Mohammad K. Khan

Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases.

Background: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). Materials and Methods: We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. Results: Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumab-treated and non-ipilimumab–treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P=0.40) and intracranial control (12.7% vs. 29.1%, P=0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P=0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. Conclusions: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes.

Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases

Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.

Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy.

PURPOSE The role of consolidative radiation therapy (RT) after complete response (CR) to rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for stage III-IV diffuse large B-cell lymphoma (DLBCL) patients is unclear. We aimed to evaluate our institutional experience when consolidative RT is delivered to initial presenting sites or bulky sites in these patients. METHODS AND MATERIALS We identified 211 histologically confirmed stage III-IV DLBCL patients who received R-CHOP from January 2000 to May 2012 at our institution. Patterns of failure for patients who achieved CR to R-CHOP were analyzed. Local control (LC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method and compared between patients who received R-CHOP alone versus R-CHOP plus consolidative RT using the log-rank test. Multivariate analyses were also performed using Cox proportional hazards model. RESULTS Detailed treatment records were available for 163 patients. After a median 6 cycles of R-CHOP, 110 patients (67.5%) achieved CR and were entered for analysis. Fourteen patients (12.7%) received consolidative RT. After median follow-up of 32.9 months, 43.8% of patients who received R-CHOP alone failed at the initial sites with or without distant recurrence (DR), whereas isolated DR only occurred in 3.7% of these patients. Consolidative RT was associated with significantly improved LC (91.7% vs 48.8%), DC (92.9% vs 71.9%), PFS (85.1% vs 44.2%), and OS (92.3% vs 68.5%; all Ps<.0001) at 5 years compared with patients with R-CHOP alone. On multivariate analysis, consolidative RT and nonbulky disease were predictive of increased LC and PFS, whereas bone marrow involvement was associated with increased risk of DR and worse OS. Consolidative RT was also associated with marginal improved OS. CONCLUSIONS Forty-four percent of patients with advanced stage DLBCL failed at initial presenting sites after achieving CR to R-CHOP. Incorporation of consolidative RT as part of upfront treatment in these patients was associated with improved LC, PFS, and a trend towards improved OS.

Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma.

Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse-free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells.

Definitive radiotherapy for early (T1-T2) Glottic Squamous cell carcinoma: a 20 year Cleveland clinic experience

PurposeTo report our 20 yr experience of definitive radiotherapy for early glottic squamous cell carcinoma (SCC).Methods and materialsRadiation records of 141 patients were retrospectively evaluated for patient, tumor, and treatment characteristics. Cox proportional hazard models were used to perform univariate (UVA) and multivariate analyses (MVA). Cause specific survival (CSS) and overall survival (OS) were plotted using cumulative incidence and Kaplan-Meir curves, respectively.ResultsOf the 91% patients that presented with impaired voice, 73% noted significant improvement. Chronic laryngeal edema and dysphagia were noted in 18% and 7%, respectively. The five year LC was 94% (T1a), 83% (T1b), 87% (T2a), 65% (T2b); the ten year LC was 89% (T1a), 83% (T1b), 87% (T2a), and 53% (T2b). The cumulative incidence of death due to larynx cancer at 10 yrs was 5.5%, respectively. On MVA, T-stage, heavy alcohol consumption during treatment, and used of weighted fields were predictive for poor outcome (p < 0.05). The five year CSS and OS was 95.9% and 76.8%, respectively.ConclusionsDefinitive radiotherapy provides excellent LC and CSS for early glottis carcinoma, with excellent voice preservation and minimal long term toxicity. Alternative management strategies should be pursued for T2b glottis carcinomas.

Surface Dose Investigation of the Flattening Filter-Free Photon Beams

PURPOSE Flattening filter-free (FFF) x-rays can provide more efficient use of photons and a significant increase of dose rate compared with conventional flattened x-rays, features that are especially beneficial for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). The available data on the entrance doses of the FFF photon beams remain limited. The purpose of this study was to investigate the entrance dose of FFF photons in the buildup region and to compare it with that of conventional flattened photons. METHODS AND MATERIALS A Varian TrueBeam linear accelerator has been in full clinical operation with 6-MV and 10-MV FFF and flattened x-ray photons. Entrance dose at the surface was measured using a parallel plate ionization chamber in a solid water phantom with buildup depth = 0~15 mm for 6X and 0~25 mm for 10X. Different field size (FS) patterns were created in the Eclipse Treatment Planning System by multileaf collimator (MLC) rather than jaws (FS = 2 × 2, 3 × 3, 4 × 4, 6 × 6, and 10 × 10 cm(2) by MLC and jaw size = 2.2 × 2.2, 3.2 × 3.2, 4.2 × 4.2, 6 × 6, and 10 × 10 cm(2)). The smallest FS was about four times larger than the ion chamber dimension. All buildup dose measurements were normalized to FS = 10 × 10 cm(2) at the depth of dose maximum (dmax). RESULTS Good repeatability was demonstrated and surface dose increased linearly with FS for both flattened and FFF photons. The entrance dose of the FFF photons was modestly larger than that of the corresponding flattened photons for both 6X and 10X for different FS ranging from 2 × 2 cm(2) to 10 × 10 cm(2). CONCLUSIONS The FFF photons have a higher entrance dose than that of the corresponding flattened photons for FS smaller than 10 × 10 cm(2). However, the difference is not substantial and may be clinically insignificant.

Comparison of image-guided radiotherapy technologies for prostate cancer.

Radiation oncology has seen a rapid increase in the use of image-guided radiotherapy technology (IGRT) for prostate cancer patients over the past decade. The increase in the use of IGRT is largely driven by the fact that these technologies have been approved by the Food and Drug Administration and are now readily reimbursed by many insurance companies. Prostate cancer patients undergoing intensity modulated radiotherapy (IMRT) now have access to a wide variety of IGRTs that can cost anywhere from

The importance of the conformality, heterogeneity, and gradient indices in evaluating Gamma Knife radiosurgery treatment plans for intracranial meningiomas.

500,000 or more in upfront costs, and can add anywhere from 10 to 15 thousand dollars to a course of IMRT. Some of the IGRT options include daily cone beam computed tomography, ultrasound, orthogonal x-ray units using implanted fiducial markers, implanted radiofrequency markers with the ability to localize and track prostate motion during radiotherapy (Calypso 4D), and cine magnetic resonance imaging. Although these technologies add to the cost of IMRT, there is little direct comparative effectiveness data to help patients, physicians, and policy makers decide if one technology is better than another. In our critical review, the first of its kind, we summarize the advantages, disadvantages, and the limitations of each technology. We also provide an overview of existing literature as it pertains to the comparison of existing IGRTs. Lastly, we provide insights about the need for future outcomes research that may have a significant impact on health policies as it comes to reimbursement in the modern era.

The Effects of Androgen Deprivation Therapy on Cardiac Function and Heart Failure: Implications for Management of Prostate Cancer

PURPOSE To investigate the relationship between the conformality index (CIn), heterogeneity index (HIn), and gradient index (GIn) and the development of toxicity in patients treated with Gamma Knife radiosurgery (GKRS) for intracranial meningiomas. METHODS AND MATERIALS Treatment records of patients treated from 1997 to 2009 with at least 6 months of follow-up were reviewed. The following parameters were collected: CIn, HIn, GIn (ratio of the volume receiving half the prescription isodose to the volume receiving the full prescription isodose), brainstem (BS) maximum dose (MD), BS volume receiving ≥ 12 Gy (V12), optic apparatus (OA) MD, OA V8 Gy, OA V10, number of isocenters, number of isocenters outside target volume, and the occurrence of six toxicities. Univariate and multivariate logistic regression modeling were used for analysis. RESULTS This study included 145 patients (148 meningiomas) with a median follow-up time of 27 months (range, 6-113.9 months). The majority of meningiomas were located in the skull base (53%). The median prescription dose was 13 Gy (range, 10-24 Gy) to the 51.50% (range, 50-92%) isodose. A lower HIn was correlated with a higher GIn (p = 0.007). CIn was not associated with any toxicity. Higher HIn was associated with the development of dizziness (odds ratio [OR] 1.9; p = 0.02), whereas a lower GIn was associated with motor deficits (OR 0.38; p = 0.04) and auditory changes (OR 0.59; p = 0.04). The OA MD, V8, and V12 were not associated with visual changes, but visual changes were associated with a higher number of isocenters outside the target volume (OR 1.93; p = 0.07). BS V12 was correlated with the development of auditory changes (OR 1.05; p = 0.05), whereas patients with higher BS MD tended to have increased toxicity. CONCLUSIONS Close attention must be paid to all three indices (CIn, HIn, GIn) when optimal treatment plans are determined. We recommend that the target CIn should be ≤ 2.0, the HIn ≤ 2.0, and the GIn ≥ 3.0 for intracranial meningiomas.

Prognostic factors for overall survival after radiosurgery for brain metastases from melanoma.

Conflicting clinical evidence regarding the possible association between androgen deprivation therapy (ADT) with heart failure in men with prostate cancer is reviewed, including 2 population-based registries showing such an association, and 1 showing no association. Studies of the effects of androgens on cardiomyocyte contractility at the molecular level, the effects of testosterone on the cardiovascular system, particularly cardiac function, and the beneficial effects of testosterone therapy for patients with heart failure might help illuminate this controversy. Future studies are needed to evaluate the effect of ADT on end points of heart failure. The authors weigh the possible adverse effects of ADT on cardiac function and heart failure against its known benefits to cancer outcomes, defined according to published, randomized trials, in a discussion of the implications of the preclinical and clinical literature on the management of prostate cancer in men at risk for heart failure. In the absence of conclusive evidence that ADT causes heart failure, the authors discuss clinical situations in which ADT may be delayed, given on a short-term or intermittent basis, or withheld from treatment with the goal of reducing the risks of heart failure without compromising prostate cancer outcomes.