Outcomes of a cancer clinical trial matching service.

The American Cancer Society (ACS) and Coalition of Cancer Cooperative Groups (CCCG) provide a clinical trial (CT) information/matching/eligibility service (Clinical Trials Matching Service [CTMS]). Patients' demographic and clinical data, enrollment status, and self-reported barriers to CT participation were analyzed to assess enrollment rates and determinants of enrollment. During 3 years beginning October 1, 2007, the CTMS served 6,903 patients via the ACS call center. Among the 1,987 patients with follow-up information on enrollment, 219 (11.0%) enrolled in a CT; 48 of these 219 enrollees chose a CT they found via the CTMS. Patients were less likely to enroll if they had poor ECOG performance status (P = 0.032); were African American (P = 0.0003), were uninsured or had Medicaid coverage (P = 0.024), or had lower stage disease (P = 0.018). Enrollment varied by trial type/cancer site/system (P = .026). Several barriers significantly predicted nonenrollment. Broader availability of a CTMS might help improve patient participation in cancer clinical trials.

Statistical modeling of lung cancer: answering relative questions.

THE OBJECTIVE OF THIS PAPER IS TO PERFORM PARAMETRIC AND NONPARAMETRIC ANALYSIS TO ADDRESS SOME VERY IMPORTANT QUESTIONS CONCERNING LUNG CANCER UTILIZING REAL LUNG CANCER DATA: What is the probabilistic nature of mortality time in ex-smoker lung cancer patients and non-smoker lung cancer patients, for female, male, and the totality of female and male patients? Is there significant difference of mortality time between ex-smoker and non-smoker patients? For ex-smokers, are there any differences with respect to the key variables such as mortality time, cigarettes per day (CPD), and duration of smoking between female and male patients? For non-smokers, can we notice a difference in mortality time between female and male patients? Can we accurately predict mortality time given information on CPD, starting time and quitting time for a specific lung cancer patient who smokes? Thus best fitting probability distributions are identified and their parameters are estimated. Mean mortality times are compared between non-smokers and ex-smokers, female non-smokers and male non-smokers, and female ex-smokers and male ex-smokers. Important entities related to lung cancer mortality time, such as cigarettes per day (CPD), and duration of smoking (DUR), are compared between female and male ex-smoker lung cancer patients. Finally, a model is developed to predict the mortality time of ex-smokers with a high degree of accuracy.

Theory-based evaluation of an online cancer fatigue class.

Fatigue is a common problem faced by cancer patients and survivors, yet is often overlooked. An online fatigue class is evaluated using measures based on the Health Belief Model (HBM). A sample of 26 survivors and seven caregivers completed pre-class and post-class surveys and a facilitated discussion. Statistically significant improvements were detected in both the fatigue knowledge (p < 0.001) and belief (p < 0.001) scores. Participants reported that the content was accessible and useful. The class had a positive impact on their knowledge and beliefs about cancer fatigue. This suggests that HBM may be an appropriate framework for the evaluation of Internet-based educational interventions.

Use of a liquid nicotine delivery product to promote smoking cessation.

BACKGROUND: Despite access to various pharmacotherapies and counseling support to aid cessation, smokers typically demonstrate quit rates below 50%. This report describes the results of a Phase 2a study exploring the efficacy of a liquid nicotine delivery system as an aid to smoking cessation assessed after 12 weeks of therapy. METHODS: A single-arm Phase 2a study was conducted. Community-based smokers (ages 18+ years, smoking at least 10 cigarettes daily for the past year and interested in making a quit attempt) were recruited and completed clinic visits at 2 week intervals over the 12 week study period where carbon monoxide levels were assessed and the Smoke-Break product was rated on taste and overall satisfaction. Participants were provided with a supply of liquid nicotine cigarettes (e.g., Smoke-Break) at each clinic visit. A total of 69 smokers were enrolled and received the intervention product (intention to treat group, ITT) and 52 smokers verified participation (according to protocol group, ATP). RESULTS: The cessation rate at 12 weeks after the baseline visit, assessed as the bioverified point prevalence of abstinence, was 71.1% (95% confidence interval [CI] 58.8%-83.5%) in the ATP group and 53.6% (41.8%-65.4%) in the ITT group. Participants rated the liquid nicotine delivery system highly and also expressed general satisfaction. Few adverse events were identified with no serious adverse events. CONCLUSIONS: These results support the efficacy of the liquid nicotine delivery system in smoking cessation. If this nicotine delivery product proves to be effective in larger trials, it could represent an inexpensive, readily accessible and well-tolerated agent to promote smoking cessation.

