Chelsea C. Pinnix

Double hit lymphoma: The MD Anderson Cancer Center clinical experience

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B‐cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18–85), 84% of patients had advanced‐stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low‐grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH‐BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two‐year event‐free survival (EFS) rates in all patients and patients who received R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R‐HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2‐year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.

Fertility drugs and the risk of breast cancer: a meta-analysis and review

The risk of breast cancer has been associated with reproductive history. The purpose of this study was to determine the relationship between fertility drugs used in assisted reproductive procedures and the risk of breast cancer. We performed a literature search using the MEDLINE, the COCHRANE Library, and Scopus to identify studies linking breast cancer to fertility drugs. We excluded case series, case reports, and review articles from our analysis. The study populations included women who were treated for infertility with clomiphene, gonadotropins, gonadotropin-releasing hormones, or other unspecified fertility agents. We extracted information on study design, sample size, type of fertility drugs and number of treatment cycles, breast cancer incidence, and follow-up time from these studies. Eight case–control studies and fifteen cohort studies were included in the quantitative analyses. The Newcastle–Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. We found that the risk of breast cancer was not significantly associated with fertility drug treatment. The follow-up periods were short in some of the studies analyzed in our study; however, we proceeded to test the trend in risk estimates across different durations of follow-up and found a trend for association using the nonparametric test; this was interpreted with caution in view of the lack of adjustment with other confounding factors. The current published data do not suggest higher risk of breast cancer in women who receive fertility treatment, but the lack of long-term follow up and the inherent weaknesses in some of the published studies have to be cautiously taken into account.

Predictors of survival in contemporary practice after initial radiosurgery for brain metastases

PURPOSE The number of brain metastases (BM) is a major consideration in determining patient eligibility for stereotactic radiosurgery (SRS), but the evidence for this popular practice is equivocal. The purpose of this study was to determine whether, following multivariate adjustment, the number and volume of BM held prognostic significance in a cohort of patients initially treated with SRS alone. METHODS AND MATERIALS A total of 251 patients with primary malignancies, including non-small cell lung cancer (34%), melanoma (30%), and breast carcinoma (16%), underwent SRS for initial treatment of BM. SRS was used as the sole management (62% of patients) or was combined with salvage treatment with SRS (22%), whole-brain radiation therapy (WBRT; 13%), or resection (3%). Median follow-up time was 9.4 months. Survival was determined using the Kaplan-Meier method. Cox regression was used to assess the effects of patient factors on distant brain failure (DBF), local control (LC), and overall survival (OS). RESULTS LC at 1 year was 94.6%, and median time to DBF was 10 months. Median OS was 11.1 months. On multivariate analysis, statistically significant predictors of OS were presence of extracranial disease (hazard ratio [HR], 4.2, P<.001), total tumor volume greater than 2 cm(3) (HR, 1.98; P<.001), age ≥60 years (HR, 1.67; P=.002), and diagnosis-specific graded prognostic assessment (HR, 0.71; P<.001). The presence of extracranial disease was a statistically significant predictor of DBF (HR, 2.15), and tumor volume was predictive of LC (HR, 4.56 for total volume >2 cm(3)). The number of BM was not predictive of DBF, LC, or OS. CONCLUSIONS The number of BM is not a strong predictor for clinical outcomes following initial SRS for newly diagnosed BM. Other factors including total treatment volume and systemic disease status are better determinants of outcome and may facilitate appropriate use of SRS or WBRT.

Duodenal Toxicity after Fractionated Chemoradiation for Unresectable Pancreatic Cancer

PURPOSE Improving local control is critical to improving survival and quality of life for patients with locally advanced unresectable pancreatic cancer (LAPC). However, previous attempts at radiation dose escalation have been limited by duodenal toxicity. In order to guide future studies, we analyzed the clinical and dosimetric factors associated with duodenal toxicity in patients undergoing fractionated chemoradiation for LAPC. METHODS AND MATERIALS Medical records and treatment plans of 106 patients with LAPC who were treated with chemoradiation between July 2005 and June 2010 at our institution were reviewed. All patients received neoadjuvant and concurrent chemotherapy. Seventy-eight patients were treated with conventional radiation to 50.4 Gy in 28 fractions; 28 patients received dose-escalated radiation therapy (range, 57.5-75.4 Gy in 28-39 fractions). Treatment-related toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to assess prognostic influence of clinical, pathologic, and treatment-related factors by using Kaplan-Meier and Cox regression methods. RESULTS Twenty patients had treatment-related duodenal toxicity events, such as duodenal inflammation, ulceration, and bleeding. Four patients had grade 1 events, 8 had grade 2, 6 had grade 3, 1 had grade 4, and 1 had grade 5. On univariate analysis, a toxicity grade ≥2 was associated with tumor location, low platelet count, an absolute volume (cm(3)) receiving a dose of at least 55 Gy (V(55 Gy) > 1 cm(3)), and a maximum point dose >60 Gy. Of these factors, only V(55 Gy) ≥1 cm(3) was associated with duodenal toxicity on multivariate analysis (hazard ratio, 6.7; range, 2.0-18.8; P=.002). CONCLUSIONS This study demonstrates that a duodenal V(55 Gy) >1 cm(3) is an important dosimetric predictor of grade 2 or greater duodenal toxicity and establishes it as a dosimetric constraint when treating patients with unresectable pancreatic cancer with concurrent chemoradiation.

