Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

BACKGROUND: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. PATIENTS AND METHODS: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. RESULTS: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. CONCLUSIONS: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. CLINICALTRIALS.GOV: NCT01006980.

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients.

INTRODUCTION: Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients. MATERIALS AND METHODS: A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients. RESULTS: Baseline cfDNA concentration correlated with pre-treatment tumour burden (ρ = 0.52, P < 0.001). Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/µl identified two distinct prognostic groups (HR = 2.22 for high cfDNA, P = 0.004). Patients with cfDNA ≥89 pg/µl had shorter OS (10.0 versus 22.7 months, P = 0.009; HR = 2.22 for high cfDNA, P = 0.004) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden (ρ = 0.49, P = 0.002). In addition, the ratio between baseline cfDNA and tumour burden was prognostic (HR = 2.7 for cfDNA/tumour volume ≥8 pg/(µl*cm3), P = 0.024). CONCLUSIONS: We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.

PURPOSE: To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS: In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS: The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION: The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.

Temozolomide, an oral imidazotetrazine derivative, was given to 31 patients with advanced soft tissue sarcoma. The dose of 750 mg/m2 was divided over 5 consecutive days, and escalated to 1000 mg/m2 over 5 days at cycle 2 if myelosuppression no worse than common toxicity criteria grade 2 was noted in the first 28-day cycle. A total of 99 treatment cycles were given to 31 patients. The drug was well tolerated, with nausea and vomiting as the most common side-effects. Only one partial tumour response was documented, giving a response rate of 3.33%, 95% confidence interval, (CI) 0.1-17.2%. The median time to progression was 8 weeks and the median survival was 27 weeks. These results indicate that temozolomide in this schedule is not active as second-line treatment in advanced soft tissue sarcoma.

Gestational choriocarcinoma of the ovary diagnosed by analysis of tumour DNA.

Gestational choriocarcinoma of the ovary is a rare form of malignancy which can be difficult to distinguish from primary ovarian choriocarcinoma. The ability to make such a diagnosis could, however, have important implications for therapy. We report here a case of choriocarcinoma whose origins were difficult to determine and which behaved clinically more like a primary rather than a gestational choriocarcinoma. We have analysed DNA from this tumour by using polymerase chain reaction (PCR) amplification of a range of polymorphic alleles and have demonstrated that the tumour was in fact gestational. Furthermore, the lack of chromosome Y sequences and the presence of heterozygosity of the spouse's alleles, indicated that this tumour arose as a result of dispermic fertilisation of an empty ovum by sperm carrying the X chromosome.

Current drug treatment guidelines for epithelial ovarian cancer.

The management of ovarian cancer is developing rapidly with the improvements in specialist multidisciplinary care. Most patients present with advanced disease and require careful surgical debulking followed by platinum-based chemotherapy. The recent introduction of paclitaxel appears to have improved the prognosis of advanced ovarian cancer by an increment that is similar in size to that seen after the introduction of cisplatin in the 1970s. Further clinical trials are required to define the optimum combination and dose of the platinum and taxane analogues, and to establish the role of the many new agents currently undergoing clinical testing. Useful chemotherapy for second-line treatment in platinum-refractory patients is now available, which, combined with more aggressive surgical management, is leading to modest improvements in survival. Improvements in supportive care have enabled increasingly intensive chemotherapy to be given safely. Bone marrow support and inhibitors of specific organ toxicities are likely to be incorporated into treatment protocols over the next decade. The impact of these treatments on patients' quality of life and the economic consequences of a more active approach to management will require careful evaluation.

VEDex (vincristine, epirubicin dexamethasone): an effective and well tolerated palliative chemotherapy regimen for non-Hodgkin's lymphoma.

An evaluation was carried out of the efficacy and toxicity of a novel weekly palliative chemotherapy regimen comprising vincristine, epirubicin and dexamethasone (VEDex) in 57 patients with non-Hodgkin's lymphoma (NHL) treated at this centre. The age range was 34-88 years and the median age was 67 years. Twenty-three patients (40%) had low grade disease and 4 patients (7%) had transformed NHL. Thirty patients (53%) had high grade NHL; 7 had relapsed after conventional chemotherapy and were not fit for high-dose chemotherapy, 7 were heavily pre-treated, 8 had received prior radiotherapy and 8 had not received any prior therapy. Responding patients received a total of 8 weeks of treatment, but treatment could be repeated at a later stage if required. The overall response rate was 66.6%; 11 patients (19.3%) achieved a complete response and 27 (47.3%) achieved a partial response. A further 11 patients (19.3%) had stable disease. Twenty-four patients (42.1%) reported complete resolution of symptoms and 21 (36.8%) had partial resolution of symptoms. The median survival from the onset of treatment was 6 months. Grade III neutropenia was seen in 9 patients (15.8%). Other toxicity included nausea and vomiting grade II (3.5%), grade III (1.8%) and alopecia grade III (1.8%). There were no treatment related deaths. We conclude that VEDex is an effective palliative treatment in patients with indolent or aggressive lymphoma with poor performance status or who have been heavily pre-treated. It is well tolerated in the elderly.

