Relationship between Treatment Plan Dosimetry, Toxicity, and Survival following Intensity-Modulated Radiotherapy, with or without Chemotherapy, for Stage III Inoperable Non-Small Cell Lung Cancer.

Concurrent chemoradiotherapy (cCRT) is the preferred treatment for stage III NSCLC because surgery containing multimodality treatment is often not appropriate. Alternatives, often for less fit patients, include sequential CRT and RT alone. Many reports describing the relationship between overall survival (OS), toxicity, and dosimetry are based on clinical trials, with strict criteria for patient selection. We performed an institutional analysis to study the relationship between dosimetric parameters, toxicity, and OS in inoperable patients with stage III NSCLC treated with (hybrid) IMRT/VMAT-based techniques in routine clinical practice. Eligible patients had undergone treatment with radical intent using cCRT, sCRT, or RT alone, planned to a total dose ≥ 50 Gy delivered in ≥15 fractions. All analyses were performed for two patient groups, (1) cCRT (n = 64) and (2) sCRT/RT (n = 65). The toxicity rate differences between the two groups were not significant, and OS was 29 and 17 months, respectively. For sCRT/RT, no dosimetric factors were associated with OS, whereas for cCRT, PTV-volume, esophagus V50 Gy, and contralateral lung V5 Gy were associated. cCRT OS was significantly lower in patients with esophagitis ≥ G2. The overall rate of ≥G3 pneumonitis was low (3%), and the rate of high-grade esophagitis the OS in this real-world patient population was comparable to those reported in clinical trials. Based on this hypothesis-generating data, more aggressive esophageal sparing merits consideration. Institutional auditing and benchmarking of the planning strategy, dosimetry, and outcome have an important role to play in the continuous quality improvement process.

Factors influencing multi-disciplinary tumor board recommendations in stage III non-small cell lung cancer.

OBJECTIVES: Treatment patterns in patients with stage III non-small cell lung cancer (NSCLC) vary considerably between countries, for reasons that are not well understood. We studied factors influencing treatment decision-making at thoracic multidisciplinary tumor boards (MDT's) and outcome for patients treated between 2015-2017, at a regional network comprising 5 hospitals. MATERIALS AND METHODS: Details of all patients, including comorbidities, with stage III NSCLC were collected in an ethics-approved database. Weekly MDT's were conducted. The preferred radical intent treatments (RIT) for suitable patients were assumed to be concurrent chemoradiotherapy and/or surgery and other therapies were non-radical intent treatments (n-RIT). RESULTS: Of 197 patients identified, 95 % were discussed at an MDT. RIT were recommended in 61 % of patients, but only 48 % finally received RIT. The estimated median OS was significantly better for patients undergoing RIT (28.3 months, CI-95 % 17.3-39.3), versus those who did not (11.2 months, CI-95 % 8.0-14.3). Patient age ≥70 years and a WHO-PS ≥2 were the most important predictors of not recommending RIT. Deaths due to progressive lung cancer within 2 years were observed in 36, 26 and 29 % of patients who received RIT, sequential chemoradiotherapy or radical radiotherapy. Corresponding comorbidity related deaths within 2 years were 3, 12 and 38 %. CONCLUSION: A large number of patients who underwent MDT review were considered too old or not fit for RIT. More effective and better tolerated systemic treatments are required for patients presenting with stage III NSCLC.

Optimizing SABR delivery for synchronous multiple lung tumors using volumetric-modulated arc therapy.

BACKGROUND: Volumetric-modulated arc therapy (VMAT) delivery for stereotactic ablative radiotherapy (SABR) of multiple lung tumors allows for faster treatments. We report on clinical outcomes and describe a general approach for treatment planning. MATERIAL AND METHODS: Patients undergoing multi iso-center VMAT-based SABR for ≥2 lung lesions between 2009 and 2014 were identified from the VU University Medical Center and London Health Sciences Centre. Patients were eligible if the start date of the SABR treatment for the different lesions was within a time range of 30 days. SABR was delivered using separate iso-centers for lesions at a substantial distance from each other. Tumors were either treated with a single fraction of 34 Gy, or using three risk-adapted dose-fractionation schemes, namely three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, depending on the tumor size and the location. Multivariable analysis was performed to assess factors predictive of clinical outcomes. RESULTS: Of 84 patients (188 lesions) identified, 46% were treated for multiple metastases and 54% for multiple primary NSCLC. About 97% were treated for two or three lesions, and 56% had bilateral disease. After a median follow-up of 28 months, median overall survival (OS) for primary tumors was 27.6 months, and not reached for metastatic lesions (p = .028). Grade ≥3 toxicity was observed in 2% of patients. Multivariable analysis showed that grade 2 or higher radiation pneumonitis (n = 9) was best predicted by a total lung V35Gy of ≥6.5% (in 2Gy/fraction equivalent) (p = .007). CONCLUSION: Severe toxicity was uncommon following SABR using VMAT for up to three lung tumors. Further investigations of planning parameters are needed in patients presenting with more lesions.

Outcomes of Hypofractionated High-Dose Radiotherapy in Poor-Risk Patients with "Ultracentral" Non-Small Cell Lung Cancer.

INTRODUCTION: We defined "ultracentral" lung tumors as centrally located non-small cell lung cancers with planning target volumes overlapping the trachea or main bronchi. Increased toxicity has been reported after both conventional and stereotactic radiotherapy for such lesions. We studied outcomes after 12 fractions of 5 Gy (BED10 = 90 Gy, heterogeneous dose distribution) to ultracentral tumors in patients unfit for surgery or conventional chemoradiotherapy. METHODS: Clinical outcomes and dosimetric details were analyzed in 47 consecutive patients with single primary or recurrent ultracentral non-small cell lung cancer treated between 2010 and 2015. Those irradiated previously or with metastasis to sites other than the brain and adrenal glands were excluded. Treatments were delivered using volumetric modulated arc therapy. RESULTS: The median age was 77.5 years, 49% of patients had a World Health Organization performance score of 2 or higher, and the median planning target volume was 104.5cm(3) (range 17.7-508.5). At a median follow-up of 29.3 months, median overall survival was 15.9 months, and 3-year survival was 20.1%. No isolated local recurrences were observed. Grade 3 or higher toxicity was recorded in 38% of patients, with 21% scored as having a "possible" (n = 2) or "likely" (n = 8) treatment-related death between 5.2 and 18.2 months after treatment. Fatal pulmonary hemorrhage was observed in 15% of patients. CONCLUSIONS: Unfit patients with ultracentral tumors who were treated using this scheme had a high local control and a median survival of 15.9 months. Despite manifestation of rates of a fatal lung bleeding comparable to those seen with conventional radiotherapy for endobronchial tumors, the overall rate of G5 toxicity is of potential concern. Additional work is needed to identify tumor and treatment factors related to hemorrhage.

High-dose, conventionally fractionated thoracic reirradiation for lung tumors.

BACKGROUND: Loco-regional recurrences and second primary lung tumors are not uncommon after high-dose thoracic radiotherapy. The availability of improved radiotherapy techniques increases options for reirradiation. We describe a single-institutional experience with high-dose conventional thoracic reirradiation for both loco-regional recurrences and new primary tumors. METHODS: Retrospective chart review of patients undergoing reirradiation between February 2004 and February 2013. RESULTS: Of 24 patients identified, 54% had a loco-regional recurrence, and 46% a new primary tumor. The majority (63%) had stage III NSCLC at both initial and second treatment; median interval between treatments was 51 months (5-189), median follow-up after reirradiation was 19.3 months (95% CI: 2.8-35.9). Median overall survival (OS) after reirradiation was 13.5 months, with 1-year survival 51%. Median event-free survival (EFS) was 8.4 months. Median time between reirradiation and local progression (n=8) or distant progression (n=8) was 6.7 and 11.8 months, respectively. Three patients died with possible grade 5 bleeding. Other toxicities were uncommon. Planning target volume (PTV) at reirradiation was the most important prognostic factor; PTV <300 versus ≥300cc was significantly associated with median OS (17.4 vs 8.2 months, p=0.03) and EFS (14.1 vs 5.5 months, p=0.03). Magnitude of overlap between the initial and subsequent PTVs, and between dose distributions, did not influence survival. CONCLUSION: Thoracic reirradiation with high dose conventional radiotherapy appears to deliver a meaningful survival benefit in low volume new primary or recurrent lung cancer. Further studies are needed to confirm these findings, and to establish reliable normal tissue tolerance doses for reirradiation.

Changes in non-surgical management of stage III non-small cell lung cancer at a single institution between 2003 and 2010.

