Additive homeopathy in cancer patients: Retrospective survival data from a homeopathic outpatient unit at the Medical University of Vienna

Background: Current literature suggests a positive influence of additive classical homeopathyon global health and well-being in cancer patients. Besides encouraging case reports, thereis little if any research on long-term survival of patients who obtain homeopathic care duringcancer treatment. Design: Data from cancer patients who had undergone homeopathic treatment complementaryto conventional anti-cancer treatment at the Outpatient Unit for Homeopathy in MalignantDiseases, Medical University Vienna, Department of Medicine I, Vienna, Austria, were collected,described and a retrospective subgroup-analysis with regard to survival time was performed.Patient inclusion criteria were at least three homeopathic consultations, fatal prognosis ofdisease, quantitative and qualitative description of patient characteristics, and survival time. Results: In four years, a total of 538 patients were recorded to have visited the OutpatientUnit Homeopathy in Malignant Diseases, Medical University Vienna, Department of Medicine I, Vienna, Austria. 62.8% of them were women, and nearly 20% had breast cancer. From the 53.7%(n = 287) who had undergone at least three homeopathic consultations within four years, 18.7%(n = 54) fulfilled inclusion criteria for survival analysis. The surveyed neoplasms were glioblas-toma, lung, cholangiocellular and pancreatic carcinomas, metastasized sarcoma, and renal cellcarcinoma. Median overall survival was compared to expert expectations of survival outcomesby specific cancer type and was prolonged across observed cancer entities (p < 0.001). Conclusion: Extended survival time in this sample of cancer patients with fatal prognosis butadditive homeopathic treatment is interesting. However, findings are based on a small sample,and with only limited data available about patient and treatment characteristics. The relationshipbetween homeopathic treatment and survival time requires prospective investigation in largersamples possibly using matched-pair control analysis or randomized trials.

An investigation into the factors that encourage learner participation in a large group medical classroom

BACKGROUND: Effective lectures often incorporate activities that encourage learner participation. A challenge for educators is how to facilitate this in the large group lecture setting. This study investigates the individual student characteristics involved in encouraging (or dissuading) learners to interact, ask questions, and make comments in class. METHODS: Students enrolled in a Doctor of Veterinary Medicine program at Ross University School of Veterinary Medicine, St Kitts, were invited to complete a questionnaire canvassing their participation in the large group classroom. Data from the questionnaire were analyzed using Excel (Microsoft, Redmond, WA, USA) and the R software environment (http://www.r-project.org/). RESULTS: One hundred and ninety-two students completed the questionnaire (response rate, 85.7%). The results showed statistically significant differences between male and female students when asked to self-report their level of participation (P=0.011) and their confidence to participate (P<0.001) in class. No statistically significant difference was identified between different age groups of students (P=0.594). Student responses reflected that an "aversion to public speaking" acted as the main deterrent to participating during a lecture. Female participants were 3.56 times more likely to report a fear of public speaking than male participants (odds ratio 3.56, 95% confidence interval 1.28-12.33, P=0.01). Students also reported "smaller sizes of class and small group activities" and "other students participating" as factors that made it easier for them to participate during a lecture. CONCLUSION: In this study, sex likely played a role in learner participation in the large group veterinary classroom. Male students were more likely to participate in class and reported feeling more confident to participate than female students. Female students in this study commonly identified aversion to public speaking as a factor which held them back from participating in the large group lecture setting. These are important findings for veterinary and medical educators aiming to improve learner participation in the classroom. Potential ways of addressing this challenge include addition of small group activities and audience response systems during lectures, and inclusion of training interventions in public speaking at an early stage of veterinary and medical curricula.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Survival analysis of longevity in siblings

