Kyle E. Rusthoven

Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases

PURPOSE To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three lung metastases. PATIENTS AND METHODS Patients with one to three lung metastases with cumulative maximum tumor diameter smaller than 7 cm were enrolled and treated on a multi-institutional phase I/II clinical trial in which they received SBRT delivered in 3 fractions. In phase I, the total dose was safely escalated from 48 to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points included toxicity and survival. RESULTS Thirty-eight patients with 63 lesions were enrolled and treated at three participating institutions. Seventy-one percent had received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, zero to five). Two patients had local recurrence after prior surgical resection. There was no grade 4 toxicity. The incidence of any grade 3 toxicity was 8% (three of 38). Symptomatic pneumonitis occurred in one patient (2.6%). Fifty lesions were assessable for local control. Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Actuarial local control at one and two years after SBRT was 100% and 96%, respectively. Local progression occurred in one patient, 13 months after SBRT. Median survival was 19 months. CONCLUSION This multi-institutional phase I/II trial demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma

The objective of this study was to compare survival in patients with squamous cell carcinoma (SCC) of the oral tongue with that in patients with SCC in other oral cavity subsites.

Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis

Introduction. The pattern of failure (POF) after first-line systemic therapy in advanced non-small cell lung cancer (NSCLC) is unknown. We evaluate the POF in this setting to estimate the potential value of consolidative stereotactic body radiation therapy (SBRT). Materials and methods. The records of consecutive NSCLC patients presenting to the University of Colorado, Denver (UCD) between January 2005 and June 2008 were reviewed. Patients with measurable advanced stage NSCLC who received first-line systemic therapy and follow-up at UCD were eligible. In these patients, sites of disease at maximal response were evaluated for theoretical SBRT eligibility, based on institutional criteria. All patients were followed to extracranial progression. The POF was categorized as local (L) for lesions known prior to treatment or distant (D) for new lesions. Results. Among 387 consecutive lung cancer patients (all stages), 64 met the eligibility criteria and 34 were SBRT-eligible. Among all eligible patients, first extra-cranial progression was L-only in 64%, D-only in 9% and L + D in 27%. Among SBRT-eligible patients, POF was L-only in 68%, D-only in 14% and L + D in 18%. In SBRT-eligible patients, time to first progression was 3.0 months in those with L-only failure versus 5.7 month in those with any D failure (HR 0.44; 95% CI 0.22–0.90). Conclusions. The predominant POF in patients with advanced NSCLC after first-line systemic therapy is local-only. The current analysis suggests that SBRT could improve time to progression in a substantial proportion of patients. The estimated increase in time to progression using this approach would be approximately 3 months.

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.

Effect of Radiation Techniques in Treatment of Oropharynx Cancer

Objectives: To compare the toxicity and outcomes of three radiotherapy techniques—three‐dimensional conformal (3D‐RT), accelerated fractionation with concomitant boost (AFxCB), and intensity modulated radiotherapy (IMRT)—in the combined modality treatment of stage III–IV squamous cell carcinoma (SCC) of the oropharynx.

Toxicity assessment of pelvic intensity-modulated radiotherapy with hypofractionated simultaneous integrated boost to prostate for intermediate- and high-risk prostate cancer.

PURPOSE To evaluate the toxicity of pelvic intensity-modulated radiotherapy (IMRT) with hypofractionated simultaneous integrated boost (SIB) to the prostate for patients with intermediate- to high-risk prostate cancer. METHODS AND MATERIALS A retrospective toxicity analysis was performed in 30 consecutive patients treated definitively with pelvic SIB-IMRT, all of whom also received androgen suppression. The IMRT plans were designed to deliver 70 Gy in 28 fractions (2.5 Gy/fraction) to the prostate while simultaneously delivering 50.4 Gy in 28 fractions (1.8 Gy/fraction) to the pelvic lymph nodes. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to score toxicity. RESULTS The most common acute Grade 2 events were cystitis (36.7%) and urinary frequency/urgency (26.7%). At a median follow-up of 24 months, late toxicity exceeding Grade 2 in severity was uncommon, with two Grade 3 events and one Grade 4 event. Grade 2 or greater acute bowel toxicity was associated with signficantly greater bowel volume receiving > or =25 Gy (p = .04); Grade 2 or greater late bowel toxicity was associated with a higher bowel maximal dose (p = .04) and volume receiving > or =50 Gy (p = .02). Acute or late bladder and rectal toxicity did not correlate with any of the dosimetric parameters examined. CONCLUSION Pelvic IMRT with SIB to the prostate was well tolerated in this series, with low rates of Grade 3 or greater acute and late toxicity. SIB-IMRT combines pelvic radiotherapy and hypofractionation to the primary site and offers an accelerated approach to treating intermediate- to high-risk disease. Additional follow-up is necessary to fully define the long-term toxicity after hypofractionated, whole pelvic treatment combined with androgen suppression.

