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Previous observational research has indicated the effectiveness of a 12-step, dual-focus mutual aid group, Double Trouble in Recovery (DTR), for assisting individuals to recover from co-occurring substance use and psychiatric disorders. The current study extends this line of research by evaluating DTR with a quasi-experimental design; controlled designs are rare in studies of mutual aid. Patient outcomes in the same psychiatric day treatment program were compared for two consecutive admission cohorts characterized by high rates of co-occurring disorders. The first cohort did not have DTR available while the second cohort was exposed to DTR after it was established at the program. Both cohorts were assessed at program admission and at a six month follow-up. Using intent to treat analysis, the Post-DTR cohort as compared with the Pre-DTR cohort had significantly fewer days of alcohol and drug use, more frequent traditional 12-step groups outside of the program and higher psychiatric medication adherence. There were no differences in psychiatric symptoms or program retention, however. This study helps demonstrate the benefits of introducing 12-step, dual-focus mutual aid into psychiatric treatment programs that serve patients with co-occurring disorders.

Double Trouble in Recovery (DTR) is a “dual focus,” 12 step-based mutual aid program tailored to assist recovery from co-occurring substance use and psychiatric disorders.

Objective

To determine consumers’ perceptions of DTR’s usefulness for their recoveries and the relationships between perceived DTR usefulness and self-help processes, self-efficacy to cope with problems in recovery, and changes in behaviors conducive to dual recovery.

Methods

Consumers attending DTR groups, located within a psychiatric day-treatment program, completed anonymous surveys 8 months (N=19) and 20 months (N=61) after DTR was implemented.

Results

DTR participants rated DTR favorably and length of DTR attendance was significantly associated with increased self-efficacy for recovery and positive changes in recovery-oriented behaviors. Perceived DTR usefulness was significantly associated with greater engagement in three specific self-help processes and increased self-efficacy for recovery; notably, these associations were independent of consumers’ overall satisfaction with the treatment program.

Conclusion

This study is the first to document consumers’ perceived usefulness of DTR in relation to indicators of recovery. Overall, the study provides additional evidence for the benefits of implementing consumer-led dual focus groups in treatment programs.

Purpose

To explore whether progression-free survival (PFS) or biochemical PFS can be used as a predictor of overall survival (OS) and to investigate the dependence between PFS and OS in men with castrate-resistant prostate cancer.

Patients and Methods

Data from nine Cancer and Leukemia Group B trials that enrolled 1,296 men from 1991 to 2004 were pooled. Men were eligible if they had prostate cancer that had progressed during androgen deprivation therapy and did not receive prior treatment with chemotherapy, immunotherapy, or other nonhormonal therapy. Landmark analyses of PFS at 3 and 6 months from randomization/registration were performed to minimize lead time bias. The proportional hazards model was used to assess the significance effect of PFS rate at 3 and at 6 months in predicting OS. In addition, biochemical progression using the definitions of Prostate-Specific Antigen Working Group (PSAW) Criteria PSAWG1 and PSAWG2 were analyzed as time-dependent covariates in predicting OS.

Results

The median survival time among men who experienced progression at 3 months was 9.2 months (95% CI, 8.0 to 10.0 months) compared with 17.8 months in men who did not experience progression at 3 months (95% CI, 16.2 to 20.4 months; P < .0001). Compared with men who did not progress at 3 and at 6 months, the adjusted hazard ratios for death were 2.0 (95% CI, 1.7 to 2.4; P < .001) and 1.9 (95% CI, 1.6 to 2.4; P < .001) for men who experienced progression at 3 and 6 months, respectively. In addition, biochemical progression at 3 months predicted OS. The association between PFS and OS was 0.30 (95% confidence limits = 0.26, 0.32).

Conclusion

PFS at 3 and 6 months and biochemical progression at 3 months predict OS. These observations require prospective validation.

Purpose

Radiation Therapy Oncology Group 85-31 was a randomized trial of androgen suppression for life for patients with locally advanced prostate cancer. However, not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrence. We correlated duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued hormonal therapy.

