The present state of the art in chemotherapy for soft tissue sarcomas in adults: the EORTC point of view.
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Adult↗
Biomedical subjects
J Verweij
Publications and source records attributed to J Verweij.
Current sample handling methods for measurement of platinum-DNA adducts in leucocytes in man lead to discrepant results in DNA adduct levels and DNA repair.
DNA adduct levels were measured with atomic spectroscopy in white blood cells (WBCs) from patients with solid tumours who were treated with six weekly courses of cisplatin. In 21 patients (I) the WBCs were collected after thawing frozen whole-blood samples according to a previously described method. In 32 other patients (II) WBCs were collected immediately after blood sample collection. The two methods for WBC collection were also compared in vitro. The maximal DNA adduct levels in vivo after the first course were in I 2.48 +/- 1.14 and in II 1.28 +/- 0.40 pg of platinum per microgram of DNA (P < 0.0001). The DNA 'repair' in the first course (DNA adduct level at the end of the infusion minus the level 15 h post infusion) was in I 40% +/- 29% and in II 18% +/- 29% (P = 0.009). These differences were consistent in all measured courses. In vitro, the DNA adduct levels in the freshly prepared WBCs were significantly lower at 0, 1 and 4, but not 24 h, after start of the incubation with cisplatin than in the WBCs collected after freezing and thawing the blood sample. The same experiment with carboplatin in vitro also resulted in significantly lower adducts in freshly isolated WBCs. The higher DNA adduct levels and DNA 'repair' in I are caused by remaining unbound cisplatin in the sample tubes, which can form DNA adducts ex vivo. The same results in vivo can be anticipated when carboplatin is used.
Antineoplastic Combined Chemotherapy Protocols↗
Topoisomerase I inhibition: a new target or new missiles?
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Antineoplastic Agents, Phytogenic↗
Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study.
BACKGROUND: CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks. RESULTS: Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%-25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade > or = 3) were diarrhea, leukocytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. These toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents. CONCLUSION: CPT-11 is an interesting moderately effective drug in pancreatic cancer.
Adult↗
Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors.
BACKGROUND: In a previous phase I study we showed that single-agent cisplatin can be given weekly for six weeks at a dose of 80 mg/m2/wk. It has been suggested that etoposide has synergistic activity with cisplatin and the drug can be given orally continuously. We therefore performed a phase I study with weekly cisplatin combined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were entered in the study. Cisplatin was administered in hypertonic saline (NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m2 for six weeks combined with daily oral etoposide at a dose of 50 mg. At the maximum tolerable dose of cisplatin 75 mg/m2/wk and etoposide 50 mg/m2 daily, leukocytopenia and thrombocytopenia were dose-limiting toxic effects which resulted in frequent treatment delays. Other toxicities were mild. Finally, a dose of cisplatin 70 mg/m2/wk weeks 1-2-3 and weeks 5-6-7 in combination with etoposide 50 mg orally days 1-15 and days 29-43 combined a high median cisplatin dose intensity of 52.5 mg/m2/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combination with oral etoposide. Leukocytopenia and thrombocytopenia are dose-limiting toxicities. The schedule will be explored further in phase II studies.
Administration, Oral↗
Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in pleural mesothelioma.
BACKGROUND: In a previous phase II study with a dose-intensive weekly cisplatin schedule for six cycles, we observed a partial response in 5 of 14 patients with pleural mesothelioma. However, response duration was short (median 6 months). Since oral etoposide may theoretically be synergistic to cisplatin, we performed a phase II study with the combination of both drugs. PATIENTS AND METHODS: Twenty-five chemo-naive patients with pleural mesothelioma were treated with cisplatin 70 mg/m2 days 1-8-15 and days 29-36-43 in combination with oral etoposide 50 mg days 1-15 and days 29-43. Patients with stable disease, or better, continued treatment with oral etoposide 50 mg/m2/day days 1-21 every 28 days RESULTS All patients were evaluable for response and toxicity. Complete response was observed in one patient and partial responses in 5 patients (RR% 24%; 95% Cl: 10%-45%) for a median duration of 30 weeks. Twelve patients had stable disease. The response status never improved during maintenance treatment with oral etoposide. Most patients tolerated the regimen very well. Toxicity was manly haematologic with leukocytopenia causing treatment delays in 8 patients. Ototoxicity grade 1 or 2 was observed in 8 patients, neurotoxicity grade 1 in 9 patients and nephrotoxicity grade 1 in 1 patient. CONCLUSION: Frequently administered cisplatin in combination with oral etoposide has a moderate but definite activity in pleural mesothelioma.
