MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen.

In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass-by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs-celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan-to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of-not a replacement for-previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

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.

Transdermal fentanyl to parenteral morphine route switch and drug rotation in refractory cancer cachexia.

It is recommended not to use transdermal fentanyl (Fe) patches (TFP) in cancer cachexia but TFP may be the only available option for pain. Limited evidence suggests lower Fe absorption from TFP in cachexia. We describe a case of metastatic breast cancer with refractory cachexia. Her pain was uncontrolled on TFP and was route switched and drug rotated to intravenous morphine (M). We were conservative and did not use the 1:100 TFP to oral M conversion ratio. Assuming opioid needs were similar before and after switch/rotation, the suitable conversion ratio in this case was about 1:25. Absent clear guidelines on converting from TFP in cachexia, it is better to avoid TFP. When essential to use TFP in cachexia, caution should be taken when switching from TFP to avoid overdose.

Caregiver burden among family caregivers of incurable cancer patients in two eastern Mediterranean countries.

BACKGROUND: Although family caregivers (FCs) play an important role in the care provided to incurable cancer patients in our region, little is known about the burden they experience. This study was conducted to determine the prevalence of caregiver burden (CB) among FCs of incurable cancer patients in two Eastern Mediterranean countries and to identify factors that may be associated with significant CB. METHODS: The study included 218 FCs, 165 from Egypt and 53 from Saudi Arabia. The 22-item Zarit Burden Interview (ZBI-22) was used to assess caregiver burden CB. Significant CB was defined as a ZBI-22 score ≥ 21. The assistance with basic ADLs was classified into 3 levels according to FCs' assistance with early/middle/late-loss basic ADLs. The relationship between CB and the assistance with ADLs and other factors was studied. RESULTS: The mean (SD) ZBI-22 score among FCs was 23.4 (9.3) and the majority (128/218, 59%) had significant CB. Eighty-nine percent of FCs assisted with at least one basic ADL. Assistance with late-loss basic ADLs, best supportive care treatment plan and poorer performance status were associated with higher CB (p < 0.0001, =0.018 and = 0.005). However, in logistic regression analysis, only assistance with late-loss ADLs was independently associated with significant CB (OR = 3.4 [95%CI:1.2-9.7], p = 0.024). CONCLUSION: A substantial proportion of FCs of incurable cancer patients in our region experience significant CB. Family caregivers assisting with late-loss basic ADLs are at risk of significant CB and should be routinely screened for CB.

Interleukin-27 and interleukin-35 in de novo acute myeloid leukemia: expression and significance as biological markers.

BACKGROUND AND OBJECTIVES: IL27 and IL35 are regulatory T cells (T-regs) related cytokines; they were accused in eukemogenesis of acute myeloid leukemia (AML). This study aimed to assess the expression of these cytokines in de novo AML and investigate their role as biomarkers. SUBJECTS AND METHODS: Seventy newly diagnosed patients with primary AML and 30 matched healthy volunteers were recruited. AML diagnosis was confirmed with flowcytometric and immunophenotypic analyses, while ELISA was used to assess serum levels of IL27 and IL35 in patients and controls. Receiver operating characteristic curve analysis was used to estimate IL27 and IL35 optimum cutoff values for predicting AML. RESULTS: Serum levels of both cytokines were significantly higher in AML patients than controls (P<0.001), with no effect of gender or French-American-British subtypes. Significant correlations of IL27 and IL35 with poor prognostic factors and with each other were detected in patients only. IL27 optimum cutoff for predicting AML was >43, AUC (0.926) with a sensitivity 74% and specificity 96.6% (P<0.001), while for IL35>27.8, AUC (0.972) with 88% and 98% sensitivity and specificity, respectively (P<0.001). CONCLUSION: Conclusively, this study proved that IL27and IL35 could identify AML patients from healthy subjects, and their overexpression denotes poor prognosis. Based on the simplicity and wide availability of their detection technique we recommend the inclusion of IL27 and IL35 in the diagnostic/prognostic workup of AML; however, further longitudinal research is needed to prove their exact prognostic value.

Patterns of failure and survival in patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy in Saudi Arabia.

