Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer.

BACKGROUND: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life. METHODS: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE. RESULTS: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2-3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04). CONCLUSIONS: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients. TRIAL REGISTRATION NUMBER: ISRCTN 39679215.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.

Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

Poor uptake of influenza vaccinations in patients receiving cytotoxic chemotherapy.

This audit was designed to assess whether existing UK vaccination programmes mean that patients receiving chemotherapy are being vaccinated against influenza. One hundred and ten adult patients receiving chemotherapy at a south London tertiary referral centre were interviewed when they attended for their chemotherapy. Thirty-six of the 110 (33%) patients had received their influenza vaccination at the time of the study. Vaccination rates were significantly higher in those patients older than 65 years (53% vs 17%, p<0.001), and in those with co-morbidities (49% vs 25%, p<0.05). The vaccination rate in this at-risk population is lower than the overall national uptake in those aged 65 and over. Those patients most likely not to receive their influenza vaccination are those who have no indication for vaccination other than the fact they are receiving chemotherapy. Increased awareness of the benefits of influenza vaccine and its safety is needed among general practitioners, patients and oncologists.

Neutrophilic dermatoses in two children with idiopathic neutropenia: association with granulocyte colony-stimulating factor (G-CSF) therapy.

Painful neutrophilic skin lesions were observed in two children receiving granulocyte colony-stimulating factor (G-CSF) for treatment of idiopathic neutropenia. A girl with cystic fibrosis and cyclic neutropenia developed an erythematous papular eruption without fever or neutrophilia 7 months after commencing therapy with G-CSF. A skin biopsy specimen revealed microscopic, sterile, neutrophilic abscesses. A boy with chronic neutropenia and recurrent inflammatory skin lesions developed multiple erythematous nodules following administration of G-CSF. A biopsy specimen showed neutrophilic panniculitis. We believe that these skin eruptions belong to a spectrum of neutrophilic dermatoses that can be induced or aggravated by G-CSF therapy.

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

An unusual presentation of doxycycline-induced photosensitivity.

Photoonycholysis in association with a generalized phototoxic reaction or as an isolated event is a well-recognized complication of the tetracycline group of antibiotics. We describe a 14-year-old white girl with cystic fibrosis who developed photoonycholysis of all 20 nails while receiving treatment with doxycycline. Pediatricians who prescribe tetracyclines should be aware of this potential complication.

Continuous infusional combination chemotherapy in inflammatory breast cancer: a phase II study.

Despite the introduction of systemic chemotherapy, inflammatory breast cancer (IBC) remains a disease with a poor prognosis. We performed this phase II study to evaluate the efficacy of infusional chemotherapy as initial treatment in patients with IBC. Fifty-four patients with newly diagnosed IBC were offered infusional chemotherapy and 34 accepted. The schedule consisted of continuous infusional ECF (bolus epirubicin and cisplatin, substituted by carboplatin or cyclophosphamide in some patients) plus continuous 5-FU, given three weekly for six cycles. Following chemotherapy patients went on to have surgery and/or radiotherapy. The chemotherapy was well tolerated and resulted in an overall response rate of 79% with 35% of patients achieving a complete clinical response. The median response duration, time to progression and overall survival were 12 months (4-89+ months), 12 months (4-89+ months) and 23 months (7-89+ months), respectively. Patients had a 5 year disease free and overall survival of 11% and 29%, respectively. Infusional ECF is well tolerated and achieves a high clinical response rate in patients with IBC, but survival results do not appear to be superior to those achieved with conventional bolus chemotherapy schedules.

Surgery plus chemotherapy or chemotherapy alone for primary intermediate- and high-grade gastric non-Hodgkin's lymphoma: the Royal Marsden Hospital experience.