Administration, Oral↗
Topotecan in colorectal cancer: a phase II study of the EORTC early clinical trials group.
PURPOSE: This phase II study with the topoisomerase I inhibitor topotecan was performed to determine its clinical activity and toxicity in patients with metastatic or locally unresectable colorectal cancer. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 was administered intravenously by 30-minute infusion for 5 days. Fifty-nine patients entered the study, 2 were considered ineligible and 57 were evaluable for response and toxicity. RESULTS: Partial response was obtained in 4 of 57 evaluable patients (7%). The median duration of the response was 11 months (range 9.3 to 12.2). This topotecan regimen was very well tolerated. A total of 290 courses were given, with a median of 4 courses per patient (range, 1 to 18). The major toxic effects were leuko- and neutropenia (91%), grade 3-4 in 48% and 79% of courses, respectively, but with only 2 infectious complications. Other side effects were grade 1 alopecia (77%) in 46%, nausea (35%), vomiting (10%), and maculo-papular rash (6%). CONCLUSIONS: Topotecan administered as a daily-times-five regimen has only minor activity as a single-agent therapy in colorectal cancer.
Adult↗
Docetaxel: an interesting new drug for the treatment of head and neck cancers and soft tissue sarcomas.
Results are summarized for two phase II studies of docetaxel as first-line therapy for advanced squamous cell carcinoma of the head and neck (SCCHN) and one study of docetaxel as second-line therapy for advanced soft tissue sarcomas. In all three studies, docetaxel was administered at a dose of 100 mg/m2 by intravenous infusion over 1 h every 3 weeks. A total of 62 patients were enrolled in the SCCHN trials, of whom 57 were evaluable for response. The combined overall response rate in the SCCHN patients was 35%. Median duration of overall response was 6.5 months in the EORTC-ECTG study. In the DFCI study, median durations of complete and partial remission were 6.75 months and 4.45 months, respectively. These results are at least comparable to those achieved with other single-agent therapies in this setting. In the soft tissue sarcoma study, 29 of the 31 patients enrolled were evaluable for response. Five patients (17%) achieved a partial response to docetaxel as second-line therapy and a further nine (31%) had stable disease. Median duration of response in these patients with soft tissue sarcomas was 5 months. Again, these results are similar to those seen with the three most active single agents in soft tissue sarcomas when used as second-line therapy. Docetaxel may therefore represent a useful drug in both advanced SCCHN and soft tissue sarcomas.
Adult↗
Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
PURPOSE: The aim of this trial was to compare the activity and toxicity of single-agent doxorubicin with that of two multidrug regimens in the treatment of patients with adult advanced soft tissue sarcomas. PATIENTS AND METHODS: This was a prospective randomized phase III trial performed by 35 cancer centers within the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer (EORTC). Six hundred sixty-three eligible patients were randomly allocated to receive either doxorubicin 75 mg/m2 (arm A), cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC) (arm B), or ifosfamide 5 g/m2 plus doxorubicin 50 mg/m2 (arm C). RESULTS: The overall response rate was 24% (95% confidence interval, 20.7% to 27.3%) among eligible patients and 26% among assessable patients. No statistically significant difference was detected among the three study arms in terms of response rate (arm A, 23.3%; arm B, 28.4%; and arm C, 28.1%), remission duration (median, 46 weeks on arm A, 48 weeks on arm B, and 44 weeks on arm C), or overall survival (median, 52 weeks on arm A, 51 weeks on arm B, and 55 weeks on arm C). The degree of myelosuppression was significantly greater for the combination of ifosfamide and doxorubicin than for the other two regimens. Cardiotoxicity was also more frequent in this arm, but other toxicities were similar. CONCLUSION: In advanced soft tissue sarcomas of adults, single-agent doxorubicin is still the standard chemotherapy against which more intensive or new drug treatments should be compared. Combination chemotherapy cannot be recommended outside a controlled clinical trial with the exclusion of some subsets of sarcoma patients for whom significant tumor volume reduction may be an important end point of a chemotherapy regimen.
Antineoplastic Combined Chemotherapy Protocols↗
Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.
PURPOSE: To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival. PATIENTS AND METHODS: Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity. RESULTS: Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups. CONCLUSIONS: Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.
Agranulocytosis↗
Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site.
PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.
Adenocarcinoma↗
Antineoplastic agents. Drug interactions of clinical significance.
With the use of numerous drugs in the treatment of cancer, the potential for drug interactions is considerable. Because of the limited therapeutic indices of anticancer drugs, one should be aware that even small alterations in pharmacokinetics or pharmacodynamics may result in serious adverse effects. Pharmacokinetic drug interactions may alter absorption, bioavailability, distribution, metabolism and elimination patterns. For example, allopurinol inhibits the enzyme xanthine oxidase, thereby blocking the first-pass metabolism of mercaptopurine. Due to this drug interaction, plasma concentrations of mercaptopurine can increase up to 5-fold. Pharmacodynamic drug interactions are characterised by a similar or opposing pharmacological effect of both drugs upon the same biological system. For example, cotrimoxazole (trimethoprim-sulfamethoxazole) inhibits folic acid metabolism through direct binding to dihydrofolate reductase, an enzyme which is also inhibited by methotrexate. More pharmacological investigations are needed to understand the mechanisms and clinical implications of drug interactions with antineoplastic agents.
Antineoplastic Agents↗
New drugs for the treatment of sarcomas.
Despite the fact that many new active drugs recently became available for phase II studies of the different sarcoma types, only soft tissue sarcoma has been included in these phase II testing programs. The groups active in the treatment of osteosarcomas and Ewing's sarcomas should be encouraged to investigate the new active drugs in the relapsing patients. For soft tissue sarcoma, many new drugs have been tested by different groups. The results to date have been disappointing, because only docetaxel has been identified as a new active drug in one phase II study. Hints of activity have also been observed for edatrexate and topotecan. Further studies with these three drugs are necessary to identify their proper role.
Antibiotics, Antineoplastic↗
Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09.
BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.
Adult↗
The use of hematological growth factors to enable dose intensification in chemotherapy for soft tissue sarcomas.
The systemic treatment of soft tissue sarcomas is difficult due to the limited availability of active cytotoxic drugs. Combinations of cytotoxic drugs at standard doses do increase toxicity but do not improve response rates or survival. All combinations are limited by myelosuppression, mainly leukocytopenia. For at least two of the four active drugs (doxorubicin and ifosfamide) studies have shown a clear dose-response relationship. Recent studies have focused on increasing dose-intensity by increasing dosages or shortening treatment intervals, which is only possible by the use of hematological growth factors. This review will focus on the latter concept.
Antineoplastic Agents↗
A phase II study of pirarubicin in patients with advanced recurrent head and neck squamous cell carcinoma.
BACKGROUND: Head and neck squamous carcinoma (HNSCC) is a chemotherapy-sensitive tumour, but this sensitivity is not reflected in an impact on survival. The study of new drugs is therefore indicated. Pirarubicin (4'-O-tetrahydropyranyl-doxorubicin) has a higher preclinical index than doxorubicin, with low cardiotoxicity in animal models. PATIENTS AND METHODS: Twenty-six patients with squamous cell carcinoma of the head and neck and documented progression after or during previous chemotherapy were entered into the study. Two patients were ineligible for evaluation. Pirarubicin was given at a dose of 70 mg/m2 every 3 weeks. RESULTS: Partial remission was seen in 1 of the 24 evaluable patients. The predominant toxicity was bone marrow depression, with leucopenia in 62% of the patients. One patient died due to a gastrointestinal haemorrhage during a period with WHO grade IV thrombocytopenia. CONCLUSION: On the basis of these results, pirarubicin cannot be recommended as second-line treatment in patients with recurrent and metastatic HNSCC. Its possible relevance for first-line treatment cannot be judged from these data.
Adult↗
Topoisomerase I inhibitors: topotecan and irenotecan.
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Antineoplastic Agents↗
Increases in leucocyte and platelet counts induced by the alkyl phospholipid hexadecylphosphocholine.
Hexadecylphosphocholine (HePC) is a new alkyl phospholipid that has been shown to have antitumour activity in vitro and in vivo. In vivo studies have shown absence of bone marrow toxicity at therapeutic doses. In addition, at the highest dosage group in rats, an increase in white blood cell counts (WBC) was observed. To study the presence of a similar phenomenon in man, frequent measurements of haematological parameters were performed in a series of phase II studies. 70 patients were treated with daily doses of 100-200 mg of the oral formulation of HePC. WBC and platelet counts were performed weekly. In a subgroup of 23 patients serum levels of haemopoietic growth factors were measured before and during treatment. A significant increase in WBC and platelet counts was seen in 74 and 73% of the patients, respectively. In 4 patients, bone marrow showed normal cellularity, and in 1 patient, bone marrow culture showed normal numbers and sizes of colony forming units. No abnormal levels or trends over time of cytokines were observed. We conclude that oral HePC induces an increase in WBC and platelet counts in the majority of those treated.
Administration, Oral↗