Latest information in the diagnoses of ovarian carcinoma

Despite improvements in median and overall survival from a combination of improved operation techniques and chemotherapy with platinum-compounds and paclitaxel, long-term survival rates for patients with epithelial ovarian carcinoma remain disappointing, and ongoing efforts are aimed at developing more effective primary therapies. In early ovarian carcinoma, conservative management is used to denote surgery that preserves reproductive potential without compromising curability. With some exceptions, such a strategy may be applicable for women younger than 40, who wish to bear children. A major dilemma facing gynecologic oncologists is to determine whether the accurate staging laparotomy is needed for apparent low-risk stage I ovarian carcinoma and how many cycles of chemotherapy will be needed for high-risk stage I ovarian carcinoma. In advanced ovarian carcinoma, main objectives of salvage therapy include: a improvement in quality of life and symptoms; b. tumor load reduction and survival advantage; c. evaluation of potentially active new drugs to be included in first-line treatment. We need to evaluate the potential benefit on survival of systematic pelvic and para-aortic lymphadenectomy during primary or secondary cytoreductive surgery in patients with advanced ovarian carcinoma. Paclitaxel/cisplatin is considered to be the international standard treatment based on the data of GOG 111 trial showing that paclitaxel/cisplatin has provided a survival benefit better than that of cyclophosphamide/cisplatin. This choice of standard therapy might, however, be questioned based on the results of the largest randomised study, ICON3. There were no statistically significant differences in progression-free or overall survival among paclitaxel/carboplatin and carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). The best selection for adjuvant chemotherapy is still controversial and a large number of studies are now ongoing.     

Controversies in chemotherapy — what is standard treatment?

This paper discusses some current controversies regarding optimal first-line treatment for patients with advanced ovarian cancer.Despite improvements seen in median and overall survival using platinum-based chemotherapy, longterm survival rates for patients with advanced epithelial ovarian carcinoma remain disappointing and several efforts have been made recently to develop more effective primary therapy. In the early 1990s, paclitaxel was first tested in ovarian cancer. In GOG111, the cisplatin+paclitaxel regimen was judged to be superior compared with the platinum-cyclophosphamide control arm, with an improvement of overall response rate, median progression-free interval and overall median survival. These favourable data were confirmed by the OV 10 trial. In contrast, in a further GOG trial (GOG132), there was no difference in survival between cisplatin alone and the combination of paclitaxel and cisplatin. ICON3, the first and only trial comparing paclitaxel plus carboplatin against carboplatin alone or a (non-taxane) cisplatin-based control arm, again failed to demonstrate any advantage for the platinum-taxane arm, either in progression-free survival or in overall survival. The results of ICON3, in accordance with the GOG132 study, appear to contradict the earlier positive results seen for paclitaxel and cisplatin in the GOG111 and OV10. Several hypotheses have been raised to explain this discrepancy including differences in the extent and timing of crossover to taxanes in the control group, differences in the type of patients included, differences in the efficacy of research regimens or in the efficacy of the control regimens. A meta-analysis with individual patient data demonstrated a substantial heterogeneity between groups using different control arms, possibly indicating that the cyclophosphamide/cisplatin regimen used in the two “positive” trials may be less effective than the control regimen used in the other trials. It will be almost impossible to achieve an agreement on these proposed explanations. However, this meta-analysis provides evidence that the introduction of taxanes can lead to a survival advantage vastly inferior to that expected after the results of the GOG111 and OV10 trials.Ongoing research is focusing on the addition of a third drug to platinum/taxane in regimens consisting of triplets or sequential doublets.Determining the characteristics to define the patient population with relapse is important to evaluate the therapeutic options with the greatest likelihood of success. Appropriate salvage therapy is based on the timing and nature of the recurrence and the extent of prior chemotherapy. The main objectives of salvage chemotherapy include (1) improvement in quality of life and symptoms, (2) tumour load reduction and survival advantage, and (3) evaluation of potentially active new drugs to be included in first-line treatment.Since the goal is palliation in most cases, monotherapy is generally indicated. Unfortunately, durable responses to salvage chemotherapy are rare and cure almost impossible. The sequential use of the agents currently available for salvage treatment in monotherapy may transform ovarian cancer into a chronic disease and increase the length of survival. Perhaps the most interesting role of second-line chemotherapy is to identify, new potentially active drugs, which can then be used upfront.For patients with platinum-sensitive disease, it was unclear, until recently, whether the platinum-based combination was superior to single-agent platinum at the time of relapse. The recent results of ICON4 seem to indicate an advantage in both survival and progression-free survival for patients with relapsing platinum-sensitive ovarian cancer treated with the combination platinum/taxane compared with conventional platinum-based chemotherapy.     

Part I: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis

Ovarian cancer leads to more deaths than any other gynaecological cancer in the more developed countries. During the past 30 years, survival has increased owing to improvements in diagnosis, surgery, and chemotherapy. Despite these advances, most patients will die from the disease, and the overall 5-year survival is less than 50%. Most patients with ovarian cancer need cytotoxic chemotherapy. Platinum agents (cisplatin and carboplatin) are the most important drugs to be included in first-line regimens. Randomised trials have recently confirmed the benefit of the addition of taxanes to platinum, and the standard of care has become the combination of carboplatin and paclitaxel. However, unanswered questions remain over the optimum schedule, duration, and intensity of treatment, and the benefit or otherwise of the addition of other drugs to carboplatin and paclitaxel. The roles of intraperitoneal therapy and consolidation treatment after first-line chemotherapy are as yet undefined.     

A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel na?ve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets.     

Gemcitabine plus carboplatin in platinum-sensitive recurrent ovarian carcinoma

Although the general intent of treatment for patients with recurrent ovarian cancer is palliative, and cure does not seem to be a realistic objective in this setting, median overall survival is greater than 12 months in platinum-sensitive recurrent ovarian cancer. Patients with ovarian cancer can now expect that the time from first relapse of their disease to death will be longer than the period from diagnosis to that first relapse. There is current evidence from prospective randomized trials that carboplatin combined with either paclitaxel or gemcitabine confers a progression-free survival advantage over platinum monotherapy for patients with platinum-sensitive relapsed ovarian cancer. Since the efficacy of paclitaxel/platinum and gemcitabine/carboplatin regimens appears to be comparable based on similar progression-free survival (both combinations confer a 3-month advantage), toxicity profiles should be taken into account when deciding on the combination to be used. The gemcitabine/carboplatin combination should be preferred in patients with underlying peripheral neuropathy. Since alopecia associated with paclitaxel can diminish the overall quality of life, the gemcitabine plus carboplatin combination may be preferable for patients in whom alopecia is a major consideration. This review provides an update on the role of the gemcitabine/carboplatin combination in platinum-sensitive recurrent ovarian cancer.     

Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate. Pharmacokinetic analysis showed an approximately 2-fold reduction of DNA-adduct formation in leucocytes compared with cisplatin without paclitaxel. No pharmacokinetic interaction was found between paclitaxel and cisplatin. After (re-)induction, additional chemotherapy consisted of conventional paclitaxel/cisplatin, paclitaxel/carboplatin, paclitaxel single agent or carboplatin/cyclophosphamide. The overall response rate was 94% in 17 evaluable chemotherapy-nai;ve patients and 84% in 25 patients with recurrent disease. Median progression-free survival (PFS) was 17 months (chemotherapy-nai;ve: 23 months, recurrent: 11 months) and median overall survival was 41 months (chemotherapy-nai;ve: 48 months, recurrent: 24 months). In conclusion, both cisplatin/paclitaxel regimens showed excellent activity with manageable toxicity in patients with advanced ovarian cancer.     

Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study.

PURPOSE: In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. PATIENTS AND METHODS: Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). RESULTS: Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). CONCLUSION: In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.     

Recent advances in ovarian cancer chemotherapy]

The standard approach for epithelial ovarian cancer has been maximum cytoreductive surgery followed by combination therapy. Several prospective control studies individually failed to demonstrate improved survival advantage for the Adriamycin containing combination compare with cisplatin plus cyclophosphamide. The two drug combination of carboplatin plus cyclophosphamide will be thought to become the treatment of choice, because it is equally effective as and less toxic than a regimen of cisplatin plus cyclophosphamide. Clinical trials are also in progress with more dose-intense regimens based on considerable retrospective evidence that survival is correlated with the dose intensity of platinum compounds. Currently, high dose carboplatin plus Gm-CSF, two-drug combination of carboplatin and cisplatin and super high dose carboplatin combined with autologous bone marrow transplantation are undergoing clinical trials. Taxol and taxotere, most important cancer drugs after emergence of cisplatin compound, has been shown to have clinical activity in drug resistant ovarian cancer patients. Majority of patients even with advanced germ cell tumors of the ovary is now cured because of the development of effective platinum-based combination chemotherapy of PVB or BEP.     

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.     

Therapeutic strategies in epithelial ovarian cancer

Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube.Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma.The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.     

Platinum compounds in the treatment of advanced breast cancer

Interest in platinum compounds for the treatment of breast cancer has been reawakened because of preclinical studies indicating synergy of platinum salts with the monoclonal antibody trastuzumab in human breast cancer cell lines that overexpress HER2/neu. Cisplatin, carboplatin, and iproplatin are not very active as single agents in patients with previously treated metastatic breast cancer (MBC). The activity of oxaliplatin has not been adequately tested in refractory MBC. On the other hand, cisplatin is very active as first-line chemotherapy, with response rates (RR) of 50%; carboplatin appears to be moderately active in patients without prior chemotherapy (RR around 30%). The clinical effectiveness of the other platinum compounds (iproplatin, oxaliplatin, and others) has not yet been fully tested as first-line chemotherapy. Platinum compounds have been extensively tested in combination with other antitumoral agents. Cisplatin combinations have been employed as neoadjuvant chemotherapy in women with locally advanced breast cancer. These combinations are very active, although the precise contribution of cisplatin to the overall activity is not known. Combinations with cisplatin have been investigated, essentially, as salvage therapy for patients with previously treated MBC. The combinations of cisplatin with older pharmacological agents (5-fluorouracil, etoposide) have moderate activity, while the combinations of cisplatin with the newer agents (vinorelbine, paclitaxel, docetaxel, gemcitabine) appear to be more active. The combinations of carboplatin with the classical agents (5-fluorouracil, etoposide) are poorly active in previously treated MBC; however, the combination of carboplatin with the taxanes (docetaxel, paclitaxel) is more active. Of greatest interest is the synergy between the platinum derivatives and the monoclonal antibody trastuzumab demonstrated in vitro in breast cancer cell lines overexpressing HER2/neu. Currently, several combinations of platinum compounds (either cisplatin or carboplatin) with docetaxel and trastuzumab are under clinical testing in patients with MBC who overexpress HER2/neu. The preliminary results are very promising, and these combinations will soon be tested in the adjuvant setting. Cisplatin, carboplatin, and perhaps, oxaliplatin appear to have some antitumor activity in MBC and can be combined safely with other agents that are active in this disease. However, the precise role that platinum compounds play in the treatment of breast cancer remains to be defined.     

Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline

This evidence-based practice guideline on the use of paclitaxel (Taxol^®) or docetaxel (Taxotere^®) as first-line treatment for patients with advanced non-small cell lung cancer who are candidates for palliative first-line chemotherapy is based on a systematic search and review of literature published in full or in abstract form between 1985 and April 2005. Forty-five randomized trials, including 11 abstracts, were reviewed and clinicians in the province of Ontario, Canada, provided feedback on a draft version of the guideline. Two phase III trials detected a statistically significant survival advantage for a taxane (paclitaxel or docetaxel) with best supportive care versus best supportive care alone. Among the nine fully published phase III trials comparing platinum-based chemotherapies, taxane-platinum combinations achieved higher response rates compared with older chemotherapy combinations, although significantly longer survival was observed only for docetaxel-cisplatin compared with vindesine-cisplatin. Response rates and survival were generally not significantly different for taxane-platinum combinations compared with other current chemotherapy combinations, although the toxicity profile of the regimens varied. However, in one large trial, improved tumor response and modest survival and quality of life benefits were associated with docetaxel-cisplatin compared with vinorelbine-cisplatin. No statistically significant survival differences were detected in the three fully published phase III trials comparing a taxane-gemcitabine combination with a taxane-platinum regimen.

Recommendations: (i) paclitaxel or docetaxel combined with cisplatin is recommended as one of a number of chemotherapy options for the first-line treatment of advanced non-small cell lung cancer in patients with a good performance status; (ii) carboplatin may be combined with a taxane if a patient is unable or unwilling to take cisplatin; (iii) a taxane-gemcitabine combination may be considered for patients with a contraindication to cisplatin and carboplatin; (iv) no firm recommendation can be made on the optimal dose and schedule of taxane-based chemotherapy; however, commonly used regimens include cisplatin 75 mg/m² combined with either docetaxel 75 mg/m² or paclitaxel 135 mg/m² (24-h infusion) and carboplatin AUC 6 combined with paclitaxel 225 mg/m² (3-h infusion); (v) a single-agent taxane may be used if combination chemotherapy is considered inappropriate.     

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional ‘window of opportunity’ endpoints should be included.     

Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications

Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube. Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma. The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.     

Primary chemotherapy-associated effect of second-line chemotherapy on survival of patients with advanced ovarian cancer

Background The current treatment of patients with recurrent ovarian cancer who have received initial platinum- or taxane-based chemotherapy depends on the results of the initial chemotherapy. The purpose of this study was to evaluate how to make the selection of second-line agents for patients with recurrent ovarian carcinoma initially diagnosed as stage II to IV. Methods We conducted a retrospective crossover study in patients who received second-line chemotherapy at Jikei University School of Medicine. We evaluated the responses, progression-free survivals, survivals of second-line chemotherapy, and overall survivals after primary surgery for 51 patients. The treatment cohorts were defined as follows: TC1, patients who were given paclitaxel and carboplatin as first-line chemotherapy and who, upon recurrence, were treated with a platinum-based combination as second-line; and TC2, patients who were given a non-taxane-based platinum combination as first-line chemotherapy, followed, at the time of recurrence, with paclitaxel and carboplatin. Results The response rates of the second-line chemotherapy for the TC1 and TC2 groups were 44% and 25% (P = 0.09). The median progression-free survivals of TC1 and TC2 were 12.9 and 6.4 months (P = 0.018; hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.16–5.04). The median survivals after second-line chemotherapy for the two groups were 16.8 and 10.4 months (P = 0.007; HR, 2.78; 95% CI, 1.33–5.84) and overall survivals after primary surgery were 36.6 and 27.9 months (P = 0.007; HR, 2.36; 95% CI, 1.07–5.21). Conclusion The TC1 group demonstrated a significantly better response and extension of progression-free survival, as well as significantly better survival after crossover and overall survival after primary surgery. As this was a retrospective analysis, this effect should be considered as hypothesis-generating and assessed prospectively in other trials comparing these two chemotherapy schedules.     

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma

Background: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin–paclitaxel.Design: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients.Patients and methods: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m² followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg·ml^-1·min.Results: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%–54%). Response rates for platinum-refractory patients and those with early (3 and <12 months) and late (>12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy.Conclusion: This combined paclitaxel–carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.     

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.     