Primary gastric lymphomas (PGL) have traditionally been treated with surgery followed by chemotherapy or radiotherapy. Surgery was thought to improve staging, optimise local disease control and reduce risk of perforation or bleeding, but recent studies question its role. In this study, patients with intermediate- or high-grade PGL who received chemotherapy from 1985 to 1996 at the Royal Marsden Hospital were identified using a prospectively accrued database. A total of 37 patients (6 with low-grade mucosa-associated lymphoid tissue lymphoma (MALT-L), 9 with high-grade MALT-L, 20 with diffuse large B-cell (DLBC) lymphoma and 2 other histologies), 17 of whom had localised disease, were treated with either surgery plus chemotherapy or chemotherapy alone. 5-year overall survival for localised and advanced PGL was 94 and 50%, respectively, with no differences between the two treatments over a 53 months median follow-up. No perforations or serious bleeding occurred. Surgery is associated with important morbidity and we detected no benefit of surgery prior to chemotherapy in this limited series of patients.

Pain management of junctional epidermolysis bullosa in an 11-year-Old boy.

Epidermolysis bullosa is a group of hereditary blistering disorders for which there is no definitive therapy. Wound care is an important component of management. Regular dressing changes are required to protect blistered and eroded skin, and to prevent secondary infection and sepsis. These dressing changes can be very painful for patients with extensive erosions. We report our experience of pain management in an 11-year-old boy with severe junctional epidermolysis bullosa. Amitryptiline and cognitive behavioral techniques were effective in relieving chronic pain and discomfort. Oral midazolam 0.33 mg/kg administered 20 minutes prior to baths and dressing changes substantially improved his tolerance of wound care.

High-performance liquid chromatographic assay for the novel antitumor drug, bryostatin-1, incorporating a serum extraction technique.

An HPLC assay incorporating a solid-phase extraction technique has been devised for bryostatin-1. Quantitation of bryostatin was found to be linear over the concentration range 0.012-25 microg/ml (0.2-25 ng on column) and was found to have a limit of detection of 0.2 ng on column, with a correlation coefficient of 0.9999. Following extraction of bryostatin over a range of concentrations from horse serum (0.012-25 microg/ml) and human serum (0.01-0.32 microg/ml) using a 100-mg C18 solid-phase extraction cartridge, extraction efficiencies consistently greater than 90% were obtained for extraction from horse serum and varied between 57 and 85% from human serum. However, on extending this work to blood samples from patients undergoing therapy with bryostatin-1, the drug was not detectable even at the maximum dose given, demonstrating the rapid loss of this agent from peripheral circulation.

Randomized phase II trial of infusional fluorouracil, epirubicin, and cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in patients with advanced breast cancer.

PURPOSE: We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.

Localized dystrophic periocular calcification: a complication of intralesional corticosteroid therapy for infantile periocular hemangiomas.

Two female infants with eyelid hemangiomas developed prickly, rock-hard, subcutaneous crystals following intralesional corticosteroid injections. In each case, the crystals were isocentered on the injection locus and partly eroded the skin, causing local discomfort and inflammation. This complication occurred after two treatment sessions and presented 8 to 9 months after the second injection. An MRI scan showed subcutaneous calcification in the location of the injected orbital hemangioma in one patient. Histopathologic examination confirmed calcification in areas of degenerate hemangioma. There was no recurrence of either hemangioma or calcium deposition following surgical excision. Localized dystrophic calcification may be a late complication of intralesional corticosteroid therapy of periocular hemangiomas.

A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer.

BACKGROUND: To compare protracted venous infusion (PVI) 5-fluorouracil (5-FU) with and without mitomycin C (MMC) in a prospectively randomised study and analyse for tumour response, survival, toxicity and quality of life (QL). PATIENTS AND METHODS: Two hundred patients with advanced colorectal cancer received PVI 5-FU 300 mg/m2/day for a maximum of 24 weeks and were randomised to PVI 5-FU alone or PVI 5-FU + MMC 10 mg/m2 (7 mg/m2 from June 1995) 6 weekly for 4 courses. RESULTS: Overall response was 54% (95% confidence interval [CI] 44.1%-63.9%) with PVI 5-FU + MMC compared to 38% (95% CI: 28.3%-47.7%) for PVI 5-FU alone (P = 0.024). The median failure free survival was 7.9 months in PVI 5-FU plus MMC and 5.4 months with PVI 5-FU alone (P = 0.033) and at one year 31.9% for the combination compared to 17.7% for PVI 5-FU alone. Median survival was 14 months with MMC and 15 months in 5-FU alone; one-year survival 51.7% vs. 57.2%. PVI 5-FU + MMC caused more overall haematological toxicity but CTC grades 3/4 was increased only for thrombocytopaenia. Two patients treated with a cumulative dose of MMC of 40 mg/m2 developed haemolytic uraemic syndrome warranting the reduction in cumulative MMC dose to 28 mg/m2. The global QL scores were better for PVI 5-FU + MMC arm at 24 weeks, but the remaining QL data showed no differences. CONCLUSIONS: PVI 5-FU + MMC results in failure-free survival and response advantage, tolerable toxicity and better QL when compared to PVI 5-FU alone but no overall survival advantage. There is no irreversible toxicity with MMC at a cumulative dose of 28 mg/m2.

Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature.

BACKGROUND: Chronic granulomatous disease represents a group of genetic disorders in which impaired intracellular microbial killing by phagocytes leads to recurrent bacterial and fungal infections and granuloma formation. Cutaneous disease occurs in 60% to 70% of cases. The characteristic histologic finding of pigmented lipid macrophages in visceral granulomas has not been described previously in the skin. OBJECTIVE: Our purpose was to review our experience of skin disorders in chronic granulomatous disease. METHODS: We studied the clinical and histologic findings in four patients with chronic granulomatous disease and unusual skin lesions. We reviewed the skin disorders seen in five additional patients with chronic granulomatous disease referred to the pediatric dermatology clinic. The literature was reviewed for previously reported cutaneous manifestations of chronic granulomatous disease. RESULTS: A teenage boy with chronic granulomatous colitis had nonulcerating cutaneous granulomas from which no organisms were isolated. Histologic examination of both skin and bowel revealed the characteristic golden-yellow granular pigment in macrophages. A second boy had cutaneous aspergillosis involving the left foot; histologic examination revealed macrophages containing yellow-brown pigment at the periphery of the granulomatous inflammation. Two children had vesicular skin lesions. These lesions were recurrent in one boy for several years. In the second child they were associated with fatal intracranial and pulmonary infection. Histologic examination in both cases revealed a subcorneal polymorphonuclear infiltrate and perivascular macrophages containing yellow-brown pigment. Cultures were either negative or revealed organisms that are normally nonpathogenic skin commensals, such as coagulase-negative staphylococci. CONCLUSION: The cutaneous manifestations of chronic granulomatous disease encompass a variety of infections and inflammatory lesions. Diagnostic and therapeutic problems may arise because of difficulty in isolating a causative organism. The characteristic pigmented macrophages of visceral granulomas can also be found in skin lesions.

Gemcitabine.

There is widespread consensus that a plateau has been reached in the effectiveness of known DNA interactive drugs against most malignancies. Combination treatments, dose intensification and schedule alterations (e.g. infusional and neoadjuvant treatments) represent exciting research opportunities and possibly the means for making meaningful progress. However, frustration with the slow pace of even these most novel approaches has led to a search for newer drug targets and great expectations of new drugs.

Topical calcipotriol in childhood psoriasis.

BACKGROUND: The use of topical calcipotriol in adults with psoriasis is safe and effective. OBJECTIVE: Our purpose was to study the efficacy and safety of calcipotriol in children. METHODS: A multicenter, prospective, 8-week, double-blind, parallel group study was conducted in 77 children. Response to treatment was assessed by means of the Psoriasis Area and Severity Index (PASI) in that the intensity of redness, thickness, and scaliness as well as the area involved are scored. The children were 2 to 14 years of age and had stable psoriasis, involving less than 30% of the body surface. Forty-three children were assigned to receive calcipotriol ointment and 34 to receive placebo. Nine children dropped out of the study, six in the calcipotriol-treated group and three in the placebo-treated group. RESULTS: Both treatment groups (calcipotriol and placebo) showed significant improvement in PASI from baseline to the end of treatment, and the difference was not statistically significant. No serious side effects, in particular including those relating to calcium and bone metabolism, were recorded. CONCLUSION: Calcipotriol ointment was statistically significantly more effective than its vehicle in terms of the investigator's overall assessment and reduction in redness and scaliness but not in terms of PASI score.

Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children.

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.