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Background: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery., Methods: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses., Results: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant., Conclusion: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors., (© 2022. The Author(s).)

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis.

The effect of breast cancer surgery timing during the menstrual cycle on prognosis remains controversial. We conducted a multicentre prospective study to establish whether timing of interventions influences prognosis. We report 3-year overall and disease-free survival (OS/DFS) results for 'primary analysis' patients (regular cycles, no oral contraceptives within previous 6 months). Data were collected regarding timing of interventions in relation to patients' last menstrual period (LMP) and first menstrual period after surgery (FMP). Hormone profiles were also measured. Cox's proportional hazards model incorporated LMP in continuous form. Exploratory analyses used menstrual cycle categorisations of Senie, Badwe and Hrushesky. Hormone profiles with LMP and FMP data were also used to define menstrual cycle phase. Four hundred and twelve 'primary analysis' patients were recruited. Three-year OS from first surgery was 90.7, 95% confidence interval (CI) [87.9, 93.6%]. Menstrual cycle according to LMP was not statistically significant (OS: hazard ratio (HR)=1.02, 95%CI [0.995,1.042], P=0.14; DFS: HR=1.00, 95%CI [0.980,1.022], P=0.92). Timing of surgery in relation to menstrual cycle phase had no significant impact on 3-year survival. This may be due to 97% of patients receiving some form of adjuvant therapy. Survival curves to 10 years indicate results may remain true for longer-term survival.

A total of 53 women with chemotherapy-naïve stage Ic-IV ovarian cancer were treated with four cycles of carboplatin area under the curve 7 every 3 weeks, followed by four cycles of paclitaxel 70 mg m(-2) (days 1, 8, and 15) and gemcitabine 1000 mg m(-2) (days 1 and 8) every 3 weeks. In all, 37 (70%) had stage III/IV disease, with 22 (42%) having tumour >2 cm; 38 patients (72%) completed all planned treatment; 27 of the 32 (84%) patients with radiologically evaluable disease had partial or complete responses; and 30 of the 39 patients (77%) with elevated cancer antigen (CA) 125 had a greater than 75% fall in this value. At a median follow-up of 28 months, 31 patients had relapsed with a median progression-free survival of 19.5 months. In total, 79% of patients were alive at 2 years. Common Toxicity Criteria grade 3/4 haematological toxicity, predominantly neutropenia, was seen in 57% of the patients. A certain degree of pulmonary toxicity was observed; eight patients had symptomatic breathlessness, +/- decreased diffusing capacity of the lung for carbon monoxide, and interstitial chest X-ray changes during the weekly phase. In all cases, this toxicity was reversible. No significant neurotoxicity was seen. This regimen is generally well tolerated with encouraging efficacy. However, the observation of pulmonary toxicity, potentially a feature of the weekly taxane-gemcitabine regimen, was of some concern. Alternative schedules, including 3-weekly taxanes, are currently being evaluated.

A randomised phase III trial was conducted to assess the role of interferon-alpha (INFalpha) 2a as maintenance therapy following surgery and/or chemotherapy in patients with epithelial ovarian carcinoma. Patients were randomised following initial surgery/chemotherapy to interferon-alpha 2a as 4.5 mega-units subcutaneously 3 days per week or to no further treatment. A total of 300 patients were randomised within the study between February 1990 and July 1997. No benefit for interferon maintenance was seen in terms of either overall or clinical event-free survival. We conclude that INF-alpha is not effective as a maintenance therapy in the management of women with ovarian cancer. The need for novel therapeutics or strategies to prevent the almost inevitable relapse of patients despite increasingly effective surgery and chemotherapy remains.

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Ovarian clear cell carcinoma (OCCC) accounts for a small but significant proportion of all ovarian cancers and is a distinct clinical and pathological entity. It tends to be associated with poorer response rates to chemotherapy and with a worse prognosis. Little is known about possible underlying genetic changes. DNA extracted from paraffin-embedded samples of 18 pure OCCC cases was analysed for genetic imbalances using comparative genomic hybridisation (CGH). All of the 18 cases showed genomic alterations. The mean number of alterations detected by CGH was 6 (range 1-15) indicating a moderate level of genetic instability. Chromosome deletions were more common than amplifications. The most prominent change involved chromosome 9 deletions in 10 cases (55%). This correlates with changes seen in other epithelial ovarian cancers. This deletion was confirmed using microsatellite markers to assess loss of heterozygosity (LOH) at four separate loci on chromosome 9. The most distinct region of loss detected was around the IFNA marker at 9p21 with 41% (11 out of 27 cases) LOH. Other frequent deletions involved 1p (five out of 18; 28%); 11q (four out of 18; 22%) and 16 (five out of 18; 28%). Amplification was most common at chromosome 3 (six out of 18; 33%); 13q (four out of 18; 22%) and 15 (three out of 18; 17%). No high-level amplifications were identified. These features may serve as useful prognostic indicators in the management of OCCC.

