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PubMed2004

Vincristine liposomal--INEX: lipid-encapsulated vincristine, onco TCS, transmembrane carrier system--vincristine, vincacine, vincristine sulfate liposomes for injection, VSLI.

INEX Pharmaceuticals is developing a liposomal formulation of vincristine [Onco TCS, vincacine, VSLI, Vincristine sulfate liposomes for injection] for the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) and other cancers. It is being developed using INEX's proprietary drug-delivery technology platform called the transmembrane carrier systems (TCS), which enables the targeted intracellular delivery of various therapeutic agents. Liposomal vincristine is expected to have certain advantages over the existing standard preparation of vincristine because the use of TCS technology enables the vincristine to circulate in the blood for longer, accumulate in the tumour, and be released over an extended period of time at the tumour site. The application of TCS technology to any agent, including vincristine, has the potential to increase the efficacy and decrease the side effects of the agent. INEX decided in 1998 to focus on gaining approval for liposomal vincristine in the treatment of relapsed aggressive NHL because no standard therapy was approved for this indication. In 1999, liposomal vincristine was granted accelerated development status by the US FDA, which enables the FDA to approve it based on the surrogate endpoint of a single clinical trial. In addition, the FDA granted liposomal vincristine fast track status in August 2000. In April 2001, INEX and Elan Corporation formed a joint venture for the development and commercialisation of liposomal vincristine, with both companies contributing assets to the venture including worldwide rights to the product and intellectual property rights. The joint venture was called IE Oncology. However, in June 2002, Elan announced that it was going to focus its business strategy on three specific areas, which would not include cancer therapies. INEX announced it had regained 100% ownership of liposomal vincristine in April 2003, by reacquiring the 19.9% equity interest held by Elan and in addition retaining a fully paid-up licence to Elan's intellectual property pertaining to liposomal vincristine. All obligations to Elan under the agreement will be met through three milestone payments totalling $8 million. Some of the milestones may be paid in shares valued at the then current market price. In January 2004, INEX and Enzon Pharmaceuticals formed a strategic partnership to develop and commercialise liposomal vincristine. Under the terms of the agreement, Enzon receives the exclusive North American commercialisation rights for liposomal vincristine for all indications. INEX will receive upfront and milestone payments as well as a percentage of commercial sales. Additionally, the formation of this partnership triggered a US$3 million payment from INEX to the former joint venture partner, Elan Corporation. Nine clinical trials of liposomal vincristine are currently being conducted, including one phase I/II trial and eight phase II trials. A phase II/III trial was completed in December 2002. In September 2003, Inex commenced a 'rolling submission' for liposomal vincristine by submitting the first of three major sections of the NDA to the FDA. The second major section was submitted to the FDA in December 2003. INEX expects to complete the filing with the submission of the clinical section of the NDA in the first quarter of 2004. Dow Jones Newswires reported on 1 October 2001 that the CEO of INEX expects Onco TCS to achieve sales of between $US100 and $US400 million annually for the company. FDA approval was then predicted for late 2002 or early 2003.

Antineoplastic Agents↗
PubMed1989

Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group.

A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multicenter trial. Patients were randomly assigned to receive one of the following three regimens: cyclophosphamide 1,000 mg/m2 intravenously (IV) day 1, vincristine 1.4 mg/m2 IV day 1, and etoposide 50 mg/m2 IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclophosphamide 1,000 mg/m2 IV day 1, vincristine 1.4 mg/m2 IV day 1, and doxorubicin 50 mg/m2 IV day 1 (CAV); cyclophosphamide 2,000 mg/m2 day 1 and vincristine 1.4 mg/m2 IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with respect to extent of disease, age, sex, performance status, and metastatic sites. No significant differences in response rates, response duration, or survival could be detected in limited disease, although there appeared to be a trend favoring CEV. Among extensive-disease patients, response duration on the CEV regimen was longer than on the CV regimen or the CAV program (P less than .001). The superiority of the CEV regimen was also demonstrated in the survival analysis in which differences attained statistical significance (P = .01). In this group the median survival was increased from 29 weeks on CV to 31 weeks on CAV and 39 weeks on CEV. Myelosuppression was the most frequent toxicity. It was more severe with CV than CEV or CAV. Most nonhematologic side effects were comparable among the three treatment groups. However, the high doses of cyclophosphamide in the CV regimen produced a higher incidence of hemorrhagic cystitis than in the CEV or CAV programs (P less than .001). Cardiotoxicity only occurred in the CAV group (P = .05). The addition of etoposide to the CV regimen resulted in significantly longer response duration and survival without increased toxicity. Similarly, the substitution of etoposide for the doxorubicin in the CAV regimen was associated with prolonged survival and reduced cardiotoxicity.

Adult↗
PubMed1988

Identification of the bromosulfophthalein-sensitive efflux route for methotrexate as the site of action of vincristine in the vincristine-dependent enhancement of methotrexate uptake in L1210 cells.

The mechanism by which vincristine enhances the uptake of methotrexate in leukemic L1210 mouse cells has been investigated. Methotrexate uptake after 30 min at 37 degrees C increased 44% relative to untreated controls in cells suspended in a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid/bicarbonate-buffered saline medium containing 20 microM vincristine. This stimulation was half-maximal at a vincristine concentration of 4 microM. An enhancement of methotrexate uptake by vincristine was also observed in the presence of glucose but a reversal could be achieved by prior treatment of the cells with taxol, a drug which prevents microtubule disassembly by vincristine. When the effect of vincristine was determined on the individual influx and efflux components for methotrexate, the increased uptake of methotrexate correlated with the inhibition of the unidirectional efflux route for methotrexate that is sensitive to bromosulfophthalein. Inhibition of this route was half-maximal at 3 microM vincristine and it exceeded 90% at high concentrations of the inhibitor. Transport via the bidirectional exchange carrier for methotrexate was not affected by vincristine, while the unidirectional efflux route sensitive to probenecid was inhibited by vincristine but only at concentrations 10-fold higher than required to inhibit the bromosulfophthalein-sensitive route. Vincristine did not increase methotrexate uptake in CCRF-CEM lymphoblasts, a human cell line which contains much lower levels of bromosulfophthalein-sensitive efflux route for methotrexate. Concentrations of vincristine which inhibited the bromosulfophthalein-sensitive efflux route of L1210 cells by 80-90% had little or no effect on the intracellular pH or on intracellular levels of ATP, GTP, cyclic AMP, K+, or oxidized glutathione. A significant increase was observed in the cellular uptake of tetraphenylphosphonium ions, suggesting that vincristine causes a hyperpolarization of the plasma membrane.

Adenosine Triphosphate↗
PubMed1992

Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine.

Recent studies using bile canalicular membrane vesicles have suggested that P-glycoprotein may play a role in excreting some anticancer drugs from the liver to the bile. At steady state after a continuous single-pass perfusion of a tracer concentration of [3H]vincristine in the rat liver, the extraction ratio was approximately 0.6, and 70% of the extracted drug was excreted into the bile mostly in unchanged form. The liver/perfusate and bile/liver unbound concentration ratios obtained after correction for intracellular binding and the inside-negative membrane potentials and/or pH difference between the inside and outside of the cells, were approximately 2-3 and 160-280, respectively, suggesting a highly concentrated biliary excretion process. We also examined the effects of verapamil, a P-glycoprotein-related transport inhibitor in cancer cells, on the hepatobiliary transport of [3H]vincristine. Verapamil 50 microM in the perfusate caused a decrease in the biliary excretion rate of [3H]vincristine, whereas [14C]taurocholate (reference compound) remained constant. In contrast, the hepatic uptake rate of [3H]vincristine exhibited minimum reduction, suggesting that verapamil selectively inhibited the biliary excretion of [3H]vincristine at the canalicular membrane. The fact that verapamil had little effect on the initial velocity of [3H]vincristine uptake by isolated hepatocytes also supports the above findings. Since the effect of 150 microM verapamil in the perfusate was not selective for vincristine, the biliary excretion rates of both compounds ([3H]vincristine, [14C]taurocholate) were reduced by this concentration of verapamil. In conclusion, the concentrative excretion of vincristine into the bile and its selective inhibition by a moderate concentration of verapamil provide indirect evidence for the contribution of P-glycoprotein to the biliary excretion of vincristine in a perfused rat liver system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Vincristine hyperalgesia in the rat: a model of painful vincristine neuropathy in humans.

