Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial.

PURPOSE: Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. METHODS AND MATERIALS: Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination. RESULTS: Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib-radiation therapy combination. CONCLUSIONS: Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors.

Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis.

BACKGROUND: Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. METHODS: Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging. RESULTS: High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. CONCLUSIONS: We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.

Is stroke incidence increased in survivors of adult cancers? A systematic review and meta-analysis.

PURPOSE: Existing research hints that people living with and beyond cancer are at an increased risk of stroke. However, there is insufficient evidence to appropriately inform guidelines for specific stroke prevention or management for cancer patients. We conducted a systematic review and meta-analysis to describe and quantify stroke incidence in people living with and beyond cancer. METHODS: Medline, CINAHL, and EMBASE were searched for epidemiological studies comparing stroke incidence between cancer and non-cancer patients. Reviewers independently extracted data; random-effects meta-analyses and quality assessment were performed. RESULTS: Thirty-six studies were narratively synthesised. Meta-analysis was conducted using seven studies. Methodological quality was high for most studies. Study populations were heterogeneous, and the length of follow-up and risk factors varied. There was a variation in risk between different cancer types and according to stroke type: pancreatic (HR 2.85 (95% CI 2.43-3.36), ischaemic) (HR 2.28 (95% CI 1.43-3.63), haemorrhagic); lung (HR 2.33 (95% CI 1.63-3.35), ischaemic) (HR 2.14 (95% CI 1.45-3.15), haemorrhagic); and head and neck (HR 1.54 (95% CI 1.40-1.69), haemorrhagic) cancers were associated with significantly increased incidence of stroke. Risk is highest within the first 6 months of diagnosis. Narrative synthesis indicated that several studies also showed significantly increased incidence of stroke in individuals with colorectal cancer, breast cancer, ovarian cancer, nasopharyngeal cancer, leukaemia, and myeloma, and those who have received radiotherapy for head and neck cancers and platinum-based chemotherapy may also have higher stroke incidence. CONCLUSIONS: Stroke incidence is significantly increased after diagnosis of certain cancers. IMPLICATIONS FOR CANCER SURVIVORS: Cardiovascular risk should be assessed during cancer survivorship care, with attention to modifying shared cancer/cardiovascular risk factors.

Radiotherapy-Poly(ADP-ribose) Polymerase Inhibitor Combinations: Progress to Date.

Radiation resistance remains a huge clinical problem for cancer patients and oncologists in the 21st century. In recent years, the mammalian DNA damage response (DDR) has been extensively characterized and shown to play a key role in determining cellular survival following ionizing radiation exposure. Genomic instability due to altered DDR is a hallmark of cancer, with many tumors exhibiting abnormal DNA repair or lack of redundancy in DDR. Targeting the abnormal DDR phenotype of tumor cells could lead to substantial gains in radiotherapy efficacy, improving local control and survival for patients with cancers that are refractory to current therapies. Poly(ADP-ribose) polymerase inhibitors (PARPi) are the most clinically advanced DDR inhibitors under investigation as radiosensitisers. Preclinical evidence suggests that PARPi may provide tumor specific radiosensitisation in certain contexts. In addition to inhibition of DNA single strand break repair, PARPi may offer other benefits in combination treatment including radiosensitisation of hypoxic cells and targeting of alternative repair pathways such as microhomology mediated end joining which are increasingly recognized to be upregulated in cancer. Several early phase clinical trials of PARPi with radiation have completed or are in progress. Early reports have highlighted tumor specific challenges, with tolerability dependent upon anatomical location and use of concomitant systemic therapies; these challenges were largely predicted by preclinical data. This review discusses the role of PARP in the cellular response to ionizing radiation, summarizes preclinical studies of PARPi in combination with radiotherapy and explores current early phase clinical trials that are evaluating these combinations.

Advanced Penile Cancer Presenting With Renal Failure.

"MK," a man aged 67 years, presented with fatigue and nausea to his primary care physician. Routine blood tests showed a stage III acute kidney injury and the patient was admitted urgently into the hospital for investigation. On initial assessment by the nursing staff, with urine dip and bladder scan, he was found to have a large fungating mass on his penis. Upon further questioning, MK reported having had trouble with urination for a number of years and that he had been concealing the mass for at least 1 year due to embarrassment. He required a suprapubic catheter as the mass had completely obstructed his urethra. Clinical examination revealed that the external component on the penile shaft was entirely destroyed by the tumor, with extension deep into the entirety of the scrotum, and perineal soft-tissue invasion was also apparent. CT staging scans confirmed the primary tumor and a suspicious left 1.2-cm inguinal lymph node but no distant metastases. MRI of the pelvis revealed complete replacement of the penis with tumor as well as invasion into the scrotum and bilateral groin soft tissue; additionally, early pubic bone invasion was present, with left groin lymphadenopathy. Biopsy verified squamous cell carcinoma of the penis, and discussion with the multidisciplinary team uroradiologist confirmed bony invasion.

Single modality radical radiotherapy is an acceptable alternative for the older patient with squamous cell carcinoma of the oesophagus.

BACKGROUND: Oesophageal cancer remains a common cause of cancer mortality worldwide. Increasingly, oncology centres are treating an older population and comorbidities may preclude multimodality treatment with chemoradiotherapy (CRT). We review outcomes of radical radiotherapy (RT) in an older population treating squamous cell carcinoma (SCC) oesophagus. METHODS: Patients over 65 years receiving RT for SCC oesophagus between 2013 and 2016 in the West of Scotland were identified. Kaplan-Meier and Cox-regression analysis were used to compare overall survival (OS) between patients treated with radical RT and radical CRT. RESULTS: There were 83 patients over 65 years treated with either RT (n=21) or CRT (n=62). There was no significant difference in median OS between CRT versus RT (26.8 months vs 28.5 months, p=0.92). All patients receiving RT completed their treatment whereas 11% of CRT patients did not complete treatment. CONCLUSION: Survival in this non-trial older patient group managed with CRT is comparable to that reported in previous trials. RT shows better than expected outcomes which may reflect developments in RT technique. This review supports RT as an alternative in older patients, unfit for concurrent treatment.

An unusual cause of paraesthesia in a neo-adjuvant gastro-oesophageal cancer.

There is ongoing debate about the best neo-adjuvant strategy for localised resectable oesophageal cancer, however chemotherapy is often employed. Both oesophageal cancer and cisplatin carry an increased risk of thrombosis. Here, we look at an unusual finding in a previously fit woman who presented following neo-adjuvant chemotherapy for resectable oesophageal cancer with increasing difficulty in walking and lower limb paraesthesia. This case looks particularly at the diagnostic challenge and concerns raised in a patient undergoing radical treatment as well as the challenge of complications secondary to treatment with chemotherapy. Willingness to reassess and revisit is a vital part of the diagnostic process. Vascular complications of a disease can be notorious to diagnose and, as in this case can mimic arguably more logical diagnoses. Cancer care provides the unique challenge of investigating unusual presentations related both to disease and treatment.