Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study.

Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20-69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6.2 (0.3-28) months. At a median follow-up of 19 months, the PFS-6 rate was 66%, with a median PFS of 7.6 (5.7-9.4) months. In terms of Grade ≥ 3 hematological adverse events, thrombocytopenia and neutropenia occurred in 7% and 12% of patients, respectively. In multivariate analyses, high baseline low-density lipoprotein levels were associated with worse survival (P = 0.046). Atorvastatin was not shown to improve PFS-6. However, this study identified that high low-density lipoprotein levels are an independent predictor of poor cancer-related outcomes. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors.Clinical trial information: NCT0202957 (December 12, 2013).

Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency.

Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. KEY POINTS: Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.

Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Outcome analysis of breast cancer patients who declined evidence-based treatment.

BACKGROUND: To analyze the characteristics and outcomes of women with breast cancer in the Northern Alberta Health Region (NAHR) who declined recommended primary standard treatments. METHODS: A chart review was performed of breast cancer patients who refused recommended treatments during the period 1980 to 2006. A matched pair analysis was performed to compare the survival data between those who refused or received standard treatments. RESULTS: A total of 185 (1.2%) patients refused standard treatment. Eighty-seven (47%) were below the age of 75 at diagnosis. The majority of those who refused standard treatments were married (50.6%), 50 years or older (60.9%), and from the urban area (65.5%). The 5-year overall survival rates were 43.2% (95% CI: 32.0 to 54.4%) for those who refused standard treatments and 81.9% (95% CI: 76.9 to 86.9%) for those who received them. The corresponding values for the disease-specific survival were 46.2% (95% CI: 34.9 to 57.6%) vs. 84.7% (95% CI: 80.0 to 89.4%). CONCLUSIONS: Women who declined primary standard treatment had significantly worse survival than those who received standard treatments. There is no evidence to support using Complementary and Alternative Medicine (CAM) as primary cancer treatment.

Treatment Patterns and Outcomes Among Elderly Glioblastoma Patients in Riyadh, Saudi Arabia.

BACKGROUND: Management of elderly patients with glioblastoma (GBM) is a controversial scenario and needs careful assessment and selection for aggressive radical treatment and chemotherapy protocols vs short-course radiotherapy without chemotherapy. METHODS: We evaluated treatment patterns and outcome among elderly GBM patients treated in KFMC, Riyadh. The primary endpoint is overall survival (OS) and the secondary endpoint is progression-free survival (PFS); patients were reviewed regarding radiotherapy (Rth) fractionation modalities, surgery, and chemotherapy (CTR) given in correlation to PFS, OS. RESULTS: Fifty-nine patients were recruited in our study with median age 66 (range: 60-81) years, and 47 (80%) were males. Thirty-seven patients (62.7%) had ECOG performance status (PS) ≥2, and 22 patients (37.3%) had PS <2. Gross total resection (GTR) and subtotal resection (STR) were done in 49 (82.9%) patients, and the median follow-up was 12 months. Thirty-eight (64%) patients received conventional Rth 60 Gray (Gy)/30 fractions or equal doses and 21 (36%) patients received hypofractionation Rth (40 Gy/15, 25 Gy/5 or 30 Gy/10 fractions). The median OS was 12 months (95%CI: 9.52-14.48). Receiving conventional Rth and completion of six months adjuvant CTR were significant factors for O.S (P=0.043 and 0.026), respectively. The median PFS was nine months (95%CI: 6.13-11.87). For univariate analysis, PS, time to start adjuvant treatment, and completion of six months CTR were significant factors for PFS. CONCLUSION: Conventional Rth and completion of adjuvant CTR lead to better OS, while earlier start of adjuvant treatment and the completion of adjuvant CTR were associated with a better PFS.

Papillary Tumor of the Pineal Region Rare Pediatric CNS Tumor Case Series Treated in King Fahad Medical City (KFMC).

The clinical behaviors, prognosis, and appropriate treatments of papillary tumors of the pineal region (PTPR) are not fully defined due to the rarity of these tumors. At diagnosis, PTPR may present with clinical symptoms, including headache with obstructive hydrocephalus, diplopia, vomiting, and lethargy, as well as neurological signs, including Argyll Robertson pupils and Parinaud's syndrome due to compression of the dorsal midbrain, specifically the periaqueductal region with horizontal nystagmus. Radiological assessment of pineal region lesions is challenging, with a wide range of potential differential diagnoses. PTPR typically presents as a heterogeneous, well-circumscribed mass in the pineal region, which might contain cystic areas, calcifications, hemorrhages, or protein accumulations. Here, we report three female pediatric patients with PTPR treated in King Fahad Medical City (KFMC) in Saudi Arabia. Histological and immunohistochemical diagnosis was confirmed by analysis of genome-wide DNA methylation profiles. This case series expands on the available reports on the clinical presentations of PTPR and provides important information on the responses to different treatment modalities.

Impact of Rural vs. Urban Residence on Survival Rates of Patients with Glioblastoma: A Tertiary Care Center Experience.

Purpose: Although the association between residential location and survival in patients with different cancer types has been established, the conclusions are contentious, and the underlying mechanisms remain unknown. Here, we reviewed the impact of residence on the survival of patients with glioblastoma (GBM). Methods: We conducted a retrospective study to compare the impact of rural and urban residence on the survival rates of patients with GBM diagnosed in Riyadh City and outside Riyadh. All patients in this study were treated in a tertiary care hospital, and their survival rates were analyzed in relation to their residence and other related factors, namely radiotherapy timing. Results: Overall, 125 patients were included: 61 from Riyadh City and 64 from outside. The majority of patients in both groups were aged >50 years (p = 0.814). There was no statistically significant difference between the groups in the Eastern Cooperative Oncology Group Performance Status (p = 0.430), seizure (p = 0.858), or initiation timing of radiotherapy (p = 0.781). Furthermore, the median survival rate in the Riyadh group versus the other group was 14.4 months and 12.2 months, respectively, with no statistical significance (p = 0.187). Conclusions: Our study showed that residential location had no significant effect on GBM prognosis. However, further studies with a larger sample size are required to delineate the other factors of referral within the healthcare system to facilitate the management of these patients within a specific timeframe.

Survival after therapy for pediatric ependymoma in a tertiary care center in Saudi Arabia.

BACKGROUND: There is limited data from Saudi Arabia on the demographic characteristics, outcomes and effectiveness of different treatment modalities in children with intracranial ependymoma. OBJECTIVE: Study the characteristics of pediatric ependymoma and outcomes of treatment modalities in Saudi Arabia. DESIGN: Retrospective. SETTING: Tertiary care center. PATIENTS AND METHODS: Children with intracranial ependymoma who were younger than 14 years of age and treated between 2006 and 2015 were included in the study. Patients with prior radiation, chemo-therapy, or surgical resection at other centers were excluded. MAIN OUTCOME MEASURES: Kaplan-Meier survival curves were used to estimate the event-free (EFS) and overall survival (OS) rates of the patients. SAMPLE SIZE: 22. RESULTS: Of the 22 children, 4 (18.2%) were less than three years old. All intracranial ependymomas had upfront surgical resection of the primary tumor. Gross total resection was achievable in 9 (42.9%) cases and subtotal resection in another 9 (42.9%). Near-total resection was done in 3 (14.3%) cases. Median time from surgery to start of radiotherapy was 62 days. RT was given to 17 (77.3%) patients. Both mean and median RT dose was 55.8 Gy. Only 5 (22.7%) of the children received chemotherapy. The median duration of follow-up was 5.38 years and the median time for EFS was 2.27 years. The cumulative OS rate of the study was 44.5%. The cumulative EFS survival rate of the study was 18.6%. Among demographic, pathological, radiological features, none had a statistically significant effect on the survival. CONCLUSIONS: The outcomes are comparable to those reported by international investigators for similar populations. Further improvements can be achieved by avoiding delays in radiation therapy and adding molecular staging. LIMITATIONS: The limited number of cases, retrospective nature, lack of molecular biology and size of the tumors. CONFLICT OF INTEREST: None.