After the publication of the 10-year survival data from Milan on the adjuvant use of the block sequential regimen consisting of four cycles of adriamycin followed by eight cycles of intravenous CMF, many centres adopted this as standard of care for high risk, multiple node-positive breast cancer. For this reason it was identified as the standard arm for the Anglo-Celtic adjuvant high-dose chemotherapy trial. This study reports on the experience of this regimen in 329 women with early breast cancer involving at least four axillary nodes, who were treated outside any adjuvant chemotherapy trial. At a median follow-up of 3 years, the overall 5-year disease-free survival is 61%, and the overall survival is 70%. These data confirm the efficacy of this regimen in non-trial patients, and, for the same high risk subgroup, indicate that this approach offers an outcome at least as good as that seen in the CALGB 9344 AC-Taxol arm, and the NCIC days 1 and 8 CEF., (Copyright 2002 Cancer Research UK)

The combination of 5-fluorouracil (5-FU) and interferon-alpha (IFN-alpha) has reported activity in the treatment of advanced colorectal carcinoma. Laboratory studies of IFN-beta suggest that this agent may offer theoretical advantages over IFN-alpha in combination with 5-FU. A total of 27 patients with advanced or recurrent colorectal carcinoma were treated in a non-randomized open phase II study with a combination of 5-fluorouracil (750 mg m(-1) daily for 5 days as a continuous intravenous (i.v.) infusion followed, from day 15, by i.v. bolus 750 mg m(-2) every 7 days) and recombinant interferon-beta [r-hIFN-beta-1a; 9 MIU (total dose) by subcutaneous injection from day 1 on every Monday, Wednesday and Friday throughout the treatment period]. Toxicity was less than that seen with this schedule of 5-FU in combination with IFN-alpha. Among 21 evaluable patients, four objective responses were seen. Recombinant human interferon-beta-1a in combination with 5-FU is an acceptable regimen in terms of toxicity. However, the study did not demonstrate a superior response rate when compared with previous reports of treatment with 5-FU alone or in combination with IFN-alpha.

The purpose of our study was to investigate the efficacy and toxicity of paclitaxel in patients with relapsed or refractory epithelial ovarian cancer in the context of a large multicentre study performed in the UK and Eire. Patients with previously treated epithelial carcinoma of the ovary or fallopian tube who fulfilled the eligibility criteria were entered in the study. Eligibility criteria included: measurable or evaluable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; up to three prior chemotherapy regimens, one of which had to contain a platinum agent; adequate haematological, renal and hepatic function; and no significant cardiac history. Patients received either 175 mg m-2 or 135 mg m-2 paclitaxel. The lower dose was administered to patients who had received more than two prior chemotherapy regimens. Paclitaxel was given by i.v. infusion over 3 h every 21 days. Response was assessed at three-cycle intervals or earlier if required. A total of 155 patients were registered for the study in the UK of whom 140 were eligible for response and toxicity evaluation, and 12 patients were assessed for toxicity only. Hair loss was the most frequently reported toxicity, with 74% (119/152) of patients reporting grade 3 alopecia. The most frequently reported serious toxicity was neutropenia, with 49% (74/152) of patients experiencing neutropenia grade 3 or 4. The response rate was 16% [two complete responders (CR), 20 partial responders (PR)], the median duration of response was 275 days and median survival was 244 days. Paclitaxel is active in relapsed and platinum-resistant epithelial ovarian cancer. It is well tolerated and can be given in an out-patient setting. The UK and Eire experience is very similar to that of US investigators in this group of patients. Further work is required to assess the optimal use of the drug in both first- and second-line therapy.

