The AJCC staging proposal for cutaneous melanoma: comments by the EORTC Melanoma Group.
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Humans↗
Biomedical subjects
C J Punt
Publications and source records attributed to C J Punt.
Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-early clinical studies group (ECSG).
BACKGROUND: E7070 is a novel antitumor sulfonamide which blocks the cell in G1 phase. A phase I study was initiated to investigate the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of this compound when administered intravenously at a daily times five schedule once every three weeks. PATIENTS AND METHODS: Patients with solid tumors not amenable to standard forms of therapy were eligible. E7070 was administered to cohorts of 3-6 patients per dose level, the starting dose was 10 mg/m2/day. Dose escalation was performed according to a Fibonacci-like scheme. RESULTS: Thirty-three patients entered the study. At E7070 doses of 200 and 160 mg/m2/day dose-limiting toxicities occurred, which consisted of febrile neutropenia, thrombocytopenia. diarrhea, skin folliculitis, asthenia, and stomatitis. The pharmacokinetic profile of E7070 at this schedule is non-linear with increasing dose. A partial response was observed in a patient with heavily pretreated breast cancer. Disease stabilizations and some minor responses were also documented. CONCLUSIONS: Myelosuppression is the predominant toxicity of E7070. Clinical efficacy with E7070 was observed. The recommended dose for further studies at this daily times five schedule is 130 mg/m2/day.
Adult↗
Adjuvant interferon-alpha for melanoma revisited: news from old and new studies.
Currently the data from 12 randomised phase III trials investigating the role of interferon-alpha (IFNalpha) in patients with stage II-III high-risk melanoma are available. The most prominent differences between these trials concern the dose of IFNalpha, the duration of IFNalpha administration, and the stage of disease. Some of these trials have not yet reached maturity, but despite this the positive results from some immature trials have attracted considerable attention. When only data from mature trials is considered, one may conclude that the use of high-dose IFNalpha does prolong disease-free survival (DFS) but not overall survival (OS). Combined data from low-dose IFNalpha trials does not suggest a benefit in either DFS or OS. A trial with intermediate-dose IFNalpha is still immature. Therefore currently the routine use of IFNalpha cannot be recommended outside the scope of clinical trials.
Antineoplastic Agents↗
Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors.
R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.
Administration, Oral↗
[Interferon for adjuvant therapy in melanoma; although approved, not indicated].
The Dutch melanoma group reconsidered their 1997 consensus statement on treatment of melanoma because new studies on adjuvant treatment with interferon(IFN)-alpha have been published. These have resulted in its registration for stage IIa; for stage IIb/III IFN-alpha was already registered. Overall survival should be the main endpoint of adjuvant clinical studies, especially when treatment is associated with toxicity. Since a benefit has not been unequivocally demonstrated in melanoma with Breslow thickness > 1.5 mm and/or regional lymph node metastases, there is no need to change the Dutch consensus statement. Drug registration authorities and medical professionals should cooperate more closely.
Antineoplastic Agents↗
'Hold the Mayo': solid facts or pulp fiction?
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Antimetabolites, Antineoplastic↗
Dendritic cell-based vaccines: from mouse models to clinical cancer immunotherapy.
B and T lymphocytes are the effectors of specific immunity. However, their function is critically dependent on dendritic cells (DC). DC are professional antigen presenting cells that both initiate and modulate the immune response. The recent breakthrough in the generation of DC from their progenitors has stimulated research on DC in both fundamental and clinical immunology. Objective immune response induction has now been reported in clinical studies using DC. In this review we discuss the development and potential of DC-based vaccines to induce antitumor immunity.
Animals↗
Analysis of melanoma cells in peripheral blood by reverse transcription-polymerase chain reaction for tyrosinase and MART-1 after mononuclear cell collection with cell preparation tubes: a comparison with the whole blood guanidinium isothiocyanate RNA isolation method.
Melanoma cell detection in peripheral blood by tyrosinase reverse transcription-polymerase chain reaction (RT-PCR) is usually performed on RNA isolated from whole blood using a guanidinium isothiocyanate (GITC)/phenol extraction method or from Ficoll Hypaque isolated mononuclear cells. The first method contains environmentally harmful reagents, and the second is laborious in the preanalytical steps. Cell preparation tubes (CPTs) are ready-to-use Ficoll Hypaque-based tubes that avoid the time-consuming and critical loading on Ficoll Hypaque. We examined whether CPTs can be used to determine melanoma cell dissemination in peripheral blood. We first investigated whether melanoma cells were retained in the mononuclear cell layer. All six morphologically different melanoma cell lines studied in the spiking experiments were retained in the upper layer. In further experiments, we were able to detect low dilutions of added SK-MEL-28 cells more consistently after nested RT-PCR for tyrosinase or MART-1 in the RNA isolated from mononuclear cells from CPTs than from RNA isolated with the GITC method. In addition, RNA was extracted from paired blood samples from 24 analysable stage III and stage IV melanoma patients and analysed for the presence of tyrosinase and MART-1 RNA using both the CPT/RNeasy and the whole blood/GITC method. The quality of the CPT/RNeasy RNA was better than the RNA isolated from whole blood with GITC/phenol. However, the RT-PCR results were less unequivocal: MART-1 mRNA was more often detected with CPTIRNeasy compared with whole blood/GITC (six versus three), whereas tyrosinase mRNA was found less often in CPT/RNeasy RNA (two versus eight). Taken together these results suggest that the CPT isolation method is suitable for the isolation of mononuclear cells, including melanoma cells.
Antigens, Neoplasm↗
Trimetrexate as a biochemical modulator of 5-fluorouracil and leucovorin in colorectal cancer.
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Antidotes↗
[Immunology in medical practice. XXV. Use of dendritic cells in the immunotherapy of cancer].
Dendritic cells are among the most efficient antigen-presenting cells of our immune system and they play a crucial role in immunity reactions such as the activation of T and B cells and the induction or maintenance of tolerance. New culture methods allow us to generate dendritic cells in sufficient numbers for further studies and for the preparation of antigen-loaded dendritic cells for clinical application in cancer patients. In animal studies immunization with antigen-loaded dendritic cells offered protection from growth of injected tumour cells. In experimental clinical studies in cancer patients with e.g. metastatic renal carcinoma, melanoma and B cell lymphoma some lasting remissions were observed after administration of antigen-loaded dendritic cells. Side effects were minor. Unanswered questions on tumour vaccines with antigen-loaded dendritic cells concern specific matters, such as optimal culture methods and antigen loading, and general matters, such as dose, frequency, duration and route of administration. Also, no method is currently available by which the in vivo immune response can be measured accurately.
Antigens, Neoplasm↗
Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration.
Dendritic cells (DCs) are professional antigen-presenting cells, well equipped to initiate an immune response. Currently, tumor antigen-derived peptide loaded DCs are used in clinical vaccination in cancer patients. However, the optimal dose and route of administration of a DC vaccine still remain to be determined. Using indium-111-labeled DCs, we investigated whether the route of administration does affect the biodistribution of DCs in lymphoid organs and whether it influences the outcome of DC vaccination in the B16 mouse melanoma tumor model. The results demonstrate that i.v. injected DCs mainly accumulate in the spleen, whereas s.c. injected DCs preferentially home to the T-cell areas of the draining lymph nodes. Using tyrosinase-related protein-2-derived peptide-loaded DC vaccination in a fully autologous B16 melanoma tumor model, we observed a delay in tumor growth, improved survival as well as increased antitumor cytotoxic T-cell reactivity after s.c. vaccination as compared to i.v. vaccination. These data demonstrate that optimal induction of antitumor reactivity against the autologous melanocyte differentiation antigen tyrosinase-related protein-2-derived peptide occurs after s.c. vaccination and correlates with the preferential accumulation of DCs in the T-cell areas of lymph nodes.
Animals↗
Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU).
The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.
Adult↗
Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule.
Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 microg m(-2). According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 microg m(-2), the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 microg m(-2). From the dose level 170 microg m(-2), the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 microg m(-2). The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml(-1)) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values.
Adult↗
Reproducibility of detection of tyrosinase and MART-1 transcripts in the peripheral blood of melanoma patients: a quality control study using real-time quantitative RT-PCR.
In recent years, large discrepancies were described in the success rate of the tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting melanoma cells in the peripheral blood of melanoma patients. We present a quality control study in which we analysed the reproducibility of detection of tyrosinase and MART-1 transcripts in 106 blood samples from 68 melanoma patients (mainly stages III and IV). With this study, we aimed to improve insight in the reproducibility of a RT-PCR for the detection of (minimal) amounts of circulating melanoma cells. We performed two reverse transcriptions on each mRNA sample and performed tyrosinase and MART-1 nested PCRs in duplicate per cDNA sample. Thus, four tyrosinase and four MART-1 measurements were performed per blood sample. In our study, the majority of blood samples was negative for tyrosinase (80%) or MART-1 (66%). Only four samples were positive in all four determinations for tyrosinase and seven for MART-1. Variable results (1-3 times positive results) were obtained for tyrosinase and MART-1 in 16% and 27% respectively. MART-1 PCR had a better performance than tyrosinase PCR. Sensitivity increased when both markers were used. We reasoned that the low number of melanoma marker PCR-positive blood samples can be explained by differences in mRNA quality. By using real-time quantitative PCR, we found that this was not the case: amplification of porphobilinogen deaminase (PBGD), a low copy household gene, was not different in blood samples in which a melanoma marker was not detected from groups in which this marker was detected more or less consistently (1-4 times). When applying real-time quantitative PCR for tyrosinase and MART-1, we found that a low amount of SK-MEL-28 cell equivalents was present in the blood of melanoma patients, with a higher number of equivalents in the group with a consistently positive result. We conclude that low reproducibility of a repeated assay for the detection of circulating melanoma cells is not caused by differences in mRNA quality between the samples, but due to low numbers of amplifiable target mRNA molecules in the mRNA sample. Use of more than one marker and repetition of the assay will increase the probability of finding positive PCR results.
Adolescent↗
Melanoma-inhibiting activity (MIA) mRNA is not exclusively transcribed in melanoma cells: low levels of MIA mRNA are present in various cell types and in peripheral blood.
The detection of minimal amounts of melanoma cells by tyrosinase reverse transcription polymerase chain reaction (RT-PCR) is seriously hampered by false negative reports in blood of melanoma patients with disseminated melanoma. Therefore, additional assays which make use of multiple melanoma markers are needed. It has been shown that introduction of multiple markers increases the sensitivity of detection. Melanoma inhibitory activity (MIA) is one such melanoma-specific candidate gene. To test the specificity of MIA PCR, we performed 30 and 60 cycles of PCR with two different sets of MIA specific primers on 19 melanoma and 16 non-melanoma cell lines. MIA mRNA was detected in 16 out of 19 melanoma cell lines and in seven out of 16 non-melanoma cell lines after 30 cycles of PCR. However, MIA mRNA could be detected in all cell lines after 60 cycles of PCR. Also, in 14 out of 14 blood samples of melanoma patients, five out of six blood samples of non-melanoma patients and in seven out of seven blood samples of healthy volunteers, MIA mRNA was detected after 60 cycles of PCR, whereas no MIA PCR product could be detected in any of the blood samples after 30 cycles of PCR. We conclude that low levels of MIA transcripts are present in various normal and neoplastic cell types. Therefore, MIA is not a suitable marker gene to facilitate the detection of minimal amounts of melanoma cells in blood or in target organs of the metastatic process.
Amino Acid Sequence↗
Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors.
PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.
Administration, Oral↗
Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-sample analysis.
The purpose of this study was to develop and validate limited-sampling strategies for prediction of the area under the plasma-concentration time curves (AUCs) of the lactone and total (i. e., lactone plus carboxylate) forms of the novel topoisomerase-I inhibitor 9-amino-20(S)-camptothecin (9-AC). Complete pharmacokinetic curves for both drug species were obtained from 32 patients who received the drug orally in a clinical phase I setting at dose levels ranging from 0.25 to 1.10 mg/m2. The concentrations of the lactone and carboxylate forms of 9-AC in plasma were measured by HPLC. Using data from 20 randomly selected patients, forward-stepwise multivariate regression analysis was used to generate modeling strategies incorporating data from one, two, or three plasma samples. The simultaneous optimal prediction of both 9-AC lactone and 9-AC total AUCs was obtained with sample time points at 0.33, 3.0, and 11.0 h after drug dosing. Validation of the models on an independent data set comprising data of the remaining 12 patients demonstrated that 9-AC lactone and 9-AC total AUCs could be predicted sufficiently unbiased and precise using one and two time points: [AUC (ng. h/ml) = 7.103*C3 + 4.333] for 9-AC lactone and [AUC (ng. h/ml) = 9.612*C3 + 13.77*C11 - 44.11] for 9-AC total, where C3 and C11 represent the 9-AC plasma concentrations in ng/ml at 3 and 11 h after drug dosing. Application of the proposed models will be valuable in the determination of 9-AC population pharmacokinetics and permits treatment optimization for patients on the basis of individual pharmacokinetic characteristics through restricted drug monitoring in clinical routines.
Adolescent↗
Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer.
BACKGROUND: In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial. METHODS: Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300-350 mg/m2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio. FINDINGS: 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58.8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0.001). Survival without performance-status deterioration (p=0.0001), without weight loss of more than 5% (p=0.018), and pain-free survival (p=0.003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group. INTERPRETATION: Our study shows that despite the side-effects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone.
Adult↗