Bilateral irreversible hearing loss associated with the combination of carboplatin and paclitaxel chemotherapy: a unusual side effect

The regimen with paclitaxel and platinum compound (carboplatin or cisplatin) is the standard chemotherapy for patients with advanced ovarian cancer. Ototoxity for carboplatin and paclitaxel alone or combined is rarely observed. We report the case of a 35-year old female with advanced ovarian cancer who developed sudden bilateral sensorineural hearing loss related to paclitaxel and carboplatin based chemotherapy. This uncommon adverse effect of carboplatin and paclitaxel alone or combined is discussed and the literature reviewed. Hearing monitoring should be mandatory to evaluate the real incidence of clinical and sub-clinical hearing modification induced by carboplatin and paclitaxel based chemotherapy.     

EGFR-directed monoclonal antibodies in non-small cell lung cancer

Several monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) have been evaluated in patients with non-small cell lung cancer (NSCLC). Cetuximab, a chimeric monoclonal antibody, has been studied in combination with first-line chemotherapy in phase II and two phase III trials in patients with advanced NSCLC. The phase III FLEX trial demonstrated an increase in survival for cisplatin/vinorelbine plus cetuximab compared to chemotherapy alone in patients with advanced EGFR-expressing NSCLC. Cetuximab added to carboplatin/paclitaxel failed to improve progression-free survival in the BMS099 phase III trial. However, a meta-analysis of four randomized trials confirmed a significant survival benefit for platinum-based chemotherapy plus cetuximab compared to chemotherapy alone. High EGFR expression of tumor cells was then shown to predict the benefit of cetuximab, whereas KRAS mutations and EGFR fluorescent in situ hybridization analysis were without predictive value. Matuzumab and panitumumab have also been studied in phase II trials. Necitumumab, a fully human monoclonal antibody, is currently evaluated in combination with chemotherapy in two phase III trials in patients with advanced NSCLC. Cetuximab is also studied in combination with chemoradiotherapy in patients with locally advanced NSCLC.     

Second-line chemotherapy with cisplatin-ifosfamide in patients with ovarian cancer previously treated with carboplatin-cyclophosphamide.

In an effort to use antineoplastic drug combinations which are active in platinum resistant ovarian cancer or which can induce a second response after a platinum first-line treatment, we conducted a study on 30 ovarian cancer patients previously treated with carboplatin plus cyclophosphamide who were given ifosfamide 5 g/m2 i.v. divided over days 1 to 3 plus mesma combined with cisplatin 100 mg/m2 i.v. divided over days 1 to 3 every 4 weeks as second-line treatment. Eight patients had never entered remission with first-line chemotherapy while 22 patients had tumor recurrence within 6 to 18 months after the end of chemotherapy and their tumors were considered potentially platinum sensitive. Responding patients received 6 courses while palliative treatment for nonresponders was provided. Of the 22 patients with tumor recurrence, 8 patients responded with one partial response (PR) and 7 complete clinical responses (CCR). Two out of the 8 patients with platinum resistant disease demonstrated short lasting PR. Seven patients with CCR underwent second-look operation and in two a pathological CR was documented. Median time to progression was 6 mo (4-12). The median overall survival was 12 mo (4-20). Myelotoxicity despite G-CSF administration was significant with grade 4 leukopenia in 40% and grade 3 thrombocytopenia in 20% of patients. Central nervous system (CNS) toxicity was significant with 30% somnolence, 20% disorientation and an episode of grand-mal epilepsy ascribed to ifosfamide. With a 33% response rate the combination is as effective as new agents employed in relapsed ovarian cancer. Platinum-refractory disease may respond to a lesser degree. The most important determinant of response was the progression-free interval from first-line chemotherapy. Whether patients recurring after carboplatin plus cyclophosphamide have a greater chance to respond to cisplatin plus ifosfamide or vice-versa cannot be supported by the current data and therefore randomized studies should be performed to this end.