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Biomedical subjects

F A Shepherd

Publications and source records attributed to F A Shepherd.

At least 73 records · Page 4Linked to original sources
PubMed1995

Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production.

PURPOSE: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Cushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by malignant neoplasms (ECS). PATIENTS AND METHODS: A retrospective chart review was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and for clinical, biochemical, and hormonal responses. RESULTS: There were four women and 11 men with a median age of 59 years (range, 44 to 84). Eleven patients had primary lung cancer (nine small-cell [SCLC], one mixed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one bronchial, one pancreatic); one had hepatocellular carcinoma; and one had medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle weakness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Biochemical abnormalities included hypokalemia (n = 14), metabolic alkalosis (n = 13), and new or worsened diabetes mellitus (n = 10). Patients received ketoconazole in dosages of 400 to 1,200 mg/d titrated by changes in urinary free-cortisol (UFC) levels for a median duration of 26 days (range, 3 to 1,059), and nine also received chemotherapy with ketoconazole. Hypokalemia, metabolic alkalosis, diabetes mellitus, and hypertension improved in the majority of patients. Ten patients had a hormonal response, with seven complete responses (median duration, 25 days; range, 6 to 989). The occurrence of symptomatic hypoadrenalism was definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal control by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154). CONCLUSION: Ketoconazole results in biochemical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For that reason, replacement corticosteroids should be considered for patients with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate control of the syndrome is dependent on successful treatment of the underlying tumor.

ACTH Syndrome, Ectopic↗
PubMed1995

HIV-associated lymphoma of the gastrointestinal tract: the University of Toronto AIDS-Lymphoma Study Group experience.

We present a retrospective analysis of 31 (30 male) patients with HIV-associated gastrointestinal lymphoma which was undertaken to determine the natural history and response to therapy. Only seven patients had stage I or II lymphoma and 22 had stage IV. Pathology included diffuse large cell (13), immunoblastic (10), and small cell non-cleaved (7). The median age at presentation was 39 years (range 24-59), and the median CD4 count before treatment was 100/microL (range 4-1150). Eighty-seven percent of patients received systemic chemotherapy and significant response was seen in 84% (CR 38%; PR 46%). Hematologic toxicity was high (febrile neutropenia in 44% and dose reductions were required in 81%) and perforation occurred in five patients. Median survival for all patients was 6 months and death was secondary to lymphoma in 61%, treatment toxicity in 10%, other AIDS-related illnesses in 25% and other causes in 4%. Survival was shorter for patients with bone marrow involvement and for those with poor performance status. HIV-associated GI lymphoma has a poor prognosis despite good initial response to chemotherapy and is associated with a higher perforation rate than in HIV negative patients.

Adult↗
PubMed1994

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.

Adolescent↗
PubMed1994

VP-16, ifosfamide and cisplatin (VIP) for extensive small cell lung cancer.

Thirty-seven extensive disease SCLC patients were treated with ifosfamide 1.0 g/m2 (maximum 1.75 g), VP-16 (etoposide) 75 mg/m2 and cisplatin 20 mg/m2 (VIP) daily for 5 days in hospital. Mesna was given as a continuous infusion until 12 h after the last ifosfamide dose. Treatment was reduced to 4 days after the first 8 patients experienced serious myelotoxicity. 30 patients were evaluable for response. 8 (27%) achieved a complete response and 60% had a partial response. The median duration of response was 23 weeks. The median survival of all 37 patients was 41 weeks, and 47 weeks for the 30 evaluable patients. Fifty per cent and 26% of the evaluable treatment courses were associated with grade 4 and 3 granulocytopenia, respectively. There were eight febrile events including four treatment-related deaths from sepsis on the 5-day regimen. Although the response to VIP was generally rapid, the proportion achieving complete response (27% of evaluable patients) and the median survival is similar to standard chemotherapy regimens which are less toxic and less complex to administer.

Adult↗
PubMed1994

Treatment of small cell lung cancer in the elderly.

