Ann Oncol

Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study.

Year 1998
Diaz-Rubio E. Sastre J. Zaniboni A. Labianca R. Cortes-Funes H. de Braud F. Boni C. Benavides M. Dallavalle G. Homerin M.
Hospital Clinico San Carlos, Madrid, Spain.
BACKGROUND: Oxaliplatin is a new cytotoxic agent from the diaminocyclohexane family with proven antitumor activity against colon cancer cell lines. Activity in patients with colorectal carcinoma previously treated with 5-fluorouracil has been studied in three single-agent phase II trials, showing a reproducible response rate of 10%. Here we report a phase II trial with oxaliplatin as a first-line chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: Twenty-five patients were entered in the study. All of them had metastatic disease without previous chemotherapy, and at least one lesion had to be measurable by computed tomography (CT). Therapy consisted of a two-hour infusion of oxaliplatin at a dose of 130 mg/m2 every 21 days. RESULTS: The overall response rate determined by investigators was 20% (95% CI, 6.8%-40.7%). Eight patients (32%) had stable disease. The median time to disease progression in responders was six months (range four to nine). The median progression-free survival was four months and median overall survival 14.5 months (95% CI, 10-20 months). The main toxic effects were peripheral neuropathy (92%) and laryngopharyngeal dysesthesia (75%). No severe grade 3-4 neurotoxicities (NCI-CTC) were found. Gastrointestinal and hematological toxicities were mild. CONCLUSIONS: Oxaliplatin is an active agent in first-line chemotherapy for advanced colorectal cancer. It was well tolerated, caused no toxic deaths, had low hematotoxicity, well controlled gastrointestinal toxicity, and frequent but mild peripheral neurological symptoms. Therefore, it is of interest to associate oxaliplatin with other active compounds.

High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: a phase II and pharmacodynamic study.

Year 1998
Rowinsky EK. Baker SD. Burks K. O'Reilly S. Donehower RC. Grochow LB.
Johns Hopkins Oncology Center, Baltimore, MD, USA.
PURPOSE: The premise for this study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-SCF in patients with fluoropyrimidine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. PATIENTS AND METHODS: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advance colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimidine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling with performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. RESULTS: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/microliters for longer than 5 days in 17% of courses involving seven of seventeen (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/microliters were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short--2.5 and 4 months respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANC's during course 1, although patients with severe toxic effects (ANC below 500/microliters for more than five days and/or platelets < 25,000/microliters) had higher drug exposure than patients with less severe toxicity (P < 0.018 and P = 0.09, respectively). CONCLUSIONS: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

A phase II study of oral clofazimine in unresectable and metastatic hepatocellular carcinoma.

Year 1998
Ruff P. Chasen MR. Long JE. van Rensburg CE.
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
BACKGROUND: Hepatocellular carcinoma is highly refractory to most chemotherapeutic agents. Clofazimine, a riminophenazine compound used to treat leprosy since 1962, inhibits various cancer cell lines, including hepatocellular carcinoma cell lines, via phospholipase A2 dependant processes. Clofazimine also inhibits p170-glycoprotein, the mdr1 gene product. PATIENTS AND METHODS: Thirty patients (26 males and four females) with unresectable (25) or metastatic (5) hepatocellular carcinoma received oral clofazimine 600 mg daily for two weeks, followed by 400 mg daily until progression or death. RESULTS: There were three responses (10%)--one of a soft tissue metastasis, and two of local disease, with 13 patients disease stabilizing for up to 20 months. The overall median survival was 13 weeks. Adverse events included hyperpigmentation, eczematous skin rashes and palpitations. CONCLUSIONS: Although only three patients had an objective response (10%), the 13 patients with stable disease for up to 20 months, and an overall median survival of 13 weeks, suggest that clofazimine, or other riminophenazine compounds may prove to be of value in hepatocellular carcinoma.

Determination and validation of a predictive model for Clostridium difficile diarrhea in hospitalized oncology patients.

