Stephen J. Ko

SALVAGE RADIOTHERAPY FOR RISING PROSTATE-SPECIFIC ANTIGEN LEVELS AFTER RADICAL PROSTATECTOMY FOR PROSTATE CANCER: DOSE-RESPONSE ANALYSIS

PURPOSE To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising prostate-specific antigen (PSA) level after radical prostatectomy. METHODS AND MATERIALS We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy). RESULTS A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). CONCLUSIONS Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.

Late toxicity after postprostatectomy salvage radiation therapy

PURPOSE To evaluate late toxicity in patients who received salvage external beam radiotherapy (EBRT) for a detectable prostate-specific antigen (PSA) level after radical prostatectomy (RP). METHODS A cohort of 308 consecutive patients underwent salvage EBRT from July 1987 through June 2003 for a detectable PSA level after RP. All were treated with high-energy photons (6-20 MV) to a median dose of 64.8 Gy (range: 54.0-72.4 Gy) in 1.8- to 2.0-Gy fractions. RESULTS Median follow-up from the completion of EBRT was 60 months (range: 1 day-174 months). Late toxicity occurring more than 90 days after EBRT completion was identified in 41 patients (13%). Twelve patients (3.9%) had grade 2 urethral strictures and were treated with urethral dilation, 3 patients had grade 3 cystitis, and 1 had a grade 4 rectal complication. These numbers correspond to an estimated 0.7% (95% confidence interval, 0.0-1.6%) of patients experiencing a grade 3 or 4 complication by 5 years after the start of EBRT. CONCLUSIONS Salvage EBRT for a detectable PSA level after RP is the only curative treatment in this setting. This treatment can be administered in a manner that results in a low likelihood of late complications.

Impact of Neoadjuvant Chemoradiation on the Tumor Burden Before Liver Transplantation for Unresectable Cholangiocarcinoma

The very early experience with liver transplantation (LT) for cholangiocarcinoma (CC) was dismal because of the poor survival outcomes and the high recurrence rates. However, LT for CC in conjunction with neoadjuvant chemoradiation recently has shown encouraging results, although the data are extremely limited. At our institution between 2001 and 2008, 22 CC patients underwent protocol orthotopic LT at a median age of 45 years (range = 24‐63 years). At a median follow‐up of 601.5 days (range = 111‐1388 days), the median survival time of the cohort was 3.3 years. The 1‐, 2‐, and 3‐year Kaplan‐Meier survival probabilities were 90%, 70%, and 63%, respectively, whereas the historical 5‐year survival rates were 0% to 18% for intrahepatic CC and 23% to 26% for extrahepatic CC when patients underwent transplantation without neoadjuvant therapy. These encouraging survival rates for patients with this type of tumor, which is difficult to diagnose and treat, are no less significant when they are compared to the national 1‐ and 3‐year survival rates (86% and 68%, respectively) of patients undergoing deceased donor LT for malignant neoplasms of the liver (as reported by the United Network for Organ Sharing). In our series, disease recurrence was significantly associated with a larger residual tumor [6.3 versus 2.0 cm (mean values), P = 0.008] and with a shorter waiting time for LT after the chemoradiation protocol [18 versus 56 days (mean values), P = 0.04]. Our LT protocol for CC was found to be promising for patients with truly extrahepatic CC and for patients within stages I to IIB of the American Joint Committee on Cancer Staging system (100% survival at a median follow‐up of 2.2 years), but the results were notably poor for patients with stage III extrahepatic CC (median survival = 1.2 years). These observations highlight the need for accurate preoperative staging of CC for ideal LT recipient selection and the importance of a low tumor burden and a longer wait after neoadjuvant therapy. More effective chemoradiation regimens for reducing the tumor burden and the appropriate timing of LT after neoadjuvant chemoradiation require further research. Liver Transpl, 2012.

