Avelumab in unresectable/metastatic, progressive, grade 2-3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials.

BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: This phase III randomized trial compared pemetrexed 500 mg/m(2) (P500) with pemetrexed 900 mg/m(2) (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week. RESULTS: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories. CONCLUSIONS: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

Trends in hormonal management of prostate cancer: a population-based study in Ontario.

OBJECTIVE: To provide a population-based description of current practice in the use of hormonal management of prostate cancer. DESIGN,SETTING & PARTICIPANTS: All men in Ontario, Canada, age 65 and older, with confirmed prostate cancer starting maintained hormonal therapy, from July 1992 through December 1998 (11,435 patients). Data sources included the provincial drug benefit plan, hospital services data, and Ontario Cancer Registry. OUTCOME MEASURES: Rates and trends in the use of: surgical or medical castration; total androgen blockade (TAB); and monotherapies based on steroidal or nonsteroidal antiandrogens. RESULTS: In 5.5 years, use of 'standard' therapy based on surgical or medical castration alone dropped from 36% to 26% of patients, while the use of TAB doubled from 22% to 41%. Approximately 15% of patients received nonsteroidal antiandrogens without evidence of therapy aimed at central androgen blockade. Marked regional differences were observed and not explained by patient age or practitioner specialty. CONCLUSIONS: New hormonal therapies for prostate cancer have implications in terms of disease control, patient survival, side effects, and costs. Rapid growth in prescribing of antiandrogens may represent an unnecessary expense for public or private payers, and observed regional differences likely reflect lack of consensus on the relative merit of TAB. Patients and practitioners must have current information on the advantages and disadvantages of different therapeutic options, and quality-of life, particularly with respect to emerging drug therapies.

Prostate-specific antigen testing in Ontario: reasons for testing patients without diagnosed prostate cancer.

BACKGROUND: The use of the prostate-specific antigen (PSA) test has been increasing rapidly in Canada since its introduction in 1988. The reasons for using the PSA test in patients without known prostate cancer are unclear. This paper reports on the first study in Canada to use physician records to assess the use of PSA testing. METHODS: A questionnaire was mailed to physicians attending 475 patients without diagnosed prostate cancer. The patients were randomly selected from 2 laboratory databases of PSA test records in the greater Toronto area during 1995. The physicians were asked to consult their patient records to avoid recall bias. Information obtained included physician's specialty, patient's age at time of PSA test and reason(s) for the test. RESULTS: There were 264 responses (56%), of which 240 (91%) were usable. Of these 240, 63% (95% confidence interval [Cl] 58%-70%) indicated that the test was conducted to screen for prostate cancer, 40% (95% Cl 34%-47%) said it was to investigate urinary symptoms, and 33% (95% Cl 27%-40%) responded that it was a follow-up to a medical procedure or drug therapy. More than one reason was permitted. Of 151 responses indicating screening as one reason for testing, 64% (95% Cl 56%-72%) stated that it was initiated by the patient, and 73% (95% Cl 65%-80%) stated that it was part of a routine examination. For 19%, both investigation of symptoms and screening asymptomatic patients were given as reasons for testing, and for another 19% both follow-up of a medical procedure and screening were given as reasons. Screening was recorded as a reason for testing far more commonly for patients seen by family physicians and general practitioners than for patients seen by urologists (67% v. 29%, p < 0.001). In contrast, the use of PSA testing to diagnose urinary symptoms was more common for patients seen by urologists than for those seen by family physicians and general practitioners (52% v. 37%, p = 0.044). No significant difference was found between physician groups in the use of PSA testing as a follow-up of a medical procedure (42% for urologists and 31% for family physicians and general practitioners). About 24% of the PSA test records were for patients younger than 50 and older than 70 years. PSA testing initiated by patients was more common in the practices of family physicians and general practitioners than in the practices of urologists (44% v. 13%, p < 0.001). INTERPRETATION: Screening for prostate cancer was the most common reason for PSA testing in our study group; it occurred most commonly in the family and general practice setting and was usually initiated by the patient. Differences in reasons for testing were identified by practice specialty. Although PSA screening for prostate cancer is sometimes recommended for men between 50 and 70 years of age, it is being conducted in men outside this age group.

Prostate cancer: 1. The descriptive epidemiology in Canada.

