ESMO Expert Consensus Statements on Cancer Survivorship: promoting high-quality survivorship care and research in Europe.

BACKGROUND: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship. DESIGN AND METHODS: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research. RESULTS: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care. CONCLUSIONS: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking.

Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials.

BACKGROUND: Collection and reporting of adverse events (AEs) and their relatedness to study treatment, known commonly as attribution, in clinical trials is mandated by regulatory agencies (the National Cancer Institute and the Food and Drug Administration). Attribution is assigned by the treating physician using judgment based on various factors including patient's baseline status, disease history, and comorbidity as well as knowledge about the safety profile of the study treatments. We evaluate the patterns of AE attribution (unrelated, unlikely, possibly, probably, and definitely related to the treatment) in treatment, symptom intervention (cancer patients) and cancer prevention (participants at high risk for cancer) setting. MATERIALS AND METHODS: Nine multicenter placebo-controlled trials (two treatment, two symptom intervention, and five cancer prevention) were analysed separately (2155 patients). Frequency and severity of AEs were summarized by arm. Attribution and percentage of repeated AEs whose attribution changed overtime were summarized for the placebo arms. Percentage of physician over- or under-reporting of AE relatedness was calculated for the treatment arms using the placebo arm as the reference. RESULTS: Across all trials and settings, a very high proportion of AEs reported as related to treatment were classified as possibly related, a significant proportion of AEs in the placebo arm were incorrectly reported as related to treatment, and clinician-reported attribution over-estimated the rate of AEs related to treatment. Fatigue, nausea, vomiting, diarrhea, constipation, and neurosensory were the common AEs that were over reported by clinician as related to treatment. CONCLUSIONS: These analyses demonstrate that assigning causality to AE is a complex and difficult process that produces unreliable and subjective data. In randomized double-blind placebo-controlled trials where data are available to objectively assess relatedness of AE to treatment, attribution assignment should be eliminated.

A double-blind, placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial.

BACKGROUND: Multiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month. RESULTS: Within this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70). CONCLUSION: Creatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.

Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score ≥4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory-Short Form and the EORTC QLQ-C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (≥30% reduction in pain; OR 4.036; 95% CI 0.999-16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin-induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411.

Survival following early-stage colon cancer: an ACCENT-based comparison of patients versus a matched international general population†.

BACKGROUND: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. PATIENTS AND METHODS: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5-fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. RESULTS: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3-year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. CONCLUSIONS: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies.

Endpoint comparison for bone mineral density measurements in North Central Cancer Treatment Group cancer clinical trials N02C1 and N03CC (Alliance).

UNLABELLED: Bone mineral density (BMD) measurement can vary depending upon anatomical site, machine, and normative values used. This analysis compared different BMD endpoints in two clinical trials. Trial results differed across endpoints. Future clinical trials should consider inclusion of multiple endpoints in sensitivity analysis to ensure sound overall study conclusions. INTRODUCTION: Methodological issues hamper efficacy assessment of osteoporosis prevention agents in cancer survivors. Osteoporosis diagnosis can vary depending upon which bone mineral density (BMD) anatomical site and machine is used and which set of normative values are applied. This analysis compared different endpoints for osteoporosis treatment efficacy assessment in two clinical studies. METHODS: Data from North Central Cancer Treatment Group phase III clinical trials N02C1 and N03CC (Alliance) were employed involving 774 patients each comparing two treatments for osteoporosis prevention. Endpoints for three anatomical sites included raw BMD score (RawBMD); raw machine-based, sample-standardized, and reference population-standardized T scores (RawT, TSamp, TRef); and standard normal percentile corresponding to the reference population-standardized T score (TPerc). For each, treatment arm comparison was carried out using three statistical tests using change and percentage change from baseline (CB, %CB) at 1 year. RESULTS: Baseline correlations among endpoints ranged from 0.79 to 1.00. RawBMD and TPerc produced more statistically significant results (14 and 19 each out of 36 tests) compared to RawT (11/36), TSamp (8/36), and TRef (7/36). Spine produced the most statistically significant results (26/60) relative to femoral neck (20/60) and total hip (13/60). Lastly, CB resulted in 44 statistically significant results out of 90 tests, whereas %CB resulted in only 15 significant results. CONCLUSIONS: Treatment comparisons and interpretations were different across endpoints and anatomical sites. Transforming via sample statistics provided similar results as transforming via reference or machine-based norms. However, RawBMD and TPerc may be more sensitive to change as clinical trial endpoints.

Palliative communications: addressing chemotherapy in patients with advanced cancer.

Patients with advanced cancers often endure chemotherapy late in their disease course leading to unnecessary adverse effects, loss of quality of life, and delay in hospice referral. Compassionate and honest communication about the use of chemotherapy can facilitate better patient care. This manuscript will explore communication issues regarding palliative-intent chemotherapy.

A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB).

INTRODUCTION: Hot flashes represent a significant problem in men undergoing androgen deprivation therapy. MATERIALS AND METHODS: Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication. RESULTS: In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial. CONCLUSION: These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

In vitro induction of human skin ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.

Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.

