Neoadjuvant Management of Adenocarcinoma of the Esophagus and Esophagogastric Junction: Review of Randomized Evidence and Definition of Optimum Treatment Algorithm.

BACKGROUND: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) are accepted standards of care for the management of adenocarcinoma of the esophagus and gastroesophageal junction. SUMMARY: The MRC-OEO2 study established the role of 2 cycles of neoadjuvant cisplatin/fluoropyrimidine. More recently, the FLOT-AIO4 study demonstrated the superiority of perioperative FLOT chemotherapy (5FU, oxaliplatin, and docetaxel) compared to ECX (epirubicin, cisplatin, and capecitabine) regime. The results from the pivotal CROSS study established neoadjuvant CRT as a new standard of care in OG cancer. The survival benefits observed in FLOT and CROSS studies are similar [FLOT - hazard ratio 0.75 (0.62-0.92); CROSS - 0.741 (0.55-0.98)]. KEY MESSAGES: Both nCT and nCRT have been shown to be associated with survival benefit compared to surgery alone. We have performed a comprehensive review of the available evidence to define the optimum treatment algorithm and identify specific patient sub-groups who may be appropriate for the use of one or more of these neoadjuvant options.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Oligometastatic esophageal cancer cured by systemic therapy combined with radiotherapy to primary tumor and metastasis (metastasis-directed therapy)-small case series.

The prognosis of metastatic esophageal cancer (EC) remains poor with an average life expectancy of around 9-12 months with standard systemic chemotherapy. The concept of oligometastatic disease (OMD) in EC cancer is controversial with no universally accepted definition. From the original cohort of metastatic oesophago-gastric (OG) cancer patients, 4 cases were identified that developed unusually favourable outcome with long-term survival and probable cure. In retrospect, all patients had OMD at presentation with striking similarities in terms of their clinical presentation, staging, treatment response and outcomes. All patients presented with locally advanced EC and 1-2 areas of metastatic disease (bone, lung, non-regional lymph node (LN) involvement). All were treated with combined therapeutic strategy using initial systemic chemotherapy followed by local radiotherapy to primary tumor and adjacent areas of visible/residual metastatic disease (metastasis-directed therapy). All patients experienced long-term survival (range = 7-13 years) with no evidence of recurrence and probable cure. The present case series adds to the growing pool of evidence indicating OM EC cancer represents a distinct and prognostically favorable subgroup.

Management of Oligometastatic Disease in Esophagogastric Cancer: What Is the Evidence?

BACKGROUND: The concept of oligometastatic disease (OMD) was first introduced in 1995 by Hellman and Weichselbaum and described as stage of transition between localized and widespread metastatic disease. The presence of OMD in esophagogastric (OG) cancer remains controversial. Historically, most experts believe that OG cancer is systemic disease from the outset. SUMMARY: More recently, there is emerging data indicating improved outcomes in patients with OG cancer and oligometastatic disease. The present manuscript focuses on reviewing the emerging evidence in management of metastatic OG cancer with OMD and highlighting the direction of future research. KEY MESSAGES: Multiple retrospective and at least 2 phase II retrospective studies have reported on improved outcomes in patients with metastatic OG cancer and OMD. There is indication of improved outcome with combined systemic and local therapy (surgery or radiation). Further research should include phase III randomized studies to identify the optimal management algorithm in these groups of patients.

Physical activity and dietary considerations for prostate cancer patients: future research directions.

This review considers current evidence on physical activity and dietary behaviours in the context of prostate cancer prevention and survivorship outcomes. Prostate cancer is the second most common cancer amongst men, with over 1⋅4 million newly diagnosed cases globally each year. Due to earlier detection via screening and advances in treatments, survival rates are amongst the highest of all cancer populations. However, hormone treatments (i.e. androgen deprivation therapy) can lead to undesirable body composition changes, increased fatigue and reduced health-related quality of life, which can impair the overall wellbeing of men living with and beyond prostate cancer. Existing research has only provided limited evidence that physical activity and nutrition can impact a man's risk of prostate cancer but cohort studies suggest they can influence survival outcomes after diagnosis. Additionally, data from observational and intervention studies suggest that habitual physical activity (or structured exercise) and healthy diets can help to ameliorate hormone-related treatment side-effects. Current physical activity guidelines state that prostate cancer patients should complete at least three sessions of moderate-intensity aerobic exercise per week, along with two resistance exercise sessions, but dietary guidelines for prostate cancer patients are less well defined. In conclusion, regular physical activity and nutritional interventions may improve survival outcomes and attenuate some adverse side-effects of hormone treatments in men with prostate cancer. However, further research is required to improve our understanding of the health impacts of physical activity (including structured exercise) and nutrition in relation to prostate cancer prevention and survivorship.