A 70-year-old woman who experienced a long period of depression after her first husband's death from prostate cancer at the age of 63 has become increasingly anxious about her own health and that of her close family. A few years ago she married a man her own age; he is in good physical condition. Last year the family spent much of the winter in Florida, where the woman noticed several studies in the media suggesting that an epidemic of prostate cancer is occurring in North America and that because early detection can save lives men of retirement age should be checked by their physicians as soon as possible. In addition, 2 close friends recently diagnosed with prostate cancer. On his latest fishing trip her husband learned from a friend that 1 in 8 men get prostate cancer. He has not seen his family physician for several years, but his wife has booked an appointment for them to discuss their concerns.

Free-standing health care facilities: financial arrangements, quality assurance and a pilot study.

Free-standing health care facilities now deliver many diagnostic and therapeutic services formerly provided only in hospitals. The financial arrangements available to these facilities differ according to whether the services are uninsured or insured. For an uninsured service, such as cosmetic surgery, the patient pays a fee directly to the service provider. For an insured service, such as cataract surgery, the provincial government uses tax revenues to fund the facility by paying it a facility fee and remunerates the physician who provided the service with a professional fee. No comprehensive, proactive quality assurance efforts have been implemented for either these facilities or the clinical practice provided within them. A pilot study involving therapeutic facilities in Ontario has suggested that a large-scale quality improvement effort could be undertaken in these facilities and rigorously evaluated.

Prostate cancer screening in the midst of controversy: Canadian men's knowledge, beliefs, utilization, and future intentions.

Despite controversy about prostate cancer screening, administrative data show that the use of prostate specific antigen (PSA) testing in Canada has increased. This study sought to determine awareness and knowledge of prostate cancer and screening, use to date, and future intentions to have a digital rectal examination (DRE) and PSA test among Canadian men aged 40 and over. Data were collected through a Canada-wide cross-sectional random digit dial telephone survey of 629 men. Awareness of DRE and PSA, use to date, and future intended use varied with age and education. Although only 9% of respondents had had PSA testing for screening, future intentions to undergo this test were higher than use to date. Knowledge of prostate cancer and screening controversies was low, and men received more information about PSA from the media than from doctors. Men would, therefore, benefit from age- and education-specific information regarding the factors to consider in making an informed choice about prostate cancer screening.

Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma.

MIB-1 proliferative activity is a significant prognostic factor in primary thick cutaneous melanomas.

Although the Breslow measurement of tumor thickness of melanoma is the most significant predictor of survival, the biologic behavior of thick lesions remains unpredictable. MIB-1, a monoclonal antibody to a Ki-67 epitope, recognizes all proliferating cells. Unlike Ki-67 antibody, which requires frozen tissue, MIB-1 can be used on formalin-fixed tissue. Proliferation, measured by MIB-1 expression and mitotic index, was assessed as a prognostic factor in a group of patients with clinical stage I thick cutaneous melanoma (tumor thickness 4 mm or greater), for which predicted survival is low. From a melanoma data base, 97 patients with this type of melanoma were identified. Of these, 64 had lesional tissue available for study. The median follow-up time was 3.8 years (range 0.42-13.6 years). The percentage of MIB-1 reactivity was scored as low at less than 10% (n = 33), intermediate at 10% to 20% (n = 17), and high at greater than 20% (n = 14). Melanomas with high MIB-1 reactivity were associated with significantly poorer cause-specific survival compared with tumors with intermediate (p < 0.0001) or low MIB-1 reactivity (p = 0.0025). Multivariate analysis demonstrated that MIB-1 reactivity was a significant independent prognostic factor related to cause-specific survival (p = 0.0002) and was more sensitive than tumor thickness or mitotic index in this select group of high-risk patients. Identification of individuals with stage I thick cutaneous melanoma who are at risk of recurrent disease may improve patient management as new therapeutic modalities become available.

Predicting psychological distress in patients with cancer: conceptual basis and reliability evaluation of a self-report questionnaire.

UNLABELLED: BACKGROUND/MATERIALS AND METHODS: A battery of instruments intended to predict the likelihood of future psychosocial distress in patients with cancer was developed and tested. The battery consists of newly-developed items for constructs relating to social support and to past coping experiences. Embedded within the past coping items are items on future illness-dependent expectations. The battery also incorporates previously developed instruments for recent stressful life events (Sarason) and the presence of anxiety or depression (SCL-90-R). The reliability of the entire instrument was determined in 2 similar groups of patients with cancer. RESULTS: The illness-dependent expectations items were stable and internally consistent. The past coping and social support items possessed stability, but did not possess sufficient internal consistency for either to be used as a scale. The recent stressful life event scores were not stable in either patient group over the two week retest interval. For the SCL-90-R, internal consistencies and stability coefficients are acceptable for all symptom dimensions with the exception of the stability coefficient for hostility.

Orchidectomy and hormonal therapy of prostate cancer.

The objective of this study is to document the use of hormonal therapies in treating prostate cancer in Ontario in the last decade. Drug utilization data were extracted from the Ontario Drug Benefit Program, while surgical orchidectomy rates were calculated from Hospital Medical Records Institute data. The provincial rate of orchidectomy showed a 55% relative increase from 1981 to 1991. There was a 6.4-fold variation in orchidectomy rates among counties in Ontario. As well, the expenditures on new hormonal therapies rose 38-fold between 1985 and 1990, and doubled between 1990 and 1992. There was no consistent relationship between use of orchidectomy and hormonal drug therapy at the county level. We conclude that both forms of hormonal therapy have increased in Ontario. The wide variation in surgical orchidectomy rates observed in Ontario suggests differences in practice styles and possible medical uncertainty. Guidelines for the hormonal therapy of prostate cancer may be a helpful step forward for practitioners and patients.

Temporal trends in breast cancer surgery in Ontario: can one randomized trial make a difference?

OBJECTIVE: To assess the effect of a single randomized clinical trial, the National Surgical Adjuvant Breast Project (NSABP) B-06, on the surgical management of breast cancer in women. DESIGN: Retrospective cohort study. SETTING: All hospitals in Ontario. PATIENTS: A consecutive sample of 37,447 women with breast cancer newly diagnosed from Jan. 1, 1980, to Dec. 31, 1989, linked to a surgical procedure record in the Ontario Cancer Registry. MAIN OUTCOME MEASURE: The most invasive surgical procedure used within 90 days of diagnosis. RESULTS: Unilateral breast-ablative surgery (BAS) was performed in 57.3% of the women and breast-conserving surgery (BCS) in 31.6%. The annual rate of BAS declined from 77.5% in 1980 to 44.2% in 1989 and the rate of BCS rose from 12.5% in 1980 to 43.5% in 1989. The decline was linear from 1980 to 1984 and then accelerated significantly in 1985 (p < 0.0001), after the results of the NSABP B-06 trial were published. CONCLUSION: One randomized clinical trial can have an immediate and profound effect on medical practice.

Extragonadal germ cell tumors. A 14-year Toronto experience.

BACKGROUND: Extragonadal germ cell tumors (EGCT) represent only 2-5% of adult germ cell malignancies. Because they are rare and biologically distinct from testis cancer, their natural history and optimal management continue to be defined. The clinical characteristics, treatment, and outcome of 40 patients are presented here. METHODS: Patients were identified through the medical records of four University of Toronto teaching hospitals. All patients were treated in specialized oncology units between 1978 and 1993. RESULTS: Thirty-seven males and three females age 16-54 years (median, 24 years) with primary mediastinal (n = 24), retroperitoneal (n = 7), CNS (n = 7), and widespread (n = 2) EGCT were identified. Eight of nine patients (88%) with mediastinal seminoma are alive with no evidence of disease (NED) at 4-132 months (median, 45 months). After combined modality therapy, only 8 of 15 patients (53%) with mediastinal nonseminomas achieved complete remission (CR); 1 experienced relapse and died, resulting in 7 of 15 patients (47%) with NED at 45-86 months (median, 70 months). All three patients with retroperitoneal seminomas achieved CR and all have NED at 77, 103, and 120 months, respectively. Two of four patients with retroperitoneal nonseminomas have died, and the other two are alive at 36 and 54 months. Seven patients with CNS germinomas (seminoma) achieved CR after craniospinal radiation therapy, but one subsequently died after local relapse. The overall survival rate was 87% (median, 74 months). One patient with widespread choriocarcinoma died and the other achieved CR. CONCLUSIONS: Regardless of site of presentation, extragonadal seminomas have a greater than 80% 5-year disease-free survival rate. Mediastinal nonseminomas are biologically distinct, with a poorer prognosis. Treated with cisplatin-based chemotherapy followed by aggressive resection, approximately 50% of patients survive. CNS seminomas have a good prognosis. Nonseminomas of the CNS are extremely rare and were not represented in the current series. These findings concur with other reported series.

Variation in breast cancer surgery in Ontario.