Do siblings of centenarians tend to have longer life spans? To answer this question, life spans of 184 siblings for 42 centenarians have been evaluated. Two important questions have been addressed in analyzing the sibling data. First, a standard needs to be established, to which the life spans of 184 siblings are compared. In this report, an external reference population is constructed from the U.S. life tables. Its estimated mortality rates are treated as baseline hazards from which the relative mortality of the siblings are estimated. Second, the standard survival models which assume independent observations are invalid when correlation within family exists, underestimating the true variance. Methods that allow correlations are illustrated by three different methods. First, the cumulative relative excess mortality between siblings and their comparison group is calculated and used as an effective graphic tool, along with the Product Limit estimator of the survival function. The variance estimator of the cumulative relative excess mortality is adjusted for the potential within family correlation using Taylor linearization approach. Second, approaches that adjust for the inflated variance are examined. They are adjusted one-sample log-rank test using design effect originally proposed by Rao and Scott in the correlated binomial or Poisson distribution setting and the robust variance estimator derived from the log-likelihood function of a multiplicative model. Nether of these two approaches provide correlation estimate within families, but the comparison with the comparison with the standard remains valid under dependence. Last, using the frailty model concept, the multiplicative model, where the baseline hazards are known, is extended by adding a random frailty term that is based on the positive stable or the gamma distribution. Comparisons between the two frailty distributions are performed by simulation. Based on the results from various approaches, it is concluded that the siblings of centenarians had significant lower mortality rates as compared to their cohorts. The frailty models also indicate significant correlations between the life spans of the siblings. ^

Modeling survival and the development of second primary tumors among Hodgkin's disease patients

Hodgkin's disease (HD) is a cancer of the lymphatic system. Survivors of HD face varieties of consequent adverse effects, in which secondary primary tumors (SPT) is one of the most serious consequences. This dissertation is aimed to model time-to-SPT in the presence of death and HD relapses during follow-up.^ The model is designed to handle a mixture phenomenon of SPT and the influence of death. Relapses of HD are adjusted as a covariate. Proportional hazards framework is used to define SPT intensity function, which includes an exponential term to estimate explanatory variables. Death as a competing risk is considered according to different scenarios, depending on which terminal event comes first. Newton-Raphson method is used to estimate the parameter estimates in the end.^ The proposed method is applied to a real data set containing a group of HD patients. Several risk factors for the development of SPT are identified and the findings are noteworthy in the development of healthcare guidelines that may lead to the early detection or prevention of SPT.^

Response to chemotherapy, recurrence and survival in advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish BRCA mutations, compared to those without

Objectives. Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish (AJ) BRCA founder mutations, compared to sporadic ovarian cancer patients. The purpose of this study was to determine if this association exists in ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations. In addition, we sought to account for possible "survival bias" by minimizing any lead time that may exist between diagnosis and genetic testing. ^ Methods. Patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer and a non-Ashkenazi Jewish BRCA1 or 2 mutation, seen for genetic testing January 1996-July 2007, were identified from genetics and institutional databases. Medical records were reviewed for clinical factors, including response to initial chemotherapy. Patients with sporadic (non-hereditary) ovarian, fallopian tube, or primary peritoneal cancer, without family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. When possible, 2 sporadic patients were matched to each BRCA patient. An additional group of unmatched, sporadic ovarian, fallopian tube and primary peritoneal cancer patients was included for a separate analysis. Progression-free (PFS) & overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Matched pairs were treated as clusters. Stratified log rank test was used to calculate survival data for matched pairs using paired event times. Fisher's exact test, chi-square, and univariate logistic regression were also used for analysis. ^ Results. Forty five advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations, 86 sporadic-matched and 414 sporadic-unmatched patients were analyzed. Compared to the sporadic-matched and sporadic-unmatched ovarian cancer patients, non-AJ BRCA mutation carriers had longer PFS (17.9 & 13.8 mos. vs. 32.0 mos., HR 1.76 [95% CI 1.13–2.75] & 2.61 [95% CI 1.70–4.00]). In relation to the sporadic- unmatched patients, non-AJ BRCA patients had greater odds of complete response to initial chemotherapy (OR 2.25 [95% CI 1.17–5.41]) and improved OS (37.6 mos. vs. 101.4 mos., HR 2.64 [95% CI 1.49–4.67]). ^ Conclusions. This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. Our efforts to account for "survival bias," by matching, will continue with collaborative studies. ^

Analysis of prognostic factors for the development of metastases and survival in renal cell carcinoma patients

Introduction and objective. A number of prognostic factors have been reported for predicting survival in patients with renal cell carcinoma. Yet few studies have analyzed the effects of those factors at different stages of the disease process. In this study, different stages of disease progression starting from nephrectomy to metastasis, from metastasis to death, and from evaluation to death were evaluated. ^ Methods. In this retrospective follow-up study, records of 97 deceased renal cell carcinoma (RCC) patients were reviewed between September 2006 to October 2006. Patients with TNM Stage IV disease before nephrectomy or with cancer diagnoses other than RCC were excluded leaving 64 records for analysis. Patient TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were analyzed in relation to time to metastases. Time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from metastases to death. Finally, analysis of laboratory values at time of evaluation, Eastern Cooperative Oncology Group performance status (ECOG), UCLA Integrated Staging System (UISS), time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from evaluation to death. Linear regression and Cox Proportional Hazard (univariate and multivariate) was used for testing significance. Kaplan-Meier Log-Rank test was used to detect any significance between groups at various endpoints. ^ Results. Compared to negative lymph nodes at time of nephrectomy, a single positive lymph node had significantly shorter time to metastasis (p<0.0001). Compared to other histological types, clear cell histology had significant metastasis free survival (p=0.003). Clear cell histology compared to other types (p=0.0002 univariate, p=0.038 multivariate) and time to metastasis with log conversion (p=0.028) significantly affected time from metastasis to death. A greater than one year and greater than two year metastasis free interval, compared to patients that had metastasis before one and two years, had statistically significant survival benefit (p=0.004 and p=0.0318). Time from evaluation to death was affected by greater than one year metastasis free interval (p=0.0459), alcohol consumption (p=0.044), LDH (p=0.006), ECOG performance status (p<0.001), and hemoglobin level (p=0.0092). The UISS risk stratified the patient population in a statistically significant manner for survival (p=0.001). No other factors were found to be significant. ^ Conclusion. Clear cell histology is predictive for both time to metastasis and metastasis to death. Nodal status at time of nephrectomy may predict risk of metastasis. The time interval to metastasis significantly predicts time from metastasis to death and time from evaluation to death. ECOG performance status, and hemoglobin levels predicts survival outcome at evaluation. Finally, UISS appropriately stratifies risk in our population. ^

Early stage breast cancer and comorbidities: Their impact on breast cancer disease-free survival differences by ethnicity

The retrospective cohort study examined the association between the presence of comorbidities and breast cancer disease-free survival rates among racial/ethnic groups. The study population consisted of 2389 women with stage I and II invasive breast cancer who were diagnosed and treated at the M.D. Anderson Cancer Center between 1985 and 2000. It has been suggested that as the number of comorbidities increases, breast cancer mortality increases. It is known that African Americans and Hispanics are considered to be at a higher risk for comorbid conditions such as hypertension and diabetes compared to Caucasian women (23) (10). When compared to Caucasian women, African American women also have a higher breast cancer mortality rate (1). As a result, the study also examined whether comorbid conditions contribute to racial differences in breast cancer disease-free survival. Among the study population, 24% suffered from breast cancer recurrence, 6% died from breast cancer and 24% died from all causes. The mean age was 56 with 41% of the population being women between the ages of 40-55. One or more comorbidities were reported in 84 (36%) African Americans (OR 1.57; 95% CI 1.19-2.10), 58 (31%) Hispanics (OR 1.25; 95% CI 0.90-1.74) compared to the reference group of 531 (27%) Caucasians. Additionally, African American women were significantly more likely to suffer from either a breast cancer recurrence or breast cancer death (OR 1.5; 95% CI 0.70-1.41) when compared to Caucasian women. Multivariate analysis found hypertension (HR 1.22; 95% CI 0.99-1.49; p<0.05) to be statistically significant and a potential prognostic tool for disease-free survival with African American women (OR 2.96; 95% 2.25-3.90) more likely to suffer from hypertension when compared to Caucasian women. When compared to Caucasian women, Hispanics were also more likely to suffer from hypertension (OR 1.33; 95% CI 0.96-1.83). This suggests that comorbid conditions like hypertension could account for the racial disparities that exist when comparing breast cancer survival rates. Future studies should investigate this relationship further.^

