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The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. [...]

Chemotherapy dosing only based on body surface area (BSA) results in marked pharmacokinetic and toxicity variations, which may result in an inferior outcome for some patients. A toxicity-based dosing schedule for individually tailored treatment with granulocyte colony-stimulating factor (G-CSF) supported 5-fluorouracil (F), epirubicin (E) and cyclophosphamide (C) (dFEC) was developed and studied in patients with metastatic breast cancer with the purpose to determine its efficiency and toxicity. Twenty-six women, median age 48 years, were included and the individual E and C doses were tailored stepwise based on the recorded hematological toxicity. Twenty-one patients (81%; 95% confidence interval (CI), 66% to 96%) had an objective response, including six complete responses (23%; CI, 7%–39%). At median follow-up of 113 months, the median time to progression and median overall survival were 14 and 36 months, respectively. The delivered dose intensity was high but varied substantially between patients (ranges F 126–202, E 14.4–36.0, C 160–510 mg/m2/w). The dominating grade III/IV toxicity was nausea (12% of patients) and febrile neutropenia (31% of patients). The tailored and dose-escalated FEC was highly active and feasible in metastatic breast cancer and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing. [ABSTRACT FROM AUTHOR]

Background: Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4. Methods: A total of 11 cancer patients (4 male, 7 female, aged 50-68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60-100 mg/m², on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14. Results: Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC0-last was 3.26 vs 3.17 μg h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC0-∞ 3.51 vs 3.39 μg h/ml (P>0.25; ratio B/A 0.96); geometric mean Cmax was 3.53 vs 3.37 μg/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m² (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm³ during treatment with docetaxel alone and 975/mm³ during aprepitant coadministration. Conclusions: Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy in patients with acute myeloid leukaemia (AML) is based on 129 scientific articles; one meta-analysis, 51 randomised trials, 39 prospective and 18 retrospective studies, and 20 other articles. Altogether, 39 557 patients were included in these studies. The conclusions reached can be summarized into the following points: •Standard induction therapy for patients with AML, consisting of daunorubicin and ara-C in conventional doses, results in a complete remission (CR) rate of 50-60% in an unselected population and a long-term survival of about 10-20%. The total doses of both ara-C and daunorubicin are of importance for remission duration and in some studies also for survival. •High-dose ara-C in the induction therapy prolongs remission duration in randomised trials, but has not been proven to affect long-term survival. It also increases toxicity and is not generally recommended. •Idarubicin, another anthracyclin, has been compared with daunorubicin in conjunction with ara-C, resulting in a higher CR rate, especially in younger patients. In a meta-analysis of the five-randomised trials performed, a slight survival advantage was also seen with idarubicin. Yet, there is inconclusive evidence to conclude that idarubicin is superior to daunorubicin, and further trials are needed. •Mitoxantrone improves the outcome of induction therapy in comparison with daunorubicin in some randomised studies, but conclusive evidence is still lacking. •The addition of etoposide to daunorubicin or mitoxantrone and ara-C has improved CR rates, but has not convincingly improved survival and secondary leukaemias may be induced. •New induction treatment strategies are defined by identification of prognostic subgroups. A risk stratification of AML patients as to chromosomal aberrations might be of importance for the choice of therapy. Moreover, the speed and the morphological response to the first induction course are predictive for relapse. However, no prospective randomised studies are as yet published regarding risk-adapted induction therapy. •Post-remission dose-intensive chemotherapy prolongs the duration of remission, seemingly most in patients <60 years. However, the data in support of these conclusions are sparse. A convincing effect on survival has not been shown. •Limited data indicate that post-remission maintenance therapy with long-term attenuated chemotherapy prolongs time to recurrence, without evidence for prolongation of survival. •Allogeneic bone marrow transplantation is an established practice for consolidation in first remission for young patients with an HLA-matched sibling. It is however not known which patients will really benefit from transplantation as no truly randomised comparison of allogeneic vs autologous transplantation or conventionally-dosed chemotherapy has been performed. Patients with and without an HLA-identical sibling have been compared on the basis of intention-to-treat principles ('genetic randomisation'). The disease-free survival seems to be prolonged in the donor group, due to a lower relapse rate with allogeneic transplantation. A higher procedure-related mortality makes the effects on total survival uncertain. Randomised trials with autologous transplantation vs conventional consolidation show a lower relapse rate and a trend for an improved disease-free survival. In one study, in which an autograft was added to four courses of intensive therapy, there was also a late survival advantage. Thus, the role for intensified post-remission treatment in first complete remission with high-dose chemotherapy followed by allogeneic or autologous marrow or stem cell transplantation requires further studies. Moreover, studies with stratification of therapy according to predictors for prognosis in the individual patient are needed. •Allogeneic stem cell transplantation after minimal or reduced myeloablative conditioning ('mini-transplantation' or non-myeloablative