Improving care for elderly patients living with polypharmacy: protocol for a pragmatic cluster randomized trial in community-based primary care practices in Canada.

BACKGROUND: Elders living with polypharmacy may be taking medications that do not benefit them. Polypharmacy can be associated with elevated risks of poor health, reduced quality of life, high care costs, and persistently complex care needs. While many medications could be problematic, this project targets medications that should be deprescribed for most elders and for which guidelines and evidence-based deprescribing tools are available. These are termed potentially inappropriate prescriptions (PIPs) and are as follows: proton pump inhibitors, benzodiazepines, antipsychotics, and sulfonylureas. Implementation strategies for deprescribing PIPs in complex older patient populations are needed. METHODS: This will be a pragmatic cluster randomized controlled trial in community-based primary care practices across Canada. Eligible practices provide comprehensive primary care and have at least one physician that consents to participate. Community-dwelling patients aged 65 years and older with ten or more unique medication prescriptions in the past year will be included. The objective is to assess whether the intervention reduces targeted PIPs for these patients compared with usual care. The intervention, Structured Process Informed by Data, Evidence and Research (SPIDER), is a collaboration between quality improvement (QI) and research programs. Primary care teams will form interprofessional Learning Collaboratives and work with QI coaches to review electronic medical record data provided by their regional Practice Based Research Networks (PBRNs), identify areas of improvement, and develop and implement changes. The study will be tested for feasibility in three PBRNs (Toronto, Montreal, and Edmonton) using prospective single-arm mixed methods. Findings will then guide a pragmatic cluster randomized controlled trial in five PBRNs (Calgary, Winnipeg, Ottawa, Montreal, and Halifax). Seven practices per PBRN will be recruited for each arm. The analysis will be by intention to treat. Ten percent of patients who have at least one PIP at baseline will be randomly selected to participate in the assessment of patient experience and self-reported outcomes. Qualitative methods will be used to explore patient and physician experience and evaluate SPIDER's processes. CONCLUSION: We are testing SPIDER in a primary care population with complex care needs. This could provide a widely applicable model for care improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03689049 ; registered September 28, 2018.

Treatment planning aids in prostate cancer: friend or foe?

BACKGROUND: Rectal barium is commonly used as a treatment planning aid for prostate cancer to delineate the anterior rectal wall. Previous research at the Ottawa Regional Cancer Centre demonstrated that retrograde urethrography results in a systematic shift of the prostate. We postulated that rectal barium could also cause prostate motion. PURPOSE: The study was designed to evaluate the effects of rectal barium on prostate position. METHODS AND MATERIALS: Thirty patients with cT1-T3 prostate cancer were evaluated. Three fiducial markers were placed in the prostate. During simulation, baseline posterior-anterior and lateral films were taken. Repeat films were taken after rectal barium opacification. The prostate position (identified by the fiducials) relative to bony landmarks was compared before and after rectal barium. Films were analyzed using PIPsPro software. RESULTS: The rectal barium procedure resulted in a significant displacement of the prostate in the anterior and superior direction. The mean displacement of the prostate measured on the lateral films was 3.8 mm (SD: 4.4 mm) in the superior direction and 3.0 mm (SD: 3.1) in the anterior direction. CONCLUSIONS: Rectal barium opacification results in a systematic shift of the prostate. This error could result in a geographic miss of the target; therefore, alternate methods of normal tissue definition should be used.

A prospective comparison of three systems of patient immobilization for prostate radiotherapy.

PURPOSE: The study compared the setup reliability of 3 patient immobilization systems, a rubber leg cushion, the alpha cradle, and the thermoplastic Hipfix device, in 77 patients with cT1-T3, N0, M0 prostate cancer receiving conformal radiotherapy. METHODS AND MATERIALS: Port films were analyzed and compared to simulation films to estimate the setup errors in the three coordinate axes (anterior-posterior, cranial-caudal, medial-lateral). A total vector error was calculated from these shifts. RESULTS: The Hipfix was found significantly superior to the other two devices in reducing mean setup errors in all axes (p < 0.005). The average field-positioning error with the Hipfix ranged from 1.9 mm to 2.6 mm for all axes, whereas the deviation for the other two systems ranged from 2.7 to 3. 4 mm. Errors greater than 10 mm were virtually eliminated with the Hipfix system. There was a reduction in the mean total vector error in the alpha cradle and Hipfix patient cohorts over time, reflecting improved efficacy as a result of experience. CONCLUSION: There was a significant difference in the performance of each immobilization device. The Hipfix was consistently more reliable in reducing setup errors than the other devices.

An estimate of the cost of conducting phase II trials in lung cancer.

OBJECTIVE: Although it is commonly assumed that clinical trials are more costly than standard therapy, there have been no previous studies of the cost of conducting phase II trials in lung cancer. We retrospectively analyzed two National Cancer Institute of Canada phase II trials in previously untreated small cell lung cancer (SCLC) to determine the costs of conducting the trials in a cancer treatment centre. Both studies were clinical trials undertaken as part of the NCIC's Investigational New Drug program: IND 69 and IND 50 evaluated docetaxel (taxotere) and gemcitabine, respectively. METHODS: data management costs in a Canadian cancer treatment centre were determined from the time estimates provided by data managers to complete various protocol related tasks. Nursing and pharmacy personnel measured the time and supplies necessary to prepare and administer the chemotherapy. Physician fees were determined from the type and number of care visits required by the clinical protocols. Laboratory tests and imaging studies were costed according to the Ontario Health Insurance Plan (OHIP) Schedule of Fees and Benefits. To estimate whether phase II trials are more costly than standard treatment, we determined the cost of four cycles of VP-16-cisplatin, a standard treatment for SCLC. RESULTS: The total cost of performing the docetaxel study was $18443 for an average cost per case of $1317 and an average cost per treatment cycle of $683. The gemcitabine study cost more, due to the fact that the drug proved to be active against SCLC and more cycles of therapy were administered to a larger number of patients. Laboratory and administration costs were also higher, because of the drug administration schedule. The total cost of this study was estimated to be $64670 and the average cost per patient entered was $2230 with an average cost per treatment cycle of $898. In comparison, the estimated cost of four cycles of VP-16-cisplatin chemotherapy was $3948 or $987 per treatment cycle. The major cost drivers in the clinical trials were laboratory and imaging tests which made up 17 and 39%, respectively, of the costs of the taxotere study, and 29 and 27%, respectively, for the gemcitabine study. Data management costs contributed 21 and 13% of the total costs, respectively. CONCLUSION: As the main cost drivers in these phase II clinical trials are laboratory and imaging tests, the cost of clinical trials could potentially be reduced by ensuring that only essential tests are required by protocol. Not surprisingly, the cost of conducting a trial of an active agent is greater than for an inactive agent, because more patients are treated and each patient receives more treatment. The implications for the per-case funding of phase II clinical trials are discussed.

Effects of urethrography on prostate position: considerations for radiotherapy treatment planning of prostate carcinoma.

PURPOSE: Retrograde urethrography is commonly used to define the prostate apex at simulation. This study evaluated the hypothesis that urethrography causes prostate displacement, resulting in an error in treatment planning. METHODS AND MATERIALS: Forty-five patients with carcinoma of the prostate were evaluated. Gold seeds were placed in the apex, posterior wall, and base of the gland. In the first 20 patients, the position of the seed-defined apex was compared at simulation (with urethrogram) and on day 1 of treatment (without urethrogram). In the second cohort of 25 patients, the effects of urethrography on prostate position were evaluated directly at simulation by comparing the position of apex pre- and post-urethrography. An analysis was performed to estimate the possible impact of urethrogram-induced prostate motion on target coverage. RESULTS: The mean superior displacement in the first and second cohort was 5.2 mm and 6.8 mm, respectively (combined mean shift 6.1 mm). With a 10-mm field margin below the tip of the urethrogram cone, 56% of patients in this study would have inadequate planning target volume (PTV) coverage. CONCLUSION: Retrograde urethrography causes a significant superior shift of the prostate. Strict reliance on urethrography in determining the inferior field margin could result in inadequate treatment.

Clinical characteristics and the impact of surgery and chemotherapy on survival of patients with advanced and metastatic bronchioloalveolar carcinoma: a retrospective study.

We retrospectively analyzed data from the clinical charts of 126 patients with bronchioloalveolar carcinoma (BAC) referred to the Ottawa Regional Cancer Center. The patient group consisted of 49 men (39%) and 77 women (61%). The mean age at diagnosis was 64 years. Most patients were smokers (85%). At diagnosis, 53% were stage Ia-IIIa and 47% were stage IIIb and IV. Forty-one percent of the patients with advanced and metastatic stages (IIIb, IV) underwent surgery. Multifocal disease was present at diagnosis in 41% of the patients, including 6% who had stage IIIb multifocal disease confined to a single lobe. Surgery was associated with prolonged survival in patients with multifocal unilobar or multilobar disease (P = 0.0001). While this apparent benefit of surgery may have been due to selection bias, it supports further exploration of surgery as therapy for multifocal disease. While patients receiving chemotherapy for advanced disease did not survive longer than patients not receiving chemotherapy, chemotherapy was used primarily in patients with more aggressive disease, suggesting that selection bias may have contributed to its apparent lack of benefit. Of the 30 patients treated with chemotherapy, only 3 (10%) achieved an objective response. One third of the patients (34%) developed distant metastases, with a predilection for the brain and bone.

Costs of treating and preventing nausea and vomiting in patients receiving chemotherapy.

PURPOSE: To evaluate the effect of ondansetron availability on the costs of managing nausea and vomiting. METHODS: We retrospectively assessed antiemetic costs (drug costs, nursing time, pharmacy time, physician's time, supplies, and facility "hotel" costs, in 1991 Canadian dollars) for all patients who received moderately or highly emetogenic chemotherapy from 6 months before to 6 months after ondansetron became commercially available in September 1991. We compared the costs for treating patients who received ondansetron versus those who received other antiemetic regimens, the costs for treating patients in the 6 months before versus the 6 months after ondansetron commercial availability, and the costs for treating patients in the first 4 months versus the last 4 months of the study period. RESULTS: We found no cost differences for patients treated with ondansetron versus other antiemetic regimens. However, there was a significant reduction in emesis management costs for patients treated after versus before the availability of ondansetron: for patients treated in the last third versus first third of the study period, there was a decrease in cost per patient per month of treatment of $374 (95% confidence interval, $243 to $505). These savings were achieved through a reduction in hospital bed days and other costs associated with the prevention and more effective management of nausea and vomiting. At the same time, the number of patients who received emetogenic chemotherapy and their average age increased, presumably because of the better control of gastrointestinal toxicity. CONCLUSION: Ondansetron availability has been associated with changes in the clinical management of cancer patients receiving chemotherapy and with overall cost savings compared with previously available antiemetic therapy.

Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer.

OBJECTIVES: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). METHODS: Forty-seven patients received thoracic radiotherapy (1.5 bid x 5 days x 4 weeks) in combination with low dose daily (3-6 mg/m2) cisplatin +/- weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75-80 mg/m2) and vinblastine (8-16 mg/m2) given at 3-4 week intervals (step II). RESULTS: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. CONCLUSION: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies.

Mitoxantrone in the treatment of metastatic transitional cell carcinoma of the prostate. A case report.

A 61-year-old man with pulmonary and bone metastases from a primary transitional cell carcinoma of the prostate (TCCP) refractory to MVAC was treated with mitoxantrone 16 mg/m2 i.v. at 3-week intervals. With this, he experienced an objective partial remission lasting 5 months and a significant decrease in cancer-related symptoms. Mitoxantrone deserves further evaluation in this rare disease.

Retrospective comparative analysis of 5FU + low-dose folinic acid vs. 5FU + high-dose folinic acid in the treatment of metastatic colorectal cancer. The Ottawa experience.

Two regimens of 5FU and folinic acid in the treatment of metastatic colorectal cancer were retrospectively analyzed. 33 patients received the high dose (HD) schedule (5FU 370 mg/m2 and Folinic Acid 200 mg/m2 i.v. on D1-5, every 4 weeks), 61 patients received the low dose (LD) schedule (5FU 400 mg/m2 and Folinic Acid 20 mg/m2 i.v. on D1-5, every 4 weeks). One patient in each group achieved a complete response, the overall response rate was 28% and 11% for the HD and LD groups, respectively. The median response duration was 183 days for the HD and 112 days for the LD group. The median survival duration was 387 days for the HD and 405 days for the LD group. The response rate and duration of response were higher in the HD group though this did not reach statistical significance. There was no difference in overall survival between the two patient groups. Neutropenia and gastro-intestinal symptoms were the most common toxicities, they were equal in both groups. One patient (3%) in the HD and 5 patients (9%) in LD group discontinued treatment due to toxicity. There were no treatment related deaths. It is concluded that low dose folinic acid in combination with 5FU is effective and produces similar toxicities as high dose folinic acid. It is concluded that low dose folinic acid in combination with 5FU is an effective alternative to high dose regimen in the palliative management of patients with metastatic colorectal cancer. However though it did not reach statistical significance the high dose regimen was associated with a higher response rate. This could have a significant effect when the combination is used in the adjuvant treatment of high risk patients.

Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer.

PURPOSE: To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS: Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS: Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.

Cranial radiation and concomitant cisplatin and mitomycin-C plus resistance modulators for malignant gliomas.

We studied the toxicity and efficacy of adding in sequence 4 resistance modulators to combination chemotherapy and radiotherapy in the treatment of glioblastoma multiforme and poor prognosis anaplastic astrocytomas. Patients received cisplatin plus mitomycin-C concurrently with and following 60 Gy of radiotherapy administered over 6 weeks. Resistance modulators were added in sequence to chemotherapy in each cohort of 6 patients as follows: metronidazole + pentoxifylline (cohort 1); + dipyridamole (cohort 2), + beta carotene (cohort 3). Central nervous system toxicity (which ranged from drowsiness to seizures and loss of consciousness) was frequent. The incidence of gastrointestinal symptoms was substantial, but was usually mild to moderate in severity. Three of 11 patients evaluable for response achieved a partial remission with treatment. The median survival duration for all patients was 26 weeks from initial diagnosis. The study was terminated prematurely because of significant toxicity (in this study as well as in parallel concurrent studies of similar design in other tumor types) and apparent lack of benefit.

Pilot study of multiple chemotherapy resistance modulators plus epirubicin in the treatment of resistant malignancies.

We studied the toxicity and efficacy of adding to epirubicin five resistance modulators in the treatment of resistant solid tumors. Additional drugs were added in successive cohorts of patients, such that cohort 1 patients received two drugs along with their epirubicin, while cohort 4 patients received five modulators along with their epirubicin. Metronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconazole (cohort 3) and cyclosporin (cohort 4) were administered with epirubicin. A total of 22 patients were treated. Nausea and vomiting was usually mild to moderate. There was an unexpectedly high incidence of possible cardiac toxicity associated with treatment, although in some patients it was uncertain whether or not observed cardiac events were related to treatment. Granulocytopenia was significant in all four cohorts, but it was unclear whether it was increased by the modulators. There were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of cohorts 1, 2 and 4). It was elected to discontinue enrollment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. While this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.

Recent advances in the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which represents the bulk of primary carcinomas of the lung, is an aggressive malignancy. The majority of patients with NSCLC present with advanced disease, not curable by surgery, at the time of diagnosis. Recent randomized trials have shown an improvement in survival for patients with loco-regional disease treated with combination, platinum-based, chemotherapy and curative irradiation. Similarly, randomized studies of good performance status patients with metastatic disease have documented a survival advantage, albeit a modest advantage, for those receiving chemotherapy. New chemotherapy agents with activity in NSCLC have been studied in phase II trials. These agents need to be evaluated, in loco-regional and metastatic disease, in large randomized phase III trials before conclusions can be drawn about their role in treatment. Novel treatments which among other include gene therapy, anti-angiogenic and anti-metastatic agents are currently being assessed in early phase I and II studies. Gene therapy will likely be combined with standard chemotherapy and radiation in the treatment of NSCLC, whereas anti-angiogenic and anti-metastatic agents may play a role in prevention and maintenance therapy. Finally, regardless of the approach or modality, new interventions will need to be assessed for their impact on overall survival and the quality of life of patients with NSCLC.

Oral etoposide and carboplatin. Effective therapy for elderly patients with small cell lung cancer.

PURPOSE: Elderly patients with small cell lung cancer (SCLC) and/or those with comorbid conditions are frequently not considered candidates for standard combination chemotherapy. An active, but less toxic regimen is needed for this group of patients. PATIENTS AND METHODS: Forty-seven elderly (> 65 years) or medically unfit patients with SCLC were treated with oral etoposide 100 mg/m2 x 7 days and carboplatin 150 mg/m2 day 1. Treatment was given every 3-4 weeks for six cycles in responding patients. Patients responding to the chemotherapy regimen were also treated with prophylactic cranial irradiation, and limited-stage patients received thoracic radiotherapy. The study population included 36 extensive-stage patients and 11 limited-disease patients with renal or cardiac disease that precluded standard chemotherapy. The median age of the study population was 69 years (range: 47-84). RESULTS: Nine of 47 patients were inevaluable for response, including four patients who succumbed to sepsis. Of the 38 patients evaluable for response, 71% responded (95% CI: 56-86%) (88% LD; 67% ED) with a complete response in 29% of patients (50% LD; 23% ED). Based on an analysis of intent to treat, the overall response rate was 60% and the median survival time of the whole group was 46 weeks (LD, 59 weeks; ED, 45 weeks). Treatment was generally well tolerated. Neutropenia was the dose-limiting toxicity; the median nadir granulocyte count was 1.04 x 10(9)/L (range: 0-8.2). CONCLUSION: We conclude that this regimen can provide palliation to SCLC patients who might not otherwise be considered for systemic chemotherapy.

A phase II study of 5-fluorouracil plus high-dose folinic acid in the treatment of recurrent small cell lung cancer.

Fourteen patients with small cell lung cancer (SCLC) previously treated with one or two chemotherapy regimens were entered in this study. 5-Fluorouracil 370 mg/m2 or 300 mg/m2 was given with folinic acid 200 mg/m2 by i.v. rapid infusion on days 1 through 5. Cycles were repeated every 28 days. There were no objective responses. One patient had stable disease for 47 weeks. The overall median survival duration was 23 weeks. Toxicity was comparable to that seen in other studies of 5-fluorouracil plus folinic acid.

Response of brain metastases from breast cancer to megestrol acetate: a case report.

A 56 year old women was treated with megestrol acetate (Megace) 40 mg p.o. q.i.d. for her cerebellar metastasis of primary adenocarcinoma of the breast. She had previously undergone two surgical resections of her brain metastasis, and a course of radiotherapy. After failing to tolerate tamoxifen therapy, she received Megace, with marked improvement in her cerebellar tumor on CT scans. Despite good control of her brain tumor with Megace, she developed progressive neurological symptoms thought to be due to meningeal carcinomatosis, and died two years after initiating Megace therapy. We conclude that Megace could potentially be beneficial in some patients with brain metastases from adenocarcinoma of the breast.

A phase II study of 5-fluorouracil plus folinic acid in malignant gliomas in adults.

Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.

Intraarterial cisplatin plus intravenous doxorubicin for inoperable recurrent meningiomas.

The majority of meningiomas are cured by surgical resection. There is little information in the literature on the use of chemotherapy in meningiomas. We report 2 patients with inoperable recurrences of meningiomas that responded (1 patient) or stabilized (1 patient) when treated with the combination of intracarotid cisplatin plus intravenous doxorubicin.

A pilot study of intra-arterial carboplatin in patients with recurrent carcinoma of the cervix, postradiation.

Twelve patients with recurrent squamous cell carcinoma of the cervix restricted to the pelvis were treated with intra-arterial infusion of carboplatin. The initial carboplatin dose was 300 mg/m2, every 4 weeks, and the dose was escalated to 450 mg/m2. Myelosuppression was the dose-limiting toxicity at the 450 mg/m2 dose. One patient died of treatment-related febrile neutropenia at that dose level. Two patients having received one cycle at 300 mg/m2 suffered grade 3 peripheral paresthesia. There were no objective responses but five patients had a subjective improvement of pain and performance status.