Conformal 3D computed tomography planned endoluminal brachytherapy for the local control of esophageal cancer.

PURPOSE: To outline the toxicity, tolerability, and efficacy of a 3D conformal computed tomography planned endoluminal brachytherapy (ELBT) treatment for esophageal adenocarcinoma (OAC) or squamous cell carcinoma (OSCC). METHODS AND MATERIALS: A retrospective single-center analysis of toxicity, tolerability, and outcomes for 65 consecutive patients with OAC/OSCC who received 6-8Gy in one fraction or 12-16Gy in two fractions of high-dose-rate ELBT as salvage postchemoradiotherapy (n = 7 and n = 14 respectively), or as a boost to external beam radiotherapy (n = 14 and n = 30, respectively). RESULTS: Median overall survival from the first brachytherapy application was 7.4 (IQR 5.0-14.7) months for the boost cohort and 9.2 (IQR 5.8-20.1) months for the salvage cohort. In a univariate analysis, use of a higher, fractionated dose of radiotherapy was associated with longer overall survival. At least one-third (33%; n = 7) of the salvage cohort and 28% (n = 12) of the boost cohort exhibited a local recurrence prior to death. Overall, 66.7% of the salvage and 56.8% of the boost cohort experienced odynophagia. Swallow function stabilized or improved early after treatment, with only 11.6% of the boost and 14.3% of the salvage cohort demonstrating a long-term decline in dysphagia score. CONCLUSIONS: 3D conformal planned ELBT is safe and tolerable. Most patients exhibit an early and sustained stabilization or improvement in their swallow function and greater survival is seen with higher brachytherapy doses. Further research is required to determine the place of brachytherapy in the management of esophageal cancer, particularly when planned using contemporary conformal approaches.

Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review.

Temozolomide (TMZ)-related idiosyncratic and other uncommon toxicities have been reported. To better characterize these toxicities and to identify any associated risk factors, we performed a systematic review. We searched the PubMed database, limited to the English language, published between 1999 and December 2011. We selected only those articles in which TMZ was temporally related and was the sole or main contributing chemotherapeutic drug to idiosyncratic drug reactions (IDRs) and other uncommon toxicities. Hematological IDRs are biopsy-proven aplastic anemia or grade V toxicity or grade IV toxicity with slow and incomplete hematological recovery. Seventy-three cases were identified, including 21 hematological IDRs, 31 nonhematological IDRs and uncommon infections, and 21 second primary cancers. With a caveat of publication and reporting bias, the following observations could be made. The hematological IDRs predominantly occurred in female patients (exact binomial two-tailed, P=0.0041) and most patients were receiving TMZ concomitantly with radiotherapy for glioma. The median duration of exposure to TMZ was 30 days and the median cumulative TMZ exposure was 2250 mg/m (range, 500-6900 mg/m). The sex predilection was not evident in nonhematological IDRs and other uncommon toxicities. TMZ-induced pneumonitis and cholestatic hepatitis are emerging as a nonhematological hypersensitive reaction and IDR, respectively. For TMZ-related myelodysplasia or leukemia, the cumulative dose of TMZ ranged from 1400 to 30 000 mg/m. The cumulative dose of TMZ was lower and latency was shorter with a previous exposure to other leukemogenic drugs, suggesting that TMZ may have augmented the leukemogenic potential of other drugs. Early appearance of profound myelosuppression during the course of TMZ and concurrent radiotherapy could be a hematological IDR, which warrants prompt investigations to exclude aplastic anemia. Myelodysplasia or leukemia developed after a median TMZ exposure of 15 g/m.

Avoiding radical surgery after pre-operative chemoradiotherapy: a possible therapeutic option in rectal cancer?