To investigate the mechanism of vincristine-induced pain in humans undergoing chemotherapy we have established a model of vincristine-induced hyperalgesia in rat. Vincristine (100 micrograms/kg) was administered daily over a period of two weeks. An acute dose-dependent decrease in mechanical nociceptive threshold and an increased response to non-noxious mechanical stimuli ("hyperalgesia") occurred after the second day of administration. Chronic lowered threshold and increased response to stimuli (determined 24 h after each injection) was first noted during the second week of vincristine administration. Responses gradually returned to baseline during the two weeks following discontinuation of treatment. Vincristine also increased sensitivity to heat stimulation. At a dose that produced hyperalgesia (100 micrograms/kg), vincristine did not cause a significant motor deficit. Peripheral administration of a mu-opioid agonist did not reduce vincristine-induced acute hyperalgesia. Hyperalgesia induced by vincristine in the rat provides a good model for the experimental study of painful peripheral neuropathies in human patients receiving vincristine as a chemotherapeutic agent.

Analgesics↗
PubMed1994

Liposome encapsulated vincristine: preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposomes in mice, rats and dogs.

A preclinical toxicology study of liposome encapsulated vincristine, free vincristine and empty liposomes was carried out in mice and dogs by single and multiple (daily for 5 days) intravenous injection. Single and multiple dose intravenous injection studies in mice showed the encapsulated form of vincristine to be less toxic than free vincristine. Empty liposomes injected intravenously into dogs were without significant toxicity. In dogs, the toxicities seen with liposomal vincristine were qualitatively similar to those of free vincristine with only minor quantitative differences. The principal toxicities of free and liposomal vincristine in dogs were anorexia, weight loss, pyrexia, myelosuppression and gastrointestinal toxicity. After single high doses of either formulation gastrointestinal toxicity was the dose-limiting toxicity, while either hematologic or gastrointestinal toxicity was dose limiting after multiple dose administration of either drug. Histopathologic lesions of importance were bone marrow atrophy, necrosis and atrophy of the lymphoproliferative tissues, necrosis of gastrointestinal tract mucosa, liver and pancreas, and hemorrhage. Distribution studies in rats showed significantly higher vincristine levels in serum, spleen, liver, trachea, jejunum, cerebrum, lung, ischiatic nerve and heart, and significantly lower levels in colon, stomach, salivary gland, thymus esophagus and pancreas after injection of the liposome-associated agent. No toxicities were seen that should preclude safe clinical trial of liposomal vincristine in man.

Animals↗
PubMed2005

Vincristine pharmacokinetics and response to vincristine monotherapy in an up-front window study of the Dutch Childhood Leukaemia Study Group (DCLSG).

The relationship between vincristine pharmacokinetics and its antileukaemic effect in children is unknown. Since vincristine plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL), it is worthwhile to explore if efficacy can be improved by individual dose adjustment. Therefore, we studied the relationship between vincristine antileukaemic effect and pharmacokinetics in children newly diagnosed with ALL before the start of standard induction chemotherapy. Vincristine plasma concentration was measured by high-pressure liquid chromatography analysis with electrochemical detection. Primary pharmacokinetic parameters were estimated by maximum a posteriori parameter estimation with a Bayesian algorithm using the ADAPT II software package. Secondary pharmacokinetic parameters were calculated from the model. Response to a single dose of vincristine was determined on bone marrow (BM) and peripheral blood (PB) smears after 3 days. Variability of vincristine pharmacokinetics did not explain variability of response to vincristine monotherapy. Our results do not support the clinical application of pharmacokinetically guided adaptation of a standard body surface area-based dose of vincristine.

Adolescent↗
PubMed1983

Potentiation of chemotherapeutic effect of vincristine in vincristine resistant tumor bearing mice by calmodulin inhibitor clomipramine.

Clomipramine, which is used as antidepressant and possesses calmodulin inhibitory activity, circumvented partly the vincristine resistance in vivo. Although vincristine alone at 30-200 micrograms/kg did not confer a significant therapeutic effect in vincristine resistant P388 leukemia (P388/VCR)-bearing mice, clomipramine at doses of 20 to 50 mg/kg administered daily for 10 d with vincristine enhanced the chemotherapeutic effect of vincristine in P388/VCR-bearing mice. Approximately a 30% increase in life span occurred. Although the circumvention of vincristine resistance was not achieved perfectly, it could be speculated that more than 98-99% of vincristine resistant tumor cells which could not be killed by vincristine alone could be killed by this approach.

Animals↗
PubMed1976

Methyl-CCNU, alone and in combination with vincristine, or vincristine and methotrexate, in advanced bronchogenic carcinoma.

Ninety-two patients with advanced bronchogenic carcinoma were prospectively randomized according to performance status, histology, and extent of disease to methyl-CCNU alone; methyl-CCNU and vincristine; or methyl-CCNU, vincristine, and methotrexate. Seventy-three patients were evaluable. Randomization to methyl-CCNU alone was discontinued when only three brief "static" responses were noted in 11 patients and the survival (p less than .01) and time on study (p less than .05) were noted to be significantly less than with the combination. Two of 32 patients treated with methyl-CCNU and vincristine, and two of 30 patients treated with methyl-CCNU, vincristine, and methotrexate had mixed responses with a median of 67.5 days. A static response was seen in eight of 32 and none of 30 patients, respectively. Minimal toxicity occurred in all regimens. Methyl-CCNU alone or in combination with vincristine or vincristine and methotrexate is of limited benefit in patients with lung cancer, although our data suggest (p = 0.15) that the addition of methotrexate increases time on study and survival in patients with extensive disease.

Carcinoma, Bronchogenic↗
PubMed1982

A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma.

This randomized study, conducted by the Eastern cooperative Oncology Group, compared Adriamycin (doxorubicin) (70 mg/m2) versus vincristine (1.4 mg/m2) and Adriamycin (50 mg/m2); and cyclophosphamide (750 mg/m2) versus vincristine (1.4 mg/m2), actinomycin-D (0.4 mg/m2), and cyclophosphamide (750 mg/m2) for treatment of metastatic mesenchymal malignancies. The respective response rate seen in 200 evaluable patients to the treatments were, 27, 19, and 11%. The response rate to Adriamycin was significant better than the response to vincristine, actinomycin-D, and cyclophosphamide (P = 0.03, two-sided). The respective median survivals on the three treatments were 37, 34, and 41 weeks and were not significantly different. Moderate or severe vomiting occurred in 60% of patients receiving vincristine-cyclophosphamide-adriamycin, a greater frequency than in Adriamycin alone (P = .09 two-sided) Severe or life-threatening hematologic toxicity (leukocytes less than 2000, platelets less than 50,000) occurred in 30% of patients receiving the Adriamycin combination, a markedly increased frequency when compared to the other two regimens (P equals 0.07, P = 0.02, two-sided). This trial establishes that Adriamycin has a better response rate than the combination of vincristine-actinomycin-D-cyclophosphamide in advanced sarcomas. The combination of vincristine, Adriamycin, and cyclophosphamide increased toxicity and did not add to the therapeutic effect achieved with Adriamycin alone.

Adult↗
PubMed1993

Simultaneous resistance to vincristine and adriamycin appears at higher frequencies than to vincristine and etoposide in Chinese hamster ovary cells.

Efficacy of combination chemotherapy depends on the probability of a cell being resistant to at least two drugs simultaneously. In this study, we determined the frequencies of double drug resistance in the CHO AA8 cell line under combined exposure to vincristine plus adriamycin, vincristine plus etoposide, and adriamycin plus etoposide. These frequencies were compared to the expected frequencies which are the product of the independent frequencies observed for each drug alone. The results show a high frequency (up to 700-fold) of double resistance to adriamycin plus vincristine, a low increase (up to 30-fold) in frequency of resistance to vincristine plus etoposide, and an intermediate increase (200 to 300-fold) in frequency of cells resistant to adriamycin plus etoposide. The differences observed between combinations seem to be related, at least in part, to the mechanism(s) of resistance generally involved in the resistance to each drug: P-glycoprotein overexpression and/or DNA topoisomerase II alteration.

Animals↗
PubMed1984

Alternating pulses of vincristine-prednisone with cytarabine-cyclophosphamide versus vincristine-prednisone in the maintenance therapy of acute lymphoblastic leukemia.

From January 1976 to December 1978, 347 children less than or equal to 15 years of age were entered in a collaborative controlled trial which included: induction (vincristine-daunorubicin-prednisone); intensification (cytarabine-cyclophosphamide); CNS prevention (intrathecal methotrexate-dexamethasone, three doses during induction and three weekly doses during the first month of maintenance, followed by one dose every 3 months for 48 months); and maintenance (6-mercaptopurine daily and methotrexate twice weekly with reinforcement pulse doses of either 1.5 mg/m2 X 1 of vincristine plus 40 mg/m2/day X 7 of prednisone [Arm A] or vincristine-prednisone alternating with 50 mg/m2 of cytarabine sc every 12 hours X 10 plus 600 mg/m2 X 1 of cyclophosphamide [Arm B]). Pulses were performed in both arms at 1, 2, 3, 4, and 6 months and every 3 months thereafter. Randomization was stratified according to age and initial wbc count. A total of 89% (310/347) of patients achieved complete remission. Duration of continuous complete remission was evaluated according to prognostic factor groups. At 5 years, 34.5% of patients with good prognosis, 24.8% with intermediate prognosis, and 12.8% with poor prognosis are in continuous complete remission. There is statistical difference between good versus poor prognosis (P less than 0.0005) and intermediate versus poor prognosis (P less than 0.025). Moreover, 5-year survival is 50.9%, 35.2%, and 18.2% in the good-, intermediate-, and poor-prognosis groups, respectively. Duration of continuous complete remission up to the first event (ie, bone marrow, CNS, or other extramedullary relapse, or death in complete remission), according to prognostic groups, did not differ in relation to reinforcement pulses (Arm A or B). We conclude that there was no benefit in alternating pulses of vincristine-prednisone with cyclophosphamide-cytarabine as used in this study.

Acute Disease↗
PubMed1982

[Clinical management of acute lymphocytic leukemia in adults. 1. Treatment of acute lymphocytic leukemia with VP (vincristine, prednisolone)--DVMP (daunorubicin, vincristine 6-mercaptopurine, prednisolone) regimen].

Eighteen patients with acute lymphocytic leukemia (ALL) were treated with VP (vincristine, prednisolone) followed by DVMP (daunorubicin + vincristine + 6-mercaptopurine + prednisolone) regimen (VP-DVMP regimen). Patients were all previously untreated. Complete remission (CR) was obtained in 11 of 18 patients (61.1%,) by VP alone and 4 patients, by VP-DVMP. The time required for CR varied from 14 to 60 days with a median of 28 days. The duration of CR and survivals in responders were from 1.2 to 42.3 + months with a median of 24.0 months. The hematological toxicities in VP-DVMP regimen were lower than those in NVP (neocarzinostatin + vincristine + prednisolone) and NVMP (neocarzinostatin + vincristine + 6-mercaptopurine + prednisolone) regimens.

Adolescent↗
PubMed2005

Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19).

PURPOSE: The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine + prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine + prednisone (COP) in patients with previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma. METHODS: A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m2 (days 1-5) + bendamustine 60 mg/m2 (days 1-5) or + cyclophosphamide 400 mg/m2 (days 1-5) for a total of eight 21-day cycles. RESULTS: The rate of complete remission was 22% with BOP and 20% with COP. The projected 5-year survival rate was 61% with BOP and 46% with COP. The BOP-associated 5-year survival advantage almost reached significance in the subgroup of patients who responded to therapy (74% vs. 56%; P = 0.05), and did reach significance in responders who did not receive interferon maintenance therapy (70% vs. 47%; P = 0.03). Toxicity was acceptable in both treatment groups, although alopecia and leucopenia were more severe with COP. CONCLUSIONS: Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma. Long-term survival data suggest a clinically significant benefit for patients treated with BOP.

Adult↗
PubMed1997

Validation of a high-performance liquid chromatographic assay method for quantification of total vincristine sulfate in human plasma following administration of vincristine sulfate liposome injection.

The validation of a high performance liquid chromatographic (HPLC) assay method for quantitation of total vincristine sulfate (VINC) in human plasma is described. VINC was extracted from plasma using BondElut CBA solid phase cartridges with vinblastine as the internal standard. Chromatography was accomplished using a Waters Symmetry C8 (250 mm x 4.6 mm i.d.) analytical column, a Waters Delta-Pak ODS guard column with a mobile phase of 34.9% water-0.1% diethylamine (pH 7.0)-40% acetonitrile-25% methanol pumped isocratically at 1.0 ml min(-1) with ultraviolet detection at 297 nm. Above the limit of quantitation of 28.6 ng ml(-1), the area ratio precision (R.S.D. range 3.33-11.6%) and accuracy of predicted values (R.S.D. range 8.56-23.8% with the limit of quantitation being the only value above 20%) were acceptable. The assay was linear from 28.6-2860 ng ml(-1) VINC in plasma. Recovery of VINC from plasma and VINC from plasma spiked with vincristine sulfate liposome injection ranged from 74.9-87.1%. Stability of VINC in plasma stored at -20 degrees C for at least 49 days and of extracted plasma samples was demonstrated. Potential interference in quantitation of VINC from commonly co-administered drugs was evaluated along with day-to-day variability. The assay procedure was found suitable for evaluation of VINC clinical pharmacokinetics in plasma following administration of vincristine sulfate liposome injection prepared using distearoylphosphatidylcholine (DSPC)/cholesterol liposomes for injection.

Chromatography, High Pressure Liquid↗
PubMed1993

A randomized study comparing cyclophosphamide, doxorubicin, vincristine (CAV) with cyclophosphamide, etoposide, vincristine, methotrexate (CEVM) in patients with small cell lung cancer.

This trial was carried out to assess the response rate and survival benefit achieved, if any, by substitution of etoposide for doxorubicin and addition of methotrexate in combination with cyclophosphamide and vincristine in the treatment of 113 patients with small cell lung carcinoma (SCLC). Cyclophosphamide, etoposide, vincristine, methotrexate (CEV-M) yielded a response rate of 75% in localized disease (LD) and 63% in extensive disease (ED), versus 61% in LD and 52% in ED in the cyclophosphamide, doxorubicin, vincristine (CAV) arm. There was also a significant survival benefit for the responders in favor of CEV-M (21.7 +/- 3.8 months of median survival compared to 13.6 +/- 2.8 months in CAV arm) in patients with LD.

Adult↗
PubMed2003

A randomized trial of induction therapy (daunorubicin, vincristine, prednisone versus daunorubicin, vincristine, prednisone, cytarabine and 6-thioguanine) in adult acute lymphoblastic leukemia with long-term follow-up: an Eastern Cooperative Oncology Group Study (E3486).

In this study of previously untreated adult acute lymphocytic leukemia (ALL) performed by the Eastern Cooperative Oncology Group, patients were randomized to induction therapy with either DVP (daunorubicin 45 mg/m2 daily, days 1, 2 and 3; prednisone 60 mg/m2 daily orally days 1-35; and vincristine 2 mg intravenously on days 1, 8, 15 and 22) or DATVP (daunorubicin 60 mg/m2 daily, days 1, 2 and 3; cytarabine 25 mg/m2 intravenous bolus followed by 200 mg/m2 daily as a continuous infusion on days 1-5; 6-thioguanine 100 mg/m2 orally every 12 h on days 1-5; vincristine 2 mg intravenously on days 1 and 8; and prednisone 60 mg/m2/day orally, days 1-7. Complete responders to both regimens received the same post-remission therapy, which consisted of a single course of cytarabine 3 gm/m2 infused over 1 h every 12 h for 12 doses. One month later those patients still in remission received six cycles of consolidation therapy with MACHO (cyclophosphamide 650 mg/m2, doxorubicin 40 mg/m2 vincristine 2mg all intravenously on day 1 with prednisone 100 mg/m2 orally daily on days 1-5. Methotrexate 200 mg/m2 intravenously and L-asparaginase 6000 U/m2 were given on day 22 and each course was given every 5 weeks. A single dose of intrathecal methotrexate was also given with each MACHO course. There were 276 evaluable patients randomized in this study. Complete response rates were 71% for DVP and 58% for DATVP. Median durations of complete response were 5.5 and 6.8 months, respectively. Median survival of all randomized patients was 14.4 months in each group. DATVP was more toxic than DVP. Intensification of treatment for adults with ALL may not improve outcome. Progress in the treatment of adults with ALL will require the identification of new agents for this neoplasm.

Adolescent↗
PubMed1981

Combination chemotherapy study for remission maintenance in ALL: an evaluation of vincristine, cyclophosphamide and vincristine, cyclophosphamide, and BCNU: a Southwest Oncology Group Phase II Study.

Vincristine (VCR), cyclophosphamide (CP), and BCNU have antineoplastic activity in acute lymphocytic leukemia. In animal tumor systems, and in a clinical controlled study, vincristine and cyclophosphamide have been demonstrated to be more effective when given sequentially. In animal models, cyclophosphamide and BCNU have a synergistic effect if given simultaneously. In order to evaluate this potentially synergistic schedule in man, children with ALL in their second or greater remission were randomized to receive either a standard vincristine cyclophosphamide regimen (VCR 2 mg/m2 on day 1 and CP 450 mg/m2 on days 2 and 3) or this same regimen with the addition of 50 mg of BCNU given with the CP given on days 2 and 3. The standard two-drug regimen was given every 3 weeks and the potentially synergistic combination was given on a 4-week schedule. The median duration of remission (MDR) for the 18 children receiving the two-drug combination was 13.5 weeks, and for the 20 children receiving the potentially synergistic three-drug regimen combination, 15 weeks. With 95% confidence, the population MDR for the two-drug combination is from 63% to 125% of the population with the three-drug regimen. The toxicities of both regimens was tolerable. No statistically significant synergistic benefit was demonstrated in these patients with the addition of BCNU to cyclophosphamide.

Adolescent↗