Patients and Methods

The protocol mandated pelvic radiotherapy followed by goserelin given indefinitely or until disease progression. There were 189 analyzable patients. Patients were divided in groups based on the tertile of hormonal therapy duration (HTD) as follows: ≤ 1 year, more than 1 year and ≤ 5 years, and more than 5 years. Overall survival (OS), disease-free survival (DFS), cause-specific mortality, local failure (LF), and distant metastasis (DM) were studied. Kaplan-Meier estimation and Cox proportional hazards regression model were used for OS and DFS, and Fine and Gray's regression model was used for the other outcomes.

Results

The median follow-up for surviving patients is 9.6 years. The median duration of adjuvant hormonal therapy was 2.2 years. The HTD more than 5 years group is significantly associated with an improved survival and DFS and fewer DMs than other HTD groups. After adjustment for age, radical prostatectomy, nodal status, Gleason score, and stage variables, the HTD more than 5 years group remains significantly associated with better OS and DFS than other HTD groups.

Conclusion

In this hypothesis-generating analysis, prolonged HTD of more than 5 years seems significantly associated with improvements in most outcomes. Given these data, decreasing HTD to ≤ 5 years may have a detrimental effect on patients with locally advanced prostate cancer. Only a randomized trial will conclusively clarify this issue.

Background

Most randomized controlled trials (RCTs) that have compared neoadjuvant chemoradiation followed by surgery with surgery alone for locally advanced esophageal cancer have shown no difference in survival between the two treatments. Meta-analyses on neoadjuvant chemoradiation in esophageal cancer, however, are discordant.

Methods

For the present study, published meta-analyses on neoadjuvant chemoradiation for esophageal cancer were identified from the PubMed database and critically appraised in order to make a judgment on the applicability of neoadjuvant chemoradiation in clinical practice and decision making.

Results

Two of the six meta-analyses examined did not show a significant survival benefit in patients with resectable esophageal cancer. Differences in the studies included and statistical methods applied might account for this. Moreover, there was heterogeneity between the RCTs included in the meta-analyses with regard to the patients included, tumor histology, and radiotherapy and chemotherapy regimes. Also, surgical technique was not uniform. No data on individual patients were available for most meta-analyses. The RCTs included in the meta-analyses were of inadequate sample size. All were started in the nineties, and hence methods for diagnosis, staging, treatment delivery, and outcome measurement reflect clinical practice during that decade.

Conclusions

The current data on neoadjuvant chemoradiation for esophageal cancer strongly indicate the need for designing future high-quality trials that will contribute to a better understanding of the role of neoadjuvant treatment for resectable cancer of the esophagus and help to identify patient subgroups that would benefit most.

A phase II trial of continuous oral therapy with UFT, a combination of uracil and the 5-fluorouracil analogue 1-(2-tetrahydrofuryl)-5-fluorouracil (Futraful, Ftorafur), was conducted in 40 patients with advanced colorectal cancer and 18 patients with advanced gastric cancer. Six partial responses were seen in the 36 evaluable patients with colorectal cancer (response rate 16.6%; 95% confidence limits 6.4-32.8%), and one partial response was seen in the 16 evaluable patients with gastric cancer (response rate 6%; 95% confidence limits 0.27-30.2%). The overall toxicity of the treatment was low, and all patients were treated as outpatients. The results suggest that oral UFT has comparable activity to standard regimes of 5-fluorouracil, and because of the convenience of oral administration is a useful therapy in the management of patients with advanced colorectal cancer.

Dynamic treatment regimes are the type of regime most commonly used in clinical practice. For example, physicians may initiate combined antiretroviral therapy the first time an individual’s recorded CD4 cell count drops below either 500 cells/mm3 or 350 cells/mm3. This paper describes an approach for using observational data to emulate randomized clinical trials that compare dynamic regimes of the form “initiate treatment within a certain time period of some time-varying covariate first crossing a particular threshold.” We applied this method to data from the French Hospital database on HIV (FHDH-ANRS CO4), an observational study of HIV-infected patients, in order to compare dynamic regimes of the form “initiate treatment within m months after the recorded CD4 cell count first drops below x cells/mm3” where x takes values from 200 to 500 in increments of 10 and m takes values 0 or 3. We describe the method in the context of this example and discuss some complications that arise in emulating a randomized experiment using observational data.