Survival and Patterns of Relapse in Patients With Oral Tongue Cancer

PURPOSE To evaluate the survival and patterns of relapse for patients with squamous cell carcinoma (SCC) of the oral tongue. PATIENTS AND METHODS Between 1999 and 2007, 50 patients with SCC of the oral tongue were treated at the University of Colorado Denver. Of the 50 patients, 38 had newly diagnosed SCC of the oral tongue (13 with stage I-II and 25 with stage III-IV disease), and 12 presented with locally recurrent SCC. Of the 50 patients, 49 were treated with initial surgery and 1 with definitive chemoradiotherapy. Adjuvant radiotherapy or chemoradiotherapy was administered to 42 patients after surgery. Of the 13 patients with newly diagnosed stage I-II disease, 7 did not receive adjuvant therapy. The actuarial locoregional control, freedom from distant relapse, and survival were determined using the Kaplan-Meier method, and comparisons were made using the log-rank test. RESULTS The median follow-up was 29 months (range 4 to 95) for living patients. The 2-year locoregional control and freedom from distant relapse rate was 58% and 83%, respectively. Locoregional control was particularly low among patients with stage I-II disease, for whom the 2-year locoregional control rate was only 35%. The median survival time and 2-year survival rate for all patients was 42 months and 65%, respectively. The 2-year survival rate for patients with stage I-II oral tongue cancer was 77% compared with 52% for patients with stage III-IV disease (P = .04). CONCLUSIONS Despite aggressive therapy, patients with SCC of the oral tongue have a low rate of local tumor control and survival, particularly among those with stage I-II disease. These patients should be considered for inclusion in clinical trials evaluating novel postoperative therapies.

Freedom From Local and Regional Failure of Contralateral Neck With Ipsilateral Neck Radiotherapy for Node-Positive Tonsil Cancer: Results of a Prospective Management Approach

PURPOSE To review the outcomes of a prospective management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion. METHODS AND MATERIALS Between August 2003 and June 2007, 20 patients who presented with squamous cell carcinoma of the tonsil, without involvement of the base of the tongue or midline soft palate, and with Stage N1-N2b disease were prospectively treated with radiotherapy to the primary site and ipsilateral neck. In addition, 18 patients received concurrent chemotherapy. The actuarial freedom from contralateral nodal and in-field progression was determined. Acute and late toxicity were prospectively evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3, and Radiation Therapy Oncology Group criteria. RESULTS The nodal disease was Stage N1 in 4 patients, N2a in 3 patients, and N2b in 13 patients. At a median follow-up 19 months (range, 12-40), no in-field or contralateral nodal recurrences had been observed. The 2-year freedom from distant metastasis rate was 87.4%. The actuarial 2-year disease-free and overall survival rates were both 79.5%. Late Radiation Therapy Oncology Group grade 2 xerostomia occurred in 1 patient (5%). No late Grade 3 or greater toxicity was observed. No patient was feeding tube dependent at their last follow-up visit. CONCLUSION In carefully selected patients with node-positive, lateralized tonsillar cancer, treatment of the ipsilateral neck and primary site does not appear to increase the risk of contralateral nodal failure and reduces late morbidity compared with historical controls. Although the outcomes with ipsilateral radiotherapy in the present series were promising, these findings require longer follow-up and validation in a larger patient cohort.

Outcomes and Effect of Radiotherapy in Patients With Stage I or II Diffuse Large B-Cell Lymphoma: A Surveillance, Epidemiology, and End Results Analysis

PURPOSE To assess disease-specific survival (DSS), overall survival (OS), and the effect of radiotherapy (RT) in patients with localized diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with Stage I, IE, II, or IIE DLBCL between 1988 and 2004. The analyzable data included gender, age, race, stage, presence of extranodal disease, and RT administration. Patients who had died or were lost to follow-up within 6 months of diagnosis were excluded. RESULTS A total of 13,420 patients met the search criteria. Of these, 5,547 (41%) had received RT and 7,873 (59%) had not. RT was associated with a significant DSS (hazard ratio, 0.82, p <0.0001) and OS benefit that persisted during the 15 years of follow-up. Elderly patients, defined either as those >60 or >70 years old, had significantly improved DSS and OS associated with RT. On multivariate analysis, RT was significantly associated with increased DSS and OS. The 5-year DSS outcomes were highly variable among patient subsets, defined by age, stage, and extranodal disease (range for RT-treated patients, 70% for Stage II, age >60 years to 87% for Stage I, age </=60 years). CONCLUSION This analysis presents the largest detailed data set of Stage I-II DLBCL patients. The results of our study have demonstrated that RT is associated with a survival advantage in patients with localized DLBCL, a benefit that extends to elderly patients. Outcomes for discrete patient subsets varied greatly. The development of tailored therapy according to the relapse risk is warranted, rather than uniform treatment of all early-stage DLBCL.

Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSE To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. METHODS AND MATERIALS Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. RESULTS A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. CONCLUSIONS The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.