Biomedical subjects
L F Sinks
Publications and source records attributed to L F Sinks.
Value of clinical trials.
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Notes from Connecticut: a surgeon's travail.
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Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up.
The cure rate of childhood acute lymphoblastic leukemia (ALL) has improved dramatically. Still there is a paucity of long-term data. With the improving cure rate, the quality of life and avoidance of second cancers have become important concerns. We evaluated 596 children and adolescents with ALL on Cancer and Leukemia Group B 7611 (CALGB 7611) who were randomized between 1976 and 1979 to receive intermediate-dose methotrexate (IDM) plus intrathecal methotrexate (IT MTX) or cranial radiation (CRT) plus IT MTX. After 10 additional years of follow-up, the pattern and significance of the results reported in 1983 are confirmed. IDM offered better hematologic protection (P < 0.0006), better testicular protection (P = 0.002), but CRT offered better central nervous system (CNS) protection (P < 0.0001). The retrieval rate for the 231 patients who relapsed while on therapy or within 6 months of elective cessation of therapy is 20 +/- 5%. For the 33 patients who relapsed more than 6 months after cessation of therapy, the retrieval rate is 49 +/- 10%. For all patients, the 12-year event-free survival was 37 +/- 3.6% and the overall survival was 49 +/- 3.5%. There were two cases of second malignancies reported in 3,502 person-years of survival. Both occurred following salvage therapy. There was no evidence of an excessive number of second primaries over the general population of children. There were no reported instances of clinical cardiopathy. After a median follow-up of 11 years, there have been no reports of cardiopathy and no evidence of an increased risk of second cancers in children treated on CALGB 7611. While the overall outcome is not what would be expected with modern therapy, one can conclude that CRT offered better CNS protection, but IDM offered better systemic and testicular protection. A small risk of second cancers or cardiac dys-function may be acceptable with therapies which produce long-term documented survival benefits.
Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse.
Six hundred thirty-four children with acute lymphoblastic leukemia (ALL) were randomized to receive sanctuary therapy consisting of either cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or three courses of intermediate-dose methotrexate (IDM) plus intrathecal methotrexate. Two hundred sixty-six male patients achieved a complete response and were evaluable for the effects of prophylactic therapy on the duration of remission. There was one isolated testicular relapse (0.8%) in the IDM group compared with 14 (10%) in the CRT group. The incidence of testicular relapse was significantly lower in the patients treated with IDM (P less than 0.001). High plasma levels of MTX achieved during the 24-hour infusions may result in increased penetration of MTX into the interstitium of the testes, thus allowing for the eradication of sequestered leukemic cells and preventing the emergence of drug resistance resulting from exposure to sublethal concentration of MTX.
Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity.
Twenty-two patients with newly diagnosed nonmetastatic osteosarcoma of the extremity were treated with an adjuvant chemotherapeutic regimen consisting of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin. Fourteen of the 22 patients remain continuously disease free for 65+ to 113+ months, with a median time on study of 70+ months. The 72-month disease-free survival estimate is 64%. Pulmonary metastases occurred in six patients, an isolated stump recurrence was seen in one patient, and one patient had a local recurrence following a limb-salvage procedure. For those patients in whom pulmonary metastases developed, the onset was late in three of six, and the number of metastases was three or fewer in all patients. Two patients with pulmonary metastases and one with a stump recurrence have apparently been salvaged, thus resulting in a 77% 72-month survival. Toxicity observed in patients treated with this regimen was in keeping with previous reports. This chemotherapeutic regimen is effective in the adjuvant therapy of nonmetastatic osteosarcoma of the extremity. It should be incorporated into other adjuvant protocols in an effort to continue to improve the outcome in patients with osteosarcoma.
The influence and reliability of neurologic assessment and Karnofsky performance score on prognosis.
The neurologic examination is important in the early diagnosis of brain tumors in children. Only in brain stem gliomas may the neurologic examination be better than computed tomographic scans in determining the progression. However, in general, the traditional neurologic examination has little or no value for prognosis. Reversible, associated features of brain tumors such as seizures or increased intracranial pressure may alter the patient's ability to function neurologically, but may not influence the prognosis regarding the tumor status. The Karnofsky functional status, to a large extent, reflects an adult's ability to work and has prognostic value but is largely inapplicable to children. Thus, a quality-of-life scale for children is needed.
