Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer.

UNLABELLED: : Genotype-based selection of patients for targeted therapies has had a substantial impact on the treatment of non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs) directed at cancers driven by oncogenes, such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, often achieve dramatic responses and result in prolonged survival compared with chemotherapy. However, TKI resistance invariably develops. Disease progression can be limited to only one or a few sites and might not be symptomatic, raising the important question of whether this type of oligoprogression warrants a change in systemic therapy or consideration of local treatment. Recent clinical observations suggest a growing role for stereotactic body radiation therapy (SBRT) in the treatment of oligoprogressive and perhaps even oligopersistent disease (primary and/or metastases) in oncogene-driven NSCLC. SBRT might allow patients to continue with existing TKI treatments longer and delay the need to switch to other systemic options. We review the current data with regard to the use of SBRT for metastatic NSCLC and particularly oncogene-driven disease. Although there is great promise in the marriage of targeted therapies with SBRT, prospective data are urgently needed. In the meantime, such strategies are being used in carefully selected patients, with risk-adapted SBRT dose-fractionation regimens used to optimize the therapeutic index. IMPLICATIONS FOR PRACTICE: Stereotactic body radiation therapy (SBRT) or SBRT-like treatments are increasingly being used for oligoprogression in patients with oncogene-driven non-small cell lung cancer. This approach allows patients to extend the duration of tyrosine kinase inhibitor therapy and has the potential to prolong survival times. Careful patient selection and risk-adapted radiation dosing is of critical importance to minimize toxicity and preserve patient quality of life.

Gastrointestinal stromal tumor with maxillary metastasis: a case report and literature review.

Gastrointestinal stromal tumors (GISTs) form commonly in the stomach, small intestine, colorectum, and esophagus. Metastatic GIST occurs in up to 50% of patients at presentation. The liver and peritoneal cavity are the most common (93%) metastatic sites; head and neck metastases are extremely rare. This report describes a unique case of a 77-year-old man who was diagnosed with a duodenal GIST that had been completely resected 15 years ago. Eleven years after complete resection, he presented with liver metastases and then received multiple lines of systemic therapy and ablative radiotherapy. In 2015, he presented to our oral and maxillofacial surgery department with a left exophytic maxillary mass that filled the left maxillary sinus. Incisional biopsy confirmed metastatic GIST. Further evaluation revealed extensive metastases in the patient's liver, lungs, spleen, abdominal wall, and lymph nodes. After adequate staging, the patient's condition was deemed palliative, and he was referred to the radiation oncology department for palliative treatment of the symptomatic maxillary lesion. To our knowledge, this is the first reported case of maxillary metastasis from a duodenal GIST. Inclusion of GIST in the differential diagnosis of jaw tumors in patients with nonoral malignancies is recommended. The literature on oral metastasis of GIST is reviewed and discussed in this case report.

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma.

Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear ß-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup.

Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct.

Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.

Adjuvant radiotherapy in the treatment of pediatric myxopapillary ependymomas.

OBJECTIVES: Assess the role of radiotherapy (RT) in the management of primary and recurrent myxopapillary ependymoma (MPE). MATERIALS AND METHODS: We conducted a retrospective review of patients with MPE treated at the Montreal Children's Hospital/McGill University Health Centre between 1985 and 2008. RESULTS: Seven children under the age of 18 were diagnosed and treated for MPE. All patients were treated with surgery to the primary site. Three patients underwent subtotal resection (STR) and received adjuvant post-operative RT. Only one patient who had spinal drop metastases received post-operative RT to the lumbosacral region following complete resection of the primary tumor. After a median follow up of 78 months (range 24-180 months), all patients were alive with controlled disease. The single patient treated with gross total resection (GTR) and adjuvant local radiation remained recurrence free. One of the three patients treated with STR and adjuvant RT had disease progression that was controlled with re-resection and further RT. Two of the three patients treated with surgery alone developed local and disseminated recurrent spinal disease that was controlled by salvage RT. CONCLUSION: Our data support the evolving literature which suggests that GTR alone provides suboptimal disease control in MPE. In our patients, RT resulted in control of residual, metastatic and/or recurrent disease. Routine adjuvant RT may improve outcomes in pediatric MPE.