AIM: To assess the efficiency and toxicities of irinotecan (CPT-11)-involved regimens in patients with advanced gastric cancer.

METHODS: Randomized phases II and III clinical trials on chemotherapy for advanced gastric cancer were searched from MEDLINE, EMbase, Cochrane Controlled Trials Register, and EBSCO. Relevant abstracts were manually searched. A total of 657 patients were analyzed for their overall response rate (ORR), time to treatment failure (TTF), overall survival (OS) rate, and toxicities. Overall survival rate, reported as hazard ratio (HR) with 95% CI, was used as the primary outcome measure.

RESULTS: Four randomized controlled trials on chemotherapy for advanced gastric cancer were detected. The CPT-11-containing combination chemotherapy was not significantly advantageous over the non CPT-11-containing combination chemotherapy for OS rate (HR = 1.12, 95% CI: 0.92-1.36, P = 0.266) and ORR [risk ratio (RR) = 1.23, 95% CI: 0.71-2.14, P = 0.458]. However, the CPT-11-containing combination chemotherapy was significantly advantageous over the non CPT-11-containing combination chemotherapy for TTF (HR = 1.35, 95% CI: 1.12-1.64, P = 0.002). Grade 3/4 haematological toxicity (thrombocytopenia: RR = 0.20, 95% CI: 0.09-0.48; P < 0.001) and gastrointestinal toxicity (diarrhea: RR = 4.09, 95% CI: 2.42-6.93, P < 0.001) were lower in patients with advanced gastric cancer after CPT-11-containing combination chemotherapy than after non CPT-11 -containing combination chemotherapy.

CONCLUSION: CPT-11-containing combination chemotherapy is advantageous over non CPT-11 -containing combination chemotherapy for TTF with no significant toxicity. CPT-11-containing combination chemotherapy can be used in treatment of advanced gastric cancer.

Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation.

Background

In the first line treatment of non-small cell lung cancer (NSCLC), several clinical trials have shown that not all NSCLC patients can benefit from treatment with tyrosine kinase inhibitors (TKIs) than receiving chemotherapy. Some trials treated patients with TKI according to their clinical characteristics. A few studies only chose patients with an epidermal grouth factor receptor (EGFR) mutation for TKI therapy. We aimed to determine whether patients could be treated with TKIs based on clinical factors in the first-line setting.

Methods

We performed a meta-analysis of randomized trials involving patients with advanced NSCLC treated with chemotherapy or TKIs by different selections. Efficacy outcomes of interest were the objective response rate (ORR), progression-free survival (PFS) and the overall survival (OS) of each treatment arm.

Results

Four trials enrolled unselected patients, and two trials selected East Asian patients using the clinical factors of gender and smoking history. Five trials chose patients with an EGFR mutation who were randomized for treatment with TKI or chemotherapy. For unselected patients, the risk ratio (RR) of the ORR was 3.52, the hazard ratio (HR) of the PFS was 1.29 and the HR of the OS was 1.35. For the clinically selected patients, the RR of the ORR was 0.64. The HRs of the PFS and OS were 0.83 and 0.92, respectively. The ORR and PFS were better for TKIs than for chemotherapy in patients with an EGFR mutation. The ORR was 0.47, and the HRs of the PFS and OS were 0.36 and 1.00, respectively.

Conclusions

Advanced NSCLC patients with an EGFR mutation benefit most from TKIs. EGFR-TKI treatment is justified for patients with unknown EGFR status,and those who cannot tolerate chemotherapy owing to age, poor performance status (PS) or other medical conditions, when selected according to clinical factors in the first-line setting.