Toward the development of a play performance scale for children (PPSC).
Performance scales (i.e., Karnofsky), as they measure quality of life, have been used effectively as an integral part of repeated assessment of adult cancer patients for the last several years. An equally concise measure of performance has not been developed for children. The task of developing a scale to assess performance in infants, toddlers, school-age children, and adolescents is formidable, as the activity measured should be of equal merit at each age level. Although all childhood cancer patients could benefit from a simple-to-administer, rapid assessment, children with brain tumors have the greatest need for a repeated measure of performance. The goal, then, is to develop a simplified set of criteria that can be used for assessment of children with brain tumors during hospitalization, at the time of clinic visits, and/or at the time of diagnostic procedures when the patient is in a reasonable state of health. The assessment should be able to performed by nonprofessional persons.
Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children.
We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.
Ependymoma, glioblastoma, and acute leukemia in a child.
A 5-year-old boy developed an ependymoma; 3 years later, after chemotherapy and radiotherapy, he developed glioblastoma multiforme and acute myeloblastic leukemia. His maternal grandmother had died at a young age of colon cancer. Since ependymoma is not known to predispose to other cancers, the unusual sequence of malignant disease may have been due to combined therapy in a susceptible host.
Liposomal methotrexate in the treatment of murine L1210 leukemia.
To assess the therapeutic effectiveness of methotrexate (MTX) when administered in a liposome carrier, mice bearing intracranial L1210 leukemia were tested with liposomal MTX, free MTX, or saline. Single i.p. injections of liposomal MTX at doses of 5 mg/kg and 2.5 mg/kg prolonged survival of mice bearing intracranial L1210 leukemia. The same doses of the free drug did not prolong survival of the tumor-bearing mice. This system may have clinical application not only for MTX, but also other polar anticancer agents in the treatment for central nervous system malignancy.
Cisplatin therapy in recurrent childhood brain tumors.
Twenty-two patients with brain tumors were initially treated with surgery, radiation therapy, and/or adjuvant chemotherapy. Histologic diagnosis included 11 gliomas, seven ependymomas, one dysgerminoma, one teratocarcinoma, one pinealoma, and one small cell tumor. At recurrence, documented on computerized tomographic scan, cisplatin (60 mg/m2/day iv X 2) was given every 3-4 weeks. Seventeen patients received two or more courses and were considered to be evaluable for response. Response parameters included change in the size of tumor on computerized tomographic scan and/or in clinical findings. Four patients had complete response, five had partial response, four had stable disease, and four had disease progression. Toxic effects were manageable. The number of patients with grade 3-4 toxic reactions, by category, were: thrombocytic, ten; leukocytic, four; renal, five; metabolic, four; gastrointestinal, none; and neurologic, seven. Two of the 14 patients tested had grade 3-4 ototoxicity. Acute fluid retention with decreased serum electrolytes and serious but reversible changes in the mental status, which were experienced in earlier patients, decreased in severity with increasing experience of the investigator. In summary, cisplatin appears to be active in a spectrum of brain tumors and should be studied further for therapeutic efficacy.
The treatment of primary childhood acute lymphocytic leukemia with intermediate dose methotrexate.
Fifty-four consecutive children with acute lymphocytic leukemia (ALL) were treated from August 1974 until December of 1976 at Rosewell Park Memorial Institute (RPMI) according to a protocol which substituted cranial irradiation with systemic intermediate dose methotrexate (IDM) 500 mg/m2 each 3 weeks for a total of 3 courses immediately following induction. Of 54 patients, 52 went into remission (96%). There were 35 standard risk and 17 increased risk patients according to age and presenting white blood count (WBC). As of September 1979 9 of the 35 standard risk patients had relapsed: (five central nervous system (CNS), three systemic, and one testicular. The overall disease control is comparable to other published methods of therapy involving cranial irradiation but has the added advantage of not exposing these children to the long range side effects currently being observed in children who had previously been treated with prophylactic cranial irradiation.
Familial erythrophagocytic lymphohistiocytosis: treatment with vinblastine-loaded platelets.
Identical twin Caucasian boys, age 3 months, were seen with fever of unknown origin, hepatosplenomegaly, and pancytopenia. The diagnosis of familial erythrophagocytic lymphohistiocytosis (FEL) was suspected after examination of Twin A's bone marrow and confirmed by an open liver biopsy of Twin B. Twin A died shortly after diagnosis despite treatment with vincristine and prednisone. At autopsy, the diagnosis was confirmed. Twin B responded initially to a three-week course of weekly vincristine and daily prednisone, but symptoms soon recurred. In an effort to enhance delivery of chemotherapy to the active macrophage target, platelets were loaded with vinblastine and then administered intravenously to th patient every 7-10 days. There was an encouraging response reflected by the disappearance of symptoms and the return of peripheral blood count to the normal range, although increased number of histiocytes was still demonstrable in his bone marrow. After nine weeks, he lapsed completely and became refractory to treatment. He died of pseudomonas sepsis four months after diagnosis. This is the first known attempt to deliver a chemotherapeutic agent directly to the macrophages in treating this disease and represents an interesting concept that merits further exploration.
Comparison of three methods of central-nervous-system prophylaxis in childhood acute lymphoblastic leukaemia.
A retrospective comparison was made of three methods of central-nervous-system prophylaxis in childhood acute lymphoblastic leukaemia; (1) intrathecal methotrexate only; (2) intermediate-dose methotrexate infusion and intrathecal methotrexate and, (3) 2400 rads cranial irradiation and intrathecal methotrexate. The incidence of primary meningeal relapse was statistically significantly lower in both standard-risk patients (age grear than 24 months and less than or equal to 120 months white-cell count less than 20,000) and increased-risk patients (age less than or equal to 24 months or greater than 120 months and/or white-cell count greater than 20,000) whose central-nervous-system prophylaxis included cranial irradiation. The disease-free and overall survival of irradiated increased-risk patients was significantly better than that of unirradiated increased-risk patients. The disease-free survival of standard-risk patients who received intermediate-dose methotrexate was statistically superior to that of the remaining standard-risk patients. There were no significant differences in overall survival between the three groups of standard-risk patients.
Computed tomography brain scans in children with acute lymphocytic leukemia receiving methotrexate alone as central nervous system prophylaxis.
Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.
Multimodality therapy for medulloblastoma.
Eight patients with recurrent medulloblastoma were treated with a chemotherapy regimen consisting of vincristine, BCNU, dexamethasone and intrathecal and intermediate dose intravenous methotrexate (500 mg/m2). Five also received local low dose radiotherapy (RT). All 8 patients responded to treatment; 6 completely and 2 partially. These latter 2 were in their second and third recurrences. Three remain in remission. The median duration of response was 18.8 months, and median time from start of chemotherapy to death was 32 months using the Kaplan-Meier technique. In addition, 9 other patients with newly diagnosed medulloblastoma were treated with craniospinal radiation and the same adjuvant chemotherapy as above. The first 5 patients also received intraventricular methotrexate and/or intravenous BCNU during radiotherapy. The toxicity in the 5 patients was very severe. There were three toxic deaths, one death from cancer; one patient survives disease-free, but he is demented. With the discontinuance of intraventricular methotrexate and the postponement of myelo-suppressive chemotherapy until after the completion of radiotherapy, the regimen has been well tolerated. All 4 patients treated this way remain alive, well, and disease-free at intervals up to 36 months. We conclude that recurrent medulloblastomas are sensitive to multiagent chemotherapy and that prolonged remissions may occur. With primary adjuvant chemotherapy, extreme caution with myelo-suppressive drugs must be exercised during the period of craniospinal radiotherapy. We also do not recommend the use of intraventricular methotrexate. When these two criteria were followed, the preliminary results with adjuvant chemotherapy appear encouraging.
Hepatoblastoma in child with fetal alcohol syndrome.
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