of whom 1193 were included in the quality-of-life substudy: 601 assigned to tamoxifen and 592 assigned to anastrozole. We detected no significant difference between treatment groups for: physical health scores (mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole; p=0·20), mental health scores (52·38 vs 51·48; p=0·38), energy and fatigue (58·34 vs 57·54; p=0·86), or symptoms of depression (6·19 vs 6·39; p=0·46) over 5 years. Vasomotor symptoms (1·33 vs 1·17; p=0·011), difficulty with bladder control (0·96 vs 0·80; p=0·0002), and gynaecological symptoms (0·29 vs 0·18; p<0·0001) were significantly more severe in the tamoxifen group than in the anastrozole group. Musculoskeletal pain (1·50 vs 1·72; p=0·0006) and vaginal symptoms (0·76 vs 0·86; p=0·035) were significantly worse in the anastrozole group than in the tamoxifen group. Sexual functioning did not differ significantly between the two treatments (43·65 vs 45·29; p=0·56). Younger age was significantly associated with more severe vasomotor symptoms (mean severity score 1·45 for age <60 years vs 0·65 for age ≥60 years; p=0·0006), vaginal symptoms (0·98 vs 0·65; p<0·0001), weight problems (1·32 vs 1·02; p<0·0001), and gynaecological symptoms (0·26 vs 0·22; p=0·014). INTERPRETATION Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years, decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug. For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative. FUNDING US National Cancer Institute, AstraZeneca Pharmaceuticals.

Ductal carcinoma in situ of the breast

Ductal carcinoma in situ (DCIS) of the breast represents a complex, heterogeneous pathologic condition in which malignant epithelial cells are confined within the ducts of the breast without evidence of invasion. The increased use of screening mammography has led to a significant shift in the diagnosis of DCIS, accounting for approximately 27% of all newly diagnosed cases of breast cancer in 2011, with an overall increase in incidence. As the incidence of DCIS increases, the treatment options continue to evolve. Consistent pathologic evaluation is crucial in optimizing treatment recommendations. Surgical treatment options include breast-conserving surgery (BCS) and mastectomy. Postoperative radiation therapy in combination with breast-conserving surgery is considered the standard of care with demonstrated decrease in local recurrence with the addition of radiation therapy. The role of endocrine therapy is currently being evaluated. The optimization of diagnostic imaging, treatment with regard to pathological risk assessment, and the role of partial breast irradiation continue to evolve.

Radiotherapy for marginally resected, unresectable or recurrent giant cell tumor of the bone: a rare cancer network study

The role of radiotherapy for local control of marginally resected, unresectable, and recurrent giant cell tumors of bone (GCToB) has not been well defined. The number of patients affected by this rare disease is low. We present a series of 58 patients with biopsy proven GCToB who were treated with radiation therapy. A retrospective review of the role of radiotherapy in the treatment of GCToB was conducted in participating institutions of the Rare Cancer Network. Eligibility criteria consisted of the use of radiotherapy for marginally resected, unresectable, and recurrent GCToB. Fifty-eight patients with biopsy proven GCToB were analyzed from 9 participating North American and European institutions. Forty-five patients had a primary tumor and 13 patients had a recurrent tumor. Median radiation dose was 50 Gy in a median of 25 fractions. Indication for radiation therapy was marginal resection in 33 patients, unresectable tumor in 13 patients, recurrence in 9 patients and palliation in 2 patients. Median tumor size was 7.0 cm. A significant proportion of the tumors involved critical structures. Median follow-up was 8.0 years. Five year local control was 85% . Of the 7 local failures, 3 were treated successfully with salvage surgery. All patients who received palliation achieved symptom relief. Five year overall survival was 94%. None of the patients experienced grade 3 or higher acute toxicity. This study reports a large published experience in the treatment of GCToB with radiotherapy. Radiotherapy can provide excellent local control for incompletely resected, unresectable or recurrent GCToB with acceptable morbidity.

Does Three-Dimensional External Beam Partial Breast Irradiation Spare Lung Tissue Compared With Standard Whole Breast Irradiation?

PURPOSE To determine whether three-dimensional conformal partial breast irradiation (3D-PBI) spares lung tissue compared with whole breast irradiation (WBI) and to include the biologically equivalent dose (BED) to account for differences in fractionation. METHODS AND MATERIALS Radiotherapy treatment plans were devised for WBI and 3D-PBI for 25 consecutive patients randomized on the NSABP B-39/RTOG 0413 protocol at Mayo Clinic in Jacksonville, Florida. WBI plans were for 50 Gy in 25 fractions, and 3D-PBI plans were for 38.5 Gy in 10 fractions. Volume of ipsilateral lung receiving 2.5, 5, 10, and 20 Gy was recorded for each plan. The linear quadratic equation was used to calculate the corresponding dose delivered in 10 fractions and volume of ipsilateral lung receiving these doses was recorded for PBI plans. Ipsilateral mean lung dose was recorded for each plan and converted to BED. RESULTS There was a significant decrease in volume of lung receiving 20 Gy with PBI (median, 4.4% vs. 7.5%; p < 0.001), which remained after correction for fractionation (median, 5.6% vs. 7.5%; p = 0.02). Mean lung dose was lower for PBI (median, 3.46 Gy vs. 4.57 Gy; p = 0.005), although this difference lost significance after conversion to BED (median, 3.86 Gy(3) vs 4.85 Gy(3), p = 0.07). PBI plans exposed more lung to 2.5 and 5 Gy. CONCLUSIONS 3D-PBI exposes greater volumes of lung tissue to low doses of radiation and spares the amount of lung receiving higher doses when compared with WBI.

In newly diagnosed breast cancer, screening MRI of the contralateral breast detects mammographically occult cancer, even in elderly women: The Mayo Clinic in Florida experience

Abstract:  The role of magnetic resonance imaging (MRI) in patients with newly diagnosed breast cancer is somewhat controversial. The purpose of this study was to evaluate the prevalence of synchronous, occult contralateral breast cancer detected by MRI but not by mammography or clinical breast examination in women with newly diagnosed breast cancer, including those aged 70 years or older at our institution. MRI results for women with newly diagnosed breast cancer who underwent bilateral breast MRI after negative mammography and clinical examination between February 2003 and November 2007 at Mayo Clinic in Florida were reviewed. The prevalence of pathologically confirmed contralateral carcinoma diagnosed solely by MRI was determined and analyzed in the context of age, family history, menopausal status, breast density, and primary‐tumor characteristics. Logistic regression was used to explore the association between contralateral carcinoma and potential patient risk factors. A total of 425 women were evaluated, of whom 129 (30%) were aged 70 years or older. A contralateral biopsy was recommended and performed solely on the basis of MRI in 72 of the 425 women (17%). Sixteen of these 72 women (22%) had pathologically confirmed carcinoma, including seven in the older subgroup. The prevalence of clinically and mammographically occult contralateral carcinoma detected by MRI was 3.8% (16/425) overall and 5.4% (7/129) in the group of older women. When potential risk factors for contralateral breast cancer were evaluated, postmenopausal status was the only significant predictor of contralateral cancer detected by MRI (p = 0.016). We concluded that contralateral breast screening with MRI should be considered in postmenopausal women with newly diagnosed breast cancer, even those aged 70 years or older at diagnosis.