Phase I and clinical pharmacological evaluation of pirozantrone hydrochloride (oxantrazole).

Pirozantrone hydrochloride, an anthrapyrazole analogue, was selected for clinical evaluation based on broad antitumor activity against murine tumor systems and on potentially less cardiotoxicity when compared to anthracyclines. This anthrapyrazole analogue is currently under clinical evaluation, and we now report results on a Phase I clinical trial incorporating a pharmacologically guided dose-escalation scheme. Dose escalation was designed to proceed by factors of 2 until the patient drug exposure (concentration x time) was 40% of the murine exposure at the LD10 dose (90 mg/m2). Thereafter, more moderate dose escalations were employed. The target concentration x time value (59 micrograms-min/ml) derived from preclinical pharmacology data was exceeded in all three patients at a dose of 90 mg/m2. A dose of 160 mg/m2 was found to reproducibly result in appropriate myelosuppression. This dose is recommended for further testing in Phase II studies. Nonhematological toxicities encountered in this trial were mild, the most notable being phlebitis at the infusion site. Objective responses were observed in two patients, one with metastatic breast cancer and another with metastatic melanoma. Following a 60-min infusion, pirozantrone hydrochloride plasma elimination was monoexponential, with a half-life of approximately 30 min, mean total body clearance of 1.29 liters/min/m2, and mean steady state volume of distribution of 29 liters/m2.

Understanding the utility of adjuvant systemic therapy for primary breast cancer.

PURPOSE: Physicians and patients require quantitative information on the expected benefits of adjuvant therapy for primary breast cancer to make appropriate treatment decisions. To date, there has not been any widely available method for estimating the benefits from adjuvant systemic therapy, in terms of long-term disease-free survival probabilities, in patients with primary breast cancer. METHODS: Baseline prognostic information for primary breast cancer patients was estimated by asking 11 breast cancer specialists to complete a questionnaire on baseline prognosis and then using mean values. Data on the relative benefits of adjuvant therapy were culled from systematic reviews and randomized controlled trials. A computer algorithm was developed to calculate 10-year absolute outcome data. Results from this evaluation were compared with a previously described actuarial algorithm. RESULTS: Individual prognostic estimates varied within a group of breast cancer specialists, but mean values of their estimates closely followed published data. Translation of expected benefits of adjuvant therapy from relative to absolute terms was performed with a simple computer algorithm. The data were translated into tabular forms to facilitate user-friendly clinical use. CONCLUSION: The provided data should facilitate a better understanding of the absolute magnitude of benefit for available systemic adjuvant therapies in individual women with primary breast cancer. This should allow patients to make more informed decisions about their options.

Postchemotherapy rheumatism.

PURPOSE: This report describes a previously unreported clinical phenomenon that occurs in some patients after completion of combination chemotherapy. METHODS AND RESULTS: Eight case reports are presented. Affected patients developed a syndrome of myalgias/arthralgias within several months of completing cyclophosphamide/fluorouracil (5FU)-containing adjuvant combination chemotherapy for breast cancer. These symptoms did not appear to be related to cancer recurrence or any common rheumatologic disorder. The syndrome generally resolved over several months. CONCLUSION: Postchemotherapy rheumatism is a syndrome of myalgias/arthralgias that usually develops 1 to 3 months after completion of adjuvant chemotherapy. Recognition of this syndrome can limit the need for extensive work-ups to exclude recurrent breast cancer or inflammatory rheumatologic diseases.

Do American oncologists know how to use prognostic variables for patients with newly diagnosed primary breast cancer?

PURPOSE: This project was designed to investigate how American medical oncologists actually use prognostic information to treat primary breast cancer patients, and to study their difficulties in combining complex and sometimes contradictory information. METHODS: A simple 2-page questionnaire was faxed in May and June 1993 to a sample of American medical oncologists who were members of the American Society of Clinical Oncology (ASCO). RESULTS: When presented with simple case histories of patients with newly diagnosed invasive breast cancer and asked to assess prognosis on the basis of tumor size, number of involved axillary nodes, patient age, estrogen receptor level, and progesterone receptor level, there was a wide divergence of opinions about the probability of disease-free survival at 10 years (both for cases in which the patient received no adjuvant therapy and for those in which the patient did receive such therapy). The use of additional prognostic data (such as S-phase, tumor histologic and nuclear grading, and cathepsin D status) did not refine the estimates, but led to an equal or greater dispersion of estimates of prognosis. CONCLUSION: There is a clear need for tools to help oncologists integrate prognostic information for primary breast cancer patients. Such tools might lead to greater accuracy and uniformity of prognostic estimates. Such tools might also help make clear what prognostic tests are worth using for routine clinical practice.

Inhibition of phorbol ester--induced human epidermal ornithine decarboxylase activity by oral compounds: a possible role in human chemoprevention studies.

Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.

Sex differences in fluorouracil-induced stomatitis.

PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)-based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis. PATIENTS AND METHODS: Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation. RESULTS: Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P =.002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P =. 0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P <.00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade >/= 1, (70% v 59%, respectively; P <.00001) and grade 3+ (18% v 11%, respectively; P =.004). CONCLUSION: More women than men reported 5-FU-induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.