OBJECTIVE: Since both the incidence of lung cancer and the proportion of the population over age 65 are increasing rapidly in North America, we undertook a retrospective review of elderly patients with small cell lung cancer (SCLC) in an attempt to assess the effect of age on treatment decisions, response, survival, and toxicity. DESIGN: Retrospective chart view. SETTING: Oncology Unit of a university-affiliated teaching hospital. PATIENTS: There were 123 patients age > 70 years treated from 1976-88. Chemotherapy consisted of either cyclophosphamide, doxorubicin, and vincristine, or etoposide and cisplatin. RESULTS: There were 74 patients aged 70-74, 35 aged 75-80, and 14 aged 80 years or older. No significant differences existed between the groups in sex, stage, performance status, or presence of co-morbid disease. Median survivals for patients with limited and extensive disease were 11.9 and 5.2 months, respectively (P = < 0.0001), with no significant difference for patients in any age group (P = 0.4). For both limited and extensive disease, survival correlated strongly with the treatment received. Twenty-five patients received no treatment (median survival 1.1 months), 20 had radiation only (median 7.8 months), and 27 patients had < 3 cycles of chemotherapy (median 3.9 months). Median survival for the 50 patients who had 4-6 cycles was 10.7 months (limited disease 15.0 months, extensive disease 8.61 months). In the Cox Model, survival correlated strongly with stage of disease and chemotherapy treatment (P < 0.0001), but only marginally with performance status (P < 0.077). Of the 77 patients who had chemotherapy, less than 50% in all age groups completed six cycles. Only two patients completed chemotherapy without a single dose reduction, and 76.7% required more than two reductions. CONCLUSIONS: Chemotherapy should not be withheld from elderly patients with SCLC on the basis of age. The survival of patients who receive chemotherapy is significantly longer than that of untreated patients even though frequent dose reductions for toxicity may be required. The survival benefit is due to treatment effect and is not due to a selection bias in the cohort of patients chosen for therapy.

Activities of Daily Living↗
PubMed1994

Treatment of advanced non-small cell lung cancer.

Lung cancer is now the leading cause of cancer-related mortality for men and women in North America. Non-small cell lung cancer (NSCLC) accounts for more than three quarters of all primary lung tumors. Chemotherapy, however, has had little impact on the survival of patients with NSCLC. Agents like cisplatin, ifosfamide, and mitomycin, used singly and as part of combination regimens, have shown some activity in NSCLC, but have had only a modest effect on the long-term survival of patients with locally advanced and disseminated disease. Combination chemotherapy and promising new agents like gemcitabine, vinorelbine, paclitaxel, and docetaxel warrant further study, as does the use of chemotherapy in novel combined-modality regimens. For patients with locally advanced disease (stages IIIA and IIIB), the goal of chemotherapy must be to increase cure rates, whereas for patients with advanced disease (stage IV), palliation of symptoms and prolongation of survival with an improvement in the quality of life represent reasonable treatment goals.

Antineoplastic Agents↗
PubMed1994

Future directions in the treatment of non-small cell lung cancer.

Lung cancer is now the leading cause of cancer-related mortality for both men and women in North America. Non-small cell lung cancer (NSCLC) accounts for 75% to 80% of all primary lung tumors. Although the survival rate for patients with NSCLC remains poor, recent advances in our knowledge of the pathophysiology and biology of lung cancer have paved the way for the development of new, more effective therapeutic interventions. This paper reviews the current status and future prospects for the management of NSCLC, including adjuvant therapy following surgical resection for stages I, II, and IIIA disease; induction chemotherapy for locally advanced stages IIIA and IIIB disease; chemotherapy for advanced stage IV disease; and biologic response modifiers, including interferons, interleukins, colony-stimulating factors, and monoclonal antibodies.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Induction chemotherapy for locally advanced non-small cell lung cancer.

The poor survival of patients with stage III non-small cell lung cancer has led to a reevaluation of the role of systemic chemotherapy administered before operation. The results of 15 phase-II pilot trials of induction chemotherapy (5 with chemotherapy alone; 4 with chemotherapy and radiotherapy; and 6 with chemotherapy and concurrent radiotherapy) are reviewed in this article, and recommendations for future randomized studies are made. For most trials, only patients in stage IIIa were eligible, but five trials included both IIIa and IIIb patients. The studies employed a variety of chemotherapy and radiotherapy induction protocols, but no superiority could be demonstrated for the administration of chemotherapy and radiotherapy over chemotherapy alone. Response was observed in more than 50% of patients overall, although the complete clinical remission rate was always less than 15%, and the pathologic complete response rate was usually less than 10%. After induction therapy, approximately 70% of patients were eligible for a thoracotomy, and complete resection was possible in 60% of patients. The median survival ranged from 8 to 32 months, with a median of approximately 1 1/2 years. Two-year to 3-year survival ranged from 25% to 30%. The studies reviewed showed that induction therapy followed by surgical resection is feasible and is not associated with unacceptable toxicity. The apparent survival benefit conferred by such combined modality treatment may be due to patient selection, and until randomized trials are undertaken, induction therapy and surgical intervention for locally advanced non-small lung cancer must be viewed as experimental.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Screening, diagnosis, and staging of lung cancer.

Lung cancer has now displaced coronary heart disease as the single leading cause of excess mortality among smokers in the United States. Because screening by chest radiography and sputum cytology did not result in a reduction in lung cancer mortality, current research is directed at identifying earlier markers of malignancy. Molecular genetic and immunohistochemical techniques may now be applied to sputum cytology, and it may be possible to use such tests to screen certain subpopulations who are at extremely high risk for the development of lung cancer. Computed tomography scanning remains the most sensitive imaging technique for the evaluation and staging of patients with both small cell and non-small cell lung cancer. Several prospective trials have now shown that the specificity and sensitivity of computed tomography in the assessment of mediastinal nodes are still too low to eliminate the need for mediastinoscopy. Patients should not be denied thoracotomy on the basis of enlarged lymph nodes detected by computed tomography scan alone, and histologic verification of tumor involvement is essential, especially for patients who have obstructive pneumonitis. For extrathoracic staging, the diagnostic sensitivity and specificity of computed tomography and ultrasound are similar for the detection of liver metastases, but computed tomography is a more sensitive tool for detecting extrahepatic abdominal metastases. Monoclonal antibody imaging techniques currently do not seem to be either sensitive or specific enough to replace any of the current staging procedures more commonly in use.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Importance of clinical staging in limited small-cell lung cancer: a valuable system to separate prognostic subgroups. The University of Toronto Lung Oncology Group.

PURPOSE: In an attempt to assess the response to treatment and survival of a group of patients treated with standard chemotherapy and radiotherapy, we undertook a retrospective review of small-cell lung cancer (SCLC) patients treated by the University of Toronto Lung Oncology Group. PATIENTS AND METHODS: We reviewed the records of 264 patients with limited SCLC who were treated from 1976 to 1985. Based on radiologic review and physical examination, patients were assigned to three prognostic groups: group 1 (very limited SCLC), negative mediastinoscopy and/or no evidence of mediastinal nodes on radiologic review; group 2, x-ray evidence of mediastinal node involvement or a positive mediastinoscopy; group 3, supraclavicular adenopathy or x-ray evidence of pneumonic consolidation, pleural effusion, or atelectasis. All patients received combination chemotherapy, radiotherapy to the primary site, and prophylactic cranial irradiation. RESULTS: Complete response was seen in 52% of patients and partial response in 29%. Response rates did not differ among the three prognostic subgroups. The median survival time for patients in group 1 was 15.7 months, compared with 12 months for group 2 and 11 months for group 3 (P = .0175). Projected 5-year survival for group 1 was 18%, compared with only 6% and 2% for groups 2 and 3, respectively. There was no difference among the prognostic subgroups with respect to either local or distant recurrence rates. CONCLUSION: Using simple clinical staging techniques, we were able to identify a subgroup of patients with very limited SCLC who had a significantly better prognosis. We recommend that randomized clinical trials stratify patients according to the presence or absence of clinically detectable mediastinal lymphadenopathy.

Adult↗
PubMed1992

A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma.

METHODS: Ten patients with primary hepatocellular carcinoma were treated with intraarterial instillation of yttrium-90 (Y-90) microspheres, including eight men and two women (median age, 52 years; range, 29-69 years). Four patients were treated at a targeted hepatic dose of 50 Gy, two at 75 Gy, and four at 100 Gy. RESULTS: In 8 of the 10 patients, there was a significant concentration of Y-90 in localized tumor masses with tumor-to-liver perfusion ratios from 1.0:1-10.0:1. No patient had a complete or partial response, but 10 patients had stable disease (median duration, 10 weeks; range, 5-64 weeks). The median survival was 18 weeks (range, 2-150 weeks), and three patients lived longer than 1 year. Significant bone marrow or hepatic toxicity was not seen. One patient had a radiation-induced duodenal ulcer that required surgical management. CONCLUSIONS: Intraarterial instillation of Y-90 microspheres appears to be safe and deserves additional evaluation to determine whether there is meaningful activity in patients with primary hepatocellular carcinoma.

Adult↗
PubMed1992

Using serial observations to identify predictors of progression to AIDS in the Toronto Sexual Contact Study.

The Toronto Sexual Contact Study comprises a cohort of 249 male sexual contacts of men with HIV disease which has been followed every 3 months for almost 5 years. On enrollment 143 were seropositive and 16 seroconverted during the follow-up period. By 31 December 1989, 41 of the 159 seropositive cohort members had developed AIDS. Using Cox relative risk regression models, we investigated the association of a number of laboratory and clinical variables and progression to AIDS. Fixed covariate models examined laboratory variables from the enrollment visit of cohort members, with time calculated from this date. In models assessing time dependent covariates, time was calculated from the estimated date of HIV infection. In the univariate models of either fixed or time dependent covariates, many variables were significantly associated with risk of progression to AIDS (T4 cell count, T4/T8 ratio, blastogenic responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen, serum IgA, appearance of p24 antigen, and the development of oral hairy leukoplakia, thrush, or herpes zoster). Appearance of persistent generalized lymphadenopathy was not associated with increased risk of progression. In the multivariate model which evaluated fixed laboratory covariates, T4/T8 ratio, IgA level, and PHA response at enrollment were significantly associated with elevated risk.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Serodiagnosis↗
PubMed1992

The probability of progression to AIDS in a cohort of male sexual contacts of men with HIV disease.

In a cohort of 249 male sexual contacts of men with AIDS or an AIDS-related condition (ARC), 143 cohort members were seropositive on enrollment and 16 seroconverted during follow-up. A logistic Weibull mixture model was used to estimate the probability of progression to AIDS after HIV infection when infection was assumed to occur during the period of sexual contact with the primary case. Forty cohort members developed AIDS while under study. It appears that at least 50% of men with HIV disease will progress to AIDS and that the best estimate of this probability lies anywhere in the interval 70% to 100%.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer.

PURPOSE: This study was undertaken to review the clinical and laboratory features and response to treatment of patients with Cushing's syndrome associated with ectopic corticotropin (adrenocorticotropic hormone; ACTH) production and small-cell lung cancer (SCLC). PATIENTS AND METHODS: We undertook a retrospective chart review of 545 patients with SCLC seen at Toronto General Hospital between 1980 and 1990 and identified 23 patients (4.5%) with Cushing's syndrome and ectopic ACTH production. RESULTS: There were 17 male and six female patients, with a median age of 60 years. The syndrome was diagnosed at the time of initial presentation of SCLC in 13 patients and at relapse in 10 patients. Seven patients had limited disease and 16 had extensive disease at their initial diagnosis of SCLC, but 20 of 23 had extensive disease at the time of diagnosis of Cushing's syndrome. Ten patients had bone marrow involvement. The most frequent physical findings included edema (83%) and proximal myopathy (61%). All patients had elevated plasma and urinary free cortisol levels; 22 had a hypokalemic alkalosis, and 13 had hyperglycemia. Only one patient had a normal ACTH level. The response rate (complete plus partial) to chemotherapy for patients who had the syndrome diagnosed at initial presentation of SCLC was only 46%, and their median survival was only 3.57 months. Only two patients achieved complete normalization of all hormone parameters, and neither experienced hormone relapse at the time of SCLC relapse. Complications of therapy included gastrointestinal (GI) ulceration (six patients), GI bleeding (four), perforation of a duodenal ulcer (one), pneumonia (10), septic shock (three), and fungal infections (five). CONCLUSION: Ectopic ACTH production is associated with a low response to chemotherapy, short survival, and a high rate of complication to therapy.

ACTH Syndrome, Ectopic↗
PubMed1992

Second primary malignancies following diagnosis of small-cell lung cancer.

PURPOSE AND METHODS: The records of 800 patients with small-cell carcinoma of the lung (SCLC) treated between 1971 and 1985 at University of Toronto-affiliated hospitals were reviewed for the occurrence and relative risk of second primary malignancies (SPMs). Almost all patients who developed a SPM were treated previously with chemotherapy and radiation therapy. RESULTS: Nineteen metachronous SPMs (MSPMs) and 11 synchronous SPMs (SSPMs) were identified. SSPMs were detected between 1 and 12 months after the diagnosis of SCLC. The MSPMs were identified between 1 and 10 years after the diagnosis of SCLC. MSPMs included non-small-cell lung cancer (NSCLC) (four patients), hematologic malignancies (HM) (three patients), and 12 with other solid tumors (OST). The median survival times after the diagnosis of MSPM was 33 months, 10 months, and 1 month, respectively, for those with NSCLC, OST, and HM. Expected cancer incidence rates were used to compute a relative risk rate for developing a MSPM in a subset of 392 patients on whom accurate follow-up information was available. The calculated relative risk for all tumors was 3.73. The relative risk for the development of secondary NSCLC was 6.83. CONCLUSION: We suggest that increased predisposition to SPM may relate to secondary effects of multimodality treatment and biologic considerations.

Aged↗
PubMed1992

Phase I-II study of high-dose epirubicin in advanced non-small-cell lung cancer.

PURPOSE: A phase I multicenter trial was performed to determine the maximum-tolerated dose (MTD) of epirubicin, given on 3 consecutive days every 3 weeks to previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: After appropriate staging and a baseline multiple-gated angiogram (MUGA) scan, at least four patients were entered at each dose level, starting at 35 mg/m2 of epirubicin given intravenously (IV) daily for 3 days (105 mg/m2) and escalating by 5 mg/m2 per injection in each dose level (15 mg/m2 per course). Epirubicin was administered up to a maximum dose of 60 mg/m2/d for 3 days (180 mg/m2). The MTD was determined to be 55 mg/m2/d for 3 days (165 mg/m2) after treating a total of 35 (33 assessable) patients. Nadir granulocyte counts and associated febrile episodes comprised the dose-limiting toxicity, but there were no treatment-related deaths. A phase II trial was performed using a dose of 50 mg/m2/d for 3 days (150 mg/m2) every 3 weeks with no dose escalation, but with dose reduction for toxicity as required. A total of 30 patients were entered onto this phase of the study. RESULTS: The major toxicity, as in the phase I trial, was neutropenia with five febrile episodes, again with no treatment-related deaths. An overall response rate of 12 of 63 (19%) was noted in the combined patient population of the phase I-II trial, with 95% confidence intervals of 10% to 31%. When the response rate was analyzed by histology, only one of 17 (6%) patients with squamous histology, as compared with 11 of 46 (24%) with non-squamous histology, responded, but this did not reach statistical significance (P = .15). CONCLUSIONS: High-dose epirubicin is tolerable and is an active single agent in NSCLC. It should be combined with relatively nonmyelosuppressive agents such as cisplatin to try to obtain higher response rates and extend the survival in this disease.

Adult↗
PubMed1992

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial.

PURPOSE: The 5-year survival rates with surgical resection for preoperatively identified stage IIIA N2 non-small-cell lung cancer (NSCLC) are less than 10%. A pilot study of mitomycin, vindesine, and cisplatin (MVP) induction chemotherapy was undertaken in an attempt to improve the curative potential of surgery in this group of patients. PATIENTS AND METHODS: Thirty-nine patients with mediastinoscopy stage IIIA N2 NSCLC received two cycles of MVP. Responding patients underwent thoracotomy for resection and two further courses of MVP. RESULTS: The overall response rate was 64% (25 of 39) with three complete and 22 partial responses. Twenty-two patients were resected, which included a radical mediastinal node dissection. Eighteen resections were complete and four were incomplete. Pathologically, three patients (7.7%) had no tumor remaining. Toxicity included two postoperative deaths secondary to a bronchopleural (BP) fistula, mitomycin pulmonary toxicity in two patients, and septic deaths in four patients. Twenty-eight patients have died; 20 have recurrent or progressive disease. Eight of the 18 patients completely resected have recurred, with a median time to recurrence of 20.6 months. Sites of recurrence include two locoregional, five distant (two in brain), and one in both. Median survival of all 39 patients is 18.6 months, with a 3-year survival of 26%. The median survival for those patients completely resected was 29.7 months with a 3-year survival of 40%. CONCLUSIONS: We conclude (1) that MVP is an effective but toxic chemotherapeutic regimen for limited NSCLC; (2) the median survival seems to be prolonged; and (3) the role of induction chemotherapy followed by surgery in stage IIIA N2 NSCLC requires a phase III randomized trial to compare it with other treatment modalities.

Adult↗