Evolving information priorities of hematologic cancer survivors, caregivers, and other relatives.

Little is known about information priorities of people touched by hematologic cancers. We interviewed and surveyed 29 survivors/patients, 13 caregivers, and 19 non-caregiver relatives. Qualitative interviews indicated limited information describing topics other than specific cancer subtypes and treatment options. The survey exercise revealed the following priorities: at diagnosis, cancer types and treatment options; during initial treatment, treatment options and coping with side effects; after treatment, follow-up tests and long-term side effects; at remission/during maintenance treatment at relapse, treatment options and follow-up tests; for patients, cancer types and treatment options; for caregivers, future outlook and support; for non-caregivers, finances. Information priorities vary by role and over time.

On group sequential designs comparing two binomial proportions.

Discussed is the problem of sample size determination for one- and two-stage hypothesis tests comparing two binomial proportions using two independent random samples. A FORTRAN compiled search algorithm identifies exact group sequential designs that allow early stopping only for futility or only for efficacy or for either futility or efficacy. The resulting designs yield a substantial savings in terms of total sample size in many practical cases, are seen to satisfy a number of desirable properties, and are compared to other exact one- and two-stage designs and to designs derived based upon asymptotic normal theory methods.

Exact tests using two correlated binomial variables in contemporary cancer clinical trials.

New therapy strategies for the treatment of cancer are rapidly emerging because of recent technology advances in genetics and molecular biology. Although newer targeted therapies can improve survival without measurable changes in tumor size, clinical trial conduct has remained nearly unchanged. When potentially efficacious therapies are tested, current clinical trial design and analysis methods may not be suitable for detecting therapeutic effects. We propose an exact method with respect to testing cytostatic cancer treatment using correlated bivariate binomial random variables to simultaneously assess two primary outcomes. The method is easy to implement. It does not increase the sample size over that of the univariate exact test and in most cases reduces the sample size required. Sample size calculations are provided for selected designs.

Photopheresis in HIV-1 infected patients utilizing benzoporphyrin derivative (BPD) verteporfin and light.

An ex vivo trial utilizing photopheresis with Benzoporphyrin Derivative as the photoactive compound, identified the minimum energy levels of light and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes remained viable with altered chemokine/cytokine expression. Apoptosis was induced in a minority of CD4 but not CD8 positive cells with a statistically significant increase in cytolytic T-cell activity. In the 24 week clinical trial in 7 HIV-1 infected patients, three who had rapidly rising viral loads prior to initiating therapy stabilized. Two had a sustained greater than 0.5 log decrement and 5 had stable plasma viral loads (less than a 0.5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One achieved a greater than 1 log decrement in HIV-1 plasma viral load and undetectable in vivo cell-free and cell-associated HIV-1 infectivity with an increased in vitro lymphocyte mitogen stimulation index. Under amended protocol, 5 additional 12 month courses were administered to three additional patients and two of the previous enrollees. Area under the curve for viral load showed a significant decrease from pre- to post-therapy (p 0.007). No associated toxicities were observed.

Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children's Oncology Group phase II study.

