Alan W. Katz

Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials

PURPOSE The effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested. METHODS AND MATERIALS A total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003-11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25Gy in 4-5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2ng/ml above nadir was analyzed with the Kaplan Meier method. RESULTS With a median follow-up of 36months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ⩽6, 7 and ⩾8, respectively (p=0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p<0.001). No differences were observed with ADT (p=0.71) or as a function of total dose (p=0.17). A PSA bounce of >0.2ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively. CONCLUSION PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients.

Oligometastases Treated With Stereotactic Body Radiotherapy: Long-Term Follow-Up of Prospective Study

PURPOSE To analyze the long-term survival and tumor control outcomes after stereotactic body radiotherapy (SBRT) for metastases limited in number and extent. METHODS AND MATERIALS We prospectively analyzed the long-term overall survival (OS) and cancer control outcomes of 121 patients with five or fewer clinically detectable metastases, from any primary site, metastatic to one to three organ sites, and treated with SBRT. Freedom from widespread distant metastasis (FFDM) was defined as metastatic disease not amenable to local therapy (i.e., resection or SBRT). Prognostic variables were assessed using log-rank and Cox regression analyses. RESULTS For breast cancer patients, the median follow-up was 4.5 years (7.1 years for 16 of 39 patients alive at the last follow-up visit). The 2-year OS, FFDM, and local control (LC) rate was 74%, 52%, and 87%, respectively. The 6-year OS, FFDM, and LC rate was 47%, 36%, and 87%, respectively. From the multivariate analyses, the variables of bone metastases (p = .057) and one vs. more than one metastasis (p = .055) were associated with a fourfold and threefold reduced hazard of death, respectively. None of the 17 bone lesions from breast cancer recurred after SBRT vs. 10 of 68 lesions from other organs that recurred (p = .095). For patients with nonbreast cancers, the median follow-up was 1.7 years (7.3 years for 7 of 82 patients alive at the last follow-up visit). The 2-year OS, FFDM, and LC rate was 39%, 28%, and 74%, respectively. The 6-year OS, FFDM, and LC rate was 9%, 13%, and 65%, respectively. For nonbreast cancers, a greater SBRT target volume was significantly adverse for OS (p = .012) and lesion LC (p < .0001). Patients whose metastatic lesions, before SBRT, demonstrated radiographic progression after systemic therapy experienced significantly worse OS compared with patients with stable or regressing disease. CONCLUSIONS Select patients with limited metastases treated with SBRT are long-term survivors. Future research should address the therapeutic benefit of SBRT for these patients.

A Prospective Pilot Study of Curative-intent Stereotactic Body Radiation Therapy in Patients With 5 or Fewer Oligometastatic Lesions

It is hypothesized that oligometastatic disease represents a state of potentially curable, limited metastases. Stereotactic body radiation therapy (SBRT) is an option for patients who are not amenable to or do not want resection.

Stereotactic Body Radiation Therapy (SBRT) for lung metastases.

The curative treatment of oligometastases with radiotherapy remains an area of active investigation. We hypothesise that treating oligometastases with SBRT can prolong life and potentially cure patients, while in patients with multiple lung metastases SBRT can improve quality of life. Fifty patients with lung metastases were treated on this study. Individuals with five or fewer total lesions were treated with curative intent. Individuals with > five metastases were treated palliatively. Most patients (62%) received 5 Gy/fraction for a total of 50 Gy. The number of targets treated per patient ranged from one to five (mean 2.6). Tumor sizes ranged from 0.3–7.7 cm in maximal diameter (median 2.1 cm). Mean follow-up was 18.7 months. Local control of treated lesions was obtained in 42 of 49 evaluable patients (83%). Of the 125 total lesions treated, eight progressed after treatment (94% crude local control). The median overall survival time from time of treatment completion of the curatively treated patients was 23.4 months. The progression-free survival of the same group of patients was 25% and 16% at 12 and 24 months, respectively. Grade 1 toxicity occurred in 35% of all the patients, 6.1% had grade 2 toxicity, and 2% had grade 3 toxicity. Excellent local tumor control rates with low toxicity are seen with SBRT. Median survival time and progression-free survival both appear better than that achieved with standard care alone. Long-term progression-free survival can be seen in a subset of patients when all tumors are targeted