Angiosarcoma of the Scalp and Face The Mayo Clinic Experience

IMPORTANCE The etiology and optimal treatment are unknown for angiosarcoma, an aggressive malignant tumor that affects vascular endothelial cells and can be mistaken for benign lesions such as hemangioma. OBJECTIVE To determine the treatment outcomes of patients with angiosarcoma of the face or scalp treated with a combination of surgery, radiation therapy, and/or chemotherapy. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 55 patients with angiosarcoma of the face or scalp treated between January 1, 1973, and December 31, 2012, at a tertiary-care academic medical institution. INTERVENTIONS Surgery, radiation therapy, and/or chemotherapy. MAIN OUTCOMES AND MEASURES Locoregional control (LRC), recurrence-free survival (RFS), and overall survival (OS). RESULTS Fifty-five patients had angiosarcoma localized to the face or scalp. Forty of these patients (73%) received a combination of surgery, radiation therapy, and/or chemotherapy. Eight patients (15%) were treated with surgery alone, 1 (2%) with radiation alone, 5 (9%) with chemotherapy alone, and 1 (2%) with observation alone. Median (range) follow-up for surviving patients was 25.2 (4.7-227.1) months. Five-year LRC, RFS, and OS (95% CI) were 18% (7%-32%), 16% (6%-31%), and 38% (21%-54%), respectively. Of 36 patients with failed treatment, 34 had failure in a local and/or regional site. On univariate analysis, the use of multimodality therapy (vs no multimodality therapy) was associated with higher 5-year LRC (95% CI) (20% [3%-37%] vs 11% [0%-29%]; P = .04), higher RFS (19% [2%-36%] vs 10% [0%-27%]; P = .02), and higher OS (46% [26%-66%] vs 16% [0%-43%]; P = .04). Age 70 years or older (vs <70 years) was associated with lower 5-year LRC (95% CI) (5% [0%-14%] vs 48% [23%-74%]; P = .02) and lower RFS (5% [0%-13%] vs 49% [24%-75%]; P = .04). Radiation therapy (vs no radiation therapy) was associated with higher 5-year LRC (95% CI) (20% [3%-36%] vs 12% [0%-32%]; P = .02) and higher RFS (19% [2%-35%] vs 12% [0%-31%]; P = .004). On multivariable analysis, age younger than 70 years (vs ≥70 years) was associated with improved 5-year LRC (95% CI) (48% [23%-74%] vs 5% [0%-14%]; P = .03) and RFS (49% [24%-75%] vs 49% [24%-75%]; P = .04). CONCLUSIONS AND RELEVANCE Multimodality therapy for angiosarcoma is associated with improved LRC, RFS, and OS. Younger patients with resectable disease undergoing multimodality therapy for angiosarcoma had the best clinical outcomes.

Image-guided intensity-modulated radiotherapy for prostate cancer: Dose constraints for the anterior rectal wall to minimize rectal toxicity.

Rectal adverse events (AEs) are a major concern with definitive radiotherapy (RT) treatment for prostate cancer. The anterior rectal wall is at the greatest risk of injury as it lies closest to the target volume and receives the highest dose of RT. This study evaluated the absolute volume of anterior rectal wall receiving a high dose to identify potential ideal dose constraints that can minimize rectal AEs. A total of 111 consecutive patients with Stage T1c to T3a N0 M0 prostate cancer who underwent image-guided intensity-modulated RT at our institution were included. AEs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The volume of anterior rectal wall receiving 5 to 80Gy in 2.5-Gy increments was determined. Multivariable Cox regression models were used to identify cut points in these volumes that led to an increased risk of early and late rectal AEs. Early AEs occurred in most patients (88%); however, relatively few of them (13%) were grade ≥2. At 5 years, the cumulative incidence of late rectal AEs was 37%, with only 5% being grade ≥2. For almost all RT doses, we identified a threshold of irradiated absolute volume of anterior rectal wall above which there was at least a trend toward a significantly higher rate of AEs. Most strikingly, patients with more than 1.29, 0.73, or 0.45cm(3) of anterior rectal wall exposed to radiation doses of 67.5, 70, or 72.5Gy, respectively, had a significantly increased risk of late AEs (relative risks [RR]: 2.18 to 2.72; p ≤ 0.041) and of grade ≥ 2 early AEs (RR: 6.36 to 6.48; p = 0.004). Our study provides evidence that definitive image-guided intensity-modulated radiotherapy (IG-IMRT) for prostate cancer is well tolerated and also identifies dose thresholds for the absolute volume of anterior rectal wall above which patients are at greater risk of early and late complications.

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer.

Patient-reported distress and survival among patients receiving definitive radiation therapy

Objective Patient-reported distress (PRD) has not been well assessed in association with survival after radiation therapy (RT). The aims of this study were to evaluate the association between PRD level and survival after definitive RT and to identify the main causes of distress in definitive RT patients. Methods and materials A total of 678 consecutive patients receiving definitive RT at our institution from April 2012 through May 2015 were included. All patients answered a PRD questionnaire that contained 30 items related to possible causes of distress, which could be rated from 1 (no distress) to 5 (high distress). Additionally, patients were asked to rate their overall distress level from 0 (no distress) to 10 (extreme distress). This overall distress level was our primary patient-reported distress measure and was examined as a continuous variable and as a categorical variable with 3 PRD levels (low, 0-3 [n = 295]; moderate, 4-6 [n = 222]; and high, 7-10 [n = 161]). Results As a continuous variable in multivariable Cox regression analysis, a higher overall PRD level was associated with poorer survival after RT (hazard ratio [HR], 1.39; P = .004). As a categorical variable, compared with patients with low distress, survival was poorer for patients with moderate distress (HR, 1.62; P = .038) or high distress (HR, 1.49; P = .12), but the latter difference was not significant. When the moderate and high distress levels were combined, survival was significantly poorer compared with the low distress level (HR, 1.57; P = .034). The top 5 specific causes of distress that patients mentioned were “How I feel during treatment,” “Fatigue,” “Out-of-pocket medical costs,” “Pain that affects my daily functioning,” and “Sleep difficulties.” Conclusions PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation.

