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PubMed2005

Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma.

Childhood malignant gliomas are rare, but their clinical behavior is almost as aggressive as in adults, with resistance to therapy, rapid progression, and not uncommonly, dissemination. Our study protocol incorporated sequential chemotherapy and high-dose thiotepa in the preradiant phase, followed by focal radiotherapy and maintenance with vincristine and lomustine for a total duration of one year. The induction treatment consisted of two courses of cisplatin (30 mg/m2) plus etoposide (150 mg/m2) x 3 days and of vincristine (1.4 mg/m2) plus cyclophosphamide (1.5 g/m2) plus high-dose methotrexate (8 g/m2), followed by high-dose thiotepa (300 mg/m2 x 3 doses), with harvesting of peripheral blood progenitor cells after the first cisplatin/etoposide course. From August 1996 to March 2003, 21 children, 14 females and 7 males, with a median age of 10 years were enrolled, 18 presenting with residual disease after surgery. Histologies were glioblastoma multiforme in 10, anaplastic astrocytoma in nine, and anaplastic oligodendroglioma in two; sites of origin were supratentorial areas in 17, spine in two, and posterior fossa in two. Of the 21 patients, 12 have died (10 after relapse, with a median time to progression for the whole series of 14 months; one with intratumoral bleeding at 40 months after diagnosis; and one affected by Turcot syndrome for duodenal cancer relapse). Four of 12 relapsed children had tumor dissemination. At a median follow-up of 57 months, overall survival and progression-free survival at four years were 43% and 46%, respectively. Sequential and high-dose chemotherapy can be afforded in front-line therapy of childhood malignant glioma without excessive morbidity and rather encouraging results.

Adolescent↗
PubMed2003

Recent developments in the molecular characterization and treatment of oligodendroglial tumors.

Although many patients with oligodendrogliomas (ODs) and oligoastrocytomas (OAs) benefit from a combination of surgery and adjuvant radiotherapy, most patients eventually experience recurrence of their disease. Recent evidence has shown that ODs are more chemosensitive than other gliomas, including astrocytomas or glioblastoma multiforme. These initial findings have prompted further study of chemotherapy in treating ODs and mixed OAs. Advances in molecular genetic analysis have led to improvements in predicting response to chemotherapy and prognosis for ODs, OAs, and astrocytomas. Pure ODs are more chemosensitive than mixed ODs. This difference is related to different proportions of 1p/19q loss of heterozygosity in these neoplasms. Therefore, genetic analysis is likely to be key in determining appropriate treatment. The most common first-line chemotherapy for patients with OD is a procarbazine, lomustine, and vincristine (PCV) combination regimen. However, this regimen is associated with cumulative myelosuppression, nausea, vomiting, and weight loss. Therefore, other chemotherapy agents and regimens have been investigated. Perhaps the most promising is temozolomide, a novel alkylating agent that freely crosses the blood-brain barrier. Temozolomide is approved in the United States for the treatment of recurrent anaplastic astrocytomas and in Europe for any recurrent high-grade gliomas. Initial reports suggest that temozolomide is effective in treating ODs as first- and second-line chemotherapy. Unlike the PCV regimen, temozolomide is not associated with cumulative myelosuppression and is usually well tolerated. Further studies are needed to confirm the efficacy and safety profile of temozolomide and to determine the optimal dose and schedule for treating ODs.

Animals↗
PubMed2004

Chemotherapy of anaplastic oligodendroglial tumours.

Anaplastic oligodendroglial tumours (oligodendrogliomas and oligoastro-cytomas) have a definite better prognosis than diffuse astrocytic gliomas (glioblastomas and anaplastic astrocytomas). Surgery relieves neurological symptoms and provides tissue for classification, grading and molecular characterisation of the tumour. Historically, radiation therapy has been the sole postoperative treatment for patients with anaplastic oligodendroglial tumours, but this policy has been challenged in the last few years by the discovery that these tumours are chemosensitive. Procarbazine, lomustine and vincristine (PCV) and temozolomide are the most active drugs, but it is still unclear which is the best first-line regimen. The most appropriate timing for chemotherapy (neoadjuvant, adjuvant, at recurrence) is unknown and is currently being explored in prospective studies. The goals of neoadjuvant chemotherapy (PCV, temozolomide, high-dose alkylating agents with stem cell rescue) are to defer radiotherapy or to reduce the radiation fields for a conformal treatment in responding patients. Molecular genetic analysis is increasingly employed for both diagnostic and prognostic purposes. Loss of heterozygosity on 1p and 19q is the key alteration for predicting the prognosis and the response to chemotherapy.

Antineoplastic Agents, Alkylating↗
PubMed2006

Changing paradigms--an update on the multidisciplinary management of malignant glioma.

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.

Adult↗
PubMed2005

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme.

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent with demonstrated efficacy as therapy for glioblastoma multiforme (GBM) and anaplastic astrocytoma. TMZ has widely replaced the procarbazine, lomustine plus vincristine (PCV) combination for the treatment of malignant brain tumours as a result of its oral administration and favourable toxicity profile. OBJECTIVES: This study had three related aims. First, the cost effectiveness of TMZ (from the Finnish healthcare payer perspective) was compared with PCV in patients with GBM that had relapsed after primary treatment with surgery and radiotherapy. Second, the probability that TMZ is cost effective, compared with PCV, was estimated at different societal willingness-to-pay levels. Third, the value of new information for reducing the uncertainty related to the choice of treatment between TMZ and PCV was evaluated. METHODS: The cost effectiveness of TMZ and PCV was evaluated using a decision-modelling approach. Incremental cost-effectiveness ratios (ICERs) for cost per gained life-month, progression-free life-month and QALY were calculated. Various information sources were used to acquire parameter values for the model. The efficacy information of both treatments was derived from the medical literature, quality-of-life (QOL) estimates were gathered from Finnish neuro-oncologists using visual analogue scale methods, and data on the use of healthcare resources were collected from hospital databases. The exact prices for resource use were gained from the list of Finnish health service unit costs (year 2001 prices). The model was analysed using second-order Monte Carlo simulation. The value of new information on reducing uncertainty was analysed using the expected value of perfect information (EVPI) approach. RESULTS: According to the derived ICERs, 1 extra life-month gained with TMZ costs euro2367, 1 extra progression-free life-month costs euro2165, and 1 extra QALY costs euro32 471, compared with PCV, in the treatment of GBM. The probability of TMZ being the most cost-effective choice of treatment was >60% for all levels of willingness to pay >euro5000 per gained life-month. The respective probabilities were >75% for all levels of willingness to pay >euro10 000 per gained progression-free life-month and about 85% for all levels of willingness to pay >euro20 000 per gained quality-adjusted life-month. According to EVPI analysis, future research would potentially be cost effective if the costs of research were euro4.1 million (maximum). CONCLUSIONS: On the basis of this Finnish analysis, TMZ has a high probability of being more cost effective than PCV for patients with GBM. The addition of QOL aspects to the prolonging of survival increases the probability further.

Antineoplastic Agents, Alkylating↗
PubMed2006

Treatments for astrocytic tumors in children: current and emerging strategies.

Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0-5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.

Astrocytoma↗
PubMed2004

Prognostic factors for survival of dogs with inguinal and perineal mast cell tumors treated surgically with or without adjunctive treatment: 68 cases (1994-2002).

OBJECTIVE: To determine the prognostic factors for survival and tumor recurrence in dogs with cutaneous mast cell tumors (MCTs) in the perineal and inguinal regions treated surgically with or without adjunctive radiation therapy, chemotherapy, or both. DESIGN: Retrospective study. ANIMALS: 68 dogs. PROCEDURE: Medical records of dogs with histologically confirmed MCTs in the perineal region, inguinal region, or both treated surgically with or without adjunctive radiation therapy, chemotherapy, or both were reviewed. RESULTS: Mean tumor-free interval was 1,635 days (median not reached), and 1- and 2-year tumor-free rates were 79% and 71%, respectively. Median survival time was 1,111 days (mean, 1,223 days), and 1- and 2-year survival rates were 79% and 61%, respectively. Factors that negatively influenced survival time were age at diagnosis, tumor recurrence, and treatment with lomustine. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dogs with MCTs in the inguinal and perineal regions, if appropriately treated, may have survival times and tumor-free intervals similar to dogs with MCTs in other locations.

Animals↗
PubMed1988

Treatment toxicities in long-term survivors of limited small cell lung cancer.

A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Chemotherapy for primary central nervous system lymphoma.

Chemotherapy, with or without radiotherapy, is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, and it is used in doses of 1 to 8 g/m(2), either as a single agent or in combination with other drugs such as corticosteroid agents, cytarabine, procarbazine, vincristine, carmustine, lomustine, thiotepa, cyclophosphamide, temozolomide, and rituximab. To date, an overwhelming number of different regimens in which high-dose MTX is used have been reported. Given the lack of randomized trials, however, the optimal treatment remains controversial. Varying methodology makes the comparison of available studies extremely difficult, yet some common themes can be found throughout the literature. Treatment paradigms vary considerably according to the patient's age. Most studies support the use of chemotherapy-only treatments for elderly patients (> 60 years), given the high risks of neurotoxicity associated with radiotherapy. Nevertheless, the prognosis remains poor regardless of the chemotherapy chosen, and less toxic regimens might be preferable for such elderly patients. Conversely, in younger patients (< 60 years), there is growing evidence that commonly used chemotherapy-only regimens are associated with increased relapse rates that may not justify deferral of radiotherapy. Thus, a significant focus of research has been the development of intensified chemotherapy regimens that could replace radiotherapy. In this article, the authors discuss the principles guiding the use of chemotherapy for PCNSL, and critically review the available literature, including the most recent trials.

Antineoplastic Agents↗
PubMed1992

Isolation and preliminary characterization of ACNU-resistant sublines of rat brain tumors in vivo.

Two variant cells lines resistant to the nitrosourea derivative ACNU ((1-4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), namely C6/ACNU and 9L/ACNU, were selected in vivo from rat brain tumors. Stable resistance to ACNU proved to be a characteristic of these cell lines, whether they were grown in vivo or in vitro. These cell lines exhibited a different pattern of cross-resistance to a wide range of chemotherapeutic agents with dissimilar chemical structures and mechanisms of action as compared with that of other ACNU-resistant cell lines established in vitro. Distinct cross-resistance was observed in both the C6/ACNU and 9L/ACNU cell lines to chloroethyl-nitrosoureas such as BCNU (carmustine), CCNU (lomustine), and methyl CCNU and, additionally, to vincristine, vinblastine, Adriamycin (doxorubicin), and arabinosylcytosine, but not to bleomycin, methotrexate, cis-platinum, and 5-fluorouracil. This might point to a multifactorial mechanism of drug resistance in ACNU-resistant cell lines derived from rat C6 and 9L brain tumor cells.

Animals↗
PubMed1996

Salvage chemotherapy for oligodendroglioma.

The authors present their experience with salvage chemotherapy for oligodendroglioma, an uncommon brain tumor that responds predictably to PCV (procarbazine, lomustine (CCNU), and vincristine) when given as initial therapy. The authors reviewed the records of patients with oligodendrogliomas who received a second, third, or fourth cytotoxic regimen prescribed to combat tumor recurrence documented by computerized tomography or magnetic resonance imaging following an initial chemotherapy program. Initial regimens were prescribed at various time points: as neoadjuvant therapy prior to radiotherapy, as adjuvant therapy in conjunction with radiotherapy, or at recurrence following radiotherapy. Response criteria were based on measurable changes in tumor size following published guidelines. Twenty-three patients (14 men and nine women) aged 25 to 58 years (median 36 years) received 33 salvage regimens. When non-PCV chemotherapy had been the prior regimen, seven (88%) of eight patients responded to salvage chemotherapy, all seven (100%) responding to PCV. Administration of PCV was effective after regimens of carmustine and CCNU but was ineffective after prior administration of PCV. When PCV had been given any time previously, only four (19%) of 21 patients responded to salvage chemotherapy; however, four (40%) of 10 patients who received etoposide (VP-16)/cisplatin (CDDP) responded. Despite the small number of patients, two noteworthy trends emerge from these data: first, PCV is a highly effective salvage treatment when used at tumor recurrence following non-PCV chemotherapy regimens, and second, the synergistic combination of VP-16 and CDDP may exert substantial anti-oligodendroglioma activity, and it warrants further evaluation.

Adult↗
PubMed1987

Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. A prospective, randomized trial.

STUDY OBJECTIVE: To determine the effect of concurrent chest radiation therapy on response rate, recurrence, and treatment toxicity among patients with limited stage small cell lung cancer who are receiving combination chemotherapy. DESIGN: Randomized trial with a median follow-up of 57 months. SETTING: A single government institution--the National Cancer Institute. PATIENTS: Consecutive sample of 96 patients with histologically confirmed small cell lung cancer that was confined to the hemithorax of origin or mediastinal and supraclavicular nodes, and which could be encompassed within a tolerable radiation portal ("limited stage"). All patients were followed until death or the end of the study period. INTERVENTIONS: Chemotherapy: Cyclophosphamide, methotrexate, and lomustine in 6-week cycles alternating with vincristine, adriamycin, and procarbazine in 6-week cycles, for a total of 48 weeks. Radiation therapy: Chest irradiation to 40 Gy in 15 fractions over 3 weeks, given simultaneously with the first chemotherapy cycle. MEASUREMENTS AND MAIN RESULTS: The combined therapy led to a significantly higher response rate (complete responses, 81%, compared with partial responses, 43%; 95% Cl for the difference, 20% to 56%), significantly improved local control of the chest tumor (p less than 0.001), and significantly longer survival (p less than 0.035) (median, 15.0 months, compared with 11.6 for chemotherapy alone). The combined therapy produced significantly more myelosuppression, weight loss, esophagitis, and pulmonary dysfunction. There were more infections and deaths from toxicity in the combined treatment group, but the differences between groups were not statistically significant. CONCLUSION: A regimen of combined chemotherapy and chest radiation therapy given concurrently is superior to chemotherapy given alone in inducing remission and prolonging survival in patients with limited stage small cell lung cancer, and the benefit of combined therapy is reduced by its greater toxicity.

Actuarial Analysis↗
PubMed1993

High-dose ifosfamide is associated with severe, reversible cardiac dysfunction.

OBJECTIVE: To determine the incidence and characterize the occurrence of cardiac toxicity with high-dose ifosfamide. DESIGN: Retrospective chart review. SETTING: Biomedical research referral center. PATIENTS: Fifty-two consecutive patients with advanced lymphoma or carcinoma enrolled in phase I trials of high-dose ifosfamide as part of combination chemotherapy with autologous bone marrow transplantation. INTERVENTIONS: Patients were given escalating doses (10 to 18 g/m2) of ifosfamide in combination with carboplatin and etoposide or with lomustine and vinblastine. MEASUREMENTS: The chart review focused on clinical, radiographic, or electrocardiographic evidence of cardiovascular dysfunction. Data from invasive hemodynamic monitoring, radionuclide cineangiography, and echocardiography were also reviewed. RESULTS: Nine of the patients treated with ifosfamide developed congestive heart failure (17%; 95% Cl, 8% to 30%). Eight of these patients, experiencing dyspnea, tachycardia, weight gain, and signs of pulmonary edema, required admission to an intensive care unit. Left ventricular contractility was found to be depressed when evaluated by radionuclide cineangiography, echocardiography, or both. Most patients responded to diuretic, vasodilator, and inotropic therapies. Two patients developed malignant ventricular arrhythmias. One patient died of intractable cardiogenic shock. Five patients died of multiorgan failure, despite showing improvement in left ventricular ejection fraction. Three patients survived and regained baseline left ventricular ejection fraction. CONCLUSIONS: High-dose ifosfamide is associated with severe but usually reversible myocardial depression and malignant arrhythmias.

Adolescent↗
PubMed1980

Herpes zoster in patients with small-cell carcinoma of the lung receiving combined modality treatment.

Herpes zoster, a rare complication in patients with solid tumours, was observed in 13 of 161 (8.1%) patients with small-cell anaplastic carcinoma of the lung treated in a prospective combined modality therapy trial. Induction therapy consisted of three courses of cyclophosphamide, doxorubicin, and vincristine, followed by thoracic radiation. Maintenance chemotherapy with oral lomustine, procarbazine, and methotrexate was given for 1 year. Most herpes zoster cases (11) occurred while patients were on maintenance chemotherapy. Three patients developed nonfatal disseminated herpes zoster and one, postherpetic neuralgia. Herpes zoster may be a relatively frequent complication of prolonged aggressive treatment of small-cell carcinoma of the lung.

Antineoplastic Agents↗
PubMed1999

Uveal melanoma: natural history and treatment options for metastatic disease.

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.

Combined Modality Therapy↗
PubMed2000

Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview.

Dacarbazine (DTIC) is the only single-agent approved by the Food and Drug Administration for treating metastatic melanoma. With DTIC as single agent, an approximately 20% objective response rate can be achieved with median response duration of 5 to 6 months and complete response rates of 5%. Current status of DTIC single agent and DTIC-based combination chemotherapy has been extensively reviewed in this article. Moreover, future directions including new combination chemotherapies and/or new therapeutical approaches have been considered. The addition to DTIC of agents such as cisplatin, nitrosoureas and tubular toxins has been reported to yield high response rates, up to 40%, in single-institution phase II trials. Historically, promising combination regimens like BOLD (bleomycin, vincristine, lomustine and DTIC) and CVD (cisplatin, vinblastine and DTIC) have induced responses on metastatic lesions to the liver, bone and brain, commonly unresponsive to DTIC alone, even though have failed to produce impact on patient survival. Several other studies have suggested a significant enhancement of antitumor effect associated with the addition of tamoxifen to various cytotoxic regimens. The four-drug combination CBDT (cisplatin, carmustine, DTIC and tamoxifen) or "Dartmouth regimen" has yielded high response rates, up to 55%, with continuous, maintained, complete responses, up to 82 months, in a subset of patients, that is considerably longer than observed with other combinations. Some authors recommend CBDT as reference therapy, even though recently presented results of a randomized phase III trial of CBDT versus DTIC alone, show no statistical difference in survival between the two groups. While a survival benefit from DTIC-based chemotherapy or DTIC alone has never been shown in metastatic melanoma patients and, therefore, the survival has remained unchanged over the past 30 years, some long term survivors have been reported with the "Dartmouth regimen" and/or with high dose interleukin-2 (IL-2) based regimens whose role is going to be defined in prospective randomized phase III trials. On the other hand, the better understanding of the mechanisms responsible for melanoma chemoresistance and the development of new therapeutical strategies could change the scenario in the next future.

Antineoplastic Agents, Alkylating↗
PubMed2000

[Anti-tumor drugs in the therapy of brain tumors].

In order to improve the quality of life and its duration, beside surgical operation with a patient with brain cancer, chemotherapy alone or in combination with radiotherapy may be applied in some cases. There are different protocols of chemotherapeutics (anticarcinomatous drugs) which are applied in treatment of some sorts carcinoma. The success of the therapy depends on the type and stage of the carcinoma, condition of patient well as of anticarcinomatous characteristics of the drug. Performed studies indicated that the life of the patients with glioblastom and astrocitom was prolonged through the application of carmustine or lomustine protocol of chemotherapy after x-rays. New anticarcinomatous drugs and new ways of application are investigated.

Antineoplastic Agents↗
PubMedDate not supplied

New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance.

The chloroethylating nitrosoureas (lomustine, fotemustine, cystemustine (BCNU) and methylating agents temozolomide (TMZ), dacarbazine (DTIC), procarbazine) have documented activity in metastatic malignant melanoma with single agent response rates of 15-25%. Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.

Animals↗