The role of radiation therapy in the treatment of metastatic cancer.

Radiation therapy continues to play an important role in the management of cancer. In this review, we discuss the use of radiation therapy to target and control micrometastatic disease (adjuvant use of radiation), or using stereotactic radiation therapy to address small volumes of gross disease, such as oligometastases, and finally the use of radiation therapy in the era of immunotherapy. Radiation therapy is commonly used to treat nodal basins suspected of harboring microscopic disease. More recently, computer and technical innovations have allowed radiation oncologists to treat small volumes of gross disease within the brain and also in the body with great success, adding to the cancer armamentarium. This modality of cancer treatment that began shortly after the discovery of X-rays by William Roentgen continues to evolve and finds new clinical applications which minimize toxicity while increasing effectiveness. The newly discovered interactions of high dose/fraction radiation (stereotactic radiosurgery) with immune check point inhibitors in melanoma is the latest example of how synergism can be achieved between two different modalities thus increasing the therapeutic ratio to control metastatic cancer.

Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab.

Background: To identify the optimal sequencing and timing of immunotherapy (IT) and stereotactic radiosurgery (SRS) for melanoma brain metastases (MBMs). Methods: The elapsed days between IT and SRS were correlated with local control (LC), regional brain control (RBC), time to CNS progression (TTPCNS), overall survival (OS), and radiation necrosis (RN). Logistic regression and Cox proportional models were used for statistical analysis. Results: Twenty-five patients with 58 MBMs underwent SRS and IT. Median follow-up was 22.7 mo (3.1-77.9 mo). A median of 2 SRS treatments of 21 Gy (range 16-24 Gy) and 4 cycles of Ipilimumab were delivered. SRS was delivered Before, After or Concurrently with IT in 9, 5, and 11 patients, respectively; 8/25 received SRS ≤30 d of IT and 17/25 were >30 d of IT. Median OS was 35.8 mo, 1- and 2-y OS was 83% and 64%, respectively, and LC was 94.8%. By timing, RBC and TTPCNS were significantly improved when SRS was delivered ≤30 d of IT (75% vs 23.5%, p = 0.03 and median not reached vs 5.7 mo, p = 0.02, respectively). By groups, Concurrent delivery improved TTPCNS (p = 0.04). The rate of RN was 20.7% (12/58 lesions) and RN was associated with improved OS (HR 0.21, p = 0.01). Conclusions: High OS was found for MBM treated with SRS and IT compared to historical reports. A significant association for improved RBC and TTPCNS was found when SRS was delivered concurrently and within 30 d of IT. Occurrence of RN was higher than SRS alone series but significantly associated with improved OS.

Optimizing Radiotherapy with Immunotherapeutic Approaches.

Several factors must be considered to successfully integrate immunotherapy with radiation into clinical practice. One such factor is that concepts arising from preclinical work must be tested in combination with radiation in preclinical models to better understand how combination therapy will work in patients; examples include checkpoint inhibitors, tumor growth factor-beta (TGF-ß) inhibitors, and natural killer (NK) cell therapy. Also, many radiation fields and fractionation schedules typically used in radiation therapy had been standardized before the introduction of advanced techniques for radiation planning and delivery that account for changes in tumor size, location, and motion during treatment, as well as uncertainties introduced by variations in patient setup between treatment fractions. As a result, radiation therapy may involve the use of large treatment volumes, often encompassing nodal regions that may not be irradiated with more conformal techniques. Traditional forms of radiation in particular pose challenges for combination trials with immunotherapy. This chapter explores these issues in more detail and provides insights as to how radiation therapy can be optimized to combine with immunotherapy.

Long-term benefit of electron beam radiation therapy in the treatment of scleredema of Buschke.

INTRODUCTION: Scleredema of Buschke is a rare connective tissue disorder presenting with woody thickening and induration of the nuchal and shoulder regions resulting in progressive decrease in the range of motion of the neck. Treatment options include several forms of systemic therapy with variable results. Local radiation therapy (RT) is often thought of as a secondary form of therapy. Few reports exist in the literature about the durability of its benefit, however. Here, we present a case report with the longest known follow-up after primary treatment with electron beam RT. METHODS: The patient was treated using 8-MeV en face electrons with 2000 cGy in 10 fractions with 2 separate but matched electron fields. The treatment fields included the posterior neck from the occiput superiorly to the mid-thoracic spine inferiorly with the lateral borders extending to the scapulae. The patient received no additional therapy either pre- or post-RT. Clinical follow-up was obtained at regular intervals. Published literature regarding RT for this disease was reviewed and consolidated. RESULTS: The patient was followed at regular intervals for 6 years with significant softening of the plaque starting at 2 months after RT, resulting in decrease in plaque size by 50% after 18 months. The patient regained 45° of lateral, bidirectional cervical motion from central axis and 50% improvement in neck extension that has remained durable 6 years after treatment with no additional therapy. Quality of life was restored with a simple nontoxic treatment limited to transient, grade 1 fatigue. CONCLUSION: Scleredema of Buschke is a rare connective tissue disorder commonly treated with multimodal therapy, but it can be effectively and durably controlled with RT alone. This case report documents the durability of the benefit achieved with RT and suggests that RT should be considered earlier in the treatment of this disease.

The role of biomarkers in the development of novel cancer therapies.

The etiology of diverse patient responses to a given pharmaceutical treatment has eluded science for decades. Only during the last 10-15 years has our understanding of the interplay between genetics and pharmaceuticals advanced to the point that personalized medicine may optimize therapies for each individual patient. The primary goals of personalized medicine are identifying individuals at risk of developing disease to better prevent disease in the healthy population, accurately monitoring each patient's response to therapy and predicting recurrence in order to pre-empt it. This review gives an explanation of biomarkers and addresses their role in the diagnosis and surveillance of various cancers. It also addresses the challenges of developing novel therapies utilizing newly discovered biomarkers.

BRCAness profile of sporadic ovarian cancer predicts disease recurrence.

BACKGROUND: The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. OBJECTIVE: To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. MATERIALS AND METHODS: Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function. RESULTS: High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). CONCLUSIONS: Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance.