Thomas Högberg

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - results from two randomised studies

INTRODUCTIONnEndometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.nnnMETHODSnPatients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.nnnRESULTSnIn the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).nnnCONCLUSIONnAddition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument

Summary Purpose: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor. Patients and methods: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n - 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points. Results: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNAploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001. Conclusions: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

A Systematic Overview of Chemotherapy Effects in Ovarian Cancer

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 17,291 patients, 33 prospective randomised studies including 12,340 patients, 36 prospective studies including 3,593 patients and one retrospective study including 421 patients. The studies include approximately 33,642 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.

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer

BACKGROUNDnThis randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC).nnnPATIENTS AND METHODSnPatients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0.nnnRESULTSnORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B).nnnCONCLUSIONSnBoth every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

Adjuvant chemotherapy for endometrial cancer after hysterectomy

BACKGROUNDnEndometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer.nnnOBJECTIVESnTo assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer.nnnSEARCH STRATEGYnWe searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment.nnnDATA COLLECTION AND ANALYSISnWe used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse.nnnMAIN RESULTSnFive RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly favouring the addition of postoperative platinum based chemotherapy. The HR for progression-free survival is 0.75 (0.64 to 0.89). This means that chemotherapy reduces the risk of being dead at any censorship by a quarter. Chemotherapy reduces the risk of developing the first recurrence outside the pelvis (RR = 0.79 (0.68 to 0.92), 5% absolute risk reduction; NNT = 20). The analysis of pelvic recurrence rates is underpowered but the trend suggests that chemotherapy may be less effective than radiotherapy in a direct comparison (RR = 1.28 (0.97 to 1.68)) but it may have added value when used with radiotherapy (RR = 0.48 (0.20 to 1.18)).nnnAUTHORS CONCLUSIONSnPostoperative platinum based chemotherapy is associated with a small benefit in progression-free survival and overall survival irrespective of radiotherapy treatment. It reduces the risk of developing a metastasis, could be an alternative to radiotherapy and has added value when used with radiotherapy.

Adjuvant Chemotherapy in Endometrial Carcinoma: Overview of Randomised Trials

Endometrial cancer generally has a good prognosis because most cases are diagnosed in stage I. It is possible to identify subgroups of patients with early stage endometrial cancer with a poor prognosis. Despite a traditional generous use of adjuvant radiotherapy those patients have less than an 80% 5-year overall survival. In this group there is a need for an effective systemic adjuvant therapy. Two randomised studies have shown better response rates but no significant difference in overall survival for doxorubicin-cisplatin vs doxorubicin in advanced or recurrent endometrial cancer. Mainly on the basis of the superior response rates, doxorubicin-cisplatin was for many years regarded as the standard chemotherapy in endometrial cancer. GOG-177 was the first phase III study on chemotherapy in advanced or recurrent endometrial cancer that showed a survival advantage. Paclitaxel-doxorubicin-cisplatin was better than doxorubicin-cisplatin, but the toxicity of the three-drug regimen has precluded general acceptance. Paclitaxel-carboplatin has rendered high response rates in endometrial cancer and is widely used, despite the lack of evidence based on randomised studies. GOG-122 was a pivotal randomised study that compared doxorubicin-cisplatin with whole abdominal radiotherapy in advanced optimally operated endometrial cancer and showed that chemotherapy with doxorubicin-cisplatin resulted in superior survival. Two recent studies have compared adjuvant chemotherapy (cyclophosphamide-doxorubicin-cisplatin) with adjuvant radiotherapy in early stage endometrial cancer. Both studies failed to show a difference between the treatments, but neither was powered to show non-inferiority. Another study (NSGO-EC-9501/EORTC-55991) compared adjuvant radiotherapy plus chemotherapy with adjuvant radiotherapy and showed better survival with the combination. The implications of these studies are discussed.

The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of chemotherapy effects in some major tumour types--summary and conclusions.

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), Hodgkins disease (HD), aggressive non-Hodgkins 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 1,496 studies involving 558,743 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 1,590 patients. The working groups 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 s

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer.

Previous studies including various tumor types have shown different associations between tumor tissue levels of plasminogen activator inhibitor 2 (PAI‐2) and patient survival. High tumor tissue concentrations of PAI‐2 have been associated with good prognosis in patients with breast cancer, small cell lung cancer and ovarian cancer, but with poor histologic differentiation and poor prognosis in patients with colorectal cancer. On the other hand, high tumor tissue concentrations of urokinase plasminogen activator (uPA), uPA receptor (R) and PAI‐1 have more consistently been associated with poor histologic differentiation and poor prognosis. Our study quantified PAI‐2 and uPAR using specific enzyme‐linked immunosorbent assays in homogenates of 274 samples of endometrial cancer tissue. The prognostic power of each factor was analyzed in the subgroup of patients with early stage disease, i.e., International Federation of Gynecology and Oncology (FIGO) surgical stage I–II (n = 188). This group had a median follow‐up time of 6.8 years (range 0.7–9.9), and 23 progressions were observed. The 80th percentile for PAI‐2 and uPAR was used to dichotomize the material, and the results were analyzed for associations with clinical data including progression‐free survival. The results were also compared with DNA ploidy status, S‐phase fraction, uPA and PAI‐1, which we reported in a previous study (Fredstorp Lidebring et al., Eur J Cancer 2001; in press). A high PAI‐2 level was associated with shorter progression‐free survival in univariate analysis and was an independent prognostic factor in bivariate analyses, which included PAI‐1, uPA and DNA ploidy status. In contrast, a high level of uPAR had no association with prognosis in early stage endometrial cancer. The combination of high PAI‐2 and PAI‐1 levels in tumors revealed a small group of stage I–II patients with an accumulative progression rate of 50%.

A randomized, multicenter study comparing the efficacy and tolerability of tropisetron, a new 5‐HT3 receptor antagonist, with a metoclopramide‐containing antiemetic cocktail in the prevention of cisplatin‐induced emesis

Background. Chemotherapy‐induced emesis is one of the most disturbing side effects in cancer therapy. Thus, antiemetic treatment is a mandatory adjunct in emetogenic chemotherapy.

Efficacy and tolerability of tropisetron in comparison with a combination of tropisetron and dexamethasone in the control of nausea and vomiting induced by cisplatin-containing chemotherapy

In a double-blind, randomised, multicentre study, the efficacy and tolerability of tropisetron and a combination of tropisetron and dexamethasone were compared for the control of nausea and vomiting induced by cisplatin in patients previously not entirely protected by tropisetron monotherapy. In all, 160 women with gynaecological cancers were studied during two consecutive courses of cisplatin-containing chemotherapy. During the first course (the screening course), all patients received tropisetron monotherapy [5 mg intravenous (i.v.) on day 1 and 5 mg orally on days 2-6] as antiemetic treatment. During the second course (the test course), tropisetron was compared with a combination of tropisetron and dexamethasone (20 mg i.v. on day 1 and 4.5 mg twice daily on days 2-6). This part of the study was double-blind, randomised and placebo-controlled. Candidates for randomisation were patients with partial control of nausea (< 12 h of nausea) or partial control of vomiting (1-4 episodes of vomiting) during the screening course. Patients with complete control of nausea and vomiting in the screening course continued with tropisetron monotherapy; patients with treatment failure received open rescue treatment in course 2. Total control of acute nausea was achieved in 37% of the tropisetron + placebo group and in 75% of the tropisetron + dexamethasone group (P = 0.001). Significantly more patients on tropisetron-dexamethasone than on tropisetron-placebo were also free of delayed nausea. Acute vomiting was prevented in 40% of the patients in the placebo group and in 75% in the dexamethasone group (P = 0.001). Delayed vomiting was also significantly less frequent in dexamethasone-treated patients than in placebo-treated patients. Tropisetron was well tolerated both as monotherapy and in combination with dexamethasone. The most frequent adverse events were headache (34%), constipation (12.5%) and fatigue (12.5%). Adding high doses of a corticosteroid did not induce further adverse events or disregulate concurrent diseases.