Radiation Induced Multiple Skin Neoplasms Following Craniospinal Irradiation for Medulloblastoma. A Case Report.

BACKGROUND Following craniospinal irradiation in children with medulloblastoma, secondary neoplasms are among the most serious long-term sequelae that include leukemias and solid tumors of the urinary or digestive tracts, thyroid, skin, and central nervous system. Furthermore, in children with Gorlin syndrome following craniospinal irradiation for medulloblastoma, there is a rising incidence of skin and non-skin malignancies. CASE REPORT The patient in the present study was a 19-year-old female who was treated with craniospinal irradiation and chemotherapy following gross total resection (GTR) for medulloblastoma at the age of 4 years. Fifteen years later, she developed a primary adnexal tumor at the medial aspect of her left thigh, glomangioma at the skin of her upper abdomen, dermatofibrosarcoma protruberans at the skin of her upper back, and Kaposiform hemangioendothelioma of the upper abdomen. All these tumors were successfully managed with radical resection without further adjuvant treatment. CONCLUSIONS Metachronous of development of 4 histopathologically different skin tumors following craniospinal irradiation for medulloblastoma in long-term survivors has not previously been reported. The present case warrants a detailed dermatological periodic inspection in such patients.

Defining Clinical Indications of Proton Beam Therapy at National Level in the Kingdom of Saudi Arabia.

The Saudi Particle Therapy Centre (SPTC) is establishing proton beam therapy (PBT) services within Kingdom of Saudi Arabia (KSA). Thus, national guidelines for the pertinent draft, and recommendations of PBT for cancer patients are utmost important. Saudi Particle Therapy Centre invited a panel of expert radiation oncologists practicing within KSA to formulate national clinical practice guidelines for the referral, absolute and relative indications and dose/fractionation for PBT. After identifying the key clinical questions, ample search through PubMed, EMBASE, and various search drives was accomplished for appropriate meta-analyses, clinical trials, case-control, and case series studies, and case reports. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was incorporated to formulate various recommendations. Saudi Particle Therapy Centre expert panel recommended PBT as utter modality for ocular tumors, base of skull/spine tumors, hepatocellular carcinoma, all pediatric central nervous system (CNS) malignancies, para-nasal sinuses/nasal cavity tumors and for re-irradiation of all sites aimed for cure. However, PBT may be contemplated, as a relative indication if no other parallel option is available, or when photon therapy plans exceed the dose constraints for critical structures.  Further, panel did not recommend routine PBT for other sites beyond clinical trials. However, individual oncology patients can be considered for PBT after a multidisciplinary approach and expert's opinion.

Efficacy of 8 Gy Single Fraction Palliative Radiation Therapy in Painful Bone Metastases: A Single Institution Experience.

Introduction Bone metastasis (BM) is a major complication of many solid tumors like breast, prostate, lung and renal cancers. BM leads to serious sequelae of pain, fractures, spinal cord compression and hypercalcemia. Radiotherapy has an established role in relieving pain caused by BM. Worldwide different radiotherapy schedules are being used for BM. The aim of this study is to determine the efficacy of single fraction palliative radiotherapy for painful bone metastases. Methods Between April 2014 and April 2017, single fraction radiotherapy was used to treat 73 patients in our institution. They had pathologically proven breast, prostate, lung or renal cancer with radiological evidence of bone metastases. There were 39 males (53%) and 34 females (47%). The median age was 58 years (range 33-87 years). 39% patients (n = 28) had breast cancer, 35% had prostate cancer (n = 26), 23% had lung cancer (n = 17), and 3% had renal cancer (n = 2). On presentation, all the patients had a pain score of more than five on Brief Pain Inventory (BPI). Results Response assessment to pain after three months from single fraction radiotherapy was found to be complete response (CR) in 23% patients (n = 17), partial response (PR) in 38% patients (n = 28), stable disease (SD) in 26% patients (n = 19) and progressive disease (PD) in 12% patients (n = 9). The overall efficacy of treatment was 62%, with CR 23% and PR 38%. Pre-treatment mean pain score was 8.15 compared to 4.68 post-treatment (p < 0.001). Conclusions Single fraction palliative radiotherapy of 8 Gy showed significant efficacy in painful bone metastases in our setting and merits further investigation in our population.