OBJECTIVES: To analyse the extent of variation by county and hospital in the use of breast-conserving surgery in the initial management of breast cancer and to assess some factors that might explain the observed variation. DESIGN: Population-based retrospective cohort study. SETTING: Ontario. PATIENTS: All women with breast cancer newly diagnosed from Jan. 1, 1989, to Dec. 31, 1991. MAIN OUTCOME MEASURE: Proportion of women undergoing unilateral breast cancer surgery who had breast-conserving surgery in each hospital and county. RESULTS: Of the 14,570 women with newly diagnosed breast cancer 12,815 (88.0%) underwent unilateral breast cancer surgery. The mean proportion of breast-conserving procedures by county was 52% and ranged from 11% to 84%. The proportion of breast-conserving procedures in individual hospitals with one or more cases of breast cancer per month ranged from 6% to 84%. The variations in the rates between hospitals was greater than that expected by chance alone (p < 0.0001). CONCLUSIONS: There was marked variation at the hospital and county level in the use of breast-conserving surgery in the initial management of breast cancer. This variation was strongly associated with the hospital where the surgery was performed.

A phase II study of methotrexate, vinblastine, doxorubicin and cisplatin plus recombinant human granulocyte-macrophage colony stimulating factors in patients with advanced transitional cell carcinoma.

The use of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) to treat transitional cell carcinoma is associated with high rates of granulocytopenia. To test whether the addition of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) would decrease the hematological toxicity of M-VAC 21 patients were treated with standard dose M-VAC (30 mg./m.2 methotrexate on days 1, 15 and 22, 3 mg./m.2 vinblastine on days 2, 15 and 22, 30 mg./m.2 doxorubicin on day 2 and 70 mg./m.2 cisplatin on day 2) plus 5 micrograms./kg. rhGM-CSF subcutaneously on days 4 to 13. On cycles 1 and 2 of therapy grade III or greater granulocytopenia (less than 1.0 x 10(9)/l.) was noted in 39% and 43% of the patients, respectively, and the majority were able to receive the day 15 and day 22 treatments as scheduled. This was an apparent improvement over our historical experience with M-VAC alone (p = 0.03). By cycle 3 of treatment this beneficial effect of rhGM-CSF was no longer apparent, with 80% of the patients experiencing grade III or greater granulocytopenia and thrombocytopenia also becoming apparent. Seven patients had to discontinue rhGM-CSF because of side effects. It is unlikely that clinically significant escalation of chemotherapy dosages can be achieved with M-VAC and rhGM-CSF.

A phase II study of weekly edatrexate (10-EDAM) in metastatic melanoma. A National Cancer Institute of Canada Clinical Trials Group study.

BACKGROUND: Phase I and II clinical trials have demonstrated acceptable toxicity and promising activity of Edatrexate (10-EDAM). The objective of this multicentre phase II study was to determine the efficacy and toxicity of this agent in patients with metastatic melanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanoma received 10-EDAM, 80 mg/m2/week intravenously. Patients were evaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensity of 10-EDAM actually delivered was 56.25 mg/m2/week (70% of projected). Mucositis of any degree was encountered in 93.8% of patients. Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia, thrombocytopenia, anemia and hyperbilirubinemia each were encountered in 1-2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.

The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine.

We compared the effects of controlled-release and immediate-release morphine preparations in adult patients with moderate-to-severe cancer pain and report methodologic approaches to pain evaluation. The study consisted of a two-phase randomized crossover trial preceded by a titration phase; all phases were conducted under double-blind conditions. To evaluate pain intensity, a visual analogue scale (VAS) and the Present Pain Intensity scale of the McGill Pain Questionnaire were used. Additional morphine solution for breakthrough pain was used as an outcome measure. Pain was evaluated nine times daily, which permitted correlation of pain scores with the pharmacokinetic patterns of the test drugs. Side effects were rated once daily, using a scale from 0 to 3. To assess the relative importance of side effects, a toxicity index was designed based on both the intensity and duration of each side effect. The overall VAS pain scores during treatment with controlled-release and immediate-release morphine were 1.3 (SD = 0.1) and 1.4 (SD = 0.2), respectively. Use of supplemental morphine solution for breakthrough pain expressed as the percentage of the daily dose of the test drug was 5.5% for the controlled-release drug and 10.9% for the immediate-release drug. Differences in pain scores, side effects, and supplemental morphine requirement between the two groups were not significant. We discuss methodologic issues in double-blind clinical trials of analgesics, in particular the validity of "Patient Preference" as an outcome measure and problems related to the titration phase.