A decision support tool for the detection of pancreatic cancer in general practice: A modified Delphi consensus.

BACKGROUND/OBJECTIVES: Diagnosis of pancreatic cancer is often delayed, contributing to patient and family distress and leading to worse survival. We aimed to develop a decision support tool to support primary care providers to identify patients that should undergo investigations for pancreatic cancer, and to recommend initial diagnostic pathways. METHODS: A modified Delphi process, including a series of three surveys, was undertaken to ascertain clinical expert opinion on which combinations of signs, symptoms and risk factors should be included in a tool for the early identification of pancreatic cancer. A group of clinical specialists finalised the development of the tool during a focus group meeting. RESULTS: The tool presents individual or combinations of signs, symptoms, and risk factors in three tiers which direct the urgency of investigation. Tier 1 includes 5 clinical presentation and risk factors clusters that indicate the need for urgent investigation of the pancreas. A further five clusters are included as Tier 2 aiming to elimate other causes and reduce the time to investigating the pancreas. Tier 3 includes a list of non-specific signs, symptoms and risk factors that indicate the need to consider pancreatic cancer as a potential diagnosis, but without specific recommendations for investigation. CONCLUSIONS: Prospective validation studies are now required prior to implementation in the primary care setting. Implementation into primary care practice and as an educational resource may facilitate rapid diagnosis and improve outcomes such as distress and survival.

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

PURPOSE: Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS: A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION: Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

A phase I/II study of the intralesional injection of ricin-monoclonal antibody conjugates in patients with hepatic metastases.

A phase I/II study of the intralesional administration of ricin-labelled monoclonal antibodies was conducted in patients with hepatic metastases of gastrointestinal origin. The anti-carcinoembryonic antigen (CEA) antibody I-1 was conjugated to blocked ricin via a disulphide bridge. After a test dose of antibody, patients were injected with ricin-antibody conjugates under computed tomography (CT) guidance on two occasions 1 week apart. Patients with stable or responding disease would receive a third course. The dose of ricin relative to surface area was increased in a predefined manner in cohorts of 3 patients. A total of 27 patients with hepatic metastases were entered into this study. All patients had metastatic colorectal cancer (26 patients) or adenocarcinoma of unknown primary with elevated CEA levels (1 patient). The presence of malignancy was documented cytologically in 9 of 11 patients tested. Minor responses were seen in 7 patients. However, no major objective responses or changes in the growth rate of injected lesions were observed. Toxicity was generally mild, the most common being hepatic capsular pain 24-48 h after each injection. 6 patients experienced rigors. One patient had anaphylaxis. Human anti-mouse and anti-ricin antibody responses were observed. Although substantial amounts of ricin conjugated to monoclonal antibodies were delivered into single lesions, this therapeutic approach was unsuccessful. Future studies of ricin-labelled antibodies should incorporate the systemic administration of immunoconjugates.

Severe interstitial pneumonitis following high-dose cyclophosphamide, thiotepa and docetaxel: two case reports and a review of the literature.

The use of high-dose chemotherapy for metastatic breast cancer has been an area of recent interest and the role of such treatment in the management of metastatic breast cancer is still to be defined. Multiple studies have suggested that such treatment can be given with minimal morbidity and mortality. We describe two cases of life-threatening interstitial pneumonitis, following high-dose chemotherapy (HDT) with cyclophosphamide, thiotepa and docetaxel with stem cell rescue given for metastatic breast cancer. The available relevant literature is reviewed.

A phase II study of cisplatinum and continuous infusion 5-fluorouracil for metastatic melanoma.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.

A phase II trial of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisolone rapidly alternating with doxorubicin and vincristine (CMFP/AV) in advanced breast cancer.

Sixty-seven patients with advanced breast cancer were prospectively entered into a Phase II trial of cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously (i.v.) on day 1, 5-fluorouracil 600 mg/m2 i.v. on day 1, and prednisolone 40 mg/m2 orally on days 1-14 (CMFP) rapidly alternating with doxorubicin 25-30 mg/m2 i.v. on day 8 and vincristine 1.4 mg/m2 i.v. on day 8 (AV). Complete responses (CR) were seen in 7 patients, partial responses (PR) in 25 (CR + PR, 48%), stable disease in 24, and progressive disease in 9. The median time to disease progression was 9.8 months, and the median survival 19.4 months. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia in 50% of patients. CMFP/AV is a well-tolerated, effective regimen in advanced breast cancer but does not appear to be superior to CMFP alone.

A phase II trial of zeniplatin in metastatic melanoma.

A third-generation platinum analogue, zeniplatin, was administered at a dose of 145 mg/m2 intravenously over 60-90 minutes every 21 days as the initial chemotherapy to 21 patients with metastatic melanoma. Prehydration and mannitol diuresis was introduced after the first 7 patients. There were 17 males and 4 females. The median age was 52 (range: 29-81). ECOG performance status was 0 in 10 patients, 1 in 8 patients and 2 in 3 patients. Major disease sites were lymph nodes, skin, lung, liver, and bone. Patients received a median of 2 cycles (range: 1-7). Two patients achieved partial responses. One with nodal disease progressed after 166 days and the other with buccal mucosal disease after 142 days. A third patient showed partial regression of nodal disease but developed cerebral metastases. Gastrointestinal toxicity included WHO grade 3 vomiting in 8 patients and nausea in 2. Antiemetics were used, but ondansetron was not available. WHO grade 3 hematologic toxicities included neutropenia in 8 patients and anemia and thrombocytopenia in 1 patient. Thrombocytosis was seen in 35% of courses. Dosage reduction was required in 15% of courses and escalation in 5% of courses. Three patients developed phlebitis related to the infusion. One patient developed a reversible rise in serum creatinine, but, unlike other studies, no severe nephrotoxicity was reported. Zeniplatin demonstrated only modest activity in melanoma with significant gastrointestinal and hematologic toxicity.

Flare responses in small cell carcinoma of the lung.

Two cases of small cell carcinoma of the lung in which flare responses were demonstrated are discussed. Although the primary tumor and extraskeletal metastases responded to first-line chemotherapy, bone scintigraphs performed 3 months after the start of treatment suggested tumor progression. However, following repeat bone imaging and subsequent clinical evaluation, the interim scintigraphs appeared to represent an unusual flare response, in which the activity of pre-existing hot spots increased and new lesions developed.

Patients' beliefs about cancer management.

The results of a questionnaire answered by 205 medical patients are reported (100 patients with cancer and 105 with other medical conditions). The questionnaire examined beliefs and preferences regarding various aspects of cancer, including expectations of medical management and treatment. The issues examined relate to beliefs and preferences about information giving, trust of doctors' control of decision making, expectations of help, expectations of treatment, the treatment of cancer pain including morphine use, and issues of terminal care. Some patients appear to hold the inconsistent beliefs that doctors should tell them all they want to know, but that doctors do not know a lot of what they would like to be told. They were also ambivalent about who should make decisions, patient or doctor, suggesting a preference for collaborative consensus decision making. It may be important to inform patients more clearly about what doctors can and cannot reasonably be expected to know and do. Some incorrect beliefs about management were related to fear about having cancer. The results suggest the need for better communication between patients and their professional carers and the need for accessible health information about cancer management to be available to the general public.

Medical education in palliative care.

There has been recent concern about both the care of dying patients and the adequacy of the preparation that most doctors receive for this task. The role of the doctor in palliative care is discussed and the educational needs of medical students in palliative care are suggested. A palliative care course for fifth-year students at the Austin Hospital-Repatriation General Hospital Clinical School, University of Melbourne, is described. This course recently has been adopted by the Victorian Palliative Care Council as a model for undergraduate palliative medicine education, and has been recommended to the University of Melbourne and Monash University Medical Schools for incorporation in each Clinical School curriculum.

Oral methotrexate for superficial transitional cell carcinoma of the bladder.

A total of 22 patients with superficial transitional cell carcinoma of the bladder, uncontrolled cystoscopically and unsuitable for or having failed intravesical therapy, received 50 mg. oral methotrexate per week for 12 months. Of the patients 7 (32%) achieved or remained in complete remission and 5 achieved a partial response, while 4 remained stable, 3 had progression and 3 were not evaluable. Patients who were still alive had a median followup of 2.5 years. Two patients with complete remission had relapse at 16 and 26.4 months, and 5 were disease-free at 34.5, 31.3, 18.6, 17.8 and 16.8 months, respectively. The methotrexate was generally well tolerated but 2 patients discontinued therapy because of dyspnea (1 subsequently died of respiratory failure that was possibly related to the methotrexate) and 1 because of persistent grade 2 mucositis. Grade 3/4 toxicities occurred in 3 patients: 1 each with reversible increases in creatinine and aspartate aminotransferase, and 1 with gastric bloating. There was little hematological toxicity. Reversible skin lesions developed in 4 patients. This oral treatment may provide an effective alternative to intravesical therapy but can be associated with severe toxicity.

Lean body mass, body surface area and epirubicin kinetics.

For a number of cytotoxics, a relationship between efficacy and plasma concentrations has recently been demonstrated. Lean body mass has been demonstrated to be a useful parameter for predicting drug clearance for a number of non-cytotoxic drugs. However, the role of lean body mass in predicting drug clearance for any cytotoxic drug has not been previously reported. Our purpose was to investigate lean body mass as a predictor of epirubicin clearance. Pharmacokinetic studies were performed in 10 patients receiving single agent epirubicin. Although preliminary, this study suggests that lean body should be further evaluated and tested in dose optimization studies.