Janice Lyons

Importance of high radiation doses (72 Gy or greater) in the treatment of Stage T1-T3 adenocarcinoma of the prostate

OBJECTIVES To analyze the effect of total radiation dose on the outcome of patients treated with external beam radiotherapy for early-stage prostate cancer. METHODS The records of a total of 738 patients with localized prostate cancer treated with external beam radiotherapy (RT) and no androgen deprivation at our institution between July 1986 and February 1999 were reviewed. Two risk groups were defined: favorable (Stage T1-T2, pretreatment prostate-specific antigen [PSA] level 10.0 ng/mL or less, and biopsy Gleason score 6 or less) and unfavorable (Stage T3 lesion or pretreatment PSA level greater than 10.0 ng/mL or biopsy Gleason score 7 or greater). The median RT dose was 70.0 Gy (range 57.6 to 78.0), with 192 patients (26%) receiving at least 72.0 Gy. The mean follow-up was 45 months. RESULTS The 5-year biochemical relapse-free survival (bRFS) rate was 58%. The 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 85% and 54%, respectively (P <0.001). On multivariate analysis of factors affecting bRFS rates, the number of follow-up PSA levels (P <0.001), tumor stage (P <0.001), pretreatment PSA (P <0.001), biopsy Gleason score (P <0.00 1), and RT dose (P = 0.001) were the only independent predictors of outcome. For favorable tumors, the 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 98% and 81 %, respectively (P = 0.023). For unfavorable tumors, the 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 75% and 41 %, respectively (P = 0.001). CONCLUSIONS Patients receiving radiation doses of 72 Gy or higher had a significantly better outcome. The improvement was seen in all subgroups of patients. If these results are confirmed, radiation doses exceeding 72 Gy should be considered the standard of care. Inc.

Higher than standard radiation doses (≥72 Gy) with or without androgen deprivation in the treatment of localized prostate cancer

PURPOSE To study the effect on biochemical relapse-free survival (bRFS) and clinical disease-free survival of radiation doses delivered to the prostate and periprostatic tissues for localized prostate cancer. METHODS AND MATERIALS A total of 1041 consecutive localized prostate cancer cases treated with external beam radiotherapy (RT) at our institution between 7/86 and 2/99 were reviewed. All cases had available pretreatment parameters including pretreatment prostate-specific antigen (iPSA), biopsy Gleason score (bGS), and clinical T stage. The median age was 69 years. Twenty-three percent of cases (n = 238) were African-American. The distribution by clinical T stage was as follows: T1 in 365 cases (35%), T2 in 562 cases (54%), and T3 in 114 cases (11%). The median iPSA level was 10.1 ng/ml (range: 0.4-692.9). The distribution by biopsy Gleason score (bGS) was as follows: < or =6 in 580 cases (56%) and > or =7 in 461 cases (44%). Androgen deprivation (AD) in the adjuvant or neoadjuvant setting was given in 303 cases (29%). The mean RT dose was 71.9 Gy (range: 57.6-78.0 Gy). The median RT dose was 70.2 Gy, with 458 cases (44%) receiving at least 72.0 Gy. The average dose in patients receiving <72 Gy was 68.3 Gy (median 68.4) versus 76.5 Gy (median 78.0) for patients receiving > or =72 Gy. The mean follow-up was 38 months (median 33 months). The number of follow-up prostate-specific antigen (PSA) levels available was 5998. RESULTS The 5- and 8-year bRFS rates were 61% (95% CI 55-65%) and 58% (95% CI 51-65%), respectively. The 5-year bRFS rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 87% (95% CI 82-92%) and 55% (95% CI 49-60%), respectively. The 8-year bRFS rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 87% (95% CI 82-92%) and 51% (95% CI 44-58%), respectively (p < 0.001). A multivariate analysis of factors affecting bRFS was performed using the following parameters: age (continuous variable), race, T-stage (T1-T2 vs. T3), iPSA (continuous variable), bGS (< or =6 vs. > or =7), use of AD (yes vs. no), radiation technique (conformal versus standard), and radiation dose (continuous variable). T-stage (p < 0.001), iPSA (p < 0.001), bGS (p < 0.001), and RT dose (p < 0.001) were independent predictors of outcome. Age (p = 0.74), race (p = 0.96), radiation technique (p = 0.15), and use of AD (p = 0.31) were not. We observed 11% clinical failures (local, distant, or both) at 5 years and 15% at 8 years for the entire cohort. There was a statistically significant improvement with higher radiation doses (p = 0.032). The 5-year clinical relapse rates for patients receiving > or =72 Gy versus <72 Gy were 5% and 12%, respectively. The 8-year clinical relapse rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 5% and 17%, respectively (p = 0.026). CONCLUSION Patients receiving radiation doses exceeding 72 Gy had significantly better bRFS and clinical disease-free survival rates. Although results need to be confirmed with longer follow-up, these preliminary results are extremely encouraging. If these results are confirmed by other institutions and by longer follow-up, RT doses exceeding 72 Gy should be considered as standard of care.

A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: Impact on angiogenic biomarkers

Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase II trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel. Experimental Design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m2 i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle. Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P < 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P < 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012). Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin.

Breast Conservation Surgery Achieving ≥ 2 mm Tumor-Free Margins Results in Decreased Local-Regional Recurrence Rates

Abstract:  Whether cosmetically acceptable tumor‐free (≥2 mm) surgical margins reduce the local‐regional recurrence risk for patients treated with fractionated radiation therapy, chemotherapy, and hormonal therapy is unknown. The benefit of a minimum cosmetically acceptable tumor‐free margin remains speculative because no contemporary studies have investigated the extent of invasive disease infiltration within the breast beyond the primary tumor. To address these clinical issues, we conducted a retrospective study of 341 women diagnosed with stage I or II invasive breast cancer to determine the rate of local in‐breast, elsewhere in‐breast, and ipsilateral regional lymph node recurrences of breast cancer after conservation surgery achieving either tumor‐free (≥2 mm) or close (>0 mm to <2 mm) surgical margins followed by whole breast radiation therapy over a 6‐year period from January 1996 to December 2002. Women may have received adjuvant chemotherapy or hormonal therapy as clinically indicated. After a median follow‐up of 56 months from the completion of breast conservation surgery, 14 of the 341 women (4.1%) developed breast cancer recurrences. Crude ipsilateral recurrence rates were 1.8% (4 of 222) for tumor‐free (≥2 mm) versus 8.4% (10 of 119) for close (>0 mm to <2 mm) surgical margins (p = 0.007). The estimated 5‐year cumulative local recurrence rate was significantly less for women with tumor‐free margins (2.1%) as compared to close surgical margins (8.9%) (p = 0.004). Multivariate analyses identified negative estrogen receptor expression (p = 0.004), close surgical margins (p = 0.012), and the presence of angiolymphatic invasion (p = 0.040) as prognostic factors for local‐regional recurrences. Microscopically the extent of invasive disease infiltration beyond the primary tumor was on average 1 mm, with all measured invasive disease less than 1 cm. Based on our findings, cosmetically acceptable tumor‐free (≥2 mm) surgical margins significantly reduce local in‐breast and regional lymph node recurrences with fractionated radiation therapy, chemotherapy, and hormonal therapy.

Treatment and prognosis of primary breast lymphoma: A review of 13 cases

Primary non-Hodgkins lymphoma (NHL) of the breast is a rare entity that does not have a well-defined treatment strategy. At presentation, most patients are clinically thought to have a primary breast carcinoma, and the diagnosis of lymphoma is made at biopsy. Once the diagnosis of lymphoma is made, patients are treated with some combination of chemotherapy, radiation therapy, and surgery. We review The Cleveland Clinic Foundation experience with primary breast lymphoma. Between 1980 and 1996, 17 patients with primary breast lymphoma were seen at The Cleveland Clinic Foundation, and 13 had follow-up information available. All patients underwent a staging workup including computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as bilateral bone marrow biopsies; all patients staged IE (breast involvement only) or IIE (limited to the breast and ipsilateral axilla) were included. We did not include patients with more extensive supradiaphragmatic nodal involvement who were stage IIE. Patients received some combination of surgery, radiation, and chemotherapy. The median follow-up was 34 months, with a range of 7 to 138 months. There was an equal incidence of right- versus left-sided lesions. Five patients survived at least 5 years from the time of diagnosis. Long-term survival in patients with primary NHL of the breast is possible. We recommend treating patients with aggressive NHL of the breast with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, followed by involved field radiation and treating those patients with indolent lymphoma with involved field radiation alone.

The acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous flap used in immediate breast reconstruction

PURPOSE To analyze the acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous (TRAM) flap reconstruction following modified radical mastectomy for breast cancer. METHODS AND MATERIALS Twenty-five consecutive patients were treated with postoperative radiation therapy after TRAM flap reconstruction between 1985 and 1999. The radiation records for these patients were retrospectively reviewed. Information regarding treatment techniques, timing, and dose was obtained and correlated with the extent of erythema, desquamation, and the need for treatment break. RESULTS The median age was 48 years. The median dose of chest wall radiation was 5040 cGy. Additional boost doses were delivered in 13 patients. Twelve patients (48%) developed mild erythema in the treatment field during the course of treatment and 13 patients (52%) developed moderate (40%) or brisk (12%) erythema. Only 10 patients (40%) developed any kind of desquamation; 5 patients (20%) developed dry desquamation and another 5 patients (20%) developed moist desquamation. No patients required a break in the course of treatment because of acute side effects. None of the parameters evaluated (the use of chemotherapy prior to radiation, the interval between surgery and radiation, smoking, prior incidence of fat necrosis, the use of bolus during radiation, and the use of a boost) were predictive of an increased incidence of either the extent of erythema or the development of desquamation in the treatment field. CONCLUSION Postmastectomy radiation for TRAM flap reconstruction is well tolerated and is not associated with an increased incidence of acute side effects. Radiation technique and the use of preradiation chemotherapy do not appear to be correlated with an increased incidence of acute side effects.

Phase II trial of neoadjuvant docetaxel with or without bevacizumab in patients with locally advanced breast cance.

727 Background: The anti-angiogenic agent, bevacizumab (rhuMAbVEGF) is a humanized monoclonal antibody against VEGF which, when combined with docetaxel in preclinical models, results in synergistic suppression of capillary vessel formation. Based on these data, a randomized phase II trial was developed to evaluate the vascular effects on tumor regression with combination bevacizumab/docetaxel vs. docetaxel in the treatment of locally advanced breast cancer. METHODS 33 patients (pts) were randomized to receive neoadjuvant therapy with bevacizumab (10 mg/kg qowk) and docetaxel (two 8-week cycles of 35 mg/m2 weekly x 6 with a 2 wk break) or docetaxel alone. Eligible pts had locally unresectable breast cancer with or without metastasis. Pts who responded underwent definitive surgery, radiation, 4 cycles of adjuvant conventional Adriamycin/cyclophosphamide, followed by tamoxifen (if ER/PR+). RESULTS 26 pts completed pre-operative treatment. 3 pts with inflammatory breast cancer were not operable at the conclusion of therapy because of residual disease. The median number of pathologically + lymph nodes (ln) was 1 (range 0-16); 40% were ln negative. The median size of residual tumor was 3.2cm (range 0-14cm). Toxicity included: grade 4 neutropenia-4; grade 3: anorexia-3; GI bleed-1; stomatitis-3; neuropathy-1; wound healing-1. There was no change in LVEF, no hypertension, protienuria, or thrombosis. Preliminary analysis of correlative studies suggests a reduction in tumor Kep by DCE-MRI and a reduction of tumor microvessel density. CONCLUSIONS Neoadjuvant therapy for locally advanced breast cancer using docetaxel with or without bevacizumab is well tolerated and effective. This study requires a total of 60 pts before an analysis can be made of a treatment difference in vascular and disease response. Laboratory correlatives evaluating effects on tumor vasculature are ongoing. (Sponsored by grants: K23CA 87725-01, M01 RR 00080, UO1 CA 62502, P30 CA43703S NCI/Avon) No significant financial relationships to disclose.

Postoperative Single-Fraction Radiation for Prevention of Heterotopic Ossification of the Elbow