BACKGROUND: The prognosis for children with brain stem glioma remains grim. Based on studies suggesting efficacy of vincristine and oral VP-16, The Pediatric Oncology Group (POG, now part of the Children's Oncology Group) conducted a study using these agents in combination with standard external beam radiation for children with newly diagnosed brain stem glioma. METHODS: Children were eligible for the study if they 3-21 years of age, had MRI-evidence of a diffuse intrinsic pontine glioma, and had neurologic deficits of <6 months duration. Patients received local radiotherapy to a dosage of 54 Gy. Chemotherapy consisted of two 28-day cycles of vincristine, 1.5 mg/m(2), days 1, 8, and 15 and oral VP-16, 50 mg/m(2), days 1-21, starting concurrent with radiation, and continuing for ten cycles following radiation. RESULTS: Of the 31 children enrolled, 30 were eligible and evaluable for survival and toxicity. Their median age was 8 years (range 3-14 years). Seven patients (23%) had a partial response following radiation, 18 (60%) had stable disease, 2 (7%) had progressive disease, and response in 3 patients (10%) was not measured. All 30 children have died. Overall survival at 1 year was 27 +/- 7% and at 2 years, 3 +/- 2%. The median survival was 9 months (range 3-36 months). Hematologic toxicity was significant; other toxicities included constipation, mucositis, emesis, and infection. CONCLUSION: The addition of vincristine and oral VP-16 to standard external beam radiation causes moderate toxicity and does not improve survival of children with diffuse intrinsic brain stem glioma.

An evaluation of the American Cancer Society research scholar program.

BACKGROUND: The American Cancer Society (ACS) allocated competitive funding for Research Project Grants (RPG) to investigators and health care professionals early in their careers. This study explored the process of applying for an ACS grant and determined the differences, if any, in applicants that were funded and applicants that were not funded. METHODS: Applicants applying for RPG funding in the spring of 1996 were sent a questionnaire. RESULTS: Most variables between funded and unfunded applicants did not show significant differences. The perception of the application process varied significantly between groups. CONCLUSIONS: The application process of RPG was highly valued among funded applicants.

A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study.

AIM: To determine the clinical benefit response (CBR), time to tumor progression (TTP), overall survival, and effect on quality of life (QOL) of gemcitabine and capecitabine in patients with advanced biliary cancer. METHODS: Gemcitabine (1000 mg/m2 i.v. over 30 minutes on days 1 and 8) and capecitabine (650 mg/m2 orally twice daily for 14 days) were administered and repeated every 21 days. All patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Pancreatic Cancer Module (EORTC QLQ-C30-PAN 26) questionnaire on day 1 of each cycle. Cumulative QOL scores were calculated. The two-stage design required 17 patients to evaluate the confirmed response at nine weeks. RESULTS: Twelve patients with a median age of 54 years were enrolled. A median of eight cycles per patient were completed. With a median follow-up of 18.2 months, the CBR (two partial response and five stable disease) was 58% [95% confidence interval (CI) 28-85%]. Four out of seven patients with CBR had no decline in QOL with chemotherapy. The probability of survival at one year was 0.58. Median TTP and overall survival were 9.0 and 14.0 months, respectively. Nine patients had grade 3 or 4 toxicities. There were no treatment-related deaths. CONCLUSIONS: Gemcitabine and capecitabine at this dose and schedule are well tolerated and effective and may offer clinical benefit and maintain QOL in patients with advanced biliary cancer. This regimen merits further investigation in the neoadjuvant setting.

The rationale, design, and implementation of the American Cancer Society's studies of cancer survivors.

The American Cancer Society (ACS) defines cancer survivorship as beginning at diagnosis with cancer and continuing for the balance of life and views quality of life (QOL) as a key outcome. In this article, the authors describe the rationale, methodology, and sample characteristics of the 2 ACS Studies of Cancer Survivors (SCS): 1) a longitudinal study identifying and surveying survivors approximately 1 year postdiagnosis that includes plans to resurvey the panel at 2 years, 7 years, and 12 years postdiagnosis to identify predictors of QOL; and 2) a cross-sectional study of QOL among 3 separate cohorts of survivors who were approximately 3 years, 6 years, and 11 years postdiagnosis at the time of data collection. Survivors of prostate, breast, lung, colorectal, bladder, skin, kidney, ovarian, and uterine cancers and of non-Hodgkin lymphoma were sampled from 25 different central cancer registries, with African-American and Hispanic survivors over sampled. Survivors completed either mail or telephone surveys that described their physical, psychological, social, and spiritual functioning. The overall recruitment rate was 34.0%; 15411 participants completed surveys, of whom 40.1% had a high school education or less and 19.4% were racial/ethnic minorities. The SCS surveys provide a large diagnostically, geographically, and demographically diverse database on cancer survivorship that was designed to overcome some of the limitations of past research. Future reports will compare QOL of survivors at different well-defined times postdiagnosis, investigate the issues of understudied populations and diagnostic groups, and describe survivor QOL at state levels. Insights valuable to those considering registry-based studies are offered on issues of ascertainment, sampling, and recruitment.

Changes in treatment of advanced laryngeal cancer 1985-2001.

OBJECTIVE: In 1991, a randomized study was published and demonstrated that use of nonsurgical therapy (chemoradiation) provided similar survival to total laryngectomy (the gold standard) for patients with advanced-stage laryngeal cancer. The purpose of this study was to assess how treatment of advanced laryngeal cancer was influenced by such developments in non-surgical therapy. STUDY DESIGN: Patterns of care study using National Cancer Database (1985-2001). RESULTS: The percentage of advanced-stage patients treated with chemoradiation increased from 8.3% to 20.8% while the proportion treated with radiation alone decreased from 38.9% to 23.0%. Use of chemoradiation increased at a significantly faster rate after the 1991 publication at both community cancer centers and teaching research facilities. The use of total laryngectomy decreased slightly during this period. CONCLUSIONS: The use of chemoradiation increased after the 1991 publication. It was impossible to determine from the NCDB whether additional patients who could benefit from chemo-RT were not offered or did not complete this treatment option. We recommend that treatment recommendations discussed at tumor boards be recorded in cancer registries.

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

PURPOSE: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. EXPERIMENTAL DESIGN: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. RESULTS: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). CONCLUSIONS: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

A Phase II study of St. John's Wort for smoking cessation.

OBJECTIVES: To examine the feasibility and efficacy of St. John's Wort (SJW) for smoking cessation. DESIGN: This one-arm Phase II study utilized an exact two-stage group sequential design with a 1-week run-in period between the start of SJW treatment and the designated quit date. A total of 37 smokers (ages 18-65 years, smoking > or = 10 cigarettes/day) were started on SJW. Thirteen failed to make a verified quit attempt on the predesignated date and were taken off study resulting in 24 evaluable subjects. SETTING: Smokers completed clinic visits at a cancer center with interval telephone calls and mailings. INTERVENTION: Standardized SJW, 450 mg capsules taken orally twice daily along with cessation counseling messages. MAIN OUTCOME MEASURES: Subjects completed validated surveys and a focused physical examination at baseline. Evaluable subjects were defined as those subjects who made a confirmed quit attempt on their "quit date" 1 week following initiation of SJW. Smoking status was determined through self-report and bioverification using carbon monoxide (CO) testing. RESULTS: Among evaluable subjects, the 12-week quit rate was 37.5% (9/24). Quitters had no significant change in weight from baseline to 12-weeks cessation. Use of SJW was generally well tolerated. CONCLUSIONS: Based upon these results (which suggest that SJW may be effective in maintaining smoking cessation) and the high compliance and few AEs, we conclude that SJW demonstrates feasibility for use in smoking cessation. If SJW proves to be effective in larger controlled studies, it could represent a less expensive, more readily accessible and well-tolerated agent to promote tobacco cessation.

Radiotherapy in pediatric medulloblastoma: quality assessment of Pediatric Oncology Group Trial 9031.

PURPOSE: To evaluate the potential influence of radiotherapy quality on survival in high-risk pediatric medulloblastoma patients. METHODS AND MATERIALS: Trial 9031 of the Pediatric Oncology Group (POG) aimed to study the relative benefit of cisplatin and etoposide randomization of high-risk patients with medulloblastoma to preradiotherapy vs. postradiotherapy treatment. Two-hundred and ten patients were treated according to protocol guidelines and were eligible for the present analysis. Treatment volume (whole brain, spine, posterior fossa, and primary tumor bed) and dose prescription deviations were assessed for each patient. An analysis of first site of failure was undertaken. Event-free and overall survival rates were calculated. A log-rank test was used to determine the significance of potential survival differences between patients with and without major deviations in the radiotherapy procedure. RESULTS: Of 160 patients who were fully evaluable for all treatment quality parameters, 91 (57%) had 1 or more major deviations in their treatment schedule. Major deviations by treatment site were brain (26%), spinal (7%), posterior fossa (40%), and primary tumor bed (17%). Major treatment volume or total dose deviations did not significantly influence overall and event-free survival. CONCLUSIONS: Despite major treatment deviations in more than half of fully evaluable patients, underdosage or treatment volume misses were not associated with a worse event-free or overall survival.

