A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.     

Angiogenesis inhibition by an oncolytic herpes virus expressing interleukin 12.

PURPOSE: Oncolytic herpes simplex viruses (HSVs) may have significant antitumor effects resulting from the direct lysis of cancer cells. HSVs may also be used to express inserted transgenes to exploit additional therapeutic strategies. The ability of an interleukin (IL)-12-expressing HSV to treat squamous cell carcinoma (SCC) by inhibition of tumor angiogenesis is investigated in this study. EXPERIMENTAL DESIGN: A replication-competent, attenuated, oncolytic HSV carrying the murine IL-12 gene (NV1042), its non-cytokine-carrying analog (NV1023), or saline was used to treat established murine SCC flank tumors by intratumoral injection. The expression of secondary antiangiogenic mediators was measured. Angiogenesis inhibition was assessed by in vivo Matrigel plug assays, flank tumor subdermal vascularity, and in vitro endothelial cell tubule formation assay. RESULTS: Intratumoral injections of NV1042 (2 x 10(7) plaque-forming units) into murine SCC VII flank tumors resulted in smaller tumor volumes as compared with NV1023 or saline. IL-12 and IFN-gamma expression in tumors was 440 and 2.2 pg/mg, respectively, at 24 h after NV1042 injection, but both IL-12 and IFN-gamma were undetectable (<0.2 pg/mg) after NV1023 or saline injections. Expression of two antiangiogenesis mediators, monokine induced by IFN-gamma and IFN-inducible protein 10, was elevated after NV1042 treatment. Matrigel plug assays of NV1042-transfected SCC VII tumor cells demonstrated significantly decreased hemoglobin content and microvessel density as compared with NV1023 and PBS. Excised murine flank tumors treated with NV1042 had decreased subdermal vascularity as compared with NV1023 and PBS. Both splenocytes and IL-12 expression by NV1042 were required for in vitro inhibition of endothelial tubule formation. CONCLUSIONS: IL-12 expression by an oncolytic herpes virus enhances therapy of SCC through antiangiogenic mechanisms. Strategies combining HSV oncolysis with angiogenesis inhibition merit further investigation for potential clinical application.     

Clonogenic survival and cytokinesis-blocked binucleation of skin fibroblasts and normal tissue complications in soft tissue sarcoma patients treated with preoperative radiotherapy.

BACKGROUND AND PURPOSE:To evaluate the clonogenic and cytokinesis-blocked assays in skin fibroblast cultures for their utility as tools for predicting normal tissue responses in soft tissue sarcoma (STS) patients treated with preoperative radiotherapy. PATIENTS AND METHODS:Dermal fibroblast strains were established from skin biopsies of 26 STS patients who received preoperative radiotherapy. Cultures were subjected to the colony forming and cytokinesis-blocked assays after low (approximately 0.02 Gy/min) dose-rate 60Co -irradiation. Fibroblast radiosensitivity was expressed as the dose for 1% clonogenic survival, D0.01, based on colonies/clusters with >or=10 cells. Fibroblast proliferative capability was represented by binucleation index (BNI) and genomic damage was expressed in terms of micronucleus frequency. Wound healing complications (WHC) and subcutaneous fibrosis were the clinical endpoints examined. The ability of each in vitro parameter to detect patients at high risk of a given normal tissue complication was assessed using receiver operating characteristic (ROC) analysis. RESULTS:While fibroblasts from patients without WHC were marginally more radiosensitive than fibroblasts from patients with WHC (P=0.08), the reduction in BNI following a dose of 2.4 Gy was significantly higher in strains from patients without WHC compared to those from patients with WHC (P=0.01). The area under the ROC curve (c-index) is indicative of the power of discrimination of D0.01 and BNI for WHC, and was found to be 0.68 and 0.79, respectively. Subcutaneous fibrosis was not associated with D0.01 (rs=0.09, P=0.66) and the percent reduction in BNI after 2.4 Gy (rs=-0.19, P=0.36). Micronucleus frequency did not reflect differences in normal tissue responses. CONCLUSION:These data suggest that it is the ability of fibroblasts to undergo one-three divisions in vitro following radiation treatment that may reflect the development of wound healing morbidity or subcutaneous fibrosis in this population of patients.     

A Correlational Test of the Relationship Between Posttraumatic Growth,Religion, and Cognitive Processing

The present study examined the degree to which event related rumination, a quest orientation to religion, and religious involvement is related to posttraumatic growth. Fifty-four young adults, selected based on prescreening for experience of a traumatic event, completed a measure of event related ruminations, the Quest Scale, an index of religious participation, and the Posttraumatic Growth Inventory. The three subscales of the Quest Scale, the two groups of rumination items (soon after event/within past two weeks), and the index of religious participation were entered in a standard multiple regression with the total score of the Posttraumatic Growth Inventory as the dependent variable. The degree of rumination soon after the event and the degree of openness to religious change were significantly related to Posttraumatic Growth. Congruent with theoretical predictions, more rumination soon after the event, and greater openness to religious change were related to more posttraumatic growth. Present findings offer some confirmation of theoretical predictions, and also offer clear direction for further research on the relationships of religion, rumination, and posttraumatic growth.     

Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy.