PURPOSE Heterotopic ossification (HO) about the elbow has been described after surgery, trauma, and burns. Even limited deposits can lead to significant functional deficits. Little data exist regarding outcomes of patients treated with radiation therapy (RT) after elbow surgery. We report here the Cleveland Clinic experience with single-fraction radiation following surgery to the elbow. The primary endpoint was the rate of new HO after RT. Secondary endpoints were range of motion, functional compromise, and toxicity. METHODS AND MATERIALS From May 1993 to July 2006, 36 patients underwent elbow surgery followed by single-fraction RT. Range of motion data were collected before and during surgery and at last follow-up. Radiographs were reviewed for persistent or new HO. Patient and treatment factors were analyzed for correlation with development of HO or functional compromise. RESULTS Median follow-up was 8.7 months, median age was 42 years, and 75% of patients were male. Twenty-six (72%) patients had HO prior to surgery. All patients had significant limitations in flexion/extension or pronation/supination at baseline. Thirty-one (86%) patients had prior elbow trauma, and 26 (72%) patients had prior surgery. RT was administered a median of 1 day postoperatively (range, 1-4 days). Thirty-four patients received 700 cGy, and 2 patients received 600 cGy. Three (8%) patients developed new HO after RT. All patients had improvement in range of motion from baseline. No patient or treatment factors were significantly associated with the development of HO or functional compromise. CONCLUSIONS Single-fraction RT after surgery to the elbow is associated with favorable functional and radiographic outcomes.

Neglecting to Screen Women Between the Ages of 40 and 49 Years With Mammography: What Is the Impact on Breast Cancer Diagnosis?

OBJECTIVE The purpose of this study was to compare breast cancer stage at diagnosis in two groups of women between 40 and 49 years old: women undergoing screening mammography and women with a symptom needing diagnostic workup. This comparison is indicative of the impact of forgoing screening in this age group, as recommended by the United States Preventive Services Task Force. MATERIALS AND METHODS A retrospective chart review was used to collect the results of imaging-guided core needle biopsies performed in women between the ages of 40 and 49 years from January 1, 2008, to December 31, 2009. In patients diagnosed with breast cancer or a high-risk lesion, the reason for presentation, pathology, tumor size, stage, and receptor characteristics were recorded. The chi-square test was used for statistical analysis. RESULTS Of 108 primary breast cancers, 71 were detected in the screened group and 37 in the unscreened group. The screened group was significantly more likely to be diagnosed with ductal carcinoma in situ than the unscreened group (22 vs 1, chi-square = 11.6, p = 0.001). Furthermore, screened patients with invasive carcinoma were significantly more likely to be diagnosed at earlier stages (chi-square = 5.02, p = 0.025). The size of invasive breast cancer in the screened group was significantly smaller as well (chi-square = 9.3, p = 0.002). Of the high-risk lesions, atypical ductal hyperplasia (n = 29) and lobular carcinoma in situ (n = 8) were most frequently seen. CONCLUSION Breast cancer patients undergoing screening mammography were diagnosed at earlier stages with smaller tumors. Screening also allows detection of high-risk lesions, which may prompt chemoprevention and lower subsequent breast cancer risk. We continue to support screening mammography in women between the ages of 40 and 49 years.

Neglecting to screen women between 40 and 49 years old with mammography: What is the impact on treatment morbidity and potential risk reduction?

OBJECTIVE The purpose of this study is to determine whether there were significant differences with respect to treatment recommendations, stage at diagnosis, and identification of high-risk lesions for women 40-49 years old undergoing screening mammography (screened) compared to women with a symptom needing a diagnostic evaluation (nonscreened). MATERIALS AND METHODS We reviewed the pathology results of all imaging-guided biopsies performed at the three breast center locations of University Hospitals Case Medical Center from January 1, 2008, to December 31, 2011. In patients diagnosed with a high-risk lesion or breast cancer, the reason for presentation, pathology, tumor size, stage, receptor characteristics, and treatment were recorded. The chi-square test was used for statistical analysis. RESULTS Of 230 primary breast cancers, 149 were in the screened group and 81 were considered nonscreened. Nonscreened patients were more likely to undergo chemotherapy (p = 0.042). Eighty-one percent of the high-risk lesions were diagnosed in the screened patients. Screened patients with cancer were significantly more likely to receive a diagnosis at earlier stages (p = 0.001), to have negative axillary lymph nodes (p = 0.005), and to have smaller tumors (p < 0.001). CONCLUSION In addition to the benefits of receiving a diagnosis at earlier stages, with smaller tumors and node negativity, patients with breast cancer undergoing screening mammography aged 40-49 years are less likely to require chemotherapy and its associated morbidities. The majority of high-risk lesions were diagnosed in the screened group, which may lead to the benefit of chemoprevention, lowering their risk of subsequent breast cancer, or screening with MRI, which may diagnose future mammographically occult malignancies.