Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030).

BACKGROUND: The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030. METHODS: Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. RESULTS: Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. CONCLUSION: Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.

Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer.

Twenty-six patients with advanced cancer refractory to standard therapy were treated with recombinant human tumor necrosis factor (rTNF) in a study aimed at determining the toxicity and tolerance of rTNF and at seeking evidence of antitumor activity. The study design involved two treatments per week for 4 weeks with alternating subcutaneous and intravenous (IV) administration, and weekly dose escalation through four levels in each patient. The dose range was 1 to 200 micrograms/m2 for IV bolus injection, and 5 to 250 micrograms/m2 for subcutaneous injection. Thirteen patients completed the full course. Early discontinuation of treatment was related to rTNF toxicity in seven cases. The major side effects were rigors, fever, headache, fatigue, and hypotension. Acute changes in granulocyte, lymphocyte, and monocyte counts, changes in serum zinc levels and plasma cortisol levels consistent with an acute phase response, and inflammation at the site of subcutaneous injection were also seen. At doses of 125 to 250 micrograms/m2, inflammation at the subcutaneous injection site was unacceptably severe. Minor changes were seen in hemostatic parameters. Hypotension was corrected by fluid administration and did not require treatment with vasopressors. Initial serum concentrations of rTNF were measured at five minutes after IV administration and were found to range from 2.5 ng/mL after a dose of 35 micrograms/m2 to 80 ng/mL after a dose of 200 micrograms/m2. The half-life of rTNF in the blood was 20 minutes. A decrease in lymph node size was observed in a patient with B cell lymphoma.

Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer.

BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.

Outpatient chemoimmunotherapy for the treatment of metastatic melanoma.

The prognosis for most patients with metastatic melanoma is poor, as the median survival is only 7 months. Phase II trials of chemoimmunotherapy have, however, reported response rates of 40% to 70% and prolonged disease-free survival in small subgroups of patients. Most chemoimmunotherapy trials have used high doses of recombinant interleukin-2 (rIL-2) and recombinant interferon alpha (rIFN-alpha) that produce significant toxicity and require prolonged hospitalization to manage side effects. To develop a treatment regimen for metastatic melanoma that would minimize costly hospitalization, we initiated a phase II trial of outpatient chemoimmunotherapy. Patients were treated with monthly cycles of intravenous carmustine, dacarbazine, cisplatin, and tamoxifen plus self-administered subcutaneous rIL-2 and rIFN-alpha as outpatients. To date, 32 patients have received 94 cycles of therapy. The most common toxicity was nausea and vomiting. Hospitalization for the management of toxicity was required in only seven cycles (7%). Thirty patients have been assessed for clinical response. The overall response rate was 43% (13% complete and 30% partial response). This phase II trial has established a tolerable regimen of outpatient chemoimmunotherapy, which has shown significant antitumor activity.

Interleukin-12 induced cytolytic activity in lymphocytes from recipients of autologous and allogeneic stem cell transplants.

Interleukin-12 (IL-12) has been reported to enhance the cytolytic activity of NK and activated T cells and to induce low levels of lymphokine-activated killer (LAK) activity in normal human lymphocytes. Therapy with IL-12 has induced tumor eradication in murine models. These observations suggest that IL-12 might have a role as treatment for minimal residual disease following transplantation. To determine whether PBL from recipients of autologous (autoSCT) and allogeneic (alloSCT) bone marrow or peripheral blood stem cell transplants respond to IL-12 with generation of LAK activity, PBL were incubated with IL-12 for 5 days, then tested in a 51Cr release assay for lysis of Daudi. PBL from 17 normal 'control' individuals were similarly tested and lysis was observed in only 3/17 (mean 16.9% of the three). By contrast, PBL from 10/12 patients obtained a median of 30 days after autoSCT, exhibited significant IL-12-induced LAK activity (mean lysis, 35.3%, P < 0.005 vs controls). PBL from 18 of 20 patients tested a median of 44 days after alloSCT also exhibited significant LAK activity (mean lysis, 30.0%, P < 0.005 vs controls). In autoSCT recipients, IL-12 and IL-2 at high concentrations (1000 U/ml each) were additive for induction of LAK activity, whereas low, suboptimal concentration of IL-12 (250 U/ml) and IL-2 (1 U/ml) were synergistic in 3/5 experiments. The percentage of PBL expressing IL-12 receptor beta 1 chain (IL-12r beta 1) was higher in stem cell recipients than in normal individuals, P < 0.05. Moreover, a higher percentage of IL-12r beta 1-positive PBL was associated with greater IL-12-induced LAK activity in transplant recipients. These studies demonstrate that PBL obtained early after stem cell transplantation have a higher percentage of cells expressing IL-12r beta 1 and respond to IL-12 with significantly greater LAK cytotoxicity than PBL from normal controls. These results suggest that IL-12 is a potentially attractive candidate for study as consolidative immunotherapy after stem cell transplantation.