Management and treatment recommendations for World Health Organization Grade III and IV gliomas.

The treatment recommendations provided in this manuscript are intended to serve as a knowledge base for clinicians and health personals involved in treating patients with high-grade malignant glioma. In newly diagnosed patients, complete resection or biopsy is required for histological characterization of the tumor, which in turn is essential to decide the treatment strategy. In patients with good or borderline performance score, radiotherapy (RT), and chemotherapy are the preferred management. In patients with poor performance score, RT with best possible supportive care is the mainstay of the management. All patients have to undergo brain magnetic resonance imaging procedure quarterly or half-yearly for 5 years and then on an annual basis. In patients with recurrent malignant glioma, wherever possible re-resection or re-irradiation or chemotherapy can be considered along with supportive and palliative care. High-grade malignant glioma should be managed in a multidisciplinary center with the best of the possible care that is available based on the evidence as discussed in this manuscript.

Comparative clinicopathological and outcome analysis of differentiated thyroid cancer in Saudi patients aged below 60 years and above 60 years.

INTRODUCTION: The aim of this study was to evaluate the treatment outcomes of differentiated thyroid cancer in Saudi patients aged above 60 years. MATERIALS AND METHODS: Comparative analysis was performed in 252 patients aged 46-60 years (Group A) and 118 patients aged above 60 years (Group B), who had thyroidectomy, radioactive iodine-131, and thyroid-stimulating hormone suppression therapy between July 2000 and December 2012. Different clinicopathological features, treatment, complications, disease-free survival, and overall survival rates were compared. RESULTS: Mean age of patients in Group A was 51.9 years (range: 46-60), and mean age of those in Group B was 68.6 years (range: 62-97). Group B patients had higher positive lymph nodes (43.2%), P=0.011. The frequency of extrathyroidal extension, multifocality, and lymphovascular space invasion was seen more in Group B than in Group A. Postsurgical complications (permanent hypoparathyroidism, bleeding, and wound infections) were also seen more in Group B (P=0.043, P=0.011, and P=0.021, respectively). Group B patients experienced more locoregional recurrences (11.0%, P=0.025); similarly, more distant metastases were observed in Group B (15.3%, P=0.003). The 10-year disease-free survival rates were 87.6% in Group A and 70.8% in Group B (P<0.0001). CONCLUSION: Differentiated thyroid cancer in patients aged above 60 years are more aggressive biologically and associated with a worse prognosis, and the morbidity is significantly high as compared to patients aged below 60 years.

Outcome of patients with glioblastoma in Saudi Arabia: Single center experience.