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer.

In a recent report, [Zhang et al. (2003) N. Engl. J. Med. 348, 203-213], the presence of CD3+ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18-0.60; P = 0.0003]. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16-0.55; P = 0.0001). These results indicate that CD4+ TILs influence the beneficial effects of CD8+ TIL. This unfavorable effect of CD4+ T cells on prognosis was found to be due to CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17-0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8+ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+ TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.

Review of tonsillar lymphoma in pediatric patients from the pediatric oncology group: what can be learned about some indications for microscopic examination?

Financial considerations have led to suggestions that routine microscopic evaluation of tonsils and adenoids is neither cost effective nor clinically indicated. However, the possibility of tonsillar lymphoma must be carefully weighed when making institutional policy decisions. One way to find an appropriate algorithm for pathologic examination is to examine the characteristics of biopsy-proved tonsillar lymphomas. To investigate the clinicopathologic characteristics of tonsillar lymphoma, we performed a retrospective analysis of patients who had non-Hodgkin lymphoma (NHL) and large-cell or Burkitt lymphoma involving the tonsils and adenoids and were registered on Pediatric Oncology Group (POG) protocols. Seventy-seven (9%) of 832 POG cases of NHL involved the tonsils and adenoids. Review of the pathology reports available from 29 of these cases revealed that NHL was incidentally discovered by pathologic examination in only 5 cases, all of which had clinical evidence of unilateral tonsillar enlargement or size discrepancy by gross examination. The other 24 cases indicated a clinical suspicion of tonsillar cancer, as judged by a preoperative diagnosis or by a request for frozen-section examination. We conclude that in most cases there is a clinical suspicion of tonsillar NHL at the time of gross examination. With routine cases, we predict that the use of comparative organ weights, a clinical impression of tonsillar asymmetry, and review of clinical history will increase the recognition of tonsillar lymphoma when "gross-only" protocols are employed for specimen handling.

Postoperative computed tomography scan surveillance for patients with stage II and III colorectal cancer: worthy of further study?

The use of computed tomography scan (CT) of the abdomen and pelvis for surveillance of colorectal cancer (CRC) after primary curative therapy (PCT) remains controversial. Surveillance guidelines at Roswell Park Cancer Institute have included annual CT for the first 2 years after PCT. Isolated metastases from CRC may be amenable to surgical resection, potentially leading to a survival advantage. To assess this, a retrospective chart review of all 203 patients diagnosed with stage II or III CRC between January 1, 1990, and December 31, 1995, was conducted. First-year surveillance CT (CT-1) was performed for 146 of 203 patients and 81 of 146 patients had second-year surveillance CT (CT-2). CT was considered "directed" when at least 1 of the following prompted evaluation: suspicious symptoms or signs, rising carcinoembryonic antigen, findings from colonoscopies, chest x-rays, or laboratory tests. Otherwise, CT was considered "nondirected." Of 121 of 146 CT-1 and 63 of 81 CT-2 with nondirected CT, 7 of 121(5.8%) and 4 of 63 (6.4%) had proven recurrence, respectively. During 2 years of follow up, the estimated lower bound for detection of recurrence by nondirected CT was 11 of 121(9.1%). There were no apparent differences between the 2 groups in demographics, clinical presentation, surgical margins, treatment, tumor site, grade, or TNM stage. Surgical resectability of the metastases for directed and nondirected groups was 10 of 28 (36%) and 6 of 11 (54%), respectively. The median survival for the patients with recurrence in the directed and nondirected groups was 35 and 50 months, respectively. In conclusion, this retrospective study generates the hypothesis that CT surveillance may be of value. A prospective study, properly sized for power, is needed to answer this question.