Can dose outside the PTV influence the risk of distant metastases in stage I lung cancer patients treated with stereotactic body radiotherapy (SBRT)?

BACKGROUND AND PURPOSE: In an era where little is known about the "abscopal" (out-of-the-field) effects of lung SBRT, we investigated correlations between the radiation dose proximally outside the PTV and the risk of cancer recurrence after SBRT in patients with primary stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study included 217 stage I NSCLC patients across 2 institutions who received SBRT. Correlations between clinical and dosimetric factors were investigated. The clinical factors considered were distant metastasis (DM), loco-regional control (LRC) and radiation pneumonitis (RP). The dose (converted to EQD2) delivered to regions of varying size directly outside of the PTV was computed. For each feature, area under the curve (AUC) and odds ratios with respect to the outcome parameters DM, LRC and RP were estimated; Kaplan-Meier (KM) analysis was also performed. RESULTS: Thirty-seven (17%) patients developed DM after a median follow-up of 24 months. It was found that the mean dose delivered to a shell-shaped region of thickness 30 mm outside the PTV had an AUC of 0.82. Two years after treatment completion, the rate of DM in patients where the mean dose delivered to this region was higher than 20.8 Gy2 was 5% compared to 60% in those who received a dose lower than 20.8 Gy2. KM analysis resulted in a hazard ratio of 24.2 (95% CI: 10.7, 54.4); p < 10-5. No correlations were found between any factor and either LRC or RP. CONCLUSIONS: The results of this study suggest that the dose received by the region close to the PTV has a significant impact on the risk of distant metastases in stage I NSCLC patients treated with SBRT. If these results are independently confirmed, caution should be taken, particularly when a treatment plan results in a steep dose gradient extending outwards from the PTV.

A Contralateral Esophagus-Sparing Technique to Limit Severe Esophagitis Associated With Concurrent High-Dose Radiation and Chemotherapy in Patients With Thoracic Malignancies.

PURPOSE: Severe (Radiation Therapy Oncology Group [RTOG] grade 3 or greater) esophagitis generally occurs in 15% to 25% of non-small cell lung cancer (NSCLC) patients undergoing concurrent chemotherapy and radiation therapy (CCRT), which may result in treatment breaks that compromise local tumor control and pose a barrier to dose escalation. Here, we report a novel contralateral esophagus-sparing technique (CEST) that uses intensity modulated radiation therapy (IMRT) to reduce the incidence of severe esophagitis. METHODS AND MATERIALS: We reviewed consecutive patients with thoracic malignancies undergoing curative CCRT in whom CEST was used. The esophageal wall contralateral (CE) to the tumor was contoured as an avoidance structure, and IMRT was used to guide a rapid dose falloff gradient beyond the target volume in close proximity to the esophagus. Esophagitis was recorded based on the RTOG acute toxicity grading system. RESULTS: We identified 20 consecutive patients treated with CCRT of at least 63 Gy in whom there was gross tumor within 1 cm of the esophagus. The median radiation dose was 70.2 Gy (range, 63-72.15 Gy). In all patients, ≥99% of the planning and internal target volumes was covered by ≥90% and 100% of prescription dose, respectively. Strikingly, no patient experienced grade ≥3 esophagitis (95% confidence limits, 0%-16%) despite the high total doses delivered. The median maximum dose, V45, and V55 of the CE were 60.7 Gy, 2.1 cc, and 0.4 cc, respectively, indicating effective esophagus cross-section sparing by CEST. CONCLUSION: We report a simple yet effective method to avoid exposing the entire esophagus cross-section to high doses. By using proposed CE dose constraints of V45 <2.5 cc and V55 <0.5 cc, CEST may improve the esophagus toxicity profile in thoracic cancer patients receiving CCRT even at doses above the standard 60- to 63-Gy levels. Prospective testing of CEST is warranted.

Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy.

