A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer.

AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Phase II clinical trial of capecitabine and gemcitabine chemotherapy in patients with metastatic renal carcinoma.

We report a single institution phase II study of gemcitabine 1200 mg m(-2) i.v. on days 1 and 8 and capecitabine 1300 mg m(-2) twice daily on days 1-14 of each 3-week cycle in patients with metastatic renal carcinoma. Patients had a WHO performance status of 0, 1 or 2. Of the 21 enrolled patients, 19 had received prior immunotherapy or chemoimmunotherapy. All had progressive disease at study entry. In all,19 patients had multiple sites of disease. The median duration of metastatic disease was 12.3 months (range 1.2-78.1 months). Three of the 19 evaluable patients achieved a partial response to treatment, with no complete responses, producing an objective overall response rate of 15.8% (95% CI, 3.4-39.6%). The median time to disease progression was 7.6 months, and median overall survival was 14.2 months. Treatment was reasonably well-tolerated, neutropenia being the most frequently observed grade 3 or 4 toxicity, occurring in 57% of patients. Other side effects were consistent with the established toxicity profile of the two drugs, including diarrhoea, palmar-plantar erythema, fatigue, nausea, vomiting and infection. This combination of gemcitabine and capecitabine has modest activity in immunotherapy-refractory metastatic renal carcinoma with manageable toxicity.

Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy.

Elderly patients are recommended to have a reduced starting dose (300 mg m(-2) once every 3 weeks) of irinotecan monotherapy. The aims of this analysis are to compare toxicity and survival according to age, performance status (PS), gender and prior radical pelvic radiotherapy (RT). The primary end points were overall survival and an irinotecan-specific toxicity composite end point (TCE) defined as the occurrence of grade 3 or 4 diarrhoea, neutropenia, febrile neutropenia, fever, infection or nausea and vomiting. Between 1997 and 2003, 339 eligible patients with advanced colorectal cancer (CRC) progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered in a multicentre randomised trial. All patients commenced irinotecan at 350 mg m(-2) once every 3 weeks. There were no differences in proportions of patients developing TCE by age (<70 vs > or =70 : 37.8 vs 45.8%; P=0.218), PS (0-1 vs 2 : 39.3 vs 41.5%; P=0.793) or prior RT (RT vs no RT : 45.1 vs 38.5%; P=0.377). Males experienced more toxicity than females (44.3 vs 32.6%; P=0.031), but this was not significant after controlling for other co-variates (P=0.06). Patients aged > or =70 had similar objective responses (11.1 vs 9%; P=0.585) and survival (median 9.4 vs 9 months; log rank P=0.74) compared to younger patients. Elderly patients derive the same benefit without experiencing more toxicity with second-line irinotecan treatment for advanced CRC. Our data do not support the recommendation to reduce the starting dose for the elderly patients.

Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers?

To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994-2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival.

Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of irinotecan and 5-fluorouracil (5-FU) in primary refractory or relapsed locally advanced or metastatic oesophagogastric (O-G) carcinoma. PATIENTS AND METHODS: Patients with documented progression on or within 3 months of chemotherapy were recruited between July 2000 and May 2002. Irinotecan (180 mg/m(2)) was given with 5-FU (400 mg/m(2) bolus) and leucovorin (folinic acid) (125 mg/m(2)) followed by 5-FU (1200 mg/m(2) infusion over 48 h) every 2 weeks. Response confirmed by computed tomography was assessed at 12 and 24 weeks. RESULTS: Thirty-eight of 40 registered patients (95%) were assessable. Median follow-up was 9.3 months and median age was 59.0 years. Thirty-three patients (86.8%) had metastatic disease and 37 patients (97.4%) had previously received platinum-based chemotherapy. Overall response rate was 29% (95% confidence interval 15.4% to 45.9%) while an additional 34% had stable disease. Improvement in tumour-related symptoms included dysphagia 78.6%, reflux 60.0%, pain 54.5%, anorexia 64.3% and weight loss 72.7%. Grade 3/4 toxicities were anaemia 13.2%, neutropenia 26.4%, febrile neutropenia 5.2%, stomatitis 2.6%, nausea and vomiting 13.2% and diarrhoea 7.9%. Median failure-free survival was 3.7 months and median overall survival was 6.4 months. CONCLUSION: 5-FU/irinotecan is a valuable regimen for second-line treatment in 5-FU/platinum-resistant O-G carcinoma.

Rapid access multidisciplinary lymph node diagnostic clinic: analysis of 550 patients.

