John A. Vargo

A Prospective Phase 2 Trial of Reirradiation With Stereotactic Body Radiation Therapy Plus Cetuximab in Patients With Previously Irradiated Recurrent Squamous Cell Carcinoma of the Head and Neck

PURPOSE Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. METHODS AND MATERIALS From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m(2) on day -7 and then 250 mg/m(2) on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. RESULTS Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. CONCLUSIONS SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time.

Treatment Selection and Survival Outcomes in Early-Stage Diffuse Large B-Cell Lymphoma: Do We Still Need Consolidative Radiotherapy?

PURPOSE The choice between chemotherapy alone and chemotherapy plus consolidative radiotherapy (RT) for diffuse large B-cell lymphoma (DLBCL) remains controversial. We aimed to define factors affecting treatment selection and the resulting survival outcomes. PATIENTS AND METHODS Using the National Cancer Data Base, we identified 59,255 patients with stages I and II DLBCL treated with multiagent chemotherapy alone or chemotherapy plus consolidative RT between 1998 and 2012. Univariable and multivariable analyses were performed to identify sociodemographic, treatment, and tumor characteristics predictive of overall survival (OS) and treatment use. Propensity-adjusted Cox proportional hazard ratios for survival were used to account for indication bias. RESULTS Of the 59,255 patients with DLBCL enrolled onto the study, 46% had stage II disease, 42% had extranodal disease, and 58% were more than 60 years of age. Only 39% received combined-modality therapy, and this proportion significantly declined from 47% in 2000 to 32% in 2012 (P < .001). Treatment selection was significantly influenced by race, comorbidity, insurance type, education quartile, facility type, age, stage, B symptoms, distance from treatment facility, and year of diagnosis. The median follow-up time was 60 months (interquartile range, 33 to 93). Estimated 5-year and 10-year OS rates were, respectively, 79% and 59% for all patients, 75% and 55% for patients receiving chemotherapy alone, and 82% and 64% for patients receiving combined-modality therapy (P < .001). Even after adjusting for immortal times and indication bias, combined-modality therapy was associated with better OS (HR, 0.66; 95% CI, 0.61 to 0.71; P < .001) than was chemotherapy alone. CONCLUSION Use of consolidative RT after multiagent chemotherapy in DLBCL is decreasing in the modern era. Selection of treatment strategy is affected by both classical prognostic features and socioeconomic factors. Abandonment of combined-modality therapy in favor of chemotherapy alone negatively affects patient survival.

Extended Field Intensity Modulated Radiation Therapy With Concomitant Boost for Lymph Node–Positive Cervical Cancer: Analysis of Regional Control and Recurrence Patterns in the Positron Emission Tomography/Computed Tomography Era

PURPOSE Positron emission tomography/computed tomography (PET/CT) is commonly used for nodal staging in locally advanced cervical cancer; however the false negative rate for para-aortic disease are 20% to 25% in PET-positive pelvic nodal disease. Unless surgically staged, pelvis-only treatment may undertreat para-aortic disease. We have treated patients with PET-positive nodes with extended field intensity modulated radiation therapy (IMRT) to address the para-aortic region prophylactically with concomitant boost to involved nodes. The purpose of this study was to assess regional control rates and recurrence patterns. METHODS AND MATERIALS Sixty-one patients with cervical cancer (stage IBI-IVA) diagnosed from 2003 to 2012 with PET-avid pelvic nodes treated with extended field IMRT (45 Gy in 25 fractions with concomitant boost to involved nodes to a median of 55 Gy in 25 fractions) with concurrent cisplatin and brachytherapy were retrospectively analyzed. The nodal location was pelvis-only in 41 patients (67%) and pelvis + para-aortic in 20 patients (33%). There were a total of 179 nodes, with a median number of positive nodes of 2 (range, 1-16 nodes) per patient and a median nodal size of 1.8 cm (range, 0.7-4.5 cm). Response was assessed by PET/CT at 12 to 16 weeks. RESULTS Complete clinical and imaging response at the first follow-up visit was seen in 77% of patients. At a mean follow-up time of 29 months (range, 3-116 months), 8 patients experienced recurrence. The sites of persistent/recurrent disease were as follows: cervix 10 (16.3%), regional nodes 3 (4.9%), and distant 14 (23%). The rate of para-aortic failure in patients with pelvic-only nodes was 2.5%. There were no significant differences in recurrence patterns by the number/location of nodes, largest node size, or maximum node standardized uptake value. The rate of late grade 3+ adverse events was 4%. CONCLUSIONS Extended field IMRT was well tolerated and resulted in low regional recurrence in node-positive cervical cancer. The dose of 55 Gy in 25 fractions was effective in eradicating disease in involved nodes, with acceptable late adverse events. Distant metastasis is the predominant mode of failure, and the OUTBACK trial may challenge the presented paradigms.