Rituximab maintenance (RM) therapy following successful induction has recently emerged as a highly effective treatment for follicular lymphoma (FL). Randomized trials analyzing the impact of RM compared to observation alone have demonstrated a significantly better outcome in terms of progression-free survival (but not overall survival) in patients (pts) who received as first-line treatment single-agent rituximab, standard chemotherapy (CVP) and recently also immunochemotherapy (R-CHOP, R-CVP or R-FND), as shown by preliminary results of the PRIMA trial. Also in the setting of relapsed disease, RM has shown significant benefit either after chemotherapy or immunochemotherapy. RM has been generally well tolerated, and treated pts developed only mild toxicity, mainly a small increased rate of neutropenia, hypogammaglobulinaemia and self-limiting upper-respiratory tract infections. Moreover, no cumulative or unexpected toxicities were observed and quality of life was not affected. These data have established RM therapy as an important part of multi-modal therapeutic strategies in patients affected by FL.

Opinion statement

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

Worldwide, gastric cancer continues as a significant healthcare issue with an unacceptably high mortality rate. Although it is clear that combination chemotherapy for advanced gastric/esophageal gastric cancer is superior to best supportive care and monotherapy, the median survival over the past two decades persists at less than 10 months. Multiple combination regimens have been evaluated in the phase III setting, producing response rates ranging between 9% and 45%. There is still debate as to whether doublet vs. triplet chemotherapy combinations represent the most appropriate platform from which to build other regimens, including those with biologic therapy.

Two published clinical trials have significantly influenced clinical practice. A randomized trial including 545 advanced gastric cancer patients compared first-line treatment with DCF (docetaxel, cisplatin, 5-FU) vs. the cisplatin/5-FU regimen. The cisplatin/5-FU combination has, over time, become a standard comparator regimen and has been supported by the FDA. Although the trial showed a significant survival advantage favoring DCF, there has been concern about toxicity, particularly the risk of increased diarrhea, neutropenia, and neutropenic fever. The REAL2 trial was a 2x2 randomized, first-line advanced gastric cancer study that compared two different platinum compounds and two different fluoropyrimidines in combination therapy. The regimens consisted of ECF (epirubicin, cisplatin, and infusional 5-FU), ECX (epirubicin, cisplatin, and capecitabine), EOF (epirubicin, oxaliplatin, and infusional 5-FU) and EOX (epirubicin, oxaliplatin, and capecitabine). The authors concluded that the oxaliplatin combinations appeared to be safer than those with cisplatin and that oxaliplatin was not inferior to cisplatin, nor was capecitabine inferior to infusional 5-FU. Furthermore, EOX appeared to have improved efficacy compared to the reference regimen (ECF).

The National Comprehensive Cancer Network (NCCN) has encompassed a listing of potential combination regimens for metastatic or locally advanced cancer in the Clinical Practice Guidelines. The NCCN cites category 1 level of evidence in support of DCF and ECF, with category 2B evidence and consensus for irinotecan plus cisplatin, oxaliplatin plus a fluoropyrimidine, DCF modifications, irinotecan plus fluoropyrimidine, and paclitaxel-based regimens.

A recently completed ECOG/CALGB collaborative, randomized phase II trial (E1206/C80403) is of interest since it integrates the monoclonal antibody cetuximab as a component of three different platform regimens: ECF, irinotecan and cisplatin, and FOLFOX (5-FU, oxaliplatin, and leucovorin). A significant challenge for future trial design will continue to address optimal chemotherapy platforms and how to best choose among a host of different biologic agents to potentially improve median survival. Identifying tumor-specific molecular/genetic characteristics that will help inform the choice of biologic agents is a significant obstacle.

A trial that generated considerable interest during the American Society of Clinical Oncology (ASCO) 2009 meeting evaluated the addition of trastuzumab to standard first-line chemotherapy for patients with human epidermal growth factor receptor (HER2)-positive advanced gastric cancer (ToGA trial). The trial screened 3,807 patients to identify the 22.1% who were HER2-positive and were subsequently randomized to receive 5-FU or capecitabine plus cisplatin (n=290) vs. 5-FU or capecitabine plus cisplatin plus trastuzumab (n=294). The trial stratified patients on the basis of gastric vs. GE cancers, measurable vs. nonmeasurable disease, ECOG performance status, capecitabine vs. 5-FU, and advanced vs. metastatic disease. Assessment was by central evaluation and included immunohistochemistry (IHC) 3+ and/or FISH+. Patients who received trastuzumab had a significant improvement in overall survival, which was the primary study end point, as well as a significant improvement in progression-free survival. Toxicity was considered acceptable, including incidence of cardiac toxicity.