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease.

Evaluation of Serum Calcium as a Predictor of Biochemical Recurrence following Salvage Radiation Therapy for Prostate Cancer

Background. Previous reports have shown a positive association between serum calcium level and prostate cancer mortality. However, there is no data regarding whether higher serum calcium levels are associated with increased risk of biochemical recurrence (BCR) following salvage radiation therapy (SRT) for prostate cancer. Herein, we evaluate the association between pretreatment serum calcium levels and BCR in a cohort of men who underwent SRT. Methods. We evaluated 165 patients who underwent SRT at our institution. Median dose was 65.0 Gy (range: 54.0–72.4 Gy). We considered serum calcium as both a continuous variable and a 3-level categorical variable (low [≤9.0 mg/dL], moderate [>9.0 mg/dL and ≤9.35 mg/dL], and high [>9.35 mg/dL]) based on sample tertiles. Results. We observed no evidence of a linear association between serum calcium and BCR (relative risk (RR): 0.96, P = 0.76). Compared to men with low calcium, there was no significantly increased risk of BCR for men with moderate (RR: 0.94, P = 0.79) or high (RR: 1.08, P = 0.76) serum calcium levels. Adjustment for clinical, pathological, and SRT characteristics in multivariable analyses did not alter these findings. Conclusion. Our results provide evidence that pretreatment serum calcium is unlikely to be a useful tool in predicting BCR risk following SRT.

Stereotactic Body Radiotherapy for Medically Inoperable Stage I-II Non–Small Cell Lung Cancer: The Mayo Clinic Experience

Objective To examine disease control and survival after stereotactic body radiotherapy (SBRT) for medically inoperable, early-stage non–small cell lung cancer (NSCLC) and determine associations of pretreatment 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) maximum standardized uptake values (SUVmax), biologically effective dose, and mediastinal staging with disease control and survival outcomes. Patients and Methods We retrospectively reviewed the cases of consecutive patients with FDG-PET–staged, medically inoperable NSCLC treated with SBRT at our institution between January 1, 2008, and August 4, 2014. Cumulative incidences of recurrence were estimated, accounting for the competing risk of death. Associations of SUVmax, biologically effective dose, and mediastinal staging with outcomes were evaluated using Cox proportional hazards regression models. Results Among 282 patients, 2-year cumulative incidences of recurrence were 4.9% (95% CI, 2.6%-8.3%) for local, 9.8% (95% CI, 6.3%-14.2%) for nodal, 10.8% (95% CI, 7.0%-15.5%) for ipsilateral lung, 6.0% (3.3%-9.8%) for contralateral lung, 9.7% (95% CI, 6.3%-14.0%) for distant recurrence, and 26.1% (95% CI, 20.4%-32.0%) for any recurrence. The 2-year overall survival was 70.4% (95% CI, 64.5%-76.8%), and the 2-year disease-free survival was 51.2% (95% CI, 44.9%-58.5%). Risk of any recurrence was significantly higher for patients with higher SUVmax (hazard ratio [per each doubling], 1.29 [95% CI, 1.05-1.59]; P=.02). A similar association with SUVmax was observed when considering the composite outcome of any recurrence or death (hazard ratio, 1.23 [95% CI, 1.05-1.44]; P=.01). The SUVmax was not significantly associated with other outcomes (P≥0.69). Two-year cumulative incidences of local recurrence for patients receiving 48 Gy in 4 fractions, 54 Gy in 3 fractions, or 50 Gy in 5 fractions were 1.7% (95% CI, 0.3%-5.6%), 3.7% (95% CI, 0.7%-11.4%), and 15.3% (95% CI, 5.9%-28.9%), respectively (P=.02); this difference was independent of lesion size (P=.02). Conclusion Disease control was excellent for patients who received SBRT for early-stage NSCLC, and this series represents the largest single-institution experience from the United States on SBRT for early-stage inoperable NSCLC. Higher pretreatment FDG-PET SUVmax was associated with increased risk of any recurrence, and the 50 Gy in 5 fractions dose prescription was associated with increased risk of local recurrence.