Stereotactic body radiation therapy for curative treatment of adrenal metastases.

The detection of oligometastatic adrenal metastases is increasing and there are limited data supporting the use of curative intent stereotactic body radiation therapy (SBRT) to treat patients with limited metastatic disease with adrenal involvement. Therefore, we utilized a prospectively maintained database of consecutive patients treated with SBRT for limited metastatic disease (≤5 sites) to identify patients with adrenal metastases. Patients were either treated on a three-fraction dose escalation protocol or a ten fraction off-protocol regimen. Outcomes including treated-metastasis control (TMC), distant control (DC), and overall survival (OS) were calculated by the Kaplan-Meier method. Ten patients with 13 adrenal metastases were identified for this case series. The median follow-up was 14.9 months. No patient experienced grade 3 toxicity. The most common grade 1-2 acute toxicities were fatigue (80%) and GI toxicity (40%). One patient experienced late grade 2 adrenal insufficiency. Overall, the 1-year TMC rate was 73%, DC was 30%, and OS was 90%. Three treated adrenal metastases progressed, all receiving the lowest BED10 (43.2 Gy), corresponding to 24 Gy in 3 fractions. After treatment of adrenal metastases with SBRT, the median time to salvage chemotherapy was 5.3 months (range 1.0-38.8 months) and 1-year freedom from salvage chemotherapy was 44%. These results suggest that SBRT to adrenal metastases was tolerated with low toxicity in limited metastatic patients and control rates are promising. This study supports the growing body of literature treating patients with adrenal metastases with SBRT.

Feasibility and toxicity of hypofractionated image guided radiation therapy for large volume limited metastatic disease.

PURPOSE: Hypofractionated image guided radiation therapy (HIGRT) is increasingly used for limited metastases. Reported studies have mostly treated small volume tumors. Here, we report the toxicity and oncologic outcomes following treatment of large volume metastases. METHODS AND MATERIALS: HIGRT patients treated from October 2005 to March 2010 were reviewed. Gross tumor volumes (GTV) and planning target volumes (PTV) were obtained from planning software. A metastasis was considered large volume if the treated PTV exceeded 50 cc. Patients were treated with either 10-fraction (4-5 Gy per fraction) or 3-5 fraction (8-14 Gy per fraction) regimens. Toxicity was obtained from both prospectively collected databases and retrospectively from patient charts. RESULTS: Sixty-four patients with 93 treated lesions >50 cc were identified. The median GTV and PTV volumes were 41 and 119 cc, respectively. The median number of treated large volume lesions was 1, and a maximum of 3 large volume lesions were treated in a single patient. Primary malignancies included non-small cell lung cancer, renal cell, colorectal, breast, bladder, pituitary, small cell lung cancer, sarcoma, head-and-neck cancer, and hepatocellular cancer. Treated sites included lung (n = 33), regional lymph nodes (n = 20), bone (n = 17), adrenal (n = 9), and liver (n = 6). The most frequently used treatment regimen was 50 Gy in 5 Gy fractions. The median follow-up was 27 months for surviving patients. Treated lesion control was 78%. Low rates of acute and late grade 3 or higher toxicity were reported, with 3 and 5 patients experiencing each, respectively. CONCLUSIONS: HIGRT to large volume oligometastatic disease is tolerable and feasible with promising tumor control. Local radiation therapy should be considered in patients with large volume, limited metastatic disease.

The effect of treatment time in locally advanced cervical cancer in the era of concurrent chemoradiotherapy.