Year 1998
Hornbuckle K. Chak A. Lazarus HM. Cooper GS. Kutteh LA. Gucalp R. Carlisle PS. Sparano J. Parker P. Salata RA.
Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, OH, USA.
BACKGROUND: Clostridium difficile colitis in the cancer patient receiving chemotherapy is a frequent cause of morbidity which may prolong hospitalization. Techniques for identifying infection often delay the initiation of therapy. PATIENTS AND METHODS: In this retrospective case-control analysis, we identified predictors for C. difficile-associated diarrhea in 29 patients hospitalized from 1988 to 1993 on a hematologic malignancy/bone marrow transplant unit (hospital A). We then validated our model with 58 C. difficile cases and 74 controls admitted to an oncology unit from a different institution (hospital B). RESULTS: We found that low intensity of chemotherapy (P < 0.001), lack of parenteral vancomycin use (P = 0.03) and hospitalization within the past two months (P = 0.05) were independently predictive of C. difficile colitis by multivariate analysis. These variables were weighted for predictive capability using a receiver operator characteristic score; low intensity chemotherapy was assigned two points, lack of parenteral vancomycin received one point and prior hospitalization one point (P < 0.001 by chi 2 for trend). The receiver operating characteristic (ROC) curve areas were 0.78 for patients at hospital A and 0.70 at hospital B indicating moderate drop off in discrimination. Compared to hospital A patients, hospital B patients hospitalized between 1989 and 1994 were more often women (P = 0.04), received less systemic vancomycin (P = 0.01), were less frequently neutropenic (P < 0.05), and received less intense chemotherapy regimens (P < 0.05). Despite these differences in demographics in patients between these institutions, our predictive model was validated in hospital B patients (P = 0.02 by chi 2 for trend). CONCLUSIONS: The results of this study may help clinicians predict the risk of C. difficile disease in the hospitalized immunocompromised oncology patient and may help guide empiric therapy while awaiting results of stool toxin assays.

Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkins lymphoma.

Year 1998
Clark FL. Drummond MW. Chambers S. Chapman BA. Patton WN.
Department of Haematology, Christchurch Hospital, New Zealand.
Chronic carriers of Hepatitis B virus (HBV) infection, who are treated for malignant lymphoma, are at high risk of mortality from reactivated HBV infection. We report a case of a 29-year-old male chronic HBV carrier who developed fulminant reactivated HBV infection following intensive chemotherapy for stage IVB large cell B-cell non-Hodgkin's lymphoma associated with extensive central nervous system and bone marrow involvement. Prior to chemotherapy the patient had normal liver function tests and was negative for HBV DNA by semiquantitative PCR assay. Fulminant HBV reactivation was confirmed following clinical deterioration, massive rises in hepatic transaminases (peak alanine aminotransferase = 2,850 U/l), liver biopsy and rising levels of serum HBV DNA. Following treatment with lamivudine 150 mg bd for 18 weeks dramatic and sustained recovery ensued. Symptoms and liver function tests improved within days and HBV DNA became negative within 12 weeks. Our patient later died from relapsed lymphoma but without evidence of reactivated HBV infection. We advise that lamivudine should be considered during intensive chemotherapy treatment of chronic carriers of HBV.

Clinical evaluation of whole-body 18F-fluorodeoxyglucose positron emission tomography in the detection of liver metastases.

Year 1998
Hustinx R. Paulus P. Jacquet N. Jerusalem G. Bury T. Rigo P.
Division of Nuclear Medicine, University Hospital, Sart Tilman, Liege, Belgium.
BACKGROUND: Assessment of metastatic involvement of the liver remains a diagnostic challenge. The objective of this study was to evaluate the potential role of FDG PET in the detection of liver metastases. PATIENTS AND METHODS: Sixty-four patients with malignancy and possible liver involvement were included. Liver metastases were present in 31 cases, demonstrated by histopathological analysis in 15 cases and by follow-up in 16 cases. The negative cases were confirmed by pathology in four cases, peroperative ultrasonography in 12 cases, and follow-up in 17 cases. Whole-body FDG PET was compared to CT (n = 53) and US (n = 43). RESULTS: PET demonstrated a 97% sensitivity, an 88% specificity and a 92% accuracy, compared to 93%, 75% and 85%, respectively, for CT (P = NS). Concordant results were obtained in 44 of 64 patients (69%: 19 TP. 25 TN). PET provided new and accurate information in 15 of 64 patients (23.4%). PET demonstrated liver metastases in 11 patients in whom conventional methods yielded negative (two cases) or doubtful (nine cases) results. Four patients free of liver involvement were correctly staged with PET, while CT/US were equivocal. PET was erroneous in five of 64 cases (7.8%, four FP, one FN). CONCLUSIONS: FDG PET allows an accurate screening of liver involvement in patients with malignancy. Combined with CT, it provides additional diagnostic information that could directly affect the management of these patients.

Survival of patients with visceral metastatic melanoma from an occult primary lesion: a retrospective matched cohort study.

Year 1998
Vijuk G. Coates AS.
Sydney Melanoma Unit, Royal Prince Alfred Hospital, Australia.
BACKGROUND: Malignant melanoma presents as metastatic disease without an apparent primary in about 4% of cases. These are referred to as occult primary melanoma (OPM). It is not known whether these represent de novo malignant transformation in non-cutaneous sites or the disappearance of an unrecognised primary, perhaps on an immunological basis. We hypothesised that OPM might have a superior prognosis compared to patients with similar disease extent from a known primary lesion (KPM). PATIENTS AND METHODS: We performed a retrospective cohort survival study of 146 patients with OPM and visceral metastases treated at the Sydney Melanoma Unit between 1983 and 1996. A control group of patients with KPM was matched for age, sex and site of visceral metastases. Survival was measured from the date of diagnosis of visceral metastases. RESULTS: Patients with OPM had a median survival of 233 days, significantly longer than the 176 days for those with KPM (P = 0.024; logrank test). Multivariate analysis allowing for simultaneous or prior involvement of lymph nodes, subcutaneous tissues or bone, and site of visceral involvement showed a significantly superior survival for OPM (hazard ratio (HR): 0.72; 95% confidence interval (CI): 0.55-0.93). A small part of the effect was explained by treatment, but models allowing for this still showed a significantly longer survival. CONCLUSIONS: Survival was longer in OPM patients. This may reflect an intrinsically superior host-tumour interaction.