Health-Related Quality of Life After Stereotactic Body Radiation Therapy for Localized Prostate Cancer: Results From a Multi-institutional Consortium of Prospective Trials

PURPOSE To evaluate the early and late health-related quality of life (QOL) outcomes among prostate cancer patients following stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS Patient self-reported QOL was prospectively measured among 864 patients from phase 2 clinical trials of SBRT for localized prostate cancer. Data from the Expanded Prostate Cancer Index Composite (EPIC) instrument were obtained at baseline and at regular intervals up to 6 years. SBRT delivered a median dose of 36.25 Gy in 4 or 5 fractions. A short course of androgen deprivation therapy was given to 14% of patients. RESULTS Median follow-up was 3 years and 194 patients remained evaluable at 5 years. A transient decline in the urinary and bowel domains was observed within the first 3 months after SBRT which returned to baseline status or better within 6 months and remained so beyond 5 years. The same pattern was observed among patients with good versus poor baseline function and was independent of the degree of early toxicities. Sexual QOL decline was predominantly observed within the first 9 months, a pattern not altered by the use of androgen deprivation therapy or patient age. CONCLUSION Long-term outcome demonstrates that prostate SBRT is well tolerated and has little lasting impact on health-related QOL. A transient and modest decline in urinary and bowel QOL during the first few months after SBRT quickly recovers to baseline levels. With a large number of patients evaluable up to 5 years following SBRT, it is unlikely that unexpected late adverse effects will manifest themselves.

Descriptive Analysis of Oligometastatic Lesions Treated With Curative-Intent Stereotactic Body Radiotherapy

PURPOSE To characterize oligometastases in patients enrolled on two prospective pilot studies, treating oligometastases with hypofractionated stereotactic body radiotherapy and stereotactic radiosurgery to cranial lesions. METHODS AND MATERIALS We describe the characteristics and local control (LC) of 293 lesions in 121 patients with five or fewer metastases treated with stereotactic body radiation and/or cranial stereotactic radiosurgery. For each lesion, the primary cancer site, tumor histology, site of metastasis, gross tumor volume, and prescribed dose were ascertained. The prescribed dose is expressed by the biologically effective dose in 2-Gy fractions (BED2), calculated using the linear quadratic model, assuming an alpha/beta ratio of 10. RESULTS Lung lesions were significantly smaller than other lesions in our cohort, whereas liver lesions were significantly larger, possibly reflecting a detection and/or referral bias. The 2-year and 4-year tumor LC rates were 77% and 73% respectively. A larger gross tumor volume was significantly (p < 0.0001) correlated with worse lesion LC. Lesions originating from primary pancreatic, biliary or liver cancer exhibited significantly poorer LC, as did lesions from colorectal cancer. Lesions from breast cancer were better controlled. A higher BED2 did not correlate with improved tumor control. CONCLUSIONS Stereotactic body radiation to aggressively treat oligometastatic lesions results in good local tumor control. Bulkier lesions are more difficult to control and may benefit from dose escalation.