stem cell transplantation) induces a host-vs-graft tolerance and an immune graft-vs-leukaemia effect. This new concept of cellular immunotherapy seems to have a low procedure-related mortality, but long-term effects are unknown and evaluation in controlled clinical studies is required. •Patients with relapsed AML can only infrequently achieve long-term remissions with chemotherapy in conventional doses. Uncontrolled data indicate that allogeneic transplantation can be a curative treatment for these patients as well as for those refractory to initial conventional chemotherapy. No studies have compared the effect of allogeneic transplantation in first compared with second remission. •Treatment of elderly patients is controversial. In selected elderly patients with good performance status and absence of concomitant diseases, a combination of ara-C with an anthracycline, both in conventional doses, is the treatment of choice to prolong survival. Oral cytotoxic drugs, e.g. hydroxyurea and 6-thioguanine, or low dose ara-C subcutaneously are other treatment options that will lead to remission in a few patients, seemingly with a good quality of life and with few days spent in hospital. •The use of haematopoietic growth factors in patients with AML is doubtful. Most controlled studies show a shortened time for neutropenia and less infectious complications, but no better effect with reference to remission or survival. [ABSTRACT FROM AUTHOR]

This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent NHL of follicular type were evaluated. These constitute about 75% of all haematological malignancies. Thirdly, ovarian cancer was included since chemotherapy has been extensively used and since, at the time of the planning of this overview, a group of very expensive drugs, the taxanes, had preliminarily shown promising results. A wealth of scientific literature has been published on cancer therapy. The review presented in this report is limited to scientific studies judged to be important for evaluating chemotherapy efficacy. Assessments of the content and quality of these studies, and a critical summary of the results in all stages of the selected tumours, have never before been attempted in this way. However, similar comprehensive overviews of certain stages of the tumours have previously been made. These overviews were also critically evaluated. Totally 1496 studies involving 558743 patients were reviewed. The survey of practice of chemotherapy use involved all departments of surgery, urology, gynaecology, internal medicine including haematologic units, pulmonary medicine and general and gynaecologic oncology at 16 hospitals in two health care regions in Sweden, covering 39% of the Swedish population. During the 4 weeks of the survey, all patients with the diagnoses concerned who received chemotherapy were registered. The study included 1590 patients. The working group's general conclusions are summarised in the following points •The literature on the effects of chemotherapy is extensive. Chemotherapy has a well-documented role in the curative and palliative treatment of patients with several types of cancer. The use of chemotherapy is of utmost importance for the possibility of cure in certain tumour types. In other tumours, chemotherapy increases the possibility of cure when added to local and regional treatments, particularly surgery. In the instances of no possibility of cure, chemotherapy may to a variable extent improve both patient survival and well-being. •In Sweden chemotherapy is largely used in accordance with that documented in the scientific literature. The extent of both over- and under-treatment seems to be limited but cannot be excluded at the individual patient level. •The literature-based knowledge is scientifically of lower quality in the most chemotherapy sensitive tumours than in tumours showing more limited sensitivity. In the more sensitive tumours, positive effects on a symptomatic stage and survival were seen several decades ago. In those days, clinical treatment studies did not fulfil the current high quality requirements. •Small life-prolonging effects of chemotherapy are sometimes very well documented in large, high quality scientific studies. Some of these studies have also documented palliative effects in a comparably limited proportion of the patients. It is of great importance to initiate a discussion whether such treatment should be recommended cancer patients in routine health care in Sweden. •The survey shows that in the instances where the literature shows small but convincing treatment effects, the use of chemotherapy is restrictive in Sweden. It is likely that this reflects the doctors' priorities of what treatments should be offered patients in routine care. It might, however, also represent an appropriate adaptation to the fact that the favourable effects have mostly been observed in selected patients with good prognosis. The patients' decisions after open information on treatment benefit and side-effects may also contribute to a limited use. Whether the same treatment benefit would be obtained in the 'whole' group of patients is not known. If such treatment should be offered all patients without medical contraindications, according to what has been demonstrated in prospective randomised trials, the number of treatments and the cost for chemotherapy would increase substantially. •Clinical trial protocols or written guidelines should preferably be widely applied as a basis for treatment decisions and for assessment of the clinical benefit from new treatments. A greater need exists for controlled clinical trials, which, when appropriate, should also include an assessment of impact on patients' quality of life (QoL) and economic consequences in conjunction with cancer treatment. This knowledge is, particularly in the palliative situation, essential for determining future recommendations, and choosing among alternative forms of treatment. Such studies usually require international collaboration. Assessment of QoL is clearly in need of further methodological development to be able to report reliable data. •The total drug cost for chemotherapy in Sweden is estimated at approximately 280 million Swedish kronor (SEK) in 1998. This represents 4% of the costs for cancer care and 1.7% of the costs for all medicinal products in Sweden. •The cost-effectiveness of chemotherapy has been studied, but these studies are mostly of low quality. They suggest, however, that chemotherapy is cost-effective, in terms of cost per life year saved, in comparison with other well-established routine treatments in a number of other diseases. •Since the treatment of cancer is far from successful, there is a need for further research. The survey showed that only about 10% of the treatments were given within clinical trial protocols aimed at further elucidating treatment effects. This figure should be considerably higher. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for breast cancer is based on 233 randomised studies, 9 meta-analysis of randomised studies, a population-based cohort study and 18 overviews/retrospective analyses including a total of 155 243 patients. The conclusions reached can be summarised into the following points: Adjuvant treatment •There is solid scientific support from randomised studies that adjuvant polychemotherapy at 10 years will result in an absolute mortality reduction for patients younger than 50 years by 12% for node positive (34% relative mortality reduction corresponding to an estimated median survival prolongation of several years) and 6% for node negative patients. For women aged 50 to 69 years, the corresponding figures for node positive and node negative patients are 6% and 2%, respectively (approximately 11% relative mortality reduction). •Anthracycline-containing combinations result in an absolute survival benefit at five years of 3% compared with non-anthracycline based polychemotherapy. •There are indications that the taxane paclitaxel may further improve the survival compared with anthracyclines. However, the limited data preclude conclusions for the routine care. •The addition of tamoxifen to chemotherapy further enhances the survival benefit for receptor positive subgroups. •The roles of more dose-intensive regimens, including high-dose therapy with stem cell support, are presently studied in randomised investigations. The data presented so far are conflicting but they do not in general support high-dose therapy. •Quality of life, based on analyses of randomised studies, demonstrate that adjuvant polychemotherapy has an initial detrimental effect, but long-term follow-up of treated patients demonstrates no impairment of quality of life compared with untreated patients. •Polychemotherapy in standard doses should be offered to premenopausal node positive patients, and the corresponding postmenopausal group with a receptor-negative breast cancer and to node negative patients with high risk factors. Polychemotherapy should be combined with tamoxifen to all patients with receptor-positive tumours. Due to a need of more knowledge in this field, patients should be included in investigational protocols. Locally advanced breast cancer •Based on current knowledge, treatment of patients with locally advanced breast cancer should include neoadjuvant/preoperative polychemotherapy since there is evidence from controlled studies that such therapy will statistically significantly increase the number of patients who can be offered breast-conserving surgery. Indirect comparisons also demonstrate survival improvements, but the scientific support is equivocal. Metastatic breast cancer •The median survival for patients with metastatic disease treated with conventional chemotherapy doses and regimens is 12 to 24 months. •Retrospective cohort studies indicate that the use of non-anthracycline containing chemotherapy compared with no chemotherapy might add a survival gain of six to nine months. However, this estimation is based on equivocal data. •Based on overview data, polychemotherapy results in a statistically significant survival gain compared with single-agent therapy. •Based on repeated randomised studies, the addition of anthracyclines increases the response rate and statistically significantly improves the survival compared with non-anthracycline containing chemotherapy, except for CMF combined with prednisone/prednisolone, which will statistically significantly improve the survival compared with some anthracycline combinations. •Second line therapy using vinorelbine or docetaxel is statistically significantly better than other regimens with a time to progression and survival benefit in the order of one to three months based on few randomised studies. The role, if any, of third line therapy is yet to be demonstrated. •In the metastatic setting, conventional chemotherapy improves the quality of life. •In standard care, first line therapy should contain an anthracycline and second line therapy using vinorelbine or docetaxel could be offered to selected patients failing first line therapy. •Based on numerous randomised studies, breast cancer demonstrates a positive dose-response relationship both in the adjuvant situation and for metastatic disease. However, in the conventional dose-range there seems to be a plateau in the dose-response curve, with no further survival gains for higher doses. •High-dose therapy with bone marrow support might result in further increases in antitumour effects with the potential of increasing survival, but additional phase III studies are required before this can be recommended for routine care. •The growth factors G-CSF and GM-CSF reduce chemotherapy-induced hematological toxicity. So far their use has given no proven effect on survival. •There is no support that unspecific immunomodulation improves the outcome in breast cancer. A clinical benefit from monoclonal HER-2 antibodies is suggested but needs further confirmation. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scientific articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126800 patients. The conclusions reached can be summarized into the following points: •The benefit of postoperative adjuvant chemotherapy with fluorouracil and levamisole in patients with colon cancer stage Dukes' C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recurrence from 56% to 39% and reduction of death from 51% to 40% after more than five years of follow-up. Although this combination has been widely accepted as standard adjuvant treatments for stage Dukes' C colon cancer, there is still debate on whether adjuvant treatment with fluorouracil alone would be equally efficacious. •Several phase III trials with postoperative adjuvant chemotherapy with fluorouracil and leucovorin in patients with colon cancer stage Dukes' C have demonstrated a similar statistically significant improvement in disease-free and overall survival in comparison with a control arm. Six months of treatment with fluorouracil and leucovorin is as efficient as twelve months of fluorouracil and levamisole. This treatment is, thus, recommended for routine use. •No convincing benefit from adjuvant chemotherapy is proven in colon cancer stage Dukes' B although some randomised trials have shown the same relative survival gain as seen in stage Dukes' C. •There is less knowledge on survival benefits from adjuvant chemotherapy for Dukes' stage B and C rectal cancer. In small randomised trials, postoperative radiochemotherapy has, however, improved survival to the same extent as chemotherapy in colon cancer Dukes' stage C. •A meta-analysis of nine randomised trials revealed a small but statistically significant benefit in five-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusion compared with controls. At present, however, the use of portal vein infusion or intraperitoneal therapy outside of a research trial cannot be recommended in the light of the limited effects. This conclusion is further supported by similarly limited effects in two recently reported very large European multicentre trials. •In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms, improve general well-being or maintain it at a high level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemotherapy in patients with metastases limited to the liver. Subjective responses and quality of life improvements are seen more frequently than objective tumour remissions. Although the impact on overall survival is modest, i.e. an improvement in median survival of five to six months, treatment is recommended also outside clinical trials. •High-dose infusional regimens with modulated fluorouracil may turn out to be superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression and possibly longer survival. A plateau seems, however, to have been reached with fluorouracil, giving objective response rates of up to 30% to 40% with a variety of modulators. •Randomised studies of regional therapy, mostly hepatic arterial infusions, of liver metastases in colorectal patients have demonstrated significantly higher response rates than systemic fluorouracil therapy alone without impact on overall survival. The importance of the higher response rates for patient benefit in the predominantly asymptomatic patients with isolated liver metastasis remains to be elucidated. Regional therapy in advanced disease cannot be recommended outside of clinical trials. •New cytotoxic agents are emerging with antitumour activity similar to fluorouracil-based chemotherapy. The addition of oxaliplatin or irinotecan to existing fluorouracil regimens improves response rates and duration of response, and possibly overall survival. Based upon the results of two randomised studies, there is a role for irinotecan as second line therapy for selected patients who have failed first-line therapy with fluorouracil plus leucovorin. The role of these agents, alone or in combinations, in clinical routine remains, however, to be determined due to more pronounced toxicity than caused by fluorouracil-based regimens. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy in the treatment of gastric cancer is based on 153 scientific papers including one meta-analysis, 18 reviews, 60 randomised studies and 57 prospective studies. The trials consist of 12 367 patients. The conclusions reached can be summarized into the following points: •A meta-analysis of 21 randomised adjuvant studies revealed a statistically significant survival benefit. The Odds Ratio (OR) is 0.84 (95% confidence interval, 95% CI, 0.74-0.96). However, by analysing Western world and Asian studies separately, a statistically significant difference can be noticed; the Western world studies showed an OR of 0.96 (95% CI 0.83-1.12) and the Asian an OR of 0.58 (95% CI 0.44-0.76). The cause of this difference is not apparent. There is not sufficient evidence to recommend adjuvant chemotherapy as routine treatment in the Western world. •Preoperative chemotherapy given to patients with non-resectable tumours or locally advanced potentially resectable tumours has achieved resectability rates of 40-100% and potentially curative resections in 37-80%. One out of two randomised studies showed a significant survival benefit, but reported data are not convincing. Experimental data in favour of preoperative therapy has not yet been confirmed in randomised clinical studies. Therapy is only justified in controlled clinical trials. •Published studies on the use of intraperitoneal chemotherapy are few and not conclusive regarding the efficiency and safety. This method of drug administration is, accordingly, justified only in controlled clinical trials. •In advanced gastric cancer, phase II studies have indicated better response rates using drug combinations than using single drug regimens, differences that have not, however, been convincingly demonstrated in randomised studies. No firm conclusions can be drawn regarding the superiority for any of the studied drug combinations with respect to response or survival gain. •A statistically significant survival benefit has been shown in trials comparing drug combinations with a best supportive care arm in the treatment of advanced gastric cancer. However, the number of included patients is small. The median survival benefit in advanced disease is in the range of three to nine months. •The use of chemotherapy in advanced gastric cancer is justified in selected patients, e.g. in younger patients in good performance status, low tumour burden and no other serious medical condition after adequate information of potential gains and risks. •The influence of chemotherapy on quality of life in advanced gastric cancer has been reported in only a few studies. It appears that about 50% of the patients have a clinically relevant relief of tumour-related symptoms and thereby improved quality of life. In one study, quality-adjusted survival was estimated to a median of six months in the treated patients compared with two months in the controls. •The quality of the literature addressing chemotherapy for gastric cancer is frequently poor with few properly designed randomised trials. In a number of randomised multi-centre adjuvant studies the inclusions rates are remarkably low, which reduces the scientific value of the studies. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy for non-small cell lung cancer (NSCLC) is based on 53 scientific publications including six meta-analyses based on 65 prospective randomised trials comprising 15 607 patients and an additional 32 prospective randomised studies including 8 902 patients. The conclusions reached can be summarised into the following points: •In stage IIIB-IV disease, published data demonstrate that cisplatin-based chemotherapy confers a modest, median 1.5-3 months, prolongation of survival. The closely related compound carboplatin seems to provide similar effects. Randomised studies indicate symptomatic relief and improvement of indices of quality of life (QoL) for patients who receive platinum-based combination chemotherapy or single drug therapy with more recent compounds. Data supporting the use of chemotherapy are not available for patients in poor general condition (WHO performance status 3-4) and evidence is limited for elderly patients (above 70-75 years). Platinum-based chemotherapy can be recommended for selective use in routine care of advanced NSCLC although patients should be encouraged to participate in controlled clinical trials to further elucidate the role of chemotherapy in advanced disease. •In advanced disease, recent data suggest that the newer agents gemcitabine, paclitaxel, irinotecan and vinorelbine, in combination with cisplatin, provide an additional survival benefit compared with earlier cisplatin-based regimens. Furthermore, paclitaxel, docetaxel and vinorelbine as single agents seemingly provide a survival benefit over supportive care alone comparable to that of older cisplatin-based combinations. •A standard regimen for advanced disease cannot yet be defined. Until more data are at hand, it is recommended to be platinum-based and preferably combined with one of the newer agents. •At progression after platinum-based chemotherapy for advanced disease, limited data indicate a small survival benefit from docetaxel over supportive care alone. Such second-line chemotherapy of advanced disease can be recommended for selected patients but should preferably be confined to controlled clinical trials. •In stage III disease, published data show that induction cisplatin-based chemotherapy before radical radiotherapy modestly prolongs long-term survival and lowers the incidence of distant metastases compared with radiotherapy alone. Furthermore, published data show that concurrent chemo- and radiotherapy with cisplatin or carboplatin may enhance local control and long-term survival. Chemotherapy in this setting can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. •In stage IIIAN2 disease, data from pilot studies demonstrate that surgery after induction chemotherapy is feasible. Pathologically complete remissions have been confirmed in 10-20% of treated patients. Two small randomised studies demonstrate a significant survival advantage for induction chemotherapy followed by surgery compared with surgery alone. Induction chemotherapy can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. The superiority of induction chemotherapy plus surgery compared with combined chemotherapy and radical irradiation has not been proven in a randomised trial but currently such studies are under way. •In the adjuvant setting, published data suggest that cisplatin-based chemotherapy after radical surgery may increase five-year survival from around 50% by a further 5% but the confidence interval for this estimate is too wide for firm conclusions. Large-scale prospective randomised trials are under way to resolve this important issue and adjuvant chemotherapy is, thus, not recommended for routine treatment. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview on chemotherapy for epithelial ovarian cancer is based on a total of 176 scientific reports. Five meta-analyses including 17291 patients, 33 prospective randomised studies including 12340 patients, 36 prospective studies including 3593 patients and one retrospective study including 421 patients. The studies include approximately 33642 patients. The conclusions reached can be summarized into the following points: •Radically operated patients with low-risk early ovarian cancer (stage IA or IB non-clear-cell well-differentiated carcinomas or borderline tumours) have a very good prognosis and there is no indication for adjuvant therapy. •Radically operated patients with high-risk early ovarian cancer (clear cell carcinomas or FIGO stage IA or IB moderately or poorly differentiated carcinomas or stage IC) have a substantial risk for micrometastatic disease. However, the role of adjuvant chemotherapy is unclear and such therapy should, thus, only be used within clinical trials. •The median overall survival for patients with advanced (FIGO stages II-IV) ovarian cancer randomised to paclitaxel/platinum-containing chemotherapy in three large studies ranged between 36-39 months. Compared with historical data, this represents a six to seven times longer median survival time than after surgery only. The probability for long-term survival for patients treated with a paclitaxel/platinum combination is too early to define. •In two prospective randomised trials in advanced ovarian cancer, paclitaxel in combination with cisplatin has