A novel cancer vaccine composed of human-recombinant epidermal growth factor linked to a carrier protein: report of a pilot clinical trial.

Year 1998
Gonzalez G. Crombet T. Catala M. Mirabal V. Hernandez JC. Gonzalez Y. Marinello P. Guillen G. Lage A.
Center of Molecular Immunology, Havana, Cuba. gisela@ict.cim.sld.cu
BACKGROUND: There is evidence of a relationship between epidermal growth factor (EGF) and tumor cell proliferation, such as the overexpression of EGF receptor (EGF-R) in different human tumors, which makes this system an interesting target for cancer treatment. Up to now, passive immunotherapy with monoclonal antibodies against the EGF-R has been assayed in clinics. Our approach consists of active immunotherapy with human EGF (hu-EGF). We conducted a pilot clinical trial to define the safety, toxicity and immunogenicity of vaccination with hu-EGF coupled to a carrier protein. PATIENTS AND METHODS: Ten patients with histologically-proven malignant carcinomas (colon, lung, stomach and prostate) in advanced clinical stages were enrolled. Patients were immunized twice (on days 0 and 15) with hu-EGF linked to either tetanic toxoid (TT, five patients) or P64K Neisseria Meningitidis recombinant protein (P64k, five patients), intradermically, using aluminium hydroxyde as adjuvant. RESULTS: In both groups 60% of patients developed anti-EGF antibody titers without evidence of toxicity. Secondary reactions were very mild, limited to erythema and itching at the site of injection, which disappeared without medication. CONCLUSIONS: We conclude that the proposed vaccination with hu-EGF was well tolerated and that antibody titers against self EGF were developed. The results of this trial may be useful in the design of new clinical trials with higher dose immunization protocols and using more effective adjuvants.

Malignant effusions contain lysophosphatidic acid (LPA)-like activity.

Year 1998
Westermann AM. Havik E. Postma FR. Beijnen JH. Dalesio O. Moolenaar WH. Rodenhuis S.
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. annie@nki.nl
BACKGROUND: Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids with mitogenic and growth factor-like activities that act via specific cell-surface receptors present in many normal and transformed cell types. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. The presence of LPA-like activity and the hypothesis that levels of this bioactivity in effusions of ovarian cancer patients are higher than those in effusions of other cancer patients was studied. MATERIALS AND METHODS: A neurite retraction bioassay in a neuroblastoma cell line previously developed for in vitro detection of LPA activity on cell lines was employed and bioactivity was expressed in virtual LPA-equivalent levels. LPA-equivalent levels were tested in effusions of 62 patients with a range of malignancies, including 13 ovarian cancer patients. Biochemical and clinical parameters were evaluated for correlations with LPA-equivalent levels. RESULTS: Average LPA-equivalent levels were 50.2 microns (range 5.4-200) for all patients, and 94.5 microns (range 15-200) for ovarian cancer patients (P = 0.004). There were no additional independent significant correlations between LPA-equivalent levels in effusions and a range of other biochemical and clinical characteristics. CONCLUSION: These data suggest a role for LPA-like lipids in the peritoneal spread of ovarian cancer and possibly that of other predominantly intraperitoneal malignancies.

Irinotecan-induced immune thrombocytopenia.

Year 1998
Bozec L. Bierling P. Fromont P. Levi F. Debat P. Cvitkovic E. Misset JL.
FSMSIT, Hopital Paul Brousse, Villejuif, France.
BACKGROUND: Irinotecan is currently used as second-line chemotherapy for advanced colorectal cancer. We report a case of severe thrombocytopenia after Irinotecan, suggesting an immune mechanism, in a 53-year-old patient. PATIENTS AND METHODS: The patient's sera were screened for platelet antibodies with an indirect platelet immunofluorescence test (PIIFT). The monoclonal antibody immobilization of platelet antigen assay (MAIPA) was used to characterize the antibody target. RESULTS: We detected an IgG platelet antibody in the patient's serum in the presence of Irinotecan by means of PIIFT, and not in the presence of SN-38, its active metabolite. The specificity of the binding was asserted after CD32 MoAb blockade. The platelet binding site could not be strictly identified with MAIPA and immunoblotting but GpIIb/IIIa can be excluded after experiments with Glanzmann platelets. CONCLUSION: This case can be considered the first documented Irinotecan-induced immune thrombocytopenia.