Stereotactic Body Radiotherapy for Treatment of Adrenal Metastases

PURPOSE To investigate the dosimetry and outcomes of patients undergoing stereotactic body radiotherapy (SBRT) for metastases to the adrenal glands. METHODS AND MATERIALS At the University of Rochester, patients have been undergoing SBRT for limited metastases since 2001. We retrospectively reviewed 30 patients who had undergone SBRT for adrenal metastases from various primary sites, including lung (n = 20), liver (n = 3), breast (n = 3), melanoma (n = 1), pancreas (n = 1), head and neck (n = 1), and unknown primary (n = 1). RESULTS Of the 30 patients, 14 with five or fewer metastatic lesions (including adrenal) underwent SBRT, with the intent of controlling all known sites of metastatic disease, and 16 underwent SBRT for palliation or prophylactic palliation of bulky adrenal metastases. The prescribed dose ranged from 16 Gy in 4 fractions to 50 Gy in 10 fractions. The median dose was 40 Gy. Of the 30 patients, 24 had >3 months of follow-up with serial computed tomography. Of these 24 patients, 1 achieved a complete response, 15 achieved a partial response, 4 had stable disease, and 4 developed progressive disease. No patient developed symptomatic progression of their adrenal metastases. The 1-year survival, local control, and distant control rate was 44%, 55%, and 13%, respectively. No patient developed Radiation Therapy Oncology Group Grade 2 or greater toxicity. CONCLUSION SBRT for adrenal metastases is well tolerated. Most patients developed widespread metastases shortly after treatment. Local control was poor, although this was a patient population selected for adverse risk factors, such as bulky disease. Additional studies are needed to determine the efficacy of SBRT for oligometastatic adrenal metastases, given the propensity of these patients to develop further disease progression.

Curcumin for Radiation Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Thirty Breast Cancer Patients

Radiation dermatitis occurs in approximately 95% of patients receiving radiotherapy (RT) for breast cancer. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the ability of curcumin to reduce radiation dermatitis severity in 30 breast cancer patients. Eligible patients were adult females with noninflammatory breast cancer or carcinoma in situ prescribed RT without concurrent chemotherapy. Randomized patients took 2.0 grams of curcumin or placebo orally three times per day (i.e., 6.0 grams daily) throughout their course of RT. Weekly assessments included Radiation Dermatitis Severity (RDS) score, presence of moist desquamation, redness measurement, McGill Pain Questionnaire-Short Form and Symptom Inventory questionnaire. The 30 evaluable patients were primarily white (90%) and had a mean age of 58.1 years. Standard pooled variances t test showed that curcumin reduced RDS at end of treatment compared to placebo (mean RDS = 2.6 vs. 3.4; P = 0.008). Fishers exact test revealed that fewer curcumin-treated patients had moist desquamation (28.6% vs. 87.5%; P = 0.002). No significant differences were observed between arms for demographics, compliance, radiation skin dose, redness, pain or symptoms. In conclusion, oral curcumin, 6.0 g daily during radiotherapy, reduced the severity of radiation dermatitis in breast cancer patients.

Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors

Abstract Background. An excess of 100 000 individuals are diagnosed with primary liver tumors every year in USA but less than 20% of those patients are amenable to definitive surgical management due to advanced local disease or comorbidities. Local therapies to arrest tumor growth have limited response and have shown no improvement on patient survival. Stereotactic body radiotherapy (SBRT) has emerged as an alternative local ablative therapy. The purpose of this study was to evaluate the tumor response to SBRT in a combined multicenter database. Study design. Patients with advanced hepatocellular carcinoma (HCC, n = 21) or intrahepatic cholangiocarcinoma (ICC, n = 11) treated with SBRT from four Academic Medical Centers were entered into a common database. Statistical analyses were performed for freedom from local progression (FFLP) and patient survival. Results. The overall FFLP for advanced HCC was 63% at a median follow-up of 12.9 months. Median tumor volume decreased from 334.2 to 135 cm3 (p < 0.004). The median time to local progression was 6.3 months. The 1- and 2-years overall survival rates were 87% and 55%, respectively. Patients with ICC had an overall FFLP of 55.5% at a median follow-up of 7.8 months. The median time to local progression was 4.2 months and the six-month and one-year overall survival rates were 75% and 45%, respectively. The incidence of grade 1–2 toxicities, mostly nausea and fatigue, was 39.5%. Grade 3 and 4 toxicities were present in two and one patients, respectively. Conclusion. Higher rates of FFLP were achieved by SBRT in the treatment of primary liver malignancies with low toxicity.

Prospective randomized double-blind pilot study of site-specific consensus atlas implementation for rectal cancer target volume delineation in the cooperative group setting

PURPOSE Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes. METHODS AND MATERIALS A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement). RESULTS Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure. CONCLUSION Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT.