The use of gemcitabine in non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group. Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTION: Is there a role for the use of gemcitabine in the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)? OBJECTIVE: To make recommendations about the use of gemcitabine in the management of medically appropriate patients with stage IIIB-IV NSCLC. OUTCOMES: The outcomes of interest were survival, response rate, symptomatic response, response duration and toxicity. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 2 members of the Provincial Lung Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The practice guideline report was reviewed by the Provincial Lung Cancer DSG and by the Systemic Treatment Disease Site Group. These committees comprise medical and radiation oncologists, surgeons, pathologists, nurses, a psychologist, a medical sociologist and administrators. One community representative participated in the development of this practice guideline. QUALITY OF EVIDENCE: Five phase II studies of single-agent gemcitabine in advanced NSCLC were reviewed. Four of these are published as full reports. Two randomized phase II studies comparing single-agent gemcitabine with etoposide plus cisplatin were also reviewed. One of these studies is fully published. Seven phase II studies of gemcitabine in combination with cisplatin and I phase II study of gemcitabine in combination with ifosfamide were reviewed. Three randomized controlled trials (RCTs) and 1 randomized phase II study, published in abstract form, compared gemcitabine combination chemotherapy with cisplatin combination chemotherapy. An additional phase II study, published in abstract form, of gemcitabine as salvage therapy in previously treated patients was also included. BENEFITS: Four phase II studies of single-agent gemcitabine at a dose of 1000 mg/m2 or more showed a combined response rate of 19% (intention-to-treat analysis; 95% confidence interval [CI] 15% to 24%) or 21% (efficacy analysis; 95% CI 17% to 26%) in advanced NSCLC. Median survival ranged from 7 to 9 months. Improvement from baseline in cough, hemoptysis and dyspnea was comparable to what would be expected with radiation therapy and with standard combination chemotherapy regimens. Improvement from baseline in their performance status was reported in 52% of treated patients. The 2 randomized phase II studies reported equivalent response rates for gemcitabine compared with etoposide plus cisplatin; the response data were pooled, which resulted in a nonsignificant benefit for gemcitabine (common odds ratio [OR] 0.90; 95% CI 0.43 to 1.90; p = 0.78). Gemcitabine has most frequently been combined with cisplatin, yielding a combined response rate of 44% (intention-to-treat; 95% CI 36% to 47%) or 45% (efficacy; 95% CI 39% to 51%) from 7 phase II studies. Median survival times ranged from 10 to 14 months. One phase II randomized study compared gemcitabine-cisplatin-vinorelbine vs. cisplatin-epirubicin-vindesine plus lonidamine and demonstrated a higher response rate (62% vs. 35%) in favour of the gemcitabine combination. Three RCTs demonstrated increased response rates for the combination of gemcitabine-cisplatin over either cisplatin alone or other combination regimens [(gemcitabine-cisplatin 35% vs. etoposide-cisplatin 12%; p = 0.001), (gemcitabine-cisplatin 31% vs. cisplatin 9%; p = 0.0001), (gemcitabine-cisplatin 40% vs. mitomycin, ifosfamide, cisplatin 28%; p = 0.03)]. HARMS: The major dose-limiting toxicity is neutropenia. Despite this, infection rates are low. Significant adverse effects that have an impact on the patient's quality of life or require the discontinuance of treatment are reported to be less than with any other single agent or combination of agents. Grade 3 or 4 dyspnea has been reported to occur in fewer than 2% of cases and may be drug related. (ABSTRACT TRUNCATED)

Lung volume reduction for emphysema and the Canadian Lung Volume Reduction Surgery (CLVR) Project.

OBJECTIVE: To review the literature on the surgical treatment of emphysema and to present preliminary results from a pilot study of lung volume reduction (LVR) surgery. DESIGN: Case series of consecutive patients referred for LVR surgery. Outcomes were quality of life, pulmonary function and exercise capacity. SETTING: Two university-affiliated hospitals in Ontario. POPULATION STUDIED: Patients between the ages of 40 and 75 years with emphysema who had severe airflow limitation, hyperinflation of the lungs and impaired quality of life. INTERVENTION: Bilateral reductions with multiple wedge resections of the lung using a linear stapling device with bovine pericardial buttressing were completed via a median sternotomy. MAIN RESULTS: Of 50 patients referred, 24 underwent LVR surgery. Mean age of the cohort was 63 years. Operative 30-day or in hospital mortality was 8%. Two other patients (8%) died from respiratory failure after LVR within the first year. Postoperative complications included prolonged air leaks (six of 24), tracheobronchitis (five of 24), mechanical ventilation (four of 24) and pneumonia (three of 24). Mean length of stay was 18 days (median 12 days). At one year, there was a sustained decrease in total lung capacity from 133% to 123% predicted. There were improvements in forced expiratory volume in 1 s, from 22% of predicted preoperatively to 32% postoperatively, and in 6 min walk performance, from 345 to 381 m. Improvements were also noted in the quality of life assessments. CONCLUSIONS: Preliminary results suggest that LVR surgery is feasible and may improve the patient's quality of life, pulmonary function and exercise capacity. A randomized clinical trial comparing LVR plus the best medical management with the best medical management alone is currently underway to determine the effectiveness of LVR.

Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative.

PURPOSE: To review noninvasive methods for diagnosis of first and recurrent deep venous thrombosis and provide evidence-based recommendations for the diagnosis of deep venous thrombosis in symptomatic, asymptomatic, and pregnant patients. DATA SOURCES: Accuracy (comparison with contrast venography) and management (safety of withholding anticoagulants when results were normal) studies that evaluated tests for diagnosis of deep venous thrombosis were identified from a MEDLINE search, personal files, and bibliographies of reviews and original studies. STUDY SELECTION: Prospective cohort studies (accuracy and management studies) and randomized comparisons (management studies) that satisfied predefined methodologic criteria were included. DATA EXTRACTION: Sensitivity, specificity, and positive and negative predictive values were determined for accuracy studies. Rates of venous thromboembolism during long-term follow-up of patients with normal results were determined for management studies. DATA SYNTHESIS: Data from individual studies were combined under a random-effects model. The accuracy of noninvasive tests was compared, with emphasis on within-study comparisons. Recommendations for diagnosis of deep venous thrombosis were developed by a multidisciplinary group and graded according to the strength of the supporting evidence. Venous ultrasonography is the most accurate noninvasive test for the diagnosis of a first symptomatic proximal deep venous thrombosis. However, neither ultrasonography nor impedance plethysmography is accurate in asymptomatic postoperative patients. Venous ultrasonography is less accurate for symptomatic isolated distal (calf) deep venous thrombosis than for proximal deep venous thrombosis, and the clinical utility of venous ultrasonography of the distal veins is uncertain. Withholding anticoagulant therapy in symptomatic patients with suspected deep venous thrombosis who have normal results on serial venous ultrasonography or impedance plethysmography is safe. Diagnosis of recurrent deep venous thrombosis requires evidence of new thrombus formation, such as a new noncompressible venous segment detected by venous ultrasonography, conversion of a normal result on impedance plethysmography to abnormal, or presence of an intraluminal filling defect on venography. Suspected deep venous thrombosis in pregnant patients can usually be managed with serial venous ultrasonography or impedance plethysmography. In symptomatic patients with a suspected first episode of deep venous thrombosis, clinical assessment and D-dimer testing are complementary to testing with venous ultrasonography and impedance plethysmography. CONCLUSIONS: Patients with suspected deep venous thrombosis can usually be managed with noninvasive testing. However, if the results of this testing are nondiagnostic or are discordant with the clinical assessment, venography should be considered.

Use of preoperative chemotherapy with or without postoperative radiotherapy in technically resectable stage IIIA non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTION: Should preoperative (neoadjuvant) cisplatin-based chemotherapy with or without postoperative radiotherapy be offered to patients with technically resectable stage IIIA non-small-cell lung cancer (NSCLC) to improve survival? (Resectability should be determined preoperatively by a thoracic surgeon.) OBJECTIVE: To make recommendations about the use of preoperative cisplatin-based chemotherapy with or without postoperative radiotherapy in technically resectable stage IIIA NSCLC. OUTCOMES: Survival is the primary outcome of interest. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (LCDSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence was then presented to the full LCDSG and discussed extensively at 5 of its meetings. The LCDSG comprises medical and radiation oncologists, pathologists, surgeons, epidemiologists, a psychologist and a medical sociologist. A community representative was present at one meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: Four small randomized controlled trials (RCTs) were available for review; 2 were completed and were reported in full in the literature, 1 was published in abstract form, and 1 was closed and was reported as an interim analysis. Although the RCTs used appropriate clinical trials methodology, including planned interim analyses and early stopping rules, retrospective review revealed inconsistencies between the treatment arms for subsets of stage IIIA disease and for prognostic factors. These factors and the small samples in each study limit the interpretation of the results. BENEFITS: The data from 2 of the 4 trials were not combined because the data were not mature in one case and not extractable in the other. The 2 fully published, completed trials reported a survival benefit for patients treated with preoperative chemotherapy with or without postoperative radiotherapy compared with those not given preoperative chemotherapy. One trial reported a median survival of 26 months in the treatment group versus 8 months in the control group (p < 0.001). A second trial reported an estimated median survival of 64 months versus 11 months (p < 0.008) and a 3-year survival rate of 56% versus 15% respectively. A pooled analysis of the 2-year survival data from the 2 completed RCTs yielded an odds ratio for death of 0.18 (95% confidence interval 0.06 to 0.51) in favour of preoperative chemotherapy. HARMS: There was no difference in the postoperative mortality between the trials reviewed. Toxic effects associated with the chemotherapy were limited primarily to neutropenic fever, nausea and vomiting.

Progress of clinical oncology guidelines development using the Practice Guidelines Development Cycle: the role of practitioner feedback.

PURPOSE: To present an update on the development of oncology practice guidelines (PGs) using the Practice Guidelines Development Cycle (Cycle), and to present the results of surveys of oncologists on the first 10 guidelines from the Cancer Care Ontario Practice Guidelines Initiative. METHODS: Practitioners' opinions about guidelines in development were sought using a mail survey method with systematic follow-up. Practitioners were identified by cancer center representatives. Survey packages included evidence-based recommendations (EBRs) and a one-page, nine-item feedback questionnaire. Data were collected between February 1995 and February 1996. RESULTS: Nine hundred fourteen surveys that pertained to 10 guidelines were mailed to 423 practitioners in Ontario. Practitioners included 112 medical oncologists/hematologists, 34 radiation oncologists, 195 surgeons, and 82 practitioners from other medical specialities. One hundred practitioners were located in cancer centers and 323 had community-based practices. The overall response rate by practitioner was 72% and by survey questionnaire, 70%. For the five questionnaire items that assessed guideline quality, approval ratings ranged from 86% to 92%. For the 10 recommendations, 77% ( 63% to 82%) of respondents agreed that the EBR could be approved as a PG. Response and approval rates were consistent across medical specialities and locations of practice. CONCLUSION: The process of obtaining practitioner feedback in the development of PGs is both feasible and useful. The high response rates to the survey indicate that it is possible to obtain broad participation in evidence-based guidelines development throughout Ontario. The changes made to the EBRs in response to feedback suggest that practitioners' opinions can be valuable in shaping evidence-based guidelines.

Surgical management of early stage invasive breast cancer (stage I and II). Provincial Breast Disease Site Group.

GUIDELINE QUESTION: What is the optimal surgical management of early stage invasive breast cancer (stage I and II)? More specifically, what is the relative efficacy (and safety) of breast conservation therapy (lumpectomy with axillary dissection) compared with modified radical mastectomy? OBJECTIVE: To make recommendations about surgical management and techniques in the treatment of early stage invasive breast disease (stage I and II). OUTCOMES: Survival, local recurrence (for lumpectomy patients) and quality of life are the primary outcomes of interest. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 6 members of the Ontario Cancer Treatment Practice Guidelines Initiative, Disease Site Group for Breast Cancer (Breast DSG). Earlier drafts of this evidence-based recommendation have been reviewed, discussed and approved by the Breast DSG, which comprises surgeons, medical oncologists, radiation oncologists, epidemiologists, a pathologist and a medical sociologist. There was no consumer participation in the development of this guideline. QUALITY OF EVIDENCE: There are 7 randomized controlled trials (RCTs) comparing breast conservation therapy with mastectomy in women with early stage breast cancer. BENEFITS: In 6 RCTs, no statistically significant differences were detected in survival rate between the mastectomy and conservative therapy (lumpectomy) groups. In 1 RCT, a statistically significant differences was detected in favour of the mastectomy arm; however, this was an early trial with substantial methodologic weaknesses. HARMS: None. PRACTICE GUIDELINE: Women with early stage invasive breast cancer (stage I and II) who are candidates for breast conservation therapy (see discussion of technical factors) should be offered the choice of either breast conservation therapy (excision of tumour with clear margins and axillary dissection) or modified radical mastectomy. The choice is an individual one for the patient, and thus she should be fully informed of the options, including the risks and benefits of each procedure. She should be informed that breast irradiation is part of the procedure for breast conservation therapy. In addition, she should be aware of the potential need for further surgery if the margins are positive. For further information about the use of radiotherapy in the management of early stage breast cancer, please refer to the Ontario Cancer Treatment Practice Guidelines Initiative's practice guideline Breast Irradiation in Women with Early Stage Invasive Breast Cancer Following Breast Conserving Surgery.

Chemotherapy in stage IV (metastatic) non-small-cell lung cancer. Provincial Lung Disease Site Group.

GUIDELINE QUESTION: In patients with metastatic, stage IV non-small-cell lung cancer (NSCLC) does chemotherapy improve survival and quality of life? OBJECTIVE: To make recommendations about the role of chemotherapy in the treatment of metastatic (stage IV) NSCLC. OUTCOMES: Survival and quality of life are the primary endpoints of interest. Specifically, 1-year survival will be considered. PERSPECTIVE: Evidence was selected and reviewed by 3 medical oncologists and the project coordinator of the Ontario Cancer Treatment Practice Guidelines Initiative. Drafts of this document have been circulated and reviewed by the Provincial Lung Disease Site Group (Lung DSG). The Lung DSG comprises medical and radiation oncologists, pathologists, surgeons, epidemiologists, a psychologists and a medical sociologist. There was no consumer participation in the development of this guideline. QUALITY OF EVIDENCE: There were 3 meta-analyses available for review, but only 1 is discussed in detail. The largest and most comprehensive meta-analysis is based on 11 randomized controlled trials involving 1190 patients. The main comparisons were chemotherapy plus supportive care versus supportive care alone. The largest trial included in the meta-analysis involved randomization of 188 patients, and the smallest trial involved randomization of 32 patients. Only trials that had accrued patients between Jan. 1, 1965, and Dec. 31, 1991, were included in the analysis. BENEFITS: A survival benefit at 1 year was seen for the group of patients treated with chemotherapy (pooled hazard ratio 0.84; 95% confidence interval [CI], 0.74 to 0.95). Subgroup analyses suggested a benefit for patients receiving chemotherapy regimens containing cisplatin (pooled hazard ratio, 0.73; 95% CI, 0.63 to 0.85; relative risk reduction for death, 27%; absolute improvement in 1 year survival, 10%; 95% CI, 5% to 18%; gain in median survival 1.5 months; 95% CI, 1 to 2.5 months). No benefit for patients treated with chemotherapy was found beyond 1 year. None of the randomized trials successfully measured quality of life using QOL assessment instruments. No firm conclusions can be made about the potential benefits (as measured by quality of life) that chemotherapy has for patients with metastatic NSCLC, as there are no available data from randomized controlled trials. However, several trials have documented relief of cancer-related symptoms, such as pain, cough, hemoptysis or dyspnea in the majority (approximately 70%) of patients. HARMS: In a subgroup analysis of trials that used long-term alkylating agents other than cisplatin (an approach no longer used as therapy in NSCLC) as part of the chemotherapy regimen, the meta-analysis demonstrated a detrimental effect of chemotherapy on survival (pooled hazard ratio, 1.26; 95% CI, 0.96 to 1.66, p = 0.09). In general, myelosuppression, sepsis resulting in hospitalization, drug-specific toxicities and death are potential complications of chemotherapy.

Use of vinorelbine in non-small-cell lung cancer. Provincial Lung Disease Site Group.

GUIDELINE QUESTION: Is there a role for the use of vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC)? OBJECTIVE: To make recommendations about the use of vinorelbine in the management of patients with NSCLC. OUTCOMES: Survival is the primary endpoint of interest. Response and toxicity are secondary endpoints. PERSPECTIVES: Evidence was selected and reviewed by the 4 members of the Lung Disease Site Group (Lung DSG). Early drafts of this practice guideline were reviewed by the Lung DSG and by the Systemic Treatment Program Committee (STPC). These committees comprise medical and radiation oncologists, pathologists, surgeons, epidemiologists, pharmacists, nurses, a psychologist, a medical sociologist and administrators. No consumers participated in the development of this guideline. QUALITY OF EVIDENCE: Only evidence from randomized controlled trials (RCTs) and phase II studies was evaluated. Six RCTs and 5 phase II studies were reviewed and are discussed in this report. Of the 6 RCTs, 3 have been fully published. BENEFITS: Vinorelbine, either as a single agent or in combination with cisplatin, produces higher response rates (12%-37%) than other single agent vinca alkaloids (10%-20%) in patients with previously untreated NSCLC. Two of 3 RCTs that reported survival differences demonstrated a survival benefit for previously untreated patients with NSCLC when treated with vinorelbine in combination with cisplatin as compared with patients treated with either vindesine plus cisplatin (p = 0.04) or leucovorin plus 5-fluorouracil (p = 0.03). The third study reported no statistically significant difference between patients treated with vinorelbine alone and those receiving vinorelbine plus cisplatin. HARMS: The major toxic effects are hematologic. Neutropenia is the dose-limiting toxic effect. However, there is less neurotoxicity than with other vinca alkaloids (e.g., vindesine) and less nausea and vomiting than with other active agents used in the treatment of NSCLC. PRACTICE GUIDELINE: Evidence from randomized controlled trials supports the use of vinorelbine as an option for the first-line treatment of patients with locally advanced or metastatic NSCLC. Whether vinorelbine is used as a single agent or in combination with cisplatin depends on the anticipated trade-offs between the expected symptomatic benefits of a higher response rate with the combination (as seen in randomized controlled trials) and the increased toxicity. Evidence for a possible survival advantage for the combination of vinorelbine and cisplatin over vinorelbine alone is conflicting. There is insufficient evidence at the present time to advocate the use of vinorelbine in previously treated patients who have recurrent or progressive disease. Similarly, there is insufficient evidence at the present time to advocate the use of vinorelbine as adjuvant or induction therapy for patients with stage I, II or early stage III disease. The enrolment of patients with NSCLC in clinical trials is encouraged.

Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the