BACKGROUND: Concurrent chemo-radiotherapy (CON-CRT) is recommended for selected patients with stage III non-small cell lung cancer (NSCLC), but utilization varies. We assessed the response to national guidelines introduced in 2004 and the impact on outcomes. MATERIAL AND METHODS: Retrospective study of stage III NSCLC patients treated with radical intent non-surgical treatment during 2003-2010 in a university medical center characterized by multidisciplinary assessment, routine use of four-dimensional computed tomography for radiotherapy planning, and rapid implementation of radiotherapy advances. RESULTS: Between 2003 and 2010, 319/435 (73%) patients with stage III NSCLC received (chemo) radiotherapy. The number receiving CON-CRT in successive two-year periods increased from 13/48 (27%) - 40/80 (50%) - 63/90 (70%), to 74/101 (73%). Median overall survival (OS) from start of radiotherapy was 18.6 months for CON-CRT (190/319) and 17.4 months for sequential (SEQ), typically hypofractionated, CRT (90/319) (p = 0.78). Eleven months OS with radiotherapy alone (39/319) was significantly shorter (p = 0.006). OS did not differ between the four periods (p = 0.87). CON-CRT was not over-represented in the 16% of patients dying within five months of starting radiotherapy. CONCLUSIONS: Between 2003 and 2010, CON-CRT for stage III NSCLC was rapidly and safely increased. However, OS did not increase and, as practiced, did not differ between CON- or SEQ-CRT.

Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors.

OBJECTIVES: Metastatic non-small cell lung carcinoma (NSCLC) generally carries a poor prognosis, and systemic therapy is the mainstay of treatment. However, extended survival has been reported in patients presenting with a limited number of metastases, termed oligometastatic disease. We retrospectively reviewed the outcomes of such patients treated at two centers. MATERIALS AND METHODS: From September 1999-July 2012, a total of 61 patients with 1-3 synchronous metastases, who were treated with radical intent to all sites of disease, were identified from records of two cancer centers. Treatment was considered radical if it involved surgical resection and/or delivery of radiation doses ≥13 × 3 Gy. RESULTS: Besides the primary tumor, 50 patients had a solitary metastasis, 9 had two metastases, and 2 had three metastases. Locations of metastases included the brain (n = 36), bone (n = 11), adrenal (n = 4), contralateral lung (n = 4), extra-thoracic lymph nodes (n = 4), skin (n = 2) and colon (n = 1). Only one patient had metastases in two different organs. Median follow-up was 26.1 months (m), median overall survival (OS) was 13.5m, median progression free survival (PFS) was 6.6m and median survival after first progression (SAFP) was 8.3m. The 1- and 2-year OS were, 54% and 38%, respectively. Significant predictors of improved OS were: smaller radiotherapy planning target volume (PTV) (p = 0.004) and surgery for the primary lung tumor (p < 0.001). Factors associated with improved SAFP included surgery for the primary lung tumor, presence of brain metastases, and absence of bone metastases. No significant differences in outcomes were observed between the two centers. CONCLUSION: Radical treatment of selected NSCLC patients presenting with 1-3 synchronous metastases can result in favorable 2-year survivals. Favorable outcomes were associated with intra-thoracic disease status: patients with small radiotherapy treatment volumes or resected disease had the best OS. Future prospective clinical trials, ideally randomized, should evaluate radical treatment strategies in such patients.

Radiotherapy for a second primary lung cancer arising post-pneumonectomy: planning considerations and clinical outcomes.

BACKGROUND: Second primary non-small cell lung cancer (SPLC) is a significant cause of death amongst lung cancer survivors. As subsequent surgery is seldom feasible post-pneumonectomy, we studied the long-term clinical outcomes achieved with curative radiotherapy using modern delivery techniques. METHODS: Retrospective review of an institutional database between 2003-2011 identified 27 patients who had received curative radiotherapy for SPLC arising post-pneumonectomy. Treatments included; stereotactic ablative radiotherapy (SABR, n=20, dose 54-60 Gy in 3-8 fractions), hypofractionated radiotherapy (HFR, n=6, dose 39-60 Gy in 12-23 fractions) and conventional radiotherapy (RT, n=1, 60 Gy in 30 fractions). Clinical follow-up with a CT scan at 3, 6 and 12 months, then yearly was performed. Toxicities were scored using the common toxicity criteria for adverse events (version 4.0). RESULTS: The median overall survival was 39 months (95% CI, 33-44 months). After a median follow-up of 52 months (95% CI, 37-67 months), any recurrence was observed in four (15%) patients. Actuarial 3-year rates of local, regional and distant recurrences were 8% (95% CI, 0-21 months), 10% (95% CI, 0-23%) and 9% (95% CI, 0-20%), respectively. Patients receiving HFR or RT all had centrally located tumors. Of the patients treated with HFR delivered 12 fractions, 75% (3/4) developed grade 3 or higher radiation pneumonitis (RP), including one probable grade 5 toxicity. Of those receiving RT or HFR in 13 or more fractions no (0/3) grade 3 or worse RP was observed, despite such treatment being used for larger tumors and resulting in worse lung dose-volume histogram metrics. All the patients who developed RP had radiotherapy plans, which prioritized the sparing of central structures over lung sparing. No non-RP grade 3 or higher toxicities were observed. CONCLUSIONS: Curative radiotherapy is an effective treatment for SPLC arising post-pneumonectomy. For larger central tumors, our data suggests that plans should prioritize reducing lung doses above the sparing of central structures.