provided a survival benefit over cyclophosphamide/cisplatin. Based on these trials, paclitaxel/cisplatin is considered to be the standard treatment. •This choice of standard therapy might, however, be questioned based on the results of the hitherto largest randomised study in advanced ovarian cancer, ICON3, which is, as yet only available in abstract form. It compared paclitaxel/carboplatin with carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). There were no statistically significant differences in progression-free or overall survival. The drug regimen in the control arms of the previous studies showing superiority of the paclitaxel-cisplatin combination may not have been the optimal non-paclitaxel platinum-containing regimen. •Three randomised studies have compared carboplatin/paclitaxel with cisplatin/paclitaxel. All three are hitherto only published as abstracts with short follow-up precluding survival analyses. None of them shows any difference in response rates. All three show less toxicity and one also better quality of life with carboplatin. Thus, there are preliminary data supporting the substitution of cisplatin with carboplatin. •Intraperitoneal therapy with cisplatin caused improved survival compared with intravenous therapy in one ramdomised study. Further studies have shown trends to better survival and longer progression-free interval with intraperitoneal therapy. The accrual to studies on intraperitoneal chemotherapy has been poor reflecting that it is a cumbersome and not easily accepted treatment. •In advanced ovarian cancer, no convincing advantage has been shown from more dose-intensive chemotherapy, without cytokines or bone marrow stem cell support, compared with standard doses. •High response rates are achieved with high-dose chemotherapy with stem cell support in the salvage situation but response duration is short. Phase III studies evaluating high-dose chemotherapy in the first-line situation are ongoing. Until supportive controlled clinical trials are presented, high-dose chemotherapy should be confined to clinical trials. •Tumour response is frequently observed on re-treatment with the same drugs as given first-line in patients sensitive to first-line platinum-based chemotherapy with a long progression-free interval. Thus, in these patients treatment with a platinum/ paclitaxel combination might be recommended, albeit based on limited data. In patients resistant to first-line therapy, a number of single agents induce tumour responses in the range of 10–30%. The literature does not permit general treatment recommendations in these patients, which are recommended to be included in controlled clinical trials. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). The conclusions of this overview in pancreatic cancer are based on 10 randomised studies with, and 18 randomised studies without, an untreated control group. Altogether, 4028 patients were included in the phase III studies. Furthermore, 32 phase II studies or retrospective analyses including 1404 patients have been evaluated. The conclusions reached can be summarized into the following points: •There is no convincing evidence that pancreatic cancer patients benefit from adjuvant chemotherapy treatment, with or without concomitant radiotherapy. Adjuvant chemotherapy in patients with pancreatic cancer should thus not be used routinely. •In locally advanced/metastatic pancreatic cancer, six randomised trials comparing combination chemotherapy with an untreated control group were retrieved. In three trials, two of which were performed recently, chemotherapy provided statistically significant prolongation in median survival in the range of three to nine months. The three other trials, all reported in the early 80s, essentially showed no difference in survival between the treatment groups. •In the locally advanced/metastatic setting there are also several randomised trials comparing various chemotherapy regimens. Except for an improvement in median survival of one to two months from gemcitabine compared with 5-FU, no differences were observed. •There is no convincing evidence that a large fraction of pancreatic cancer patients will benefit from palliative chemotherapy. The few open-design studies that have explored the influence on symptom relief/quality of life indicate that between 20-35% of the patients get clinical benefit, but usually short-lived. •Recently performed randomised studies, all using adequate methodology, indicate that the beneficial effects observed in advanced pancreatic cancer are similar to those of accepted therapy in other cancer types. However, due to the limited positive effects, palliative chemotherapy in pancreatic cancer can only be recommended selectively and should preferably be used within controlled clinical trials exploring new treatment combinations or concepts. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for urothelial bladder cancer is based on 234 scientific reports including two meta-analyses, 75 randomised studies and 143 other prospective studies, and totally comprising 31 974 patients. The conclusions reached can be summarised into the following points: •Intravesical chemotherapy administered in an adjuvant setting to transurethral resection (TUR-B) of superficial tumour reduces short-term (one to three years) recurrence rate by approximately 20%. After a median follow-up of eight years, 8% fewer recurrences were seen after intravesical chemotherapy. •Long-term maintenance instillation chemotherapy (>1 year) does not further increase the recurrence-free interval nor the long-term recurrence rate when compared with immediate postoperative short-term intravesical chemotherapy. •The majority of studies on intravesical Bacillus Calmette-Guérin (BCG) vs intravesical chemotherapy show superior protection from tumour recurrence for BCG. •Despite prolongation of the disease-free survival, adjuvant intravesical chemotherapy has, in the majority of studies, no apparent long-term impact on the evolution of superficial into muscle invasive bladder cancer. •There are no data showing a survival benefit from adjuvant intravesical chemotherapy. •Chemotherapy with cisplatin-based regimens induce objective tumour response in at least 50% of patients with metastatic disease. A prolonged disease-free and overall survival (median two to three months) is seen in patients treated with cisplatin-based polychemotherapy compared with patients treated with cisplatin alone or less intensive chemotherapy. •With the exception of one randomised study, there are no conclusive data on possible survival benefit for patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy prior to cystectomy or radiotherapy. •Although the results from use of adjuvant chemotherapy after surgery or curative radiotherapy obtained are promising, the small studies performed lack statistical power and, hence, there is insufficient data to make any conclusion regarding a possible survival benefit from adjuvant chemotherapy. •A growing body of data indicate that bladder preservation can be achieved by multi-modality approach in selected patients and that survival in these is similar to that seen after radical cystectomy, but randomised trials are still lacking. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for Hodgkin's disease (HD) is based on 113 scientific reports including four meta-analyses, 44 randomised studies, 18 prospective studies and 40 retrospective studies. These studies involve 69 196 patients. The conclusions reached can be summarised into the following points: •Chemotherapy is of utmost importance for the cure of HD. •At early stages, extended field radiotherapy cures most patients. For the majority of patients with relapse after radiotherapy, chemotherapy is curative and the total proportion of cured early stage patients is 75-90%. Chemotherapy in addition to extended field radiotherapy reduces recurrences but does not improve long-term survival. •In early stage HD with a large mediastinal mass and/or with systemic symptoms, combined treatment with chemotherapy and radiotherapy is recommended. •It is likely that chemotherapy will play a greater role in the future in the treatment also of early stage patients in order to reduce late consequences from extended field radiotherapy. However, this conclusion remains to be better documented in the literature. •At advanced stages, chemotherapy or a combination of chemotherapy and limited field radiotherapy are effective treatment options and, using the regimens available 10-20 years ago, 40-50% of the patients are cured. Based upon more favourable short-term (three to eight years) results of more recently developed regimens, it can be expected that today a higher proportion of the patients will become long-term survivors. •Several chemotherapy regimens containing four to eight drugs are effective in HD. The best regimen considering both antitumour activity and acute and late side-effects is not known. The choice of regimen is probably best done after considering various pre-treatment factors such as the number of poor prognostic signs, concomitant diseases and individual preferences. •The results of chemotherapy are more favourable in young than in elderly patients. The development of less toxic but still effective treatment programmes is therefore particularly important for the elderly. •High dose chemotherapy with stem cell support is presently often used in patients who are chemotherapy induction failures, who relapse after a short initial remission or after a longer initial remission and treated initially with seven or eight drugs, or who have had multiple relapses. However, this use is based on data from uncontrolled or small controlled studies, not being fully convincing with respect to effect on survival. •Persistent side-effects of treatment are common among long-term survivors, although most patients have an apparently normal life. The relative contributions of chemotherapy and radiotherapy to the persistent effects are not well documented. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on aggressive, high grade non-Hodgkin's lymphoma (NHL), chiefly diffuse large B-cell lymphomas, is based on 111 scientific articles, including 35 randomised trials, 44 prospective studies and 11 retrospective studies, including totally 21 830 treated patients. The conclusions reached can be summarised into the following points: •For patients with localised aggressive NHL (stage I and non-bulky II) a combination of chemo- and radiotherapy will result in cure for a large proportion of patients. For a subgroup of patients with stage I non-bulky disease and without risk factors, local radiotherapy alone is also adequate treatment. •For patients with disseminated aggressive NHL, including the elderly, the CHOP-regimen remains the standard primary chemotherapy. In an unselected population, this treatment cures about one third of the patients. •For most patients with poor prognostic factors, CHOP provides insufficient results. The results of therapy with dose-intensive combinations of cytotoxic drugs have been conflicting. Most randomised studies, using intensive regimens as first line therapy, have failed to show any benefit in comparison to CHOP. However, it is possible that regimens other than CHOP might be more beneficial in subgroups with 'high risk' disease. This remains to be investigated in prospective studies. •In young, poor prognosis, patients a further intensified induction therapy requiring haematopetic stem cell support, i.e. high dose therapy, has been suggested to be beneficial. The best results have been reported from studies with full course standard induction followed by high-dose therapy. However, the study data are conflicting, which is why additional controlled studies are recommended. •In patients refractory to or relapsing after initial therapy, different chemotherapy combinations may induce a new response. The responses are, however, rather short-lived and long-term survival is rarely seen. •In patients not attaining complete remission after initial standard therapy, high-dose therapy with stem cell support may improve the response, but the impact on survival is not established. •In patients refractory to initial standard therapy there is no evidence for a survival prolongation from high-dose therapy with stem cell support, although a subset of patients might benefit. •For patients with chemosensitive relapse, salvage therapy followed by high-dose therapy with stem cell support is recommended, since this may result in prolonged survival. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for indolent non-Hodgkin's lymphoma (NHL), predominantly follicular lymphoma, is based on 108 scientific reports including 31 randomised studies, 38 prospective studies and 18 retrospective studies. These studies involve 8 699 patients. The conclusions reached can be summarized into the following points: In initially localized disease •The addition of chemotherapy to radiotherapy as primary treatment has not convincingly prolonged remission duration or survival. In initially advanced disease •Alkylating agents are useful palliative treatment options which can result in improved well-being for most patients, often for long periods. Combinations of chemotherapy have not convincingly resulted in more or longer remissions. •There is no proof that initial combination chemotherapy will prolong survival in comparison with single drugs. •The addition of interferon to initial combination chemotherapy may increase the response rate, significantly prolong remission duration, but prolonged survival has not been unequivocally proven. •In the absence of disease-related symptoms, treatment can safely be deferred. For patients with relapsed lymphoma •Patients may repeatedly respond to alkylating agents or combinations containing an alkylating agent, although the proportion responding decreases with each relapse. •Patients relapsing after or who are refractory to treatment with alkylating agents often respond to treatment with combinations containing an anthracycline. Responses are also often seen in patients treated with purine analogues alone or in combination with other drugs. •High dose chemotherapy followed by autologous or allogeneic reestablishment of bone marrow function can induce long-term remissions but it is not proven whether they are more frequent or of longer duration than with conventionally dosed therapy. •The impact of the novel treatment strategies including high-dose therapy on overall survival is still uncertain. •A monoclonal antibody, rituximab, is a new active substance for patients with relapsed lymphoma. It can induce remissions also in chemoresistant patients. [ABSTRACT FROM AUTHOR]

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for B-cell chronic lymphocytic leukaemia (B-CLL) is based on data from 20 randomised controlled trials and one meta-analysis. Moreover, data from 19 prospective studies, one retrospective study and four other articles were used. Totally 44 scientific articles are included, involving 11 289 patients. The conclusions reached can be summarized into the following points: •Primary treatment of patients with symptomatic B-CLL is recommended to be an oral alkylating agent such as chlorambucil. This drug induces tumour remission and symptomatic relief in a majority of patients with progressive disease. Response may be long-lasting, but cure is not obtained. Optimum dose and schedule of administration of chlorambucil or other alkylating agents have not been defined. •It is recommended to defer initial therapy until required by disease progression. Large randomised trials have demonstrated that early treatment with chlorambucil in a continuous or an intermittent schedule does not prolong survival in B-CLL patients with low tumour burden (Binet stage A). •The addition of corticosteroids to alkylator regimens has not been proven to give any benefit. •Combination chemotherapy as primary treatment has not shown any advantage compared with single drugs. Early inclusion of anthracyclines to the therapy does not convincingly add to the activity of alkylating agents. •The purine analogues fludarabine and 2-chlorodeoxyadenosine are active in B-CLL. However, like other drugs, they do not appear to be curative. In randomised multicentre trials a benefit from fludarabine as primary therapy compared with polychemotherapy (CHOP or CAP) has been observed in terms of tolerance and treatment response but not yet in survival. No randomised studies have been performed to show whether one of the purine analogues should be preferred. •At relapse after single drug treatment, retreatment with the same drug often induces new remissions. However, the proportion of patients responding declines each time chlorambucil or any other single agent is readministered. •At progression on single alkylating agents, the purine analogues or various combinations, mostly CHOP, frequently induce tumour remissions. •For patients with advanced B-CLL failing to respond to fludarabine or CHOP, the prognosis is poor. None of the salvage regimens reported has produced durable remissions. •High-dose chemo-radiotherapy with stem cell transplantation has been evaluated for young patients with B-CLL. A long survival has been shown in some patients following allogeneic and autologous transplantation. However, the risk of transplantation-related mortality is still high with allo-transplants and relapse is common after auto-transplantation. A benefit of purging autologous stem cells has been proposed but evidence is lacking. Thus, transplantation remains experimental; more patients and a longer follow-up are needed to assess if cure can be achieved. •In the future an individual risk-adapted therapy will be required. The clinical heterogeneity of the disease has pointed to the necessity of new predictors for prognosis evaluated in prospective trials. [ABSTRACT FROM AUTHOR]

The author reflects on why data on the effects of cancer drugs from patient cohort studies and clinical trials are frequently over-interpreted and why preclinical cancer research findings are frequently not possible to reproduce. He mentions the improvement of median overall survival (OS) in drug treatment of metastatic colorectal cancer (mCRC). He discusses two randomised clinical trials on the benefits of bevacizumab in combination with chemotherapy in mCRC treatment.