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with one of the worst 5 year survival rates among all human cancer types. To date, no published data are available for the outcome of this disease in Saudi Arabia. The present study performed a single-center, retrospective cohort study to evaluate the outcome of patients with GBM in Saudi Arabia. The Comprehensive Cancer Center at King Fahad Medical city (Riyadh, Saudi Arabia) was used in the present study. All adult patients (≥18 years) diagnosed with histologically proven GBM between January 2008 and December 2013 were included in the present study. A total of 90 patients were treated during the specified period. Of this, 73 (81%) patients underwent resection and 17 (19%) had biopsy only. The majority of patients (n=88; 98%) received radiotherapy (XRT): 67 (76%) with standard and 21 (24%) with hypo-fractionated dosage. Of the total patients, 65 (72%) received combined modality therapy [standard XRT concurrently with Temozolmide (TMZ)]. The 6 month progression-free survival rate was 43% for all patients and 55% for the combined modality subgroup. The median overall survival (OS) for all patients was 13.7 months. However, the median OS for patients treated with combined modality was 19.7 months. In this single-center retrospective study, the outcomes of patients with GBM were similar to those in previously reported studies. An improved outcome was associated with an improved performance status, absence of residual disease and use of adjuvant TMZ.

Lumbosacral plexus delineation, dose distribution, and its correlation with radiation-induced lumbosacral plexopathy in cervical cancer patients.

BACKGROUND: To evaluate the dose distribution to the lumbosacral plexus (LSP) and its correlation with radiation-induced lumbosacral plexopathy (RILSP) in patients with cervical cancer treated with intensity-modulated radiotherapy (IMRT) and high-dose-rate brachytherapy. MATERIALS AND METHODS: After meeting eligibility criteria, 50 patients with cervical cancer were selected who were treated with IMRT and high-dose-rate brachytherapy, and the LSP was contoured. Mean volume; percentages of LSP volume absorbing 40, 50, 55, and 60 Gy (V30, V40, V50, V55, and V60) and point doses (P1, P2, P3, P4, P5, P6, P7, P8, P9, and P10); and RILSP incidence were calculated. RESULTS: At 60 months of follow-up, four patients (8%) were found to have grade 2/3 RILSP. The mean maximal LSP dose in patients with RILSP was 59.6 Gy compared with 53.9 Gy in patients without RILSP (control; P=0.04). The mean values of V40, V50, V55, and V60 in patients with RILSP versus control were 61.8% versus 52.8%, 44.4% versus 27.7%, 8.0% versus 0.3% and 1.8% versus 0%, respectively (P=0.01, 0.001, 0.001, and 0.001, respectively). CONCLUSION: The delineation of the LSP during IMRT planning may reduce the risk for RILSP. The mean values of V40, V50, V55, and V60 for LSP should be less than 55%, 30%, 5%, and 0.5%, respectively; however, further studies are warranted.

Clinicopathological features and treatment outcomes of brain stem gliomas in Saudi population.

AIM: To analyze experiences to identify treatment outcomes and prognostic factors in a Saudi population. METHODS: Medical records of patients with brainstem gliomas treated from July 2001 to December 2012 were reviewed to identify treatment outcomes of surgery, radiation therapy and chemotherapy and associated prognostic factors in a Saudi population. RESULTS: We analyzed 49 brain stem glioma (BSG) patients from July 2001 to December 2012; 31 of them were males (63.3%) with a median age of 12.6 years (range: 8-64 mo). Twenty-two patients (44.9%) had diffuse intrinsic pontine gliomas (DIPG) and 15 (30.6%) presented with focal/tectal BSG. Histopathology was available in 30 patients (61.2%). Median survival time for the whole cohort was 1.5 years. One and two year OS rates were 51.1% and 41.9% respectively. Two year OS rates for focal/tectal, dorsally exophytic, cervicomedullary and DIPG tumors were 60%, 33.3%, 33.3% and 13.6% respectively (P < 0.0001). Significant prognostic factors related to OS were age at diagnosis (worse for > 18 years) P = 0.01, KPS < 70 P = 0.02, duration of symptoms (< 60 d) P = 0.002, histology (better for favorable) P = 0.002, surgery (maximal resection) P = 0.002, and concurrent chemotherapy with radiation therapy in DIPG (better if given) P = 0.01. CONCLUSION: BSG, especially the DIPG subgroup, had a dismal prognosis, needing more aggressive neurosurgical, radiation and chemotherapy techniques, while focal and tectal tumors were found to have a better prognosis.