The clinical utility of prognostic scoring systems in patients with brain metastases treated with radiosurgery.

PURPOSE: The RTOG recursive partitioning analysis (RPA) classification is the gold standard for assessing the prognosis of patients with brain metastases (BM). Newer prognostic scoring systems for BM patients have been proposed, but their superiority over RPA needs to be established for patients treated with radiosurgery. METHODS: 380 patients with 1-3 BM were treated at the VUmc with radiosurgery (RS) from 2002 to 2011. Using baseline characteristics, patient scores were calculated for RPA, the Rotterdam-system, the score index for radiosurgery (SIR), the basic score for BM (BSBM), the graded prognostic assessment (GPA), the diagnosis-specific GPA, the Rades score, and the Golden grading system (GGS) for comparison with survival time and survival classification (≤3 months or ≥12 months). RESULTS: Median survival after RS was 7.7 months, with 3-month and 1-year overall survival (OS) of 76% and 39%, respectively. Multivariate analysis confirmed the prognostic value of performance status, age, absence of extracranial metastases, primary tumor site, gender, and steroid response for OS. The percentage of patients included within the intermediate prognostic classes ranged from 48% to 77%, and was 64% for the RPA. All scoring systems highly correlated with OS (p<0.001). The specificity for predicting early death ranged from 85% to 98% (RPA 88%), with the unfavorable classes of Rades, GGS, BSBM and SIR performing best. The sensitivity for predicting long-term survival ranged from 10% to 69% (RPA 29%), and was highest for the favorable classes of Rades and GGS. CONCLUSIONS: All prognostic scoring systems correlated very well with OS. All scores shared the limitation of unbalanced proportions of patients within the prognostic classes. As the clinical superiority of more recently developed prognostic scoring systems was only modest in predicting early death and long term survival, the well-known and easy to use RPA system currently remains the standard.

Quality assurance of radiotherapy in the ongoing EORTC 22042-26042 trial for atypical and malignant meningioma: results from the dummy runs and prospective individual case Reviews.

BACKGROUND: The ongoing EORTC 22042-26042 trial evaluates the efficacy of high-dose radiotherapy (RT) in atypical/malignant meningioma. The results of the Dummy Run (DR) and prospective Individual Case Review (ICR) were analyzed in this Quality Assurance (QA) study. MATERIAL/METHODS: Institutions were requested to submit a protocol compliant treatment plan for the DR and ICR, respectively. DR-plans (n=12) and ICR-plans (n=50) were uploaded to the Image-Guided Therapy QA Center of Advanced Technology Consortium server (http://atc.wustl.edu/) and were assessed prospectively. RESULTS: Major deviations were observed in 25% (n=3) of DR-plans while no minor deviations were observed. Major and minor deviations were observed in 22% (n=11) and 10% (n=5) of the ICR-plans, respectively. Eighteen% of ICRs could not be analyzed prospectively, as a result of corrupted or late data submission. CTV to PTV margins were respected in all cases. Deviations were negatively associated with the number of submitted cases per institution (p=0.0013), with a cutoff of 5 patients per institutions. No association (p=0.12) was observed between DR and ICR results, suggesting that DR's results did not predict for an improved QA process in accrued brain tumor patients. CONCLUSIONS: A substantial number of protocol deviations were observed in this prospective QA study. The number of cases accrued per institution was a significant determinant for protocol deviation. These data suggest that successful DR is not a guarantee for protocol compliance for accrued patients. Prospective ICRs should be performed to prevent protocol deviations.

Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer.