During ASCO 2009, there was also an update of the FLAGS study, a randomized phase III trial comparing cisplatin/S1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer. This follow-up analysis confirmed the initial findings, demonstrating that the CS regimen was not inferior to CF and appeared to be safer. An unplanned subset analysis was of interest, because it suggested a significant increase in the diffuse type of gastric cancer since 1973 and a significant decrease in the intestinal type of gastric cancer. Results of the unplanned analysis also suggested that the S1/cisplatin combination may be more effective in patients with the diffuse type of pathology, and this will require further investigation in prospective studies.

Finally, another trial updated during ASCO was the randomized phase III study of single-agent 5-FU vs. the combination of irinotecan and cisplatin vs. single-agent S1 in advanced gastric cancer (JCOG9912). The initial analysis demonstrated the superiority of irinotecan with cisplatin compared to continuous-infusion 5-FU and the non-inferiority of S1 compared to infusional 5-FU. This updated analysis showed that overall survival and hazard ratios were identical to those in the previous reports. In addition, multivariate analysis showed that the number of metastatic sites, performance status, and presence of target lesion were associated with shorter survival.

Purpose. To make recommendations for the use of doxorubicin-based chemotherapy in patients with soft-tissue sarcoma.

Patients. The recommendations apply to patients with symptomatic unresectable locally advanced or metastatic soft-tissue sarcoma who are candidates for palliative chemotherapy.

Methods. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice to develop an evidence-based practice guideline.

Results. Eight randomized trials comparing doxorubicin-based combination versus doxorubicin single-agent chemotherapy were reviewed. Response rates and overall survival were evaluated using pooled statistical analysis.The pooled response data in 2281 patients showed a slight trend favouring the combination therapy, although this did not reach statistical significance (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.60–1.05; p=0.10). Survival data could only be abstracted from six studies involving 2097 patients, and showed no significant advantage for combination therapy (OR, 0.84; 95% CI, 0.67–1.06; p=0.13). Data on adverse effects could not be combined in a meta-analysis; however nausea, vomiting and myelosuppression were consistently more severe with combination chemotherapy than with single-agent chemotherapy.

Discussion. Single-agent doxorubicin is an appropriate first-line chemotherapy option for advanced or metastatic soft-tissue sarcoma. Some doxorubicin-based combination chemotherapy regimens, given in conventional doses, produce only marginal increases in response rates, at the expense of increased adverse effects, and with no improvements in overall survival. Future randomized clinical trials should compare new regimens, whose activity has been established in single-arm studies, with single-agent doxorubicin, and include quality of life as an outcome measure.

For advanced non-small cell lung cancer (NSCLC) patients, the only treatment option is palliative therapy, with the aim of prolonging overall survival and improving disease-related symptoms and quality of life (QOL). However, to date, the effect of palliative care on QOL has not yet been thoroughly examined, and there has been no meta-analysis of previous studies reporting QOL outcomes following palliative care. We consider that it is important to evaluate not only survival and/or response rates, but also QOL in patients with advanced NSCLC receiving palliative chemotherapy. The aim of the present study was to obtain useful information for the selection of suitable chemotherapy regimens for advanced NSCLC patients, taking into consideration QOL, and to demonstrate the importance of QOL assessments during treatment. We performed a meta-analysis of QOL outcomes following treatments that compared carboplatin- to cisplatin-based chemotherapy. Trials were eligible for analysis if they had compared carboplatin- to cisplatin-based chemotherapy in advanced NSCLC patients who had not received prior chemotherapy, and if these studies reported QOL data. In the six trials eligible for analysis, 2,405 patients were randomized to receive cisplatin-based or carboplatin-based chemotherapy. The patients who received carboplatin-based chemotherapy had higher global QOL and less severe symptoms than those who received cisplatin-based chemotherapy. The survival rate, which was the primary outcome in clinical trials, and the response rate did not differ significantly between the two treatment groups. It is important to evaluate QOL in addition to the survival and response rates for advanced NSCLC, particularly when the treatment is palliative.

