Chemotherapy in metastatic cancer of unknown primary

In general a patient is considered ta have a carcinoma of unknown primary site if na primary tumor ean be identified af ter a thorough history and physical examination, and a reasonabIe laboratory and radiologie work-up. This definition a180 requires a histological diagnosis of carcinoma. The importance of histologie (re)examination in the management of patients with carcinoma of unknown primary site has been emphasized by several authors. Light microscopie examinat ion may al ready provide a clue ta suggest the site of origin. lnununohistochemistry and/or electron microscopy are of additional value, particularly in patients with undifferentiated tumors. A substantial number of patients with a light microscopie diagnosis of anaplastic tumor or undifferentiated carcinoma ultimately prove to have a lymphomas

Neoadjuvant treatment in esophageal cancer-established treatments and new developments reviewed

As the majority of patients experiences locoregional relapse and/or distant metastasis even after radical resection of esophageal cancer, many efforts have been made and are ongoing to identify the optimal multimodality treatment strategy. The true benefit and harm of neoadjuvant therapy including chemotherapy, radiotherapy or the combination, is still difficult to interpret given the heterogeneity in patient and tumor characteristics. Nonetheless, neoadjuvant chemoradiation with weekly carboplatin and paclitaxel (the CROSS regimen) is considered standard of care for squamous cell carcinoma in Europe. Definitive chemoradiation is considered an equal alternative in the United States. For adenocarcinoma, preoperative chemoradiation with a platinum and 5FU or the CROSS regimen and peri-operative chemotherapy with a platinum and 5FU or the FLOT (fluorouracil, leukovorin, oxaliplatin and docetaxel) regimen are all options. New developments in systemic anti-tumor therapy will most likely involve dual anti-HER2 inhibition or novel anti-HER2 antibody-drug conjugates for adenocarcinoma. Immunotherapy monotherapy in an unselected patient population does not seem to be as effective in esophageal cancer as it is in other cancer types. However, when we can correctly identify the subset of patients which does benefit from this treatment by employing new predictive markers, or find an effective synergistic combination of immunotherapy with chemotherapy and/or radiotherapy, immunotherapy could still improve patient outcome in the future.</p

Ifosfamide in advanced adenocarcinoma of the oesophagus or oesophageal-gastric junction area

Abstract 25 previously untreated patients with inoperable or metastatic adenocarcinoma of the oesophagus or oesophageal-gastric junction area were treated with ifosfamide 6 g/m2 over 48 hours, combined with mesna 6 g/m2. 1 complete response and 1 partial response were seen among 23 patients evaluable, with a response duration of 29+ months and 7 months, respectively. Toxicity was not severe: grade 3 infection in 2 patients, grade 3 leucopenia in 3 patients and grade 3 nausea in 4 patients. No life-threatening episodes or central nervous system toxicity were encountered. Ifosfamide has limited activity in adenocarcinoma of the oesophageal-gastric junction area

Disease monitoring by the tumour maskers Cyfra 21.1 and TPA in patients with non-small cell lung cancer

We evaluated the use of two tumour markers Cyfra 21.1 and tissue polypeptide antigen (TPA) for disease monitoring. Assessment of response to WHO criteria was compared to response assessment according to changes in the tumour marker levels. The criteria defined for marker response were a 65% decrease for a partial response and a 40% increase for progressive disease. When response evaluations with a positive lead time were included, 72% of 115 evaluations for Cyfra 21.1 and 59% of 107 evaluations for TPA yielded the same result. Most discordant evaluations were caused by those evaluations whereby the patient achieved a partial response according to the WHO criteria and had normalisation of the marker. Less cases with a positive lead time, more negative lead times, and more patients with progressive disease without an increase of the marker were seen with TPA compared to Cyfra 21.1. In conclusion, Cyfra 21.1 follows the changes in the tumour load better than TPA. Rising levels of both markers nearly always indicate disease progression, and such knowledge easily obtained may prevent the continuation of ineffective treatment

Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small-cell lung cancer

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) is involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, and liver glucose metabolism, via purinergic receptors. In nonrandomized studies involving patients with different tumor types including non-small-cell lung cancer (NSCLC), ATP infusion appeared to inhibit loss of weight and deterioration of quality of life (QOL) and performance status. We conducted a randomized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC (stage IIIB or IV). METHODS: Fifty-eight patients were randomly assigned to receive either 10 intravenous 30-hour ATP infusions, with the infusions given at 2- to 4-week intervals, or no ATP. Outcome parameters were assessed every 4 weeks until 28 weeks. Between-group differences were tested for statistical significance by use of repeated-measures analysis, and reported P values are two-sided. RESULTS: Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP. Mean weight changes per 4-week period were -1.0 kg (95% confidence interval [CI] = -1.5 to -0.5) in the control group and 0.2 kg (95% CI = -0.2 to +0.6) in the ATP group (P =.002). Serum albumin concentration declined by -1.2 g/L (95% CI= -2.0 to -0.4) per 4 weeks in the control group but remained stable (0.0 g/L; 95% CI = -0.3 to +0.3) in the ATP group (P =.006). Elbow flexor muscle strength declined by -5.5% (95% CI = -9.6% to -1. 4%) per 4 weeks in the control group but remained stable (0.0%; 95% CI= -1.4% to +1.4%) in the ATP group (P =.01). A similar pattern was observed for knee extensor muscles (P =.02). The effects of ATP on body weight, muscle strength, and albumin concentration were especially marked in cachectic patients (P =.0002, P =.0001, and P =. 0001, respectively, for ATP versus no ATP). QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores (-0.2% versus -2.4%; P =. 0002); functional scores (+0.4% versus -5.5%; P =.02); psychologic scores (-0.7% versus -2.4%; P =.11); overall QOL score (+0.1% versus -3.5%; P =.0001). CONCLUSIONS: This randomized trial demonstrates that ATP has beneficial effects on weight, muscle strength, and QOL in patients with advanced NSCLC

Prognostic significance of tissue polypeptidespecific antigen (TPS) in patients with advanced non-small cell lung cancer

In this study, we evaluated the prognostic value of the tumour marker, tissue polypeptide-specific antigen (TPS), in 203 patients with non-small cell lung cancer (NSCLC), and related this to several other known prognostic factors. TPS was significantly correlated with lactate dehydrogenase (LDH), γ-glutamyltranspeptidase and alkaline phosphatase, and the median level of TPS in patients with stage 4 disease was significantly higher as compared to stage 3A and 3B disease. In the univariate analysis, performance status, stage of disease, LDH, alkaline phosphatase, a histology of undifferentiated large cell carcinoma and TPS all had a statistically significant association with survival. Multivariate analysis showed that stage of disease, performance status, histology and TPS were the most important prognostic factors. TPS has prognostic significance for survival in patients with advanced NSCLC, independent from performance status and stage of disease

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics