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.

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.

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.

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.

The Potential Role of Radiotherapy in the Management of Hepatoid Carcinomas of the Stomach: A Case Report.

INTRODUCTION: Hepatoid adenocarcinoma (AC) of the stomach (HAS) represents a rare variant of conventional gastric AC characterised by poor prognosis. They are usually managed with surgery (localised disease) and chemotherapy. CASE REPORT: We present the first case report of a patient with HAS who presented with weight loss, poor appetite, general clinical deterioration (performance status [PS] = 3), and active gastrointestinal bleeding who was treated with fractionated palliative radiotherapy (RT) using 30 Gy in 10 fractions. The use of RT was associated with excellent symptomatic and radiological response and facilitated surgery secondary to significant improvement in general fitness and PS. CONCLUSION: RT may have a role in the multimodality management of hepatoid AC of the stomach.

Management of elderly patients with glioblastoma-multiforme-a systematic review.

The management of elderly patients with glioblastoma-multiforme (GBM) remains poorly defined with many experts in the past advocating best supportive care, in view of limited evidence on efficacy of more aggressive treatment protocols. There is randomised evidence (NORDIC and NA-O8 studies) to support the use of surgery followed by adjuvant monotherapy with either radiotherapy (RT) using hypofractionated regimes (e.g. 36 Gy in 6 fractions OR 40 Gy in 15 fractions) or chemotherapy with temozolomide (TMZ) in patients expressing methylation of promoter for O6-methylguanine-DNA methyltransferase enzyme. However, the role of combined-modality therapy involving the use of combined RT and TMZ protocols has remained controversial with data from the EORTC (European Organisation for Research and Treatment of Cancer)-NCIC (National Cancer Institute of Canada) studies indicating that patients more than 65 years of age may not benefit significantly from combining standard RT fractionation using 60 Gy in 30 fractions with concurrent and adjuvant TMZ. More recently, randomised data has emerged on combining hypofractionated RT with concurrent and adjuvant TMZ. We provide a comprehensive review of literature with the aim of defining an evidence-based algorithm for management of elderly glioblastoma-multiforme population.

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 .).

Can palliative radiotherapy influence prostate-specific antigen response in patients with castrate-resistant prostate cancer treated with systemic therapy (chemotherapy or abiraterone)?-a report of three cases.

Palliative radiotherapy (pRT) is primarily employed for palliation of bone pain in patients with castrate-resistant prostate cancer (CRPC). However, evidence that pRT influences prostate-specific antigen response in patients with CRPC on systemic therapy is lacking. We describe three cases of CRPC progressing after treatment with docetaxel (n=2) and abiraterone (n=1), who responded unusually after pRT for bone pain with the development of a significant biochemical response and restoration of response to systemic therapy. The possibility of pRT influencing metastatic disease in CRPC has not been previously reported, and raises the possibility of radiation-induced modulation of anti-tumor immune response mechanisms that may play a role in the restoration of response to systemic treatment.

Palliative Radiotherapy in the Presence of Well-Controlled Metastatic Disease after Initial Chemotherapy May Prolong Survival in Patients with Metastatic Esophageal and Gastric Cancer.

PURPOSE: We report the outcomes of patients treated with palliative radiotherapy (pRT) to the primary tumour in the context of well-controlled metastatic disease after initial chemotherapy. MATERIALS AND METHODS: Clinical records of 132 patients with metastatic esophago-gastric (OG) cancer treated with palliative chemotherapy (pCT) between January 2009 and June 2013 were reviewed. Ninetyseven patients had responding or stable disease after 3 months of chemotherapy, of whom 53 patients received pRT to the primary tumour after initial chemotherapy in the presence of well-controlled metastatic disease (group A, pCT-RT). The remaining 44 patients were treated with pCT alone (group B, pCT). Treatment-related outcomes were assessed in above groups including time to local progression (TTLP), progression-free and overall survival. RESULTS: The median overall survival for patients treated with pRT after initial chemotherapy (group A) was 23.3 months (95% confidence interval [CI], 17.70 to 28.89 months) and significantly higher than the 14 months (95% CI, 10.91 to 17.08 months) in patients treated with pCT alone (group B) (p < 0.001). The use of pCT-RT was an independent predictor of OS in multivariate analysis. Local recurrence was observed in 12/53 of patients (23%) in group A compared to 16/44 (36%) in group B. The median TTLP was significantly higher in patients after pCT-RT at 17.3 months (5.23 months to 44.50 months) compared to 8.3 months (range, 4.10 to 25.23 months) in patients treated with pCT alone (p=0.006). CONCLUSION: The possibility of pRT influencing systemic disease in advanced OG cancer has not been reported, and results from the present study present strong arguments for investigation of this therapeutic strategy in a randomized trial.

Retention of platinum sensitivity till late stages of tumour progression may imply improved prognosis of oesophageal and gastric cancers.

BACKGROUND: We report on the outcomes of patients with metastatic oesophago-gastric (OG) cancer progressing after first-line platinum-based chemotherapy (PBCT) who received a re-challenge schedule of PBCT (r-PBCT) as second-line therapy. PATIENTS AND METHODS: Patients with metastatic OG cancer treated with first-line PBCT (n = 138) between January 2009 and June 2013 were selected for the purpose of the study. Treatment-related outcomes were assessed including response rates, progression-free survival (PFS) and overall survival (OS). RESULTS: 43 (32%) patients progressed (group A: platinum resistant (PR)) and 95 (68%) patients showed a response (group B: platinum sensitive (PS)) or had stable disease after first-line PBCT. Approximately 20% (9/43) of the patients in group A received second-line chemotherapy compared to 50% (38/80) in group B. Most patients (39/47) received r-PBCT, and the remaining patients (8/47) were treated with irinotecan-based chemotherapy. More than 50% (20/39) of the patients achieved disease control, with median PFS and OS of 3 months (95% confidence interval (CI) = 2.0-4.0 months) and 5.7 months (95% CI = 4.7-6.7 months) after commencement of r-PBCT. The actuarial median OS of patients responding to second-line or second and third lines of r-PBCT was 26.7 and 30.1 months, respectively. CONCLUSION: In platinum responders, r-PBCT appears to be an appropriate second-line option with survival outcomes comparable to those of other agents.

Sequential maximum androgen blockade (MAB) in minimally symptomatic prostate cancer progressing after initial MAB: two case reports.

The management of castrate-resistant prostate cancer progressing after maximum androgen blockade (MAB) has evolved in the last decade with the development of several novel therapeutic options. However, the initial therapeutic strategy in these patients usually involves withdrawal of anti-androgen that can be associated with biochemical response in approximately 20% of patients. Notably, we have observed evidence of sustained biochemical response in two patients following second- and third-line MAB using rechallenge schedule of previously administered anti-androgen after latent interval. The possibility of response following sequential MAB using the same anti-androgen agent has not yet been reported.

Pazopanib-Induced Regression of Brain Metastasis After Whole Brain Palliative Radiotherapy in Metastatic Renal Cell Cancer Progressing on First-Line Sunitinib: A Case Report.

Pervious randomized studies have demonstrated survival benefit in favor of tyrosine kinase inhibitors (TKIs) compared to cytokines in metastatic clear cell renal cell carcinoma (RCC). However, the role of TKIs for treating brain metastasis from RCC remains unknown. Previous studies have reported possible activity of sunitinib and sorafenib in RCC patients with brain metastasis. We report on patient with metastatic RCC who responded to first-line sunitinib but then progressed with multiple brain metastasis, but with controlled extra-cranial metastatic disease. The patient was treated with whole-brain palliative radiotherapy followed by treatment schedule of pazopanib at standard dose of 800 mg/day which was associated with a response in brain metastasis. Subsequently, she was re-challenged at reduced dose of 600 mg/day and developed further response in metastatic brain lesions. She lived for more than 3 years from initial diagnosis of brain metastasis. This is the first case report of sequential TKI therapy for treating metastatic RCC with brain metastasis and supports the probable use of pazopanib as potent TKI for treating patients with cerebral metastasis.

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.

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).

The sequential use of carmustine wafers (Gliadel®) and post-operative radiotherapy with concomitant temozolomide followed by adjuvant temozolomide: a clinical review.

In patients with glioblastoma multiforme (GBM), there is no consensus on the sequential use of two existing regimens: post-operative Gliadel implantation into the surgical cavity and concomitant temozolomide with radiotherapy followed by adjuvant temozolomide ('Stupp protocol'). NICE in the guideline TA121 (July 2007) could not pass any judgement on the sequential use of both the regimens due to lack of evidence at the time of consultation. Since then, few prospective studies and retrospective series have been reported using these two regimens sequentially. Except in one study, results were indicative of an incremental gain of 2-3 months in median survival in comparison to the published results using Gliadel or 'Stupp Protocol' alone. Post-surgical complications were manageable and within an acceptable range, when the sequential regimen was managed under defined guidelines and surgery was performed in a high volume centre. Moderate degree of increased myelosuppression has been reported in few series, however. In the absence of a phase III trial and the small number of patients in each series, the reported trend of toxicities and efficacy could only be substantiated by setting up a national database. Contributing to such a national database and toxicity recording could be made mandatory through peer review programme for the neurooncological services. Based on the preclinical and albeit lower level of clinical evidence, demonstrating temporal and spatial co-operation between two regimens (Gliadel and 'Stupp Protocol'), resulting in incremental 2-3 months median survival gain, should enable NICE in its next review to issue a favourable guidance. Depending on the number of patients eligible for such a sequential regimen, which could be 15%-25% of Glioblastoma patients diagnosed in England per annum, the additional annual cost of concomitant temozolomide would be approximately £640,000 to £1 million.

Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck.

PURPOSE: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored. RESULTS: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months). CONCLUSIONS: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN.