BackgroundCancer 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.MethodsHere, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy.ResultsPatients 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.ConclusionsThese 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.

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 (CRT), and to develop a normal tissue complication probability (NTCP) model for HT. METHODS AND MATERIALS We tested associations between hematologic nadirs during CRT 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 37 identically treated patients from a prior study, forming a cohort of 81 patients for NTCP 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 (WBC) nadir and V10 (regression coefficient (β)=−0.060, p=0.009) and V20 (β=−0.044, p=0.010). In the combined cohort, the (adjusted) β estimates for log(WBC) vs. V10 and V20 were: −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) as 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.

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 metastasisdirected 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.

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 ¼ .02). The 3-year PF for >56 days versus 56 days was 26% versus 9% (P ¼ .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. Cancer 2013;119:325-31. V C 2012 American Cancer Society.KEYWORDS: cervical cancer, treatment time, radiation timing, prognostic factor, concurrent chemoradiation. INTRODUCTIONHistorically, locally advanced cervical carcinomas were treated with radical radiation therapy (RT) alone using a combination of external beam RT to the whole pelvis and a brachytherapy (BT) boost to the cervix. In 1999, the treatment paradigm shifted to concurrent chemoradiotherapy (CCRT) after the publication of 5 randomized trials that demonstrated a survival advantage with the addition of cisplatin-based chemotherapy to RT in the adjuvant and definitive setting.1-5 A number of patient and tumor characteristics have been found to be prognostic in the setting of RT alone or CCRT. For patients treated with RT alone, the detrimental effect of RT prolongation is well established. Total RT time beyond 7 to 9 weeks results in increased pelvic failures (PFs), decreased cause-specific survival, and decreased overall survival (OS).

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