Comparison of medical care costs, utilization, and satisfaction of AIDS patients with and without home care

A sample of 157 AIDS patients 17 years of age or over were followed for six months from the date of hospital discharge to derive average total cost of medical care, utilization and satisfaction with care. Those referred for home care follow-up after discharge from the hospital were compared with those who did not receive home care.^ The average total cost of medical care for all patients was $34,984. Home care patient costs averaged \$29,614 while patients with no home care averaged $37,091. Private hospital patients had average costs of \$50,650 compared with $25,494 for public hospital patients. Hospital days for the six months period averaged 23.9 per patient for the no home care group and 18.5 days for home care group. Patient satisfaction with care was higher in the home care group than no home care group, with a mean score of 68.2 compared with 61.1.^ Other health services information indicated that 98% of the private hospital patients had insurance while only 2% of public hospital patients had coverage. The time between the initial date of diagnosis with AIDS and admission to the study was longer for private hospital patients, survival time over the study period was shorter, and the number of hospitalizations prior to entering the study was higher for private hospital patients. These results suggest that patients treated in the private hospital were sicker than public hospital patients, which may explain their higher average total cost. Statistical analyses showed that cost and utilization have no significant relationship with home care or no home care when controlling for indicators of the severity of illness and treatment in public or private hospital.^ In future studies, selecting a matched group of patients from the same hospital and following them for nine months to one year would be helpful in making a more realistic comparison of the cost effectiveness of home care. ^

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of survival and clinical response in women with ovarian cancer

Background. The mTOR pathway is commonly altered in human tumors and promotes cell survival and proliferation. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first line therapy for epithelial ovarian cancer. A pathway-based approach was used to identify individual germline single nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer. ^ Methods. The case-series was restricted to 319 non-Hispanic white women with high grade ovarian cancer treated with surgery and platinum-based chemotherapy. 135 SNPs in 20 representative genes in the mTOR pathway were genotyped. Hazard ratios (HRs) for death and Odds ratios (ORs) for failure to respond to primary therapy were estimated for each SNP using the multivariate Cox proportional hazards model and multivariate logistic regression model, respectively, while adjusting for age, stage, histology and treatment sequence. A survival tree analysis of SNPs with a statistically significant association (p<0.05) was performed to identify higher order gene-gene interactions and their association with overall survival. ^ Results. There was no statistically significant difference in survival by tumor histology or treatment regimen. The median survival for the cohort was 48.3 months. Seven SNPs were significantly associated with decreased survival. Compared to those with no unfavorable genotypes, the HR for death increased significantly with the increasing number of unfavorable genotypes and women in the highest risk category had HR of 4.06 (95% CI 2.29–7.21). The survival tree analysis also identified patients with different survival patterns based on their genetic profiles. 13 SNPs on five different genes were found to be significantly associated with a treatment response, defined as no evidence of disease after completion of primary therapy. Rare homozygous genotype of SNP rs6973428 showed a 5.5-fold increased risk compared to the wild type carrying genotypes. In the cumulative effect analysis, the highest risk group (individuals with ≥8 unfavorable genotypes) was significantly less likely to respond to chemotherapy (OR=8.40, 95% CI 3.10–22.75) compared to the low risk group (≤4 unfavorable genotypes). ^ Conclusions. A pathway-based approach can demonstrate cumulative effects of multiple genetic variants on clinical response to chemotherapy and survival. Therapy targeting the mTOR pathway may modify outcome in select patients.^

Geographic variation in the utilization and survival associated with oxaliplatin chemotherapy in patients with stage III colon cancer

