Irinotecan and capecitabine as second-line treatment after failure for first-line infusional 24-h 5-fluorouracil/folinic acid in advanced colorectal cancer: a phase II study

The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine (1000 mg/m2 b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (>65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n=20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia 11/-/-/-; diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11/-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan.     

Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: Effect of different routes of administration

Dynorphins, such as dynorphin A(1-13) (Dyn A(1-13)), have been shown to enhance analgesia in morphine-tolerant animals, despite their very short half-life after intravenous administration. The potential use of dynorphins in humans is therefore of interest. This laboratory has recently evaluated the metabolic fate of stabilized dynorphin derivatives. This study was conducted to evaluate whether such stabilized derivatives, ie, [N-Met-Tyr1]-Dynorphin A(1-13) (N-MT Dyn A, stabilized at the N-terminal end) and [N-Met-Tyr1]-Dynorphin A(1-13) amide (N-MT Dyn A amide, stabilized at the C- and N-terminal ends), would enhance the antinociceptive activity of morphine not only after intravenous administration but also after subcutaneous and pulmonary delivery. Intravenous administration of N-MT Dyn A (5 micromol/kg) and N-MT Dyn A amide (5 micromol/kg) to morphine-tolerant rats resulted in significantly higher tail-flick latencies than those observed for the saline group. These effects could be observed for up to 2.0 +/- 0.1 hours after intravenous administration of N-MT Dyn A and for up to 3.4 +/- 1.4 hours for N-MT Dyn A amide. The time-averaged effects of both peptides were similar. After pulmonary delivery of the same dose, derivatives remained active. The duration of the effects after pulmonary administration of the amide was 4.4 +/- 2.5 hours while that of N-MT Dyn A was slightly shorter (2.8 +/- 0.9 hours). No effect was observed after subcutaneous administration of N-MT Dyn A. These results suggest that pulmonary delivery of stabilized dynorphin derivatives represents a possible alternative to intravenous administration.     

Dose-dependent severe cutaneous reactions to imatinib

The protein kinase inhibitor imatinib has been approved as an efficient anticancer drug with common but mild cutaneous toxicities. We here report on two out of four melanoma patients treated with high-dose imatinib presenting with severe and strongly dose-dependent skin eruptions, suggesting a cutaneous reactivity pattern different from allergic hypersensitivity.     

Auxological and endocrinological evaluation of children with hydrocephalus and /or meningomyelocele

Short stature and precocious puberty are frequently found in children with hydrocephalus and/or meningomyelocele (MMC). However, aetiology and pathophysiology have not been well characterized. In this study, 108 patients aged between 3 and 17.8 years were evaluated. Growth was documented on the basis of arm span measurements. Short arm span was found in 47 (43.5%) children with hydrocephalus and/or MMC. Mean arm span was −2.0 standard deviation score (SDS) (−6.4 to +0.8) in 43 girls and −1.4 SDS (−5.6 to +1.3) in 65 boys. When growth deficiency (more than −2.0 SDS) was diagnosed by arm span measurement (24 F, 23 M) or when early sexual maturation was found (6 F, 9 M), endocrine evaluation followed. Levels of serum insulin-like growth factor and insulin-like growth factor binding protein-3 were low in 22 of 62 (33.8%) patients. In 9 of 62 (14.5%) patients, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were found to be increased. Growth hormone (GH) deficiency was diagnosed by means of two different stimulation tests (clonidine and arginine) in 7 of 62 (11.3%) patients. In another 3 of 62 (4.8%) children, 12 h night time GH sampling showed low maximum peak levels and decreased area under the curve values, suggesting neurosecretory GH dysfunction. Precocious puberty or early onset of puberty associated with elevated luteinising hormone and follicle stimulating hormone concentrations after stimulation with luteinising hormone releasing hormone was found in 13 of 108 (12.0%) patients (age 7–9 years). Free thyroxine was abnormally low in 2 of 62 (3.2%) patients. Cortisol was within the normal range in all 62 (100%) tested patients. Conclusions Short arm span in children with hydrocephalus and/or MMC is frequently accompanied by GH deficiency or neurosecretory GH dysfunction. Early onset of puberty is another frequent finding. Both hormonal disorders may be the consequence of damage to the hypothalamus or the pituitary gland caused by increased intracerebral pressure or increased mass of cerebrospinal fluid. Received: 31 May 1996 / Accepted: 21 October 1996     

Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance.

Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.     

Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha.

Chronic myeloid leukemia (CML) in older patients has not been studied well. To assess the long-term outcome of older patients with Philadelphia- and/or BCR-ABL-positive CML, 199 patients aged >/=60 years representing 23% of 856 patients enrolled in the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan (BU) and II (IFN+HU vs HU alone) were analyzed after a median observation time of 7 years. In all, 45 patients were treated with Bu, 63 with HU, and 91 with IFN. The 5-year survival was 38% in patients >/=60 years and 47% in patients <60 years (P<0.001). Whereas 5-year survival in chemotherapy-treated older patients was inferior to that in younger patients (33 vs 46%, P=0.006 for HU and 29 vs 38%, P=0.042 for Bu), no significant survival difference could be verified in IFN-treated patients (46 vs 53%, P=0.077). Calculation of age-adjusted, relative survival confirmed these results. Adverse effects of IFN were similar in both age groups, but IFN dosage to achieve treatment goals was lower in older patients. We conclude that the course of CML is not different in the elderly. They require lower IFN doses, achieve the same hematologic and cytogenetic response rates and the same survival advantage at comparable toxicity.