PURPOSE: We evaluated the prognostic significance of indium-111 (111In)-capromab pendetide imaging for patients with prostate cancer who underwent salvage radiotherapy (RT) for recurrent disease after prostatectomy. PATIENTS AND METHODS: Records were reviewed for all men who underwent 111In-capromab pendetide imaging at a single institution from February 1997 through December 1999. We identified 30 eligible men who were radiographically negative for metastatic disease, who had increasing serum prostate-specific antigen (PSA) after primary radical prostatectomy, and who received salvage RT. Clinical interpretations of indium monoclonal antibody (In-mab) scan results were compared with postsalvage RT PSA response. RESULTS: Using an American Society of Therapeutic Radiation and Oncology definition of PSA failure, in men with a positive scan in at least one location (n = 14), the cumulative 2-year PSA control after salvage RT was 0.38 +/- 0.13 (+/- SE) compared with 0.31 +/- 0.13 for men with a normal antibody scan in and outside the prostate fossa (n = 15; proportional hazard ratio [PHR] = 1.32; 95% confidence interval [CI], 0.52 to 3.36). For men with a positive antibody scan limited to the prostate fossa (n = 9), PSA control at 2 years was 0.13 +/- 0.12 (PHR 1.77; 95% CI, 0.65 to 4.85). The 2-year probability of PSA control after salvage RT for men with positive scan results outside the prostate bed irrespective of In-mab findings in the prostate fossa (n = 5) was 0.60 +/- 0.22 (PHR 0.81; 95% CI, 0.17 to 3.78). CONCLUSION: In contrast to previous reports, for patients with postprostatectomy biochemical relapse who received salvage RT, presalvage RT In-mab scan findings outside the prostate fossa were not predictive of biochemical control after RT.     

Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501.

PURPOSE: To determine the efficacy of combination fludarabine and mitoxantrone (FN) in untreated stages III and IV low-grade lymphoma. The major end point was to estimate progression-free survival (PFS) in all eligible patients. PATIENTS AND METHODS: Seventy-eight eligible patients were registered. Chemotherapy courses were administered every 4 weeks with mitoxantrone 10 mg/m2 on day 1 and fludarabine 25 mg/m2 on days 1, 2, and 3 for a total of six to eight cycles. Pneumocystis carinii prophylaxis was required. RESULTS: Seventy-three patients (94%) attained an objective response. Complete remission was demonstrated in 34 patients (44%) and partial remission was demonstrated in 39 patients (50%). With a median follow-up time of 5.5 years, the median PFS was 32 months, with a 4-year PFS rate of 38%. Median survival has not been reached and 88% of all patients are alive at 4 years. The application of the International Prognostic Index and serologic staging showed significant differences in PFS in all risk groups, whereas overall survival was markedly worse for the highest-risk group in either prognostic model. Three prior Southwest Oncology Group trials using a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone or a combination of prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone in similar patient populations demonstrated comparable clinical outcome, although the 4-year survival for FN was better. FN was well tolerated, but mild to severe reversible myelosuppression was noted. Other complications were rare. CONCLUSION: FN is an effective, safe chemotherapy combination for patients with advanced-stage, low-grade lymphoma. Clinical outcomes were comparable to prior published data using anthracycline-based regimens.     

Serum antibodies to JC virus, BK virus, simian virus 40, and the risk of incident adult astrocytic brain tumors.

Genomic sequences of the human polyomaviruses, JC virus (JCV) and BK virus (BKV), and simian virus 40 (SV40) have been reported from several types of human brain tumors, but there have been no population-based seroepidemiologic studies to evaluate the association between polyomavirus infection and brain tumors. We conducted a case-control study, nested within a prospective cohort, to investigate the association between antibodies to JCV, BKV, and SV40, as measured in serum collected 1-22 years before diagnosis and incident primary malignant brain tumors. Brain tumor cases (n = 44) and age-, gender-, and race-matched controls (n = 88) were identified from participants of two specimen banks in Washington County, Maryland. IgG antibodies to the capsid proteins of JCV and BKV were assessed using ELISAs. SV40-neutralizing antibodies were measured using plaque neutralization assays. Similar to the general population, the prevalence of JCV and BKV infection was high in our study population (77 and 85%, respectively). Antibodies to SV40 were less prevalent (11%). The odds ratio for subsequent brain tumor development was 1.46 [95% confidence interval (CI), 0.61-3.5] for JCV, 0.66 for BKV (95% CI, 0.22-1.95), and 1.00 for SV40 (95% CI, 0.30-3.32). Given the high prevalence of JCV and BKV infections and the millions who were potentially exposed to SV40 through contaminated polio vaccines, future studies should attempt to replicate these findings.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349).

PURPOSE: To test the hypothesis that therapy of intermediate- and high-grade (excluding Burkitt lymphoblastic) lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) could be safely dose-intensified with routine filgrastim support. PATIENTS AND METHODS: Eligible patients were those who were previously untreated and who had either bulky stage II, or stage III or IV lymphoma with working formulation histology D, E, F, G, H, or J; performance status < or = 2; and acceptable end organ function. No upper age limit was specified. Therapy was dose-intensified CHOP (CHOP-DI) with filgrastim support. Each course was repeated every 14 days for six planned courses. RESULTS: Eighty-eight eligible patients were treated with CHOP-DI and had a median follow-up of 5.1 years on this phase II study, designated Southwest Oncology Group (SWOG) 9349. The progression-free survival was 51% at 2 years and 41% at 5 years. The overall survival was 60% at 5 years. Three fatal treatment-related events occurred. One patient with myelodysplastic syndrome was reported. CONCLUSION: Treatment with CHOP-DI can be safely administered in the cooperative group setting and results in improved survival. Estimated overall survival at 5 years was 14% better than that of patients treated with standard-dose CHOP in an earlier SWOG study, although progression-free survival of 60% at 2 years-the prespecified end point-was not achieved. CHOP-DI, given every 2 weeks at escalated doses, is a strategy that should be tested in a future randomized clinical trial in lymphoma.