In a study designed to compare response rates of patients with stage III epithelial ovarian carcinoma to ifosfamide and carboplatin, 152 patients were randomised to receive either sequential therapy with three cycles of ifosfamide followed by three cycles of carboplatin, or to six cycles of single agent carboplatin. Ifosfamide was given every 3 weeks in a dose of 5 gm m-2 as a 24 h infusion with mesna, 1 gm m-2 by i.v. bolus prior to ifosfamide, 3 gm m-2 with ifosfamide, and 1 gm m-2 as an 8 h infusion after ifosfamide. Carboplatin was given in a dose of 400 mg m-2 by short i.v. infusion every 4 weeks. Sixty-eight evaluable patients were randomised to sequential ifosfamide/carboplatin, and 67 to single agent carboplatin. Median follow-up is 36 months (range 5.5-82.3). After three cycles of treatment two patients in the ifosfamide/carboplatin arm achieved complete remission (CR), and 12 partial remission (PR) for an overall response rate of 29%, whereas in the carboplatin arm ten patients achieved CR, and 23 PR, for an overall response rate of 63% (P = 0.0008). Seven of 15 patients with progressive disease, and nine of 20 patients with stable disease at the initial response evaluation, following three cycles of ifosfamide, subsequently responded to carboplatin therapy so that the final response rate to the complete regimen was 65% for the ifosfamide/carboplatin arm, compared to 71% for the carboplatin arm (NS). For the ifosfamide/carboplatin arm, median recurrence free survival and overall survival were 14.1 months and 18.7 months. Corresponding figures for the carboplatin arm were 14.5 months and 21.5 months (NS). Both treatments were generally well tolerated. However 47% of patients in the ifosfamide/carboplatin arm developed alopecia sufficient to require a wig, compared to only 2% in the carboplatin arm. Ifosfamide is clearly less effective, and more toxic than carboplatin. Ifosfamide failures can however be effectively salvaged by subsequent carboplatin treatment. Ifosfamide cannot be recommended for single agent therapy in ovarian carcinoma, however the combination of carboplatin plus ifosfamide might be a suitable treatment to be tested in a future randomised study against carboplatin alone.

Cellular adhesion molecules have been implicated in tumour progression and metastasis. This study examines for the first time the serum concentrations of circulating VCAM-1 and E-selectin in a consecutive series of 110 cancer patients seen in a general medical oncology clinic, and confirms and extends previous studies reporting measurement of circulating ICAM-1. Soluble ICAM-1 and VCAM-1 levels were significantly higher in all the patient groups compared with the controls whereas soluble E-selectin was significantly higher in the ovarian, breast and GI cancer groups and lower in the myeloma group. The significance of these results together with the possible sources and stimuli for release of these adhesion molecules are discussed.

Tumour markers CEA, CA-195 and CA-242 were measured in 33 patients undergoing chemotherapy for advanced colorectal cancer. The aim was to determine whether they could be used to accurately monitor the course of the disease, and reduce the need for imaging. Treatment with a 5-fluorouracil based regimen resulted in a partial response in nine patients (27%), whereas the remainder either had disease stabilisation or suffered from progression. Before treatment the CEA was elevated in 85% of patients and the CA-195 and CA-242 in 78%. All three markers were elevated in 70% and at least one elevated in 93%. CA-195 and CA-242 appeared to be co-expressed, by contrast with the CEA. When compared to the results of serial CT scanning the CEA correlated best with the course of the disease, the positive predictive value being 54% for a partial response, 77% for minor and partial responses combined and 100% for progressive disease. The corresponding values for CA-195 were 46%, 62% and 100% respectively and for CA-242, 50%, 67% and 100% respectively. Thus, although falling levels of markers overestimate the number of responses demonstrated by imaging, rising tumour markers invariably herald progressive disease. This was often evident up to 16 weeks before progression was observed on scanning. CEA is the most useful of the three markers in the monitoring of patients being treated for advanced colorectal cancer, but other markers may prove valuable if the CEA is normal. The use of tumour markers should reduce the need for regular scanning.

Trimelamol is an analogue of hexamethymelamine which exhibited activity against refractory ovarian cancer in phase I clinical trial. The dose limiting toxicity was leukopenia. In a phase II study, 42 patients with recurrent, or platinum-complex resistant, advanced ovarian cancer were treated using the dose schedule 800 mg m-2 i.v. daily for 3 days. There were one complete, three partial and five minor responses, objective response rate: 9.5%. The main toxicity observed was nausea and vomiting, myelosuppression was minor. The role of Trimelamol in the treatment of ovarian cancer remains to be defined, but its activity is limited in refractory disease.

One hundred and twenty-seven consecutive patients presenting with small cell lung cancer were entered into a whole-brain CT scan surveillance study, starting at presentation and repeating at 3-monthly intervals for 2 years as an alternative to prophylactic cranial irradiation (PCI). The aim of the study was to detect CNS metastases at an early asymptomatic stage in the hope that prompt CNS radiotherapy could achieve long-term control; at the same time unnecessary PCI with its potential long-term morbidity could be avoided. CNS metastases were found in 56 patients (44%) including 16 (13%) at diagnosis and 40 at a median of 4 months (range 1-27 months) after completing chemotherapy. No patient developed CNS disease while on chemotherapy. Thirty-six patients were asymptomatic at diagnosis (group A) but 20 developed clinical CNS relapse between scans (group B) (interval relapse). Despite prompt radiotherapy 56% of patients in group A and 60% of patients in group B died with active CNS disease. Likewise, there was no survival difference between patients in group A, group B or those who never developed CNS disease. Regular 3-month CT scan surveillance is therefore not an effective substitute for PCI.

Two hundred and eighty-four patients with advanced Hodgkin's disease (HD) (stage II with poor prognostic features and stage III/IV) have been treated with the ChlVPP combination chemotherapy regimen (chlorambucil, vinblastine, procarbazine and prednisolone) in a single-centre unselected series. Median follow up is 92 months. Fifty-five patients had previously received radiotherapy but none had received previous chemotherapy. Eighty-five per cent of previously untreated patients and 91% of previously irradiated patients entered complete remission (CR); 71% and 68% of these respectively remain in CR at 10 years and 65% and 64% of each group respectively are alive at 10 years. On univariate analysis, age, stage, site of visceral disease and lymphocyte count predicted survival and on multivariate analysis age, absence of symptoms, absence of lung, liver or bone marrow disease and achieving a CR remained important predictors of survival. Acute toxicity was mild. The 10 year actuarial risk of acute leukaemia was 2.7%. This study adds further support to the view that chlorambucil is as effective and less toxic than mustine in combination chemotherapy for HD. We suggest that MOPP chemotherapy is no longer routinely indicated for HD.

Forty-four patients with relapsed or resistant Hodgkin's disease were treated with adriamycin 40 mg m-2 i.v. on day 1, vincristine 1.4 mg m-2 i.v. on days 1 and 8, prednisolone 40 mg m-2 orally daily for 8 days, etoposide 200 mg m-2 orally daily for 4 days according to the nadir white cell count, and bleomycin 10 mg m-2 i.v. days 1 and 8 (HOPE-Bleo). Median age was 27 (range 12-71). When stage was considered according to all sites currently or previously involved by Hodgkin's disease (cumulative stage) 26 patients (59%) had stage IV, 13 (29%) stage III and five (11%) stage II disease; 33 (75%) had B symptoms. All patients had received previous chemotherapy and 18 (41%) had received two or more regimens. Twenty-six patients (59%) achieved CR and 10 (23%) PR; the median duration of CR was 22 months and median survival for all patients was 48 months. Eight patients remain in continuous CR; none of these had received extensive previous chemotherapy. Among the 19 patients who had relapsed from CR achieved by a single previous chemotherapy regimen, six (32%) achieved long CR on HOPE-Bleo. The regimen was generally well tolerated but the principal toxicity was myelosuppression. There were two toxic deaths, one due to neutropenic sepsis and the other due to acute peritonitis. The HOPE-Bleo regimen is an effective treatment for relapsed or resistant Hodgkin's disease, with a low probability of carcinogenesis and infertility. These factors suggest that HOPE-Bleo deserves further evaluation as primary treatment for Hodgkin's disease and very careful selection of relapsed patients for high dose salvage chemotherapy with bone marrow transplants must be exercised.

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Thirty-eight patients with previously treated Hodgkin's disease were given high dose combination chemotherapy using melphalan and BCNU and autologous bone marrow transplantation. In 25 patients etoposide was added in conventional dosage. During the course of the study the dose of melphalan was increased from 80 to 140 mg m-2 and the dose of BCNU from 300 to 600 mg m-2. The response rate was 76% with 53% complete remission. Forty-five per cent of the patients are free of disease at 4-20 months follow-up. There were eight (26%) treatment-related deaths due to lung damage (seven cases) and irreversible cardiac failure (one case). Fatal lung damage occurred only in patients receiving 600 mg m-2 of BCNU with high dose melphalan. The dose of BCNU given with high dose melphalan should not exceed 500 mg m-2. This treatment is effective against relapsed Hodgkin's disease but must be used cautiously. The best time for its use remains to be determined.

Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg-1 t.d.s. for 23 days followed by oral acyclovir 800 mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.

In a series of 22 patients, high dose BCNU (800-1,000mg m-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return. Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.