INTRODUCTION: The role of stereotactic body radiation therapy (SBRT) in patients with metastatic lung cancer harboring epidermal growth factor receptor (EGFR) mutations is not defined. We evaluated the pattern of failure in patients receiving tyrosine kinase inhibitor (TKI) therapy to identify candidates for consolidation SBRT. METHODS: Computed tomography scans were reviewed in a cohort of EGFR-mutant patients enrolled on prospective TKI trials. Initial progression in sites of original disease (primary/metastatic) or new sites was classified as original site failure (OF) or distant site failure (DF), respectively. Simultaneous OF/DF was labeled ODF. Disease characteristics were analyzed for associations with patterns of failure using actuarial competing risks methodology. RESULTS: Complete serial imaging was available in 49 patients with measurable disease. Median time to any progression was 8.3 months. The majority failed initially in original disease sites with OF, ODF, and DF frequencies being 47.0%, 32.6%, and 20.4%, respectively. Primary tumor size was the most significant predictor of OF in univariate and multivariate analysis (p = 0.004). Median time to progression was 3 months shorter in patients with OF compared with DF. Ten patients (20%) were retroactively classified as consolidation SBRT candidates based on the extent of disease at time of best response to TKI therapy, and in seven of these, initial progression occurred in original tumor sites. CONCLUSION: Initial progression of TKI-treated cancers occurred predominantly in original disease sites. Consolidation SBRT was judged feasible in a subset of patients following maximum TKI response and may have prevented oligoprogression in most of these. In addition, we hypothesize that consolidation SBRT for residual disease could delay subsequent metastatic reseeding.

Cone beam CT-based three-dimensional planning in high-dose-rate brachytherapy for cervical cancer.

PURPOSE: To evaluate dose-volume histograms (DVHs) of bladder and rectum from the use of cone beam CT (CBCT)-based three-dimensional (3D) treatment planning in intracavitary high-dose-rate brachytherapy (HDRB) for cervical cancer patients and to compare these parameters with International Commission on Radiation Units and Measurements (ICRU) of rectal and bladder reference point dose measurements. METHODS AND MATERIALS: Thirteen patients with cervical cancer underwent HDRB insertions. CT-compatible tandem and ovoid applicators were used to obtain intraoperative CBCT images. The use of a rectal tube and injection of bladder contrast before scanning facilitated contouring the rectum and bladder. All patients underwent intraoperative orthogonal x-ray filming, and treatments were prescribed using standard two-dimensional planning and dosimetry. DVHs for the bladder and rectum were constructed for each treatment. The minimum dose in the most irradiated 2.0-cm(3) volume of bladder (B(D2V)) and rectum (R(D2V)) were determined from DVHs and compared to ICRU reference point estimates of bladder (B(ICRU)) and rectum (R(ICRU)) doses. RESULTS: Twenty-six CBCT-based plans were evaluated. The median B(ICRU) dose (347 cGy; range, 164-601 cGy) was significantly lower (p < 0.001) than the median B(D2V) (594 cGy; range, 260-969 cGy). The median R(ICRU) dose (405 cGy; range, 189-700 cGy) was also significantly lower (p = 0.037) than the median R(D2V) (488 cGy; range, 227-786 cGy). CONCLUSIONS: CBCT-based 3D planning can be used in HDRB for cervical cancer and is a convenient alternative to CT-based planning, with the advantage of minimizing applicator motion. Correlation with late effects will further define the role of CBCT-based 3D dosimetry in HDRB planning.

Waldenstrom's macroglobulinemia presenting with spinal cord compression: a case report.

Waldenstrom's macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma characterized by a wide range of clinical presentations related to direct tumor infiltration and the production of IgM. Most commonly it presents with cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, and hyperviscosity syndrome. We report a case of WM in an 81-year-old man who initially presented with severe back pain. The patient had no peripheral lymphadenopathy or hepatosplenomegaly and his peripheral blood smear was normal. MRI of the spine revealed an epidural mass causing spinal cord compression at T9. Surgical decompression was performed and pathological analysis of the mass revealed a lymphoproliferative B-cell process. The diagnosis of WM was established after cytomorphologic and immunohistochemical analysis of the patient's bone marrow revealed the presence of a lymphoid/lymphoplasmacytoid-like bone marrow infiltrate along with an elevated serum IgM level. The patient responded both clinically and serologically to local radiotherapy. This case is unusual because the patient lacked all common clinical features of WM. This is the first reported case of epidural spinal cord compression as the initial manifestation of WM, adding to the spectrum of clinical presentations seen in this disease.