Background: Overall objectives of this dissertation are to examine the geographic variation and socio-demographic disparities (by age, race and gender) in the utilization and survival of newly FDA-approved chemotherapy agents (Oxaliplatin-containing regimens) as well as to determine the cost-effectiveness of Oxaliplatin in a large nationwide and population-based cohort of Medicare patients with resected stage-III colon cancer. Methods: A retrospective cohort of 7,654 Medicare patients was identified from the Surveillance, Epidemiology and End Results – Medicare linked database. Multiple logistic regression was performed to examine the relationship between receipt of Oxaliplatin-containing chemotherapy and geographic regions while adjusting for other patient characteristics. Cox proportional hazard model was used to estimate the effect of Oxaliplatin-containing chemotherapy on the survival variation across regions using 2004-2005 data. Propensity score adjustments were also made to control for potential bias related to non-random allocation of the treatment group. We used Kaplan-Meier sample average estimator to calculate the cost of disease after cancer-specific surgery to death, loss-to follow-up or censorship. Results: Only 51% of the stage-III patients received adjuvant chemotherapy within three to six months of colon-cancer specific surgery. Patients in the rural regions were approximately 30% less likely to receive Oxaliplatin chemotherapy than those residing in a big metro region (OR=0.69, p=0.033). The hazard ratio for patients residing in metro region was comparable to those residing in big metro region (HR: 1.05, 95% CI: 0.49-2.28). Patients who received Oxalipaltin chemotherapy were 33% less likely to die than those received 5-FU only chemotherapy (adjusted HR=0.67, 95% CI: 0.41-1.11). KMSA-adjusted mean payments were almost 2.5 times higher in the Oxaliplatin-containing group compared to 5-FU only group ($45,378 versus $17,856). When compared to no chemotherapy group, ICER of 5-FU based regimen was $12,767 per LYG, and ICER of Oxaliplatin-chemotherapy was $60,863 per LYG. Oxaliplatin was found economically dominated by 5-FU only chemotherapy in this study population. Conclusion: Chemotherapy use varies across geographic regions. We also observed considerable survival differences across geographic regions; the difference remained even after adjusting for socio-demographic characteristics. The cost-effectiveness of Oxaliplatin in Medicare patients may be over-estimated in the clinical trials. Our study found 5-FU only chemotherapy cost-effective in adjuvant settings in patients with stage-III colon cancer.^

Impact of racial differences in medical care on breast cancer survival: Findings from a large nationwide and retrospective cohort study

Background: No studies have attempted to determine whether nodal surgery utilization, time to initiation and completion of chemotherapy or surveillance mammography impact breast cancer survival. ^ Objectives and Methods: To determine whether receipt of nodal surgery, initiation and completion of chemotherapy, and surveillance mammography impact of racial disparities in survival among breast cancer patients in SEER areas, 1992-2005. ^ Results: Adjusting for nodal surgery did not reduce racial disparities in survival. Patients who initiated chemotherapy more than three months after surgery were 1.8 times more likely to die of breast cancer (95% CI 1.3-2.5) compared to those who initiated chemotherapy less than a month after surgery, even after controlling for known confounders or controlling for race. Despite correcting for chemotherapy initiation and completion and known predictors of outcome, African American women still had worse disease specific survival than their Caucasian counterparts. We found that non-whites underwent surveillance mammography less frequently compared with whites and mammography use during a one- or two-year time interval was associated with a small reduced risk of breast-cancer-specific and all-cause mortality. Women who received a mammogram during a two-year interval could expect the same disease-specific survival benefit or overall survival benefit as women who received a mammogram during a one-year interval. We found that while adjustment for surveillance mammography receipt and physician visits reduced differences in mortality between blacks and whites, these survival disparities were eliminated after adjusting for the number of surveillance mammograms received. ^ Conclusions: The disparities in survival among African American and Hispanic women with breast cancer are not explained by nodal surgery utilization or chemotherapy initiation and chemotherapy completion. Surveillance mammograms, physician visits and number of mammograms received may play a major role in achieving equal outcomes for breast cancer-specific mortality for women diagnosed with primary breast cancer. Racial disparities in all-cause mortality were explained by racial differences in surveillance mammograms to certain degree, but were no longer significant after controlling for differences in comorbidity. Focusing on access to quality care and post treatment surveillance might help achieve national goals to eliminate racial disparities in healthcare and outcomes. ^