PURPOSE: Patients with large volume stage III non-small cell lung cancer (NSCLC) are often excluded from concurrent chemoradiotherapy (CRT) protocols due to fears about excessive toxicity and poor survival. Patients with N3 nodal disease may be excluded for the same reason. We have routinely accepted fit patients in both the above groups for CRT if they met our planning parameters. We analyzed toxicity and survival outcomes for patients undergoing CRT with a planning target volume (PTV) exceeding 700 cc, either with or without N3 nodal disease, or a PTV less then 700 cc with N3 disease. MATERIALS AND METHODS: Single center, retrospective study of patients with stage III NSCLC treated with CRT between 2004 and 2011. RESULTS: 121 patients were eligible, with 81% (98/121) having a PTV>700 cc (of whom 33% (32/98) had N3 nodal disease) and 19% (23/121) having N3 disease and a PTV≤700 cc. Grade ≥3 esophagitis and pneumonitis were recorded in respectively 34% and 4% of all patients. Median follow-up for all patients was 37.6 months (mo). Median overall (OS) and progression-free (PFS) survivals were 15.7 mo and 11.6 mo, respectively, OS for all patients with PTV>700 cc was 14.5 mo (19.5 mo with N3 and 13.2 mo without N3), compared to 26.5 mo for PTV≤700 cc with N3 (p=0.009). About 1 in 4 patients with PTV>700 cc died within 6 mo of starting radiotherapy (this was associated with Charlson comorbidity index [CCI]≥1), while about 18% were alive at 3 years. CONCLUSION: Patients undergoing CRT for stage III NSCLC with a PTV>700 cc, with or without N3 nodal disease, had a significantly shorter OS than patients with PTV≤700 cc with N3. Patients with PTV>700 cc and with CCI≥1, had a significantly higher risk of early death but longer-term survivors with PTV>700 cc are observed. The PTV and CCI should be considered in clinical decision making and used as stratification factors in future trials.

Categorizing segmentation quality using a quantitative quality assurance algorithm.

INTRODUCTION: Obtaining high levels of contouring consistency is a major limiting step in optimizing the radiotherapeutic ratio. We describe a novel quantitative methodology for the quality assurance (QA) of contour compliance referenced against a community set of contouring experts. METHODS: Two clinical tumour site scenarios (10 lung cases and one prostate case) were used with QA algorithm. For each case, multiple physicians (lung: n = 6, prostate: n = 25) segmented various target/organ at risk (OAR) structures to define a set of community reference contours. For each set of community contours, a consensus contour (Simultaneous Truth and Performance Level Estimation (STAPLE)) was created. Differences between each individual community contour versus the group consensus contour were quantified by consensus-based contouring penalty metric (PM) scores. New observers segmented these same cases to calculate individual PM scores (for each unique target/OAR) for each new observer-STAPLE pair for comparison against the community and consensus contours. RESULTS: Four physicians contoured the 10 lung cases for a total of 72 contours for quality assurance evaluation against the previously derived community consensus contours. A total of 16 outlier contours were identified by the QA system of which 11 outliers were due to over-contouring discrepancies, three were due to over-/under-contouring discrepancies, and two were due to missing/incorrect nodal contours. In the prostate scenario involving six physicians, the QA system detected a missing penile bulb contour, systematic inner-bladder contouring, and under-contouring of the upper/anterior rectum. CONCLUSION: A practical methodology for QA has been demonstrated with future clinical trial credentialing, medical education and auto-contouring assessment applications.

A pooled analysis of arc-based image-guided simultaneous integrated boost radiation therapy for oligometastatic brain metastases.

PURPOSE: To report pooled overall survival and time to radiological intracranial progression results related to arc-based image-guided radiotherapy for dose-escalation of oligometastatic disease of the brain. METHODS AND MATERIALS: Anonymized patient, tumor, and treatment data were pooled from the VU University medical center (VUmc) and the London Regional Cancer Program (LRCP) for patients treated with whole brain radiotherapy (20 Gy/5 VUmc, 30 Gy/10 LRCP) with simultaneous integrated boost (SIB) to individual intracranial lesions (40 Gy/5 VUmc, 35-60 Gy/10 LRCP) to perform survival/intracranial control outcome analyses. RESULTS: A total of 120 patients were treated by both the LRCP (n=70) and VUmc (n=50) between 2005 and 2010. Median lesional dose BED3,10 for the entire cohort of patients were 147 and 72 Gy, respectively. Median follow-up for the entire cohort of patients was 4.7 months with median follow-up of 5.2 months for living patients. On multivariable analysis, primary lung cancer (HR 2.044), presence of systemic metastatic disease (HR 1.937), and lower baseline WHO performance status (HR 1.742) were significant (p<0.05) predictors of shorter overall survival. Cumulative brain metastases volume (HR 1.014, p=0.06) was of borderline significance on analysis of intracranial control. CONCLUSIONS: This pooled analysis has provided robust outcome data regarding the use of arc-based radiotherapy with SIB.