Predictors of Radiation Pneumonitis in Patients Receiving Intensity-Modulated Radiation Therapy for Hodgkin and Non-Hodgkin Lymphoma

PURPOSE Few studies to date have evaluated factors associated with the development of radiation pneumonitis (RP) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), especially in patients treated with contemporary radiation techniques. These patients represent a unique group owing to the often large radiation target volumes within the mediastinum and to the potential to receive several lines of chemotherapy that add to pulmonary toxicity for relapsed or refractory disease. Our objective was to determine the incidence and clinical and dosimetric risk factors associated with RP in lymphoma patients treated with intensity modulated radiation therapy (IMRT) at a single institution. METHODS AND MATERIALS We retrospectively reviewed clinical charts and radiation records of 150 consecutive patients who received mediastinal IMRT for HL and NHL from 2009 through 2013. Clinical and dosimetric predictors associated with RP according to Radiation Therapy Oncology Group (RTOG) acute toxicity criteria were identified in univariate analysis using the Pearson χ(2) test and logistic multivariate regression. RESULTS Mediastinal radiation was administered as consolidation therapy in 110 patients with newly diagnosed HL or NHL and in 40 patients with relapsed or refractory disease. The overall incidence of RP (RTOG grades 1-3) was 14% in the entire cohort. Risk of RP was increased for patients who received radiation for relapsed or refractory disease (25%) versus those who received consolidation therapy (10%, P=.019). Several dosimetric parameters predicted RP, including mean lung dose of >13.5 Gy, V20 of >30%, V15 of >35%, V10 of >40%, and V5 of >55%. The likelihood ratio χ(2) value was highest for V5 >55% (χ(2) = 19.37). CONCLUSIONS In using IMRT to treat mediastinal lymphoma, all dosimetric parameters predicted RP, although small doses to large volumes of lung had the greatest influence. Patients with relapsed or refractory lymphoma who received salvage chemotherapy and hematopoietic stem cell transplantation were at higher risk for symptomatic RP.

Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: single-blind randomized phase III clinical trial.

PURPOSE To determine the efficacy of an emulsion containing hyaluronic acid to reduce the development of ≥ Grade 2 radiation dermatitis after adjuvant breast radiation compared with best supportive care. METHODS AND MATERIALS Women with breast cancer who had undergone lumpectomy and were to receive whole-breast radiotherapy to 50 Gy with a 10- to 16-Gy surgical bed boost were enrolled in a prospective randomized trial to compare the effectiveness of a hyaluronic acid-based gel (RadiaPlex) and a petrolatum-based gel (Aquaphor) for preventing the development of dermatitis. Each patient was randomly assigned to use hyaluronic acid gel on the medial half or the lateral half of the irradiated breast and to use the control gel on the other half. Dermatitis was graded weekly according to the Common Terminology Criteria v3.0 by the treating physician, who was blinded as to which gel was used on which area of the breast. The primary endpoint was development of ≥ Grade 2 dermatitis. RESULTS The study closed early on the basis of a recommendation from the Data and Safety Monitoring Board after 74 of the planned 92 patients were enrolled. Breast skin treated with the hyaluronic acid gel developed a significantly higher rate of ≥ Grade 2 dermatitis than did skin treated with petrolatum gel: 61.5% (40/65) vs. 47.7% (31/65) (p = 0.027). Only one patient developed Grade 3 dermatitis using either gel. A higher proportion of patients had worse dermatitis in the breast segment treated with hyaluronic acid gel than in that treated with petrolatum gel at the end of radiotherapy (42% vs. 14%, p = 0.003). CONCLUSION We found no benefit from the use of a topical hyaluronic acid-based gel for reducing the development of ≥ Grade 2 dermatitis after adjuvant radiotherapy for breast cancer. Additional studies are needed to determine the efficacy of hyaluronic acid-based gel in controlling radiation dermatitis symptoms after they develop.