BACKGROUND: This study sought to determine if treatment time impacts pelvic failure (PF), distant failure (DF), or disease-specific mortality (DSM) in patients undergoing concurrent chemoradiotherapy (CCRT). METHODS: A retrospective review was performed of 113 consecutive eligible patients with stage IB2 to IIIB cervical cancer. All patients received whole-pelvis radiation with concurrent chemotherapy and consolidative intracavitary brachytherapy (BT) to the cervix, followed by an external beam parametrial boost when appropriate. The effect of treatment time on PF, DF, and DSM was examined with univariate and multivariate analyses. Characteristics of patients with and without treatment prolongation were compared to explore reasons for treatment prolongation. RESULTS: The median time to completion of BT was 60 days, and the median time to complete all RT was 68 days. The 3-year cumulative incidence of PF, DF, and DSM were 18%, 23%, and 26%, respectively. On multivariate analysis, time to completion of BT >56 days was associated with increased PF (hazard ratio, 3.8; 95% confidence interval, 1.2-16; P = .02). The 3-year PF for >56 days versus ≤56 days was 26% versus 9% (P = .04). Treatment time was not associated with DF or DSM. Treatment prolongation was found to be associated with delay in starting BT and higher incidence of acute grade 3/4 toxicities. CONCLUSIONS: In the setting of CCRT, treatment time >56 days is detrimental to pelvic control but is not associated with an increase in DF or DSM. To maximize pelvic control, we recommend completing BT in 8 weeks or less.

Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma.

OBJECTIVES: Renal cell carcinoma (RCC) is considered radioresistant, but stereotactic radiosurgery can control intracranial metastases. Advances in radiotherapy, such as stereotactic body radiotherapy (SBRT), allow high-dose radiation delivery to extracranial sites. Herein, we report our experience treating oligometastatic RCC with SBRT. METHODS: Patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol (8 to 14 Gy/fraction) or off protocol with 10 fractions (4 to 5 Gy/fraction). Disease control was evaluated with serial imaging, and the Kaplan-Meier method was used to estimate lesion control (LeC), distant control, and survival. RESULTS: Eighteen consecutively treated patients with 39 metastases were treated using SBRT; 12 underwent treatment for all metastatic sites. Median follow-up was 16.2 months. Treatment was well tolerated; the most common acute toxicity was fatigue (61.1%) and late toxicity was limited. At 2 years, LeC was 91.4% and overall survival was 85%. Those who underwent treatment for all metastatic sites had a 2-year LeC of 100% and distant control of 35.7%. A shorter interval from diagnosis to SBRT predicted for distant progression. Freedom from any post-SBRT therapy was 64.2% at 1 year. CONCLUSIONS: In metastatic RCC, SBRT produces promising LeC with minimal toxicity. Further study should be expanded beyond that of managing intracranial disease. Its selected use may delay the requirement for systemic therapies.

Outcomes for patients with cervical cancer treated with extended-field intensity-modulated radiation therapy and concurrent cisplatin.

OBJECTIVE: To evaluate disease outcomes and toxicity in patients with cervical cancer treated with extended-field intensity-modulated radiotherapy. MATERIALS AND METHODS: We included all patients treated with extended-field intensity-modulated radiotherapy and concurrent weekly cisplatin from 2003 to 2010 at 2 institutions. Overall survival and disease-free survival were estimated using Kaplan-Meier method. Locoregional failure (LRF), distant failure, and competing mortality were calculated using cumulative incidence functions. Acute and late toxicity were graded using Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group late radiation morbidity scoring criteria, respectively. RESULTS: The study included 21 patients, 14 and 20 of which had positive para-aortic and pelvic nodes, respectively. The median follow-up was 22 months. Eighteen-month overall survival and disease-free survival were 59.7% (95% confidence interval [CI], 41.2%-86.4%) and 42.9% (95% CI, 26.2%-70.2%). Eighteen-month cumulative incidences of LRF, distant failure, and competing mortality were 9.5% (95% CI, 1.5-26.8%), 42.9% (95% CI, 21.3-62.9%), and 4.8% (95% CI, 0.3-20.2%), respectively. Eighteen-month cumulative incidences of late grade 3 or higher-grade genitourinary and gastrointestinal toxicity were 4.8% (95% CI, 0.2%-20.3%) and 0%, respectively. CONCLUSIONS: Intensity-modulated extended-field radiotherapy was associated with low rates of late toxicity and LRF. High rates of distant failure indicate that this group of patients could benefit from intensified systemic therapy.

Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease.

BACKGROUND: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy. METHODS: Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites. Patients were followed radiographically with CT scans of the chest, abdomen, and pelvis and metabolically with fluorodeoxyglucose-positron emission tomography, 1 month after treatment, and then every 3 months. Acute toxicities were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0, and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. RESULTS: Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 on a prospective radiation dose escalation study. Median follow-up was 20.9 months. Patients tolerated treatment well; the maximal tolerated dose was not reached in any cohort. Eleven patients (18.3%) have not progressed. One and 2-year progression-free survival are 33.3% (95% confidence interval [CI], 22.8-46.1) and 22.0% (95% CI, 12.8-34.4); 1-year and 2-year overall survival are 81.5% (95% CI, 71.1-91.1) and 56.7% (95% CI, 43.9-68.9). Seventy-two percent of patients whose tumors progressed did so in limited (1-3) metastatic sites. CONCLUSIONS: Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT. Further investigation should focus on patient selection.

Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer.

INTRODUCTION: Outcomes data treating patients with oligometastatic (≤ 5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited. METHODS: Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT. Lesions that had received prior radiation or had radiographic/metabolic resolution after chemotherapy were not treated with HIGRT. Local control of all treated lesions, distant control, progression-free survival (PFS), overall survival (OS), and control of individual lesions (LeC) were calculated. RESULTS: Twenty-five patients with median of 2 treated oligometastatic lesions were included. Median follow-up was 14 months. Median age was 66 years. Nineteen patients received systemic therapy before HIGRT and 11 had progressive disease after their most recent systemic therapy before HIGRT. Median OS and PFS were 22.7 and 7.6 months. The 18 months local control, distant control, OS, and PFS were 66.1%, 31.7%, 52.9%, and 28.0%. Greater than two sites treated with HIGRT, nonadenocarcinoma histology, prior systemic therapy, and progression after systemic therapy were associated with worse PFS. Sixty-two individual lesions of median size 2.7 cm were treated. For extracranial lesions, median total and fraction dose were 50 and 5 Gy. Median standard equivalent dose in 2 Gy fractions for extracranial lesions was 64.6 Gy yielding 18 months LeC of 70.7%. Standard equivalent dose ≥64.6 Gy increased LeC (p = 0.04). Two patients experienced grade 3 toxicity. CONCLUSIONS: HIGRT for oligometastatic NSCLC provides durable LeC and may provide long-term PFS in some patients. Future HIGRT studies should optimize patient selection and integration with systemic therapy.

MicroRNA expression characterizes oligometastasis(es).

BACKGROUND: Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤ 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy. METHODS: Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy. RESULTS: Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression. CONCLUSIONS: These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.

Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix.

PURPOSE: To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: We included all patients with Stage I-IVA cervical carcinoma treated with IMRT at three different institutions from 2000-2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. RESULTS: The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I-IIA disease and 48 had Stage IIB-IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68-88%) and 69% (95% CI, 59-81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6-22%) and 17% (95% CI, 8-25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0-7%) and 7% (95% CI, 2-13%), respectively. CONCLUSIONS: Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Outcomes in black patients with early breast cancer treated with breast conservation therapy.