Background

To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed.

Methods/Design

Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase.

Discussion

Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

Trial Registration

Trial Registry: Clinicaltrials.gov

Registration number: NCT00789373

Trial abbreviation: H3E-EW-S124

Background

Hypofractionated stereotactic body radiation therapy (SBRT) has been advanced as monotherapy for low-risk prostate cancer. We examined the dose distributions and early clinical outcomes using this modality for the treatment of intermediate-risk prostate cancer.

Methods

Forty-one sequential hormone-naïve intermediate-risk prostate cancer patients received 35–36.25 Gy of CyberKnife-delivered SBRT in 5 fractions. Radiation dose distributions were analyzed for coverage of potential microscopic ECE by measuring the distance from the prostatic capsule to the 33 Gy isodose line. PSA levels, toxicities, and quality of life (QOL) measures were assessed at baseline and follow-up.

Results

All patients completed treatment with a mean coverage by the 33 Gy isodose line extending >5 mm beyond the prostatic capsule in all directions except posteriorly. Clinical responses were documented by a mean PSA decrease from 7.67 ng/mL pretreatment to 0.64 ng/mL at the median follow-up of 21 months. Forty patients remain free from biochemical progression. No Grade 3 or 4 toxicities were observed. Mean EPIC urinary irritation/obstruction and bowel QOL scores exhibited a transient decline post-treatment with a subsequent return to baseline. No significant change in sexual QOL was observed.

Conclusions

In this intermediate-risk patient population, an adequate radiation dose was delivered to areas of expected microscopic ECE in the majority of patients. Although prospective studies are needed to confirm long-term tumor control and toxicity, the short-term PSA response, biochemical relapse-free survival rate, and QOL in this interim analysis are comparable to results reported for prostate brachytherapy or external beam radiotherapy.

Trial registration

The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009–510).

Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.

A systematic review and meta-analysis was performed to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV). The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of chemotherapy-induced nausea and vomiting.

Objectives.

We performed a systematic review and meta-analysis to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV).

Methods.

We identified randomized controlled clinical trials (RCT) comparing palonosetron with first-generation 5-HT3RA in the prevention of CINV in cancer patients. Meta-analyses were performed on homogeneous studies. Fixed or random-effects models were used to combine data.

Results.

Eight eligible trials were identified, reporting outcomes on 3,592 patients. Meta-analyses showed statistically significant differences in favor of palonosetron compared with first-generation 5-HT3RA in prevention of acute CINV (p = .0003), delayed CINV (p < .00001), and overall phase of CINV (p < .00001). Subgroup analyses showed statistically significant differences in favor of both 0.25 mg and 0.75 mg of palonosetron in prevention of all phases of CINV. There were no statistically significant differences between 0.25 and 0.75 mg of palonosetron. Compared with the first-generation 5-HT3RA, 0.75 mg of palonosetron showed a statistically significant difference in the occurrence of constipation (p = .04).

Interpretation.

The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of CINV. The 0.25 mg intravenous palonosetron dose is as effective as the 0.75 mg intravenous palonosetron dose. However, 0.75 mg intravenous palonosetron causes constipation more frequently than the first-generation 5-HT3RA.

Audit of treatment of duodenal ulcer disease has allowed management to improve and keep abreast of rapid advances in care. Eradication of Helicobacter pylori was assessed by 14C urea breath test one to two months after anti-Helicobacter therapy. The old triple therapy regime of bismuth, tetracycline and metronidazole for two weeks was found to be toxic and of low effectiveness (82%). Regimes with lansoprazole for one month and antibiotics for one week gave 90-98% success rates. The best success has been with regimes containing both clarithromycin and a nitro-imidazole. There was complete success in 98% of 109 patients given quadruple therapy with lansoprazole 30 mg daily for one month plus tetracycline 500 mg twice daily, clarithromycin 250 mg twice daily and metronidazole 400 mg twice daily for one week.