Paraneoplastic manifestations of renal cell carcinoma.

Paraneoplastic manifestations are present in up to 20% of patients with renal cell carcinoma (RCC). There is convincing evidence that RCC tumor cells elaborate proteins that serve as mediators of endocrine (eg, ectopic production of parathyroid hormone-related protein or erythropoietin) as well as nonendocrine paraneoplastic syndromes. A paraneoplastic syndrome may be the initial clinical presentation of RCC in a significant number of patients, and recognition of these syndromes may facilitate early diagnosis. Most paraneoplastic syndromes associated with RCC remit after resection of the primary RCC or treatment of metastatic sites. The natural history of metastatic RCC is extremely variable. A significant proportion of patients may survive several years with slowly progressing metastatic disease. In these patients, the accurate diagnosis and management of paraneoplastic syndromes may be important in palliative management. Except for hypercalcemia, conventional medical therapies are seldom helpful. Other paraneoplastic manifestations of RCC include cachexia, fever, hepatic dysfunction, anemia, and amyloidosis, although our understanding of the underlying pathophysiology remains incomplete.

Metastatic renal cell carcinoma: long-term survival after therapy with high-dose continuous-infusion interleukin-2.

PURPOSE: This article undertakes to define the response rate, long-term survival, and toxicity in patients with metastatic renal cell carcinoma (MRCC) treated with high-dose continuous intravenous infusion (CIV) recombinant interleukin-2 (rIL-2) with or without lymphokine-activated killer (LAK) cells. PATIENTS AND METHODS: One hundred twenty-three consecutive patients received CIV rIL-2 (18-22 MIU/m2/day on days 1-5, and 6-8 MIU/m2/day on days 10-19) on one of five sequential protocols at the University of Washington between 1988 and 1995. The first 76 patients received LAK cells. The median age was 55 years (range, 32-76 years), and 71% had undergone prior nephrectomy. RESULTS: Nine patients achieved a complete response (7.3%) and 14 patients achieved a partial response (11.4%) for an overall response rate of 19% (95% confidence interval, 12%-26%). The median survival was 19 months, and the 5-year survival was 20%. Seven of nine complete responders (78%) remain in continuing complete response at 43+ to 109+ months. Intensive care unit and vasopressor support were required in 42% and 23% of patients, respectively, who received rIL-2 + LAK cells, and in 18% and 4% of those who received rIL-2 alone. There was one treatment-related death. CONCLUSION: We report the largest single-institution experience and the longest survival for patients with MRCC treated with CIV rIL-2. The administration of rIL-2 by CIV is associated with less frequent intensive care unit and vasopressor support than with high-dose intravenous bolus regimens, and hence may enhance the therapeutic index in patients with MRCC.

Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma.

PURPOSE: Aggressive inpatient chemoimmunotherapy protocols for metastatic melanoma have yielded encouraging response rates but have required lengthy hospitalizations. To reduce or eliminate the need for hospitalization, we have developed an outpatient chemoimmunotherapy regimen and assessed its efficacy and toxicity in 53 patients treated at the University of Washington Medical Center. PATIENTS AND METHODS: Eligible patients with measurable metastatic melanoma received carmustine (150 mg/m2 every 6-8 weeks) and dacarbazine (660 mg/m2) and cisplatin (75 mg/m2) every 3 to 4 weeks in an infusion center plus tamoxifen (20 mg/day). Patients self-administered subcutaneous recombinant interleukin-2 (rIL-2) at 3 MIU/m2/day on days 3 to 9, and recombinant interferon alfa-2a (rIFN-alpha 2a) at 3 MIU on day 3 and at 5 MIU/m2/day on days 5, 7, and 9. Maintenance rIFN-alpha 2a was self-administered subcutaneously at 5 MIU/m2 tiw for 12 months after complete or stable partial response. Response and survival were assessed. RESULTS: Fifty-three patients (median age = 49 years) have received 181 cycles. To date, there have been 10 complete responses (19%) lasting 2 to 28+ months and 12 partial responses (23%) lasting 2 to 11 months, for an overall response rate of 42% (95% confidence interval, 28%-55%). The median overall survival was 12 months. Grade 3/4 vomiting occurred in 32% of cycles, but hospitalization for supplemental intravenous fluids was required in only 11% of cycles for a median of 3 days. Grade 4 thrombocytopenia and neutropenia occurred in 9% and 8% of cycles, respectively. Grade 3 renal dysfunction occurred in only one cycle and was reversible. CONCLUSION: A chemoimmunotherapy regimen for patients with metastatic melanoma has been defined that is well tolerated on an outpatient basis and is associated with a median survival comparable to that with aggressive inpatient chemoimmunotherapy regimens.