Lymphadenopathy is common, affecting patients of all ages. The current referral pattern for investigating patients with lymphadenopathy varies widely with no universally practised pathway. Our institution set up a lymph node diagnostic clinic (LNDC) accepting direct referrals from primary care physicians. Details of clinical presentation and investigations were recorded prospectively. Between December 1996 and July 2001, 550 patients were referred (M: 203; F:347). The median age was 40 years (range 14-90). The median time between initial referral and the first clinic visit was 6 days. Of 95 patients diagnosed to have malignant diseases, the median time from the first clinic visit to reaching malignant diagnosis was 15 days. Multivariate logistic regression analysis identified five significant predictors for malignant nodes: male gender (risk ratio (RR)=2.72; 95% confidence interval (CI): 1.63-4.56), increasing age (RR=1.05; 95% CI: 1.04-1.07), white ethnicity (RR=3.01; 95% CI: 1.19-7.6) and sites of lymph nodes: supraclavicular region (RR=3.72; 95% CI: 1.52-9.12) and > or = 2 regions of lymph nodes (RR=6.41; 95% CI: 2.82-14.58). Ultrasound and fine-needle aspiration cytology of palpable lymph nodes were performed in 154 and 289 patients, respectively. An accuracy of 97 and 84% was found, respectively. In conclusion, a multidisciplinary lymph node diagnostic clinic enables a rapid, concerted approach to a common medical problem and patients with malignant diseases were diagnosed in a timely fashion.

A rare case of intravascular lymphoma diagnosed on bone marrow trephine.

Intravascular lymphoma (IVL) is an extremely rare form of extra-nodal non-Hodgkins lymphoma characterised by the proliferation of neoplastic lymphocytes within the lumina of small arteries, veins and capillaries. The great majority of reported cases appear to be of B cell lineage. There is a wide variation in clinical presentation, and multiple organs are usually affected. We report a case of a 67-year-old man who presented with constitutional symptoms and neurological deficit and was diagnosed following bone-marrow trephine. His disease responded to polychemotherapy treatment but he died 15 months after diagnosis. This case in unusual in that it is generally felt that bone marrow is relatively spared until late in the disease and is often not clearly demonstrable histologically. In addition, this case supports the limited data that responses can be obtained following polychemotherapy treatment, although the prognosis remains generally poor.

A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus.

BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS: Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle. RESULTS: The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.

The case for the introduction of new chemotherapy agents in the treatment of advanced non small cell lung cancer in the wake of the findings of The National Institute of Clinical Excellence (NICE).

After years of nihilism towards the use of chemotherapy for non small cell lung cancer in the UK it would appear that we have now reached the point where the use of chemotherapy to relieve symptoms, maintain quality of life, and prolong life, are now accepted for informed patients with good performance status willing to accept short-term toxicities. The use of the new agents vinorelbine, gemcitabine and paclitaxel in combination with cisplatin or carboplatin are all active regimens which offer small but real advantages over standard UK triple therapies (MVP, MIC) in terms of resource use, toxicity profiles and response rates. Overall survival could be increased by as much as 10% at one year on indirect comparisons. The use of docetaxel as second line therapy now offers lung cancer patients a second bite of the cherry, and should overall also prolong survival. It is only in embracing these small gains that we can currently make progress in the treatment of NSCLC.

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer.

The purpose of this study was to evaluate the activity and safety of oxaliplatin and protracted venous infusion of 5-fluorouracil (PVI 5-FU) in patients with advanced or relapsed 5-FU pretreated colorectal cancer. 38 patients with advanced or metastatic colorectal carcinoma with documented progression on or within 6 months following 5-FU or thymidylate synthase inhibitor containing chemotherapy were recruited between June 1997 and September 2000. Oxaliplatin (100 mg x m(-2)) was given every 2 weeks and PVI 5-FU (300 mg x m(-2) x day(-1)) was administered. Median age of patients was 61 years. 17 patients had >2 sites of disease involvement. 10 had received 5-FU based adjuvant chemotherapy. 16 received oxaliplatin and PVI 5-FU as second-line chemotherapy for advanced disease and 22 as third or subsequent lines. Median follow up was 6.1 months. The best achieved objective tumour response rate was 29% (11 partial responses 95% confidence interval [CI] = 15-46%). 20 patients (52.6%) had stable disease. The median duration of response was 3.9 months. Even for patients who had previously received both 5-FU and irinotecan (n = 22), 27.3% had partial response with oxaliplatin and PVI 5-FU. 37 patients had symptoms on entry into the study. 25 patients had pain, 10 had anorexia and 28 had lethargy. 64%, 70% and 17.9% had symptomatic improvement after treatment respectively. Grade 3-4 toxicities were anaemia 10.6%, neutropenia 2.6%, thrombocytopenia 5.2%, diarrhoea 18.9%, nausea and vomiting 2.7%, infection 5.4% and lethargy 37.8%. The median survival was 9.1 months. Probability of overall survival at 6 months was 58.4% (95% CI = 38.7-73.7%). The median failure-free survival was 4 months. Oxaliplatin and PVI 5FU is an active and well tolerated regimen in patients with heavily pre-treated advanced colorectal cancer.

Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate the pharmacokinetics and toxicity of an antisense oligonucleotide targeting bcl-2 in patients with non-Hodgkin's lymphoma (NHL) and to determine efficacy using clinical and biologic end points. PATIENTS AND METHODS: Twenty-one patients with Bcl-2-positive relapsed NHL received a 14-day subcutaneous infusion of G3139, an 18-mer phosphorothioate oligonucleotide complementary to the first six codons of the bcl-2 open reading frame. Plasma pharmacokinetics were measured by anion exchange high-performance liquid chromatography. Response was assessed by computed tomography. Changes in Bcl-2 expression were measured by fluorescence-activated cell sorting of patients' tumor samples. RESULTS: Eight cohorts of patients received doses between 4. 6 and 195.8 mg/m(2)/d. No significant systemic toxicity was seen at doses up to 110.4 mg/m(2)/d. All patients displayed skin inflammation at the subcutaneous infusion site. Dose-limiting toxicities were thrombocytopenia, hypotension, fever, and asthenia. The maximum-tolerated dose was 147.2 mg/m(2)/d. Plasma levels of G3139 equivalent to the efficacious plasma concentration in in vivo models were produced with doses above 36.8 mg/m(2)/d. Plasma levels associated with dose-limiting toxicity were greater than 4 microg/mL. By standard criteria, there was one complete response, 2 minor responses, nine cases of stable disease, and nine cases of progressive disease. Bcl-2 protein was reduced in seven of 16 assessable patients. This reduction occurred in tumor cells derived from lymph nodes in two patients and from peripheral blood or bone marrow mononuclear cell populations in the remaining five patients. CONCLUSION: Bcl-2 antisense therapy is feasible and shows potential for antitumor activity in NHL. Downregulation of Bcl-2 protein suggests a specific antisense mechanism.

Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial.

We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37-55%) with ECF, and 21% (95% CI, 13-28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8-20%) for the ECF arm, and 5% (95% CI, 2-10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting.

New approaches to the treatment of gastro-intestinal cancer.

A number of new cytotoxic agents are currently being assessed for the treatment of gastro-intestinal cancers. Colorectal cancer has been successfully treated with several direct thymidylate synthase inhibitors, oral 5-fluorouracil analogues, irinotecan, and oxaliplatin, alone and in combination regimens. Upper gastro-intestinal malignancies are also proving responsive to combinations including irinotecan and the taxanes. Pancreatic cancer, while remaining relatively chemoresistant, is proving treatable with the new direct thymidylate synthase inhibitors, docetaxel, and gemcitabine, improvements in quality of life being an important outcome. New strategies of treatment delivery are also proving beneficial. Neo-adjuvant chemotherapy is well tolerated for the treatment of gastric cancer and results in tumour downstaging. Randomized trials will show whether this translates into a survival advantage. Combination chemoradiation for oesophageal, pancreatic, and rectal cancers also appears to be an effective strategy. Biological therapies including hormonal manipulation, immunotherapy, angiogenesis inhibition, and gene-directed therapies are the subjects of intensive research at present, with many approaches being applied in early clinical trials. These have demonstrated the tolerability of many of these treatments with evidence for activity in some cases.

The place for conservative treatment in the management of Paget's disease of the nipple.

Four cases of Paget's disease confined to the nipple are presented. Three of them were treated conservatively by local radiotherapy and the fourth was treated by mastectomy. Histopathological examination of the breast in the last case failed to show any evidence of in situ or invasive carcinoma. The first three patients are well and without evidence of recurrence 3 to 5.5 years after treatment. Could conservative treatment in the form of local excision or radiotherapy offer an alternative to mastectomy? A discussion on the place of conservative treatment is presented.

Elisa for the measurement of complement C3 activation by autoantibodies directed against thyroid membrane antigens.

This paper describes the use of an ELISA technique to assess the involvement of the complement system in the pathogenesis of autoimmune thyroid disease (AITD). Microtitre plates coated with thyroid membrane antigen were exposed to serum samples obtained from AITD patients, all of whom showed elevated levels of circulating anti-thyroid autoantibodies, and dilute guinea pig serum, as a source of complement, was then added to the microtitre wells. The degree of activation of the classical complement pathway was assessed by measuring the bound complement component C3 using a peroxidase conjugated anti-guinea pig C3 antiserum. C3 fixation and activation was greater in the presence of serum from patients with Hashimoto's disease when compared with that seen in patients with autoimmune hyperthyroidism (Graves' disease). Serum samples obtained from normal healthy volunteers and from patients with thyroid neoplasia were negative in this assay. The method allows the calculation of a putative "biologically active autoantibody" level and analysis of these data confirm our earlier observation that the species of autoantibody found in autoimmune hypothyroidism are potentially more destructive than those found in other forms of AITD.

The measurement of complement fixation by autoantibodies directed against thyroid membrane antigens.

This paper describes the use of sensitized sheep red blood cells for the detection and titration of complement fixation by autoantibodies directed against human thyroid membranes in the serum of patients with autoimmune thyroid disease. Patients with elevated circulating levels of TPO antibodies and diagnosed as having autoimmune hypothyroidism (including Hashimoto's disease) or autoimmune hyperthyroidism (Graves' disease) were studied. Complement fixation titres were highest in those patients with autoimmune hypothyroidism compared with the autoimmune hyperthyroid group. Serum samples obtained from a group of patients with thyroid neoplasia and from normal healthy volunteers were negative in this test. The TPO antibody activity when "corrected" for its CF potency suggests that the autoantibodies found in autoimmune hypothyroidism are potentially more destructive than those found in the non-destructive autoimmune thyroid diseases.