Prostate cancer is a common malignancy worldwide, and in Canada, it is the most frequently diagnosed cancer in men. The stratification of prostate cancer into risk categories has allowed for improved counselling of patients and provides guidance for treatment selection. However, the exact definition of high-risk prostate cancer remains controversial, and that lack of consensus remains a barrier to assessing available data from various institutions and from clinical trials. The proportion of patients with locally advanced high-risk disease has fallen in the last 20 years largely because of screening for prostate-specific antigen, but management in this population continues to be an important clinical problem. A factor that has emerged in recent years is the importance of local disease control, with data from multiple randomized trials suggesting that local therapy improves progression-free survival, disease-free survival, and overall survival. Further research in this population is necessary to improve outcomes.

Introduction

Poxviral vaccines have been given to over 1 billion people in the successful global eradication of smallpox. Since then, recombinant poxviruses have been investigated extensively as a novel immunotherapy for cancer, undergoing several iterations to optimize their immunogenicity and efficacy. The current platform expressing multiple costimulatory molecules plus a tumor-associated antigen such as PSA, i.e., PSA-TRICOM (PROSTVAC-V/F), is promising and is currently in a phase III randomized, placebo-controlled clinical trial in metastatic castration-resistant prostate cancer.

Areas covered

This review discusses the clinical development of poxviral-based cancer vaccines, with a particular focus on the rationale for combining vaccines with other treatment modalities, including radiotherapy, chemotherapy, hormonal therapy, other immune-based therapies, and molecularly targeted therapy. We also discuss the importance of appropriate patient selection in clinical trial design.

Expert Opinion

Preclinical and early clinical studies with poxviral vector vaccines have shown promising results with this novel immunologic approach both as vaccine alone and combined with other therapies. The challenges of translating the science of immunotherapy to clinical practice include clinical trial design that includes appropriate patient selection, appropriate endpoints, and identification of meaningful surrogate biomarkers.

The clinical development of cabazitaxel and abiraterone acetate in the treatment of castration-resistant prostate cancer is examined.

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment in patients with castration-resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)–prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone–prednisone. Several other novel agents are currently being evaluated, including sipuleucel-T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell-based immunotherapy sipuleucel-T produces longer OS times in chemotherapy-naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.

Macrophages are the most abundant immune cell within the ovary. Their dynamic distribution throughout the ovarian cycle and heterogenic array of functions suggest the involvement in various ovarian processes, but their functional role has yet to be fully established. The aim was to induce conditional macrophage ablation to elucidate the putative role of macrophages in maintaining the integrity of ovarian vasculature. Using the CD11b-diphtheria toxin receptor (DTR) mouse, in which expression of human DTR is under the control of the macrophage-specific promoter sequence CD11b, ovarian macrophages were specifically ablated in adult females by injections of diphtheria toxin (DT). CD11b-DTR mice were given DT treatment or vehicle and ovaries collected at 2, 8, 16, 24 and 48 h. Histochemical stains were employed to characterise morphological changes, immunohistochemistry for F4/80 to identify macrophages and the endothelial cell marker CD31 used to quantify vascular changes. In normal ovaries, macrophages were detected in corpora lutea and in the theca layer of healthy and atretic follicles. As macrophage ablation progressed, increasing amounts of ovarian haemorrhage were observed affecting both luteal and thecal tissue associated with significant endothelial cell depletion, increased erythrocyte accumulation and increased follicular atresia by 16 h. These events were followed by necrosis and profound structural damage. Changes were limited to the ovary, as DT treatment does not disrupt the vasculature of other tissues likely reflecting the unique cyclical nature of the ovarian vasculature and heterogeneity between macrophages within different tissues. These results show that macrophages play a critical role in maintaining ovarian vascular integrity.

Background

Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy.

Methods

Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned.

Discussion

We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials.

Trial registration

This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm).