Drug dosage and remission duration in childhood lymphocytic leukemia

Pinkel, Donald; Hernandez, Kathleen; Borella, Luis; Holton, Charlene P.; Aur, Rhomes J. A.; Samoy, Gregory; Pratt, Charles B.

doi:10.1002/1097-0142(197102)27:2<247::aid-cncr2820270202>3.0.co;2-c

Cited by 216 publications

(55 citation statements)

References 8 publications

(3 reference statements)

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“…One of the earliest studies of dose response was made in childhood acute lymphoblastic leukaemia where Pinkel (1971) showed that remission duration was significantly prolonged (15 vs 6 months) in children given 'full' rather than 'half' doses of four drug maintainance therapy. However, in a larger study (van Eys, 1989) no difference in outcome was seen for the higher dose arm.…”

Section: Dose Escalating Studiesmentioning

confidence: 99%

Dose intensity in cancer chemotherapy

Dodwell

Gurney²,

Thatcher³

1990

Br J Cancer

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There is substantial evidence that, for the majority of antitumour agents including alkylating agents, anthracycline antibiotics and anti-metabolites, there is a steep dose response curve when these agents are studied in in vitro and in vivo models (Griswold et al., 1963;Bruce et al., 1966;Schabel et al., 1984). It is this dose-response relationship which is often cited in support of high dose chemotherapy with autologous bone marrow rescue as a promising avenue for the treatment of solid tumours. The purpose of this review is to assess the evidence that dose and dose intensity are important determinants of outcome in the treatment of human cancer with cytotoxic chemotherapy. We will review retrospective and prospective studies of dose and dose intensity in a variety of tumour types, and discuss how future clinical studies may be planned and presented to provide a more informed therapeutic rationale for exposing patients to greater doses of cytotoxic drugs in an attempt to improve outcome. Retrospective dose intensity analysis Breast cancerIn 1984 Hryniuk and Bush analysed the complete and partial remission rates and median survival times of 26 published studies using CMF-type regimens in the treatment of advanced breast cancer. For each regimen they also calculated the average relative dose intensity in the following way.The doses of cyclophosphamide, methotrexate and 5-fluorouracil were converted to a standard form of mg m2 per week. The dose intensities of each agent were compared to the dose intensity of a regimen used by Cooper (1969). The dose intensities of the test regimen were expressed as a fraction of the intensities of each drug in the Cooper protocol. The relative dose intensities for each drug in an individual CMF regimen were then averaged to give the average relative dose intensity (ARDI) of CMF-containing therapy for that particular 'test' regimen. They found a linear relationship between response rate and ARDI (Figure 1). The relationship was even more clearcut when doses actually delivered to patients, rather than planned protocol doses, were used to calculate ARDI (Figure 1).When the ARDI of a variety of CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimens were calculated in the same way and expressed as a fraction of the ARDI of a dose intensive 'reference' regimen used by Bull and Tormey (1978) again there was a clear positive correlation between ARDI and response rate and again the relationship was clearer when delivered, rather than planned, doses were used. Hryniuk and Bush also extended their observations to median survival time. The median survival time (MST) (of all patients) and the remission rates in these studies (CMF and CAF)

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Section: Dose Escalating Studiesmentioning

confidence: 99%

Dose intensity in cancer chemotherapy

Dodwell

Gurney²,

Thatcher³

1990

Br J Cancer

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“…Studies 1-111 were the initial studies of combination chemotherapy and preventive craniospinal i r r a d i a t i~n .~,~ Study IV was designed to determine the need for maximumtolerated dosage of multiple chemotherapy agents and preventive CNS therapy was not given. 8 In Study V more aggressive preventive CNS therapy was first tried3 and this was tested in a controlled manner in Study VI.' Study VII compared the two forms of CNS prophylaxis employed in Studies V and VI and tested the value of periodic "reinduction" chemotherapy during remi~sion.~ The latter studies were subjected to detailed analysis more recently as welL9…”

Section: Therapymentioning

confidence: 99%

Three to ten years after cessation of therapy in children with leukemia

Simone¹,

Aur²,

Hustu³

et al. 1978

Cancer

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Therapy was stopped in 140 children with acute lymphocytic leukemia after 2-3 years of complete remission (CR). Of the 108 children who had received preventive central nervous system (CNS) therapy and were in initial CR when therapy was stopped, 85 (79%) remain in CR for a median time of 93 months (66-166) and have been off therapy for a median time of 58 months (36-128). The 23 relapses involved the bone marrow in all but four patients who had isolated testicular relapse. Six of seven children who were in initial CR, but had received no CNS therapy, relapsed after cessation of therapy; five relapses involved the CNS. Twenty-five children had at least one extramedullary relapse, usually in the CNS, with subsequent CR for 2-3 years before therapy was stopped; 18 of 25 (72%) remain in CR for a median time of 86 months (56-141) and have been off therapy for a median time of 56 months (33-103). Six of the seven relapses involved the marrow. No feature present at the time of diagnosis could be correlated with the frequency of relapse after cessation of therapy except for the significantly greater frequency among boys (25/75) than girls (1 1/67). The adequacy of therapy, especially CNS prophylaxis, was a positive factor. The hematologic recovery pattern and degree of rebound marrow lymphocytosis after cessation of therapy did not correlate with the frequency of subsequent relapse. Of the 36 patients who relapsed after cessation of therapy, all attained CR again and six are off therapy a second time for 3-21 months.Cancer 42:839-844, 1978.T IS NO LONGER controversial to state I that a significant proportion of children with acute lymphocytic leukemia can attain long-term, leukemia-free survival and, possibly, cure. However, the supporting data should be re-evaluated periodically to determine whether time has eroded the encouraging results and whether any new insights may be gleaned for future studies. In 1974 we re- Accepted for publication December 23, 1977. ported the results following cessation of therapy in a group of children with acute lymphocytic leukemia.' For this paper we have brought those results up to date and re-examined features which might be associated with relapse or continued remission after cessation of therapy. PATIENTS AND METHODS DefinitionsAcute lymphocytic leukemia is diagnosed on the basis of partial or complete replacement of aspirated bone marrow by lymphoblasts. This diagnosis includes all children with leukemia that is not characterized by Auer rods of myelocytic, monocytic or histiocytic features. Acute lymphocytic leukemia accounts for 77% of all patients with leukemia admitted to this institution.Complete remission means freedom from signs of leukemia at any site. A complete remission bone marrow has active hematopoiesis, less than 5% total blast cells and no iden-

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“…The large inter-individual differences in plasma concentration profiles after oral MT implies different intensity of therapy, and children with adverse pharmacokinetic parameters might lack hepatotoxicity and be at increased risk for relapse, due to reduced systemic drug exposure to both liver and lymphoblasts (Pinkel et al, 1971;Craft et al, 1981). In support of hepatotoxicity reflecting treatment intensity, we found a relation between mATMT and the rise in white cell counts following cessation of therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, patients with hepatoxicity seem to have delayed systemic clearance of MTX (Parker et al, 1980). If hepatotoxicity does reflect treatment intensity, reduction of the doses of MTX and 6MP for patients with abnormal liver function tests could carry an increased relapse risk (Pinkel et al, 1971), which was also indicated by the present study.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia

Schmiegelow

Pulczynska²

1990

Br J Cancer

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Summary In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT)) during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT < 40 IU I -. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r > 0.70, P < 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk (Figure 1). One hundred and twenty-eight patients completed induction and consolidation therapy. Of these, 13 were excluded from this study due to major protocol violation during induction or consolidation therapy, refusal of MT by parents, AT not measured during MT, or lack of data (3, 1, 7 and 2 patients). Thus, 115 patients (67 boys and 48 girls) were eligible for analyses, with 56 cases of standard risk (SR), 39 cases of daily for 4 days); 6MP = oral 6-mercaptopurine (75 mg m-2 day-'); MTX = oral methotrexate (20 mg m-2 week-'); M = intrathecal methotrexate (12 mg m 2); pred/p = oral prednisone (60 mg m-2 day-'); -= 6-thioguanine (60 mg m 2 day-'); | / M = 500/1,000 mg MTX 24 h infusion with leucovorin rescue; V = vincristine (2 mg m2, max. 2 mg dose-'); XXXX = CNSirradiation (2,400 cGy).

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Drug dosage and remission duration in childhood lymphocytic leukemia

Cited by 216 publications

References 8 publications

Dose intensity in cancer chemotherapy

Dose intensity in cancer chemotherapy

Three to ten years after cessation of therapy in children with leukemia

Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia

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