Cardiac motion during deep-inspiration breath-hold: Implications for breast cancer radiotherapy

PURPOSE Many patients with left-sided breast cancer receive adjuvant radiotherapy during deep-inspiration breath hold (DIBH) to minimize radiation exposure to the heart. We measured the displacement of the left anterior descending artery (LAD) and heart owing to cardiac motion during DIBH, relative to the standard tangential fields for left breast cancer radiotherapy. METHODS AND MATERIALS A total of 20 patients who had undergone computed tomography-based coronary angiography with retrospective electrocardiographic gating were randomly selected for the present study. The patients underwent scanning during DIBH to control the influence of respiration on cardiac motion. Standard medial and lateral tangential fields were placed, and the LADs were contoured on the systolic- and diastolic-phase computed tomography data sets by the clinicians. Displacement of the LAD during cardiac contractions was calculated in three directions: toward the posterior edge of the treatment fields, left-right, and anteroposterior. Displacement of the entire heart was measured on the maximal and minimal intensity projection computed tomography images. RESULTS The mean displacement of the LAD from cardiac contraction without the influence of respiration for 20 patients was 2.3 mm (range, 0.7-3.8) toward the posterior edge of the treatment fields, 2.6 mm (range, 1.0-6.8) in the left-right direction, and 2.3 mm (range, 0.6-6.5) in the anteroposterior direction. At least 30% of the LAD volume was displaced >5 mm in any direction in 2 patients (10%), and <10% of the LAD volume was displaced >5 mm in 10 patients (50%). The extent of displacement of the heart periphery during cardiac motion was negligible near the treatment fields. CONCLUSIONS Displacement of the heart periphery near the treatment fields was negligible during DIBH; however, displacement of the LAD from cardiac contraction varied substantially between and within patients. We recommend maintaining ≥ 5 mm of distance between the LAD and the field edge for patients undergoing breast cancer radiotherapy during DIBH.

Radiation Induces Acute Alterations in Neuronal Function

Every year, nearly 200,000 patients undergo radiation for brain tumors. For both patients and caregivers the most distressing adverse effect is impaired cognition. Efforts to protect against this debilitating effect have suffered from inadequate understanding of the cellular mechanisms of radiation damage. In the past it was accepted that radiation-induced normal tissue injury resulted from a progressive reduction in the survival of clonogenic cells. Moreover, because radiation-induced brain dysfunction is believed to evolve over months to years, most studies have focused on late changes in brain parenchyma. However, clinically, acute changes in cognition are also observed. Because neurons are fully differentiated post-mitotic cells, little information exists on the acute effects of radiation on synaptic function. The purpose of our study was to assess the potential acute effects of radiation on neuronal function utilizing ex vivo hippocampal brain slices. The cellular localization and functional status of excitatory and inhibitory neurotransmitter receptors was identified by immunoblotting. Electrophysiological recordings were obtained both for populations of neuronal cells and individual neurons. In the dentate gyrus region of isolated ex vivo slices, radiation led to early decreases in tyrosine phosphorylation and removal of excitatory N-methyl-D-aspartate receptors (NMDARs) from the cell surface while simultaneously increasing the surface expression of inhibitory gamma-aminobutyric acid receptors (GABAARs). These alterations in cellular localization corresponded with altered synaptic responses and inhibition of long-term potentiation. The non-competitive NMDAR antagonist memantine blocked these radiation-induced alterations in cellular distribution. These findings demonstrate acute effects of radiation on neuronal cells within isolated brain slices and open new avenues for study.

Outcomes of malignant tumors of the lacrimal apparatus

Malignant epithelial neoplasms of the lacrimal apparatus are rare and are typically treated with surgery and occasionally adjuvant radiation therapy (RT). The purpose of this study was to assess treatment outcomes by type of surgery (orbital exenteration vs eye‐sparing surgery) and clarify the role of adjuvant RT for this rare disease.

Palliative reirradiation for progressive diffuse intrinsic pontine glioma.

ObjectiveDiffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors and have a poor prognosis. Nearly all patients experience disease progression after definitive treatment, accompanied by severe neurologic deficits and morbidity. Here, we report a series of patients treated with reirradiation for palliation of symptoms. MethodsSix patients received reirradiation for progressive DIPG at MD Anderson Cancer Center from 2007 to 2009. Progression after initial chemoradiation and salvage chemotherapy had been confirmed clinically and by magnetic resonance imaging. Each case was discussed at a multidisciplinary conference before reirradiation. ResultsInterval between the initial radiation therapy and reirradiation was 8 to 28 months. The initial radiation therapy dose was 54 to 55.8 Gy. Time to initial progression was 4 to 18 months. All of the patients had further progression on salvage chemotherapy. Reirradiation was given with concurrent chemotherapy to a dose of 20 Gy (n=4) or 18 Gy (n=1); 1 patient withdrew care after a single 2-Gy fraction. Four patients had substantial clinical improvement in symptoms, with improvement in speech (n=3), ataxia (n=3), and swallowing (n=2). Three patients showed renewed ability to ambulate after reirradiation. Four patients had decreased tumor size on posttreatment magnetic resonance imaging. The median clinical progression-free survival time was 5 months. Acute radiation-related toxicities were fatigue (n=2), alopecia (n=2), and decreased appetite (n=1). No grade 3 or 4 toxicities were reported. ConclusionsReirradiation with chemotherapy may be feasible to improve symptoms and delay progression with minimal toxicity. Patients who are most likely to benefit may be those with prolonged response to initial therapy and a long interval since initial radiation.