Primary intracerebral lymphoma: A clinicopathological study of 28 patients.

Primary intracerebral lymphoma is an uncommon presenting site for non-Hodgkin's lymphoma. The authors review 28 histopathologically confirmed, consecutive cases, presenting over a 15-year period. The cohort included 20 males and 8 females with a mean age at diagnosis of 54 years (range 27-75 years). Subtotal resection was performed in 8 patients. Radical whole brain irradiation was given to 27 patients. One patient was too unwell to receive treatment and quickly died. Three patients also had chemotherapy. Clinical remission was achieved in 19 patients. Of these, 9 relapsed after a median interval of 18 months. Nine patients (32% total cohort) are still alive and in remission after a median follow-up of 2 years and 10 months (range 11 months to 11 years and 5 months). Cause of death was intracerebral lymphoma in 13 of the 19 patients who died. Median survival was 12 months in this group (range 1 week to 4 years and 9 months). Actuarial 5-year survival for all patients was 19%. The prognosis for patients with primary intracerebral lymphoma treated with radiotherapy alone is poor.

A phase II protection study of BB-10010 in patients with high grade non-Hodgkin's lymphoma undergoing intensive chemotherapy.

The aim of this study was to determine whether administration of BB-10010, a synthetic stem cell inhibitor, would allow more intensive chemotherapy to be administered to patients with newly diagnosed high grade NHL. Thirteen patients were randomised to receive BB-10010 concurrently with dose-intensified BEMOP/CA chemotherapy (7 patients) or chemotherapy alone (6 patients). Although the mean neutrophil count of BB-10010 treated patients was higher following cycles 1, 2 and 3 of chemotherapy compared with those receiving chemotherapy alone, there was no difference in the mean number of cycles tolerated, blood component usage and hospital admissions due to infections. No specific toxicity of BB-10010 was identified. Whilst BB-10010 can be administered safely, it does not improve the ability of patients to tolerate intensive chemotherapy for high grade NHL.

Small cell carcinoma of the cervix.

Small cell carcinoma of the cervix represents an uncommon variant of cervical cancer with a particularly poor prognosis. Traditionally, the diagnosis was established from routine histopathological sections, but there has been a trend to refer to this tumour as neuroendocrine carcinoma, with a requirement to demonstrate cytoplasmic granules. Five patients are described, who share the clinical features of young age of onset, early metastasis in the presence of apparently low stage disease, early failure of appropriate local treatment, and extreme chemosensitivity (features that are quite distinct from those seen in squamous cell cancer of the cervix). Light microscopy suggested a diagnosis of small cell cancer in all five tumours, but not all showed evidence of neuroendocrine differentiation. It is proposed that the present criteria for the diagnosis of cervical small cell carcinoma are too strict. The diagnosis should rely on the light microscopy of haemotoxylin and eosin sections and the distinctive clinical behaviour. The absence of neuroendocrine differentiation should not exclude the diagnosis, it does not appear to influence the clinical behaviour. The appropriate management of small cell carcinoma of the cervix is systemic, with chemotherapy as the first line of treatment. Surgery and radiotherapy may improve control of local disease but are unlikely significantly to influence the overall prognosis.

High-dose chemotherapy and peripheral blood stem cell support in refractory gestational trophoblastic neoplasia.

We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) in the largest series so far reported. In all, 11 patients have been treated at three Trophoblast Centres between 1993 and 2004. The conditioning regimens comprised either Carbop-EC-T (carboplatin, etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin, etoposide and melphalan) or ICE (ifosfamide, carboplatin, etoposide). Two patients had complete human chorionic gonadotrophin responses, one for 4 and the other for 12 months. Three patients had partial tumour marker responses for 1-2 months. High-dose chemotherapy and HSCS for GTN is still unproven. Further studies are needed, perhaps in high-risk patients who fail their first salvage treatment.

The cost-effectiveness of high dose chemotherapy in the treatment of relapsed Hodgkin's disease and non-Hodgkin's lymphoma.

As part of an NHS Executive Trent regional initiative we considered the role and cost-effectiveness of high dose chemotherapy in the treatment of relapsed Hodgkin's disease and non-Hodgkin's lymphoma. The key trials and case series show an additional patient benefit of 0.8-1.1 life years over standard chemotherapy. We estimate incremental cost per life year gained of 12 800 pound silver-17 600 pound silver, which reduces further if long-term benefits are considered. High dose chemotherapy in these conditions is both life-saving and cost-effective.

Characteristics of women with recurrent molar pregnancies.

OBJECTIVES: The aim of this study was to examine the incidence and characteristics of women who develop a second molar pregnancy after a previous episode of gestational trophoblastic disease. METHODS: A retrospective analysis was carried out on completed registration forms from referring hospitals in the North of England to the Sheffield Trophoblastic Screening Service over a 13-year period. All cases of second molar pregnancy were identified. Details of histology, blood group, ethnic origin, age, and subsequent pregnancies were examined. RESULTS: Between 1 January 1985 and 31 December 1997, 5030 patients were registered for follow-up and 275 (5.5%) required treatment for persistent disease. Thirty-five women had a subsequent molar pregnancy, a total of 0.70% of all registrations. There was no significant difference in age at first registration between those who were registered for one molar event and those who developed a subsequent molar pregnancy. The risk of a second molar event was highest in the second year after the initial diagnosis and reduced thereafter. There was a trend toward an increased risk of second molar pregnancy in Indian/Pakistani women when compared to Caucasian women (relative risk 2.4) but this was not significant at conventional levels. There was a significantly increased incidence of blood group B in patients that developed a molar pregnancy when compared to the normal population (P < 0.05), but there was no difference in distribution of blood group between those registered for their first molar event and those with two or more events. Patients who presented with a partial mole tended to have a partial mole as the second event but patients who presented with a complete mole were at risk of a subsequent complete mole, partial mole, or choriocarcinoma. Six percent of patients required chemotherapy for the second molar event, indicating no increase in aggressiveness in second moles. Two patients had three molar events. CONCLUSION: In the United Kingdom the risk of second molar pregnancy is less than 1%. There is an increased risk of molar pregnancy in women with blood group B and a trend toward an increased risk of second molar pregnancy in Indian/Pakistani women. Only 6% of patients required chemotherapy for the second mole; a second molar pregnancy is not an indication for chemotherapy.

TNF-alpha increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes.

Inflammatory mediators have been reported to promote malignant cell growth, invasion and metastatic potential. More specifically, we have recently reported that tumour necrosis factor alpha (TNF-alpha) increases melanoma cell attachment to extracellular matrix (ECM) substrates and invasion through fibronectin. In this study, we extend these investigations asking specifically whether the TNF-alpha effect on cell invasion and migration involves activation of proteolytic enzymes. We examined the effect of TNF-alpha on melanoma expression/activation of type IV gelatinases matrix metalloproteinases 2 and 9 (MMPs -2 and -9) and general proteolytic enzymes. Stimulation with TNF-alpha significantly increased both melanoma cell migration at 24 h (+21%) and invasion through fibronectin (+35%) but did not upregulate/activate the expression of latent MMP-2 constitutively produced by these cells and did not upregulate their general protease activity. However, the increased cell migration and invasion through fibronectin observed following stimulation with TNF-alpha were inhibited by the general protease inhibitor alpha(2) macroglobulin. These findings suggest that the promigratory and proinvasive effect of TNF-alpha on this melanoma cell line may be mediated to some extent by induction of localised cell membrane-bound degradative enzyme activity, which is not readily detected in biochemical assays.

Persistent gestational trophoblastic disease: results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease.

Persistent gestational trophoblastic disease is potentially fatal, but the majority of patients are cured with chemotherapy. Any developments in treatment are therefore being directed towards maintaining efficacy and reducing toxicity. We evaluated efficacy and toxicity of methotrexate, etoposide and dactinomycin (MEA) as first-line therapy for high risk disease and etoposide and dactinomycin (EA) as second-line therapy for methotrexate-refractory low risk disease in a retrospective analysis of 73 patients (38 MEA, 35 EA) treated since 1986 at a supra-regional centre. The median follow-up period was 5.5 years and the median number of cycles received was 7. The overall complete response rate was 85% (97% for EA, 75% for MEA). Of eight patients who failed to respond, four have since died and four were cured with platinum-based chemotherapy. Alopecia was universal. Grade II or worse nausea, emesis, or stomatitis was observed in 29%, 30% and 37% respectively. Fifty-one per cent experienced grade II/III anaemia, 8% grade II or higher thrombocytopenia and 64% grade III or IV neutropenia; in six cases this was complicated by sepsis. Fifty-four per cent of patients went on to have a normal pregnancy. No patient has developed a second malignancy. In conclusion, the MEA and EA chemotherapy regimens for persistent trophoblastic disease are very well tolerated, do not appear to affect future fertility and are associated with excellent, sustained complete response rates.

Serosal complications of single-agent low-dose methotrexate used in gestational trophoblastic diseases: first reported case of methotrexate-induced peritonitis.

Methotrexate (MTX) is a folate antagonist widely used both as an anticancer drug and as an immunosupressant. Administration of an 8-day methotrexate and folinic acid regime may be associated with pleuritic chest pain and pneumonitis. We have reviewed the toxicity seen in 168 consecutive patients treated with low-dose MTX for persistent trophoblastic disease. Twenty-five per cent of patients developed serosal symptoms, pleurisy was the commonest complaint. The majority of patients had mild to moderate symptoms which were controlled with simple analgesia and did not necessitate a change in treatment; 11.9% had severe symptoms which necessitated a change in treatment. One patient developed a pericardial effusion and a second patient developed severe reversible peritoneal irritation. The possible aetiology and pathophysiology of methotrexate-induced serosal toxicity is discussed.

Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma.

The purpose of this study was to identify novel areas of genomic copy number change associated with transformation from follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBL). DNA was extracted from tumour cells micro-dissected from paraffin- embedded tissue sections in 24 patients with FL and subsequent transformation to DLBL and 18 patients with de novo DLBL. Tumour DNA was compared to reference DNA using comparative genomic hybridization. Abnormalities common to all 3 groups were gains on chromosomes 4q, 5q, 7q, 11q and X and losses on 3p, 8p and 10q. Copy number changes seen in both transformed and de novo DLBL and not seen in FL were gains on 2p and losses on 1q, 15q and Xq. Gains on 2q, 6p, 7p and 17q and losses on 5p and 8q were specific to transformed DLBL cases. Gain on 12q12-14 was found in 52% of the transformed DLBL cases and was never seen in its follicular counterpart. Patterns of genomic copy number change associated with specific clinical events in NHL have been demonstrated and suggest that gains on 2q, 6p, 7p, 12q and 17q and losses on 5p and 8q may be important in the transformation from low to high-grade disease.

Phase II study of docetaxel in patients with relapsed or refractory malignant lymphoma.

We report the activity and toxicity of docetaxel in 12 evaluable heavily pretreated patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. In all, 42% achieved a partial response, 25% achieved stable disease. Median duration of response was 16 (10-21) weeks. The median overall survival was 70 (9-178) weeks and for responders it was 120 (22-178) weeks. One patient developed one episode of neutropenic sepsis. Docetaxel has limited activity in this group of patients.

Pulmonary function in patients with trophoblastic disease treated with low-dose methotrexate.

The Sheffield Trophoblastic Disease Centre treats about 25 patients with persistent trophoblastic disease each year. A total of 75% of patients are classified as low risk according to the Charing Cross Hospital prognostic scoring system and receive methotrexate (MTX) 50 mg, i.m., on days 1, 3, 5, 7 with folinic acid 7.5 mg orally 24 h after each methotrexate injection. There is a 7-day rest between treatment cycles. Remission is achieved in 85% of cases. Approximately 20% of patients experienced pleuritic chest pain and dyspnoea. We have evaluated prospectively lung function in 16 low-risk patients receiving methotrexate. All patients had pulmonary function tests [spirometry-forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), and transfer factor - TLCO, kCO] performed before and after completed treatment. A mean of 7.5 cycles of MTX were administered (range 4-11). There was a significant reduction in the mean TLCO (mean pre/post 8.15/7.38 mmol min-1 kPa-1, P = 0.01), but there were no other statistically significant changes. Three patients experienced respiratory symptoms and were found to have a 39%, 28%, and 11% reduction in TLCO from baseline, improving on follow up to pretreatment levels. Low-dose MTX is an effective therapy but may cause troublesome pulmonary toxicity.