BACKGROUND: The race-specific impact of prognostic variables for early breast cancer is unknown for black patients undergoing breast conservation. METHODS AND MATERIALS: This was a retrospective study of 1,231 consecutive patients ≥40 years of age with Stage I-II invasive breast cancer treated with lumpectomy and radiation therapy at the University of Chicago Hospitals and affiliates between 1986 and 2004. Patients were classified as either black or nonblack. Cox proportional hazards regression was used to model the effects of known prognostic factors and interactions with race. RESULTS: Median follow-up for surviving patients was 82 months. Thirty-four percent of patients were black, and 66% were nonblack (Caucasian, Hispanic, and Asian). Black patients had a poorer 10-year overall survival (64.6% vs. 80.8%; adjusted hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.23-2.06) and 10-year disease-free survival (58.1% vs. 75.4%; HR 1.49; 95% CI, 1.18-1.89) compared with nonblack patients. Tumor sizes were similar between nonblack and black patients with mammographically detected tumors (1.29 cm vs. 1.20 cm, p = 0.20, respectively). Tumor size was significantly associated with overall survival (HR 1.48; 95% CI, 1.12-1.96) in black patients with mammographically detected tumors but not in nonblack patients (HR 1.09; 95% CI, 0.78-1.53), suggesting that survival in black patients depends more strongly on tumor size in this subgroup. Tests for race-size method of detection interactions were statistically significant for overall survival (p = 0.049), locoregional control (p = 0.036), and distant control (p = 0.032) and borderline significant for disease-free survival (p = 0.067). CONCLUSION: Despite detection at comparable sizes, the prognostic effect of tumor size in patients with mammographically detected tumors is greater for black than in nonblack patients.

Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.

PURPOSE: To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy and to develop a normal tissue complication probability (NTCP) model for HT. METHODS AND MATERIALS: We tested associations between hematologic nadirs during chemoradiotherapy and the volume of BM receiving≥10 and 20 Gy (V10 and V20) using a previously developed linear regression model. The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic radiotherapy. Subsequently, these data were pooled with data from 37 identically treated patients from a previous study, forming a cohort of 81 patients for normal tissue complication probability analysis. Generalized linear modeling was used to test associations between hematologic nadirs and dosimetric parameters, adjusting for body mass index. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. RESULTS: In the validation cohort, significant negative correlations were observed between white blood cell count nadir and V10 (regression coefficient (ß)=-0.060, p=0.009) and V20 (ß=-0.044, p=0.010). In the combined cohort, the (adjusted) ß estimates for log (white blood cell) vs. V10 and V20 were as follows: -0.022 (p=0.025) and -0.021 (p=0.002), respectively. Patients with V10≥95% were more likely to experience Grade≥3 leukopenia (68.8% vs. 24.6%, p<0.001) than were patients with V20>76% (57.7% vs. 21.8%, p=0.001). CONCLUSIONS: These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain V10<95% and V20<76% may reduce HT.

Renal toxicity in children undergoing total body irradiation for bone marrow transplant.

PURPOSE: Contribution of total body irradiation (TBI) to renal toxicity in children undergoing the bone marrow transplant (BMT) remains controversial. We report our institutional retrospective study that evaluates the frequency of acute and chronic renal dysfunction in children after using total body irradiation (TBI) conditioning regimens. MATERIALS AND METHODS: Between 1995 and 2003, 60 children with hematological malignancies underwent TBI as part of a conditioning regimen before allogeneic BMT. Patients received 4-14Gy at 1.75-2Gy/fraction in six-eight fractions. Lung shielding was used in all patients to limit lung dose to less than 10Gy; renal shielding was not utilized. All patients had baseline renal function assessment and renal dysfunction post-BM was mainly evaluated on the basis of persistent serum creatinine elevation at acute (0-90 days) and chronic (>90 days) intervals after completion of BMT. RESULTS: Acute renal dysfunction (ARD) was documented in 27 patients (45%); the majority had concurrent diagnosis of veno-occlusive disease (VOD) or graft-versus-host disease (GVHD) and other potential causes (sepsis, antibiotic). The risk for delayed renal dysfunction (DRD) at 1 year approached 25% for surviving patients. The ARD was strongly linked with the risk of the DRD. There was no statistically significant relationship between ARD, DRD and underlying diagnosis, GVHD, VOD or TBI doses with both univariate and multivariate analyses. The younger age (<5 years) had significantly increased risk for the development of ARD (p=0.011). CONCLUSION: Our analysis validates high incidence of renal dysfunction in the pediatric BMT population. In contrast to other reports we did not find total body irradiation dose to be a risk factor for renal dysfunction. Future prospective studies are needed to assess risk factors and interventions for this serious toxicity in children following allogeneic BM.