BACKGROUND: In this modern era of multi-modality treatment there is increasing interest in the possibility of avoiding radical surgery in complete responders after neo-adjuvant long-course chemoradiotherapy (LCPRT). In this article, we present a systematic review of such treatments and discuss their therapeutic applicability for the future. METHODS: We searched the PubMed online libraries to identify studies that reported on the long-term surgical and pathological outcomes after local excision together with those that explored the possibility of clinical observation only in patients achieving a complete clinical response after LCPRT. RESULTS: Several retrospective (n = 10), one single-arm prospective, and one small randomised series have reported on the use of local excision after LCPRT and demonstrated acceptably low levels of local recurrence with survival comparable to patients progressing to conventional surgery. One prospective series allocated patients to observation or radical surgery based on histological parameters after local excision (ypT0 and ypT1) and showed no differences in outcomes. Two retrospective series from the same group on a Brazilian cohort of patients reported excellent long-term outcomes after "wait and watch" in complete clinical responders. However, other reports have shown no direct correlation between clinical and pathological response. CONCLUSION: Local excision may be an appropriate option for selected patients developing good clinical response after LCPRT. In our opinion, a policy of clinical observation in complete clinical responders after LCPRT may not be a safe strategy, unless we had robust predictive models for accurate identification of pathological complete response. In order to identify patients that may be potentially appropriate for such an approach we propose a clinical algorithm incorporating important clinical, radiological, and pathological parameters. The proposed model will require validation in a prospective study. Finally, we need randomised data for demonstrating the non-inferiority of clinical observation compared to conventional surgery before this can be considered as standard possible therapeutic option.

Therapeutic effect of sodium iodide symporter gene therapy combined with external beam radiotherapy and targeted drugs that inhibit DNA repair.

Adenoviral (AdV) transfer of sodium iodide symporter (NIS) gene has translational potential, but relatively low levels of transduction and subsequent radioisotope uptake limit the efficacy of the approach. In previous studies, we showed that combining NIS gene delivery with external beam radiotherapy (EBRT) and DNA damage repair inhibitors increased viral gene expression and radioiodide uptake. Here, we report the therapeutic efficacy of this strategy. An adenovirus expressing NIS from a telomerase promoter (Ad-hTR-NIS) was cytotoxic combined with relatively high-dose (50 microCi) (131)I therapy and enhanced the efficacy of EBRT combined with low-dose (10 and 25 microCi) (131)I therapy in colorectal and head and neck cancer cells. Combining this approach with ataxia-telangiectasia mutated (ATM) or DNA-dependent protein kinase (DNA-PK) inhibition caused maintenance of double-stranded DNA breaks (DSBs) at 24 hours and increased cytotoxicity on clonogenic assay. When the triplet of NIS-mediated (131)I therapy, EBRT, and DNA-PKi was used in vivo, 90% of mice were tumor-free at 5 weeks. Acute radiation toxicity in the EBRT field was not exacerbated. In contrast, DNA-PKi did not enhance the therapeutic efficacy of EBRT plus adenovirus-mediated HSVtk/ganciclovir (GCV). Therefore, combining NIS gene therapy and EBRT represents an ideal strategy to exploit the therapeutic benefits of novel radiosensitizers.

Temozolomide induced liver injury.

A 62-year female received radiotherapy over six weeks with daily 75 mg/m2 Temozolomide (TMZ) for Glioblastoma (GB). At the last week of radiotherapy, her liver enzymes and serum bilirubin started deteriorating. TMZ was discontinued. The histopathology demonstrated the features of acute cholestasis and focal parenchymal inflammation. A range of investigations failed to show any other contributory cause of hepatitis. She required in-hospital care for a prolonged period for a grade three hepatic failure. The liver functions very slowly recovered over 40 weeks, but her general condition continues to deteriorate. TMZ may cause a mild temporary rise in the liver enzymes and has been reported to reactivate hepatitis B. In few other cases concomitant medications were the possible causes of hepatitis. However, searching the Medline and other bibliographic database, we have not come across any case of TMZ-induced liver injury (TMZ-DILI). Histopathology and pattern of liver enzyme elevation suggest that unlike Dacarbazine, which causes veno-occlusive type liver damage, TMZ in this patient caused mainly cholestasis type liver injury. On Naranjo Adverse Drug Reaction (ADR) probability scale, this case falls in probable grade (Scale 7).