Prospective evaluation of patient-reported quality-of-life outcomes following SBRT ± cetuximab for locally-recurrent, previously-irradiated head and neck cancer

PURPOSE Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for unresectable, previously-irradiated recurrent squamous cell carcinomas of the head and neck (rSCCHN). Here-in, we report the first prospective evaluation of patient-reported quality-of-life (PR-QoL) following re-irradiation with SBRT±cetuximab for rSCCHN. MATERIALS AND METHODS From November 2004 to May 2011, 150 patients with unresectable, rSCCHN in a previously-irradiated field receiving >40 Gy were treated with SBRT to 40-50 Gy in 5 fractions ± concurrent cetuximab. PR-QoL was prospectively acquired using the University of Washington Quality-of-Life Revised (UW-QoL-R). RESULTS Overall PR-QoL, health-related PR-QoL, and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing (p=0.025), speech (p=0.017), saliva (p=0.041), activity (p=0.032) and recreation (p=0.039). CONCLUSIONS Especially for patients surviving >1-year, improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL resulting from rSCCHN. These improvements in PR-QoL transcend all measured domains in a validated PR-QoL assessment tool independent of age, use of cetuximab, tumor volume, and interval since prior irradiation.

Stereotactic body radiation therapy for locally recurrent, previously irradiated nonsquamous cell cancers of the head and neck

Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for patients with recurrent, previously irradiated head and neck cancer; however, data are limited predominantly to squamous cell carcinomas. Herein, we report the efficacy of SBRT in recurrent, nonsquamous cell cancers of the head and neck (NSCHNs).

Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection.

BACKGROUND Postoperative stereotactic radiosurgery for brain metastases potentially offers similar local control rates and fewer long-term neurocognitive sequelae compared to whole brain radiation therapy, although patients remain at risk for distant brain failure (DBF). OBJECTIVE To describe clinical outcomes of adjuvant stereotactic radiosurgery for large brain metastases and identify predictors of intracranial failure and their implications on optimal patient selection criteria. METHODS We performed a retrospective review on 100 large (>3 cm) brain metastases in 99 patients managed by resection followed by postoperative stereotactic radiosurgery to a median dose of 22 Gy (range, 10-28) in 1 to 5 fractions (median, 3). Primary histology was nonsmall cell lung in 40%, breast cancer in 18%, and melanoma in 17%. Forty (40%) patients had uncontrolled systemic disease. RESULTS With a median follow-up of 12.2 months (range, 0.6-87.4), the 1-year Kaplan-Meier local control was 72%, DBF 64%, and overall survival 55%. Nine patients (9%) developed evidence of radiation injury, and 6 (6%) developed leptomeningeal disease. Uncontrolled systemic disease (P=.03), melanoma histology (P=.04), and increasing number of brain metastases (P<.001) were significant predictors of DBF on Cox multivariate analysis. Patients with <4 metastases, controlled systemic disease, and nonmelanoma primary (n=47) had a 1-year DBF of 48.6% vs 80.1% for all others (P=.01). CONCLUSION Postoperative stereotactic radiosurgery to the resection cavity safely and effectively augments local control of large brain metastases. Patients with <4 metastases and controlled systemic disease have significantly lower rates of DBF and are ideal treatment candidates.

4π Noncoplanar Stereotactic Body Radiation Therapy for Head-and-Neck Cancer: Potential to Improve Tumor Control and Late Toxicity

PURPOSE To evaluate the potential benefit of 4π radiation therapy in recurrent, locally advanced, or metastatic head-and-neck cancer treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS Twenty-seven patients with 29 tumors who were treated using SBRT were included. In recurrent disease (n=26), SBRT was delivered with a median 44 Gy (range, 35-44 Gy) in 5 fractions. Three patients with sinonasal mucosal melanoma, metastatic breast cancer, and primary undifferentiated carcinoma received 35 Gy, 22.5 Gy, and 40 Gy in 5 fractions, respectively. Novel 4π treatment plans were created for each patient to meet the objective that 95% of the planning target volume was covered by 100% of the prescription dose. Doses to organs at risk (OARs) and 50% dose spillage volumes were compared against the delivered clinical SBRT plans. Local control (LC), late toxicity, tumor control probability (TCP), and normal tissue complication probability were determined. RESULTS Using 4π plans, mean/maximum doses to all OARs were reduced by 22% to 89%/10% to 86%. With 4π plans, the 50% dose spillage volume was decreased by 33%. Planning target volume prescription dose escalation by 10 Gy and 20 Gy were achieved while keeping doses to OARs significantly improved or unchanged from clinical plans, except for the carotid artery maximum dose at 20-Gy escalation. At a median follow-up of 10 months (range, 1-41 months), crude LC was 52%. The 2-year LC of 39.2% approximated the predicted mean TCP of 42.2%, which increased to 45.9% with 4π plans. For 10-Gy and 20-Gy dose escalation, 4π plans increased TCP from 80.1% and 88.1% to 85.5% and 91.4%, respectively. The 7.4% rate of grade ≥3 late toxicity was comparable to the predicted 5.6% mean normal tissue complication probability for OARs, which was significantly reduced by 4π planning at the prescribed and escalated doses. CONCLUSIONS 4π plans may allow dose escalation with significant and consistent improvements in critical organ sparing, tumor control, and coverage.

Examining tumor control and toxicity after stereotactic body radiotherapy in locally recurrent previously irradiated head and neck cancers: Implications of treatment duration and tumor volume

Stereotactic body radiotherapy (SBRT) has been studied in locally recurrent previously‐irradiated head and neck cancers; however, the optimum fractionation and patient selection continues to be defined.

Definitive salvage for vaginal recurrence of endometrial cancer: The impact of modern intensity-modulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification

PURPOSE Data for salvage radiotherapy for recurrent endometrial cancer are limited especially in the era of modern radiotherapy including IMRT and 3-dimensional image-based HDR brachytherapy. Theoretically, modern radiotherapy reduces the dose to critical organs-at-risk and maximizes dose to the target volume, possibly decreasing morbidity and increasing tumor control. MATERIALS AND METHODS Forty-one patients completing definitive salvage radiotherapy for vaginal recurrence of endometrial cancer from June 2004 to December 2013 were retrospectively reviewed. HDR Brachytherapy was completed using image-based planning with contouring/optimization with each fraction to a median dose of 23.75 Gy in 5 fractions. HDR brachytherapy was preceded by external beam radiotherapy predominately using an IMRT technique (90%) to a median dose of 45 Gy in 25 fractions. Toxicity was reported according to CTCAEv4. RESULTS At a median follow-up of 18 months (range: 3-78), the clinical complete response rate was 95%. The 3-year local control, distant control, recurrence free survival, and overall survival were 95%, 61%, 68%, and 67%. Significant predictors of both distant failure and overall survival were primary prognostic factors of depth of myometrial invasion, FIGO stage, and FIGO grade. There was no grade 3+ acute toxicity; the 3-year rate of grade 3+ late toxicity was 8%. CONCLUSIONS Salvage IMRT plus 3-dimensional image-based HDR brachytherapy shows excellent tumor control and minimal morbidity for vaginal recurrence of endometrial cancer. Anticipated salvage rates must be taken in the context of primary risk factors including depth of myometrial invasion, FIGO stage, and FIGO grade.

What is the optimal management of early‐stage low‐grade follicular lymphoma in the modern era?

Despite international practice guidelines endorsing radiotherapy (RT) as the preferred initial therapy, treatment approaches vary for patients with early‐stage follicular lymphoma. The authors engaged the National Cancer Data Base to analyze patterns of care and survival outcomes for patients with early‐stage follicular lymphoma in the era of modern therapy.