BACKGROUND: We aimed to investigate the patterns of failure (locoregional and distant metastasis), associated factors, and treatment outcomes in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy (IMRT) combined with chemotherapy. PATIENTS AND METHODS: From April 2006 to December 2011, 68 nasopharyngeal carcinoma patients were treated with IMRT and chemotherapy at our hospital. Median radiation doses delivered to gross tumor volume and positive neck nodes were 66-70 Gy, 63 Gy to clinical target volume, and 50.4-56 Gy to clinically negative neck. The clinical toxicities, patterns of failures, locoregional control, distant metastasis control, disease-free survival, and overall survival were observed. RESULTS: The median follow-up time was 52.2 months (range: 11-87 months). Epstein-Barr virus infection was positive in 63.2% of patients. Overall disease failure developed in 21 patients, of whom 85.8% belonged to stage III/IV disease. Among these, there were seven locoregional recurrences, three regional recurrences with distant metastases, and eleven distant metastases. The median interval from the date of diagnosis to failure was 26.5 months (range: 16-50 months). Six of ten (60%) locoregional recurrences were treated with reirradiation ± concurrent chemotherapy. The 5-year locoregional control, distant metastasis control, disease-free survival, and overall survival rates of whole cohort were 81.1%, 74.3%, 60.1%, and 73.4%, respectively. Cox regression analyses revealed that neoadjuvant chemotherapy, age, and Epstein-Barr virus were independent predictors for disease-free survival. CONCLUSION: Neoadjuvant chemotherapy followed by IMRT with or without chemotherapy improves the long-term survival of Saudi patients with nasopharyngeal carcinoma. Distant metastasis was the main pattern of treatment failure. Neoadjuvant chemotherapy, age, and Epstein-Barr virus status before IMRT were important independent prognostic factors.

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.

Upper Egypt experience in bladder preservation using concurrent chemoradiotherapy.

OBJECTIVE: To share our experience in bladder preservation in Upper Egypt, Assiut and Sohag Universities, using different treatment protocols. In Sohag study patients with operable muscle invasive bladder cancer were included and underwent transurethral resection followed by radiochemotherapy (5- fluorouracil and Cisplatin) for bladder preservation. In Assiut study after maximum safe resection of bladder tumor, patients received combined chemo-radiotherapy, 60 Gy of fractionated radiotherapy over 6 weeks, with Cisplatin and Gemcitabine. RESULTS: In Sohag study the age of patients ranged from 35-72ys with Median 56 years, 24 patients were male (80%) and 6 patients were female (20%). In Assiut study the mean of age was 57.30 years, median 58.5 years with peak incidence in 7th decade (9 cases) then in 6th decade 7 cases (23.33%). Performance status was represented as following, 23 patients (76.6%) were scale 1 and seven patients (23.3%) were scale 2. In Assiut study, 90% of patients were disease free at the time of cystoscopic reevaluation. Of concern is that within 18 months of follow up in Assiut study, 7 of 27 (74%) complete responding patients have had local recurrence and 66.7% of all cases. The recurrence free survival in Sohag study at the median follow up (17 months) was 84% and at the end of follow up (30 months) was 70%. The overall survival at the median follow up was 95%, and at the end of follow up was 84%. The disease free survival in Assiut study was 66.7% and the overall Survival in Assiut study was 76.7. CONCLUSION: Three significant prognostic factors were detected for overall survival, performance status, tumor size and residual of tumor and two significant prognostic factors were detected for disease free survival, tumor size and residual of tumor in Assiut study. And it was nearly similar to that reported by Sohag study as they found the completeness of TUR and early stage of the tumor had the strongest impact in response to treatment.

The optimal sequence of radiotherapy and chemotherapy in adjuvant treatment of breast cancer.

BACKGROUND: The optimal time sequences for chemotherapy and radiation therapy after breast surgery for patients with breast cancer remains unknown. Most of published studies were done for early breast cancer patients. However, in Egypt advanced stages were the common presentation. This retrospective analysis aimed to assess the optimum sequence for our population. METHODS: 267 eligible patients planned to receive adjuvant chemotherapy [FAC] and radiotherapy. Majority of patients (87.6%) underwent modified radical mastectomy while, 12.4% had conservative surgery.We divided the patients into 3 groups according to the sequence of chemotherapy and radiotherapy. Sixty-seven patients (25.1%) received postoperative radiotherapy before chemotherapy [group A]. One hundred and fifty patients (56.2%) were treated in a sandwich scheme (group B), which means that 3 chemotherapy cycles were given prior to radiotherapy followed by 3 further chemotherapy cycles. A group of 50 patients (18.7%) was treated sequentially (group C), which means that radiotherapy was supplied after finishing the last chemotherapy cycle. Patients' characteristics are balanced between different groups. RESULTS: Disease free survival was estimated at 2.5 years, and it was 83.5%, 82.3% and 80% for patient receiving radiation before chemotherapy [group A], sandwich [group B] and after finishing chemotherapy [group C] respectively (p > 0.5). Grade 2 pneumonitis, which necessitates treatment with steroid, was detected in 3.4% of our patients, while grade 2 radiation dermatitis was 17.6%. There are no clinical significant differences between different groups regarded pulmonary or skin toxicities. CONCLUSION: Regarding disease free survival and treatment toxicities, in our study, we did not find any significant difference between the different radiotherapy and chemotherapy sequences.