Denis R. Miller

The measurement of performance in childhood cancer patients

The performance status of the child with cancer is an important outcome consideration in pediatric oncology research and practice. However, no single measure for children has been available. This is a report of the development and standardization of such a scale. The play—performance scale for children is a parent‐rated instrument which records usual play activity as the index of performance. Performance status ratings were obtained on three groups of children: patients (n = 98), patients siblings (n = 29), and an independent sample of hospital employees children (n = 40). Children with all types and stages of childhood malignant neoplasms were represented. Test results established the parent as a competent, reliable rater and demonstrated the validity of the scale. Interrater reliability was examined using correlational statistics and percentage agreement. Agreement between parents was good, and there were no systematic rater biases. In addition, parents ratings significantly discriminated differences in levels of functioning (mean score, patients 75.4 versus siblings 97.4). Correlational and analysis of variance (ANOVA) procedures demonstrated that the play‐performance scale was significantly related to the global performance measures of experienced clinicians and was sensitive to change. Inpatients received a mean score of 42.3, outpatients 90.7, and normals 98.2. These findings indicate that the scale is both feasible and effective. It is concise, can be administered repeatedly even to extremely ill patients, and uses parents as observer reporters. The play‐performance scale for children provides quantifiable, reproducible, and meaningful data, which is necessary for effective monitoring and management of the child with cancer.

Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen--a new intensive therapy protocol: a report from the Childrens Cancer Study Group.

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.

Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen.

During the period 1976-1981, 3241 children were enrolled on three major studies of acute lymphoblastic leukemia by participating institutions of the Childrens Cancer Study Group. Each study included a different method of central nervous system (CNS) prophylaxis: (1) standard therapy with cranial irradiation, 2400 rads, and intrathecal methotrexate at 12 mg/m2 six times during consolidation (CCG-141); (2) a modification of CCG-141 in which the intrathecal methotrexate was initiated during induction (CCG-141A); and (3) a reduced cranial irradiation dose of 1800 rads with intrathecal methotrexate given at the same frequency as a CCG-141A, with or without maintenance intrathecal methotrexate, but with a dosage regimen derived from CNS volume considerations rather than based on body surface area (CCG-160 series). Strategy 3, a change in the intrathecal methotrexate dosage, has resulted in the lowest incidence of CNS leukemia to date (p less than 0.007). The cumulative 3-yr CNS relapse rate has decreased from 8%-10% to 2%-5% in average-risk patients (p less than 0.02; life table estimate) and from 23%-27% to 6% in high-risk patients (p less than 0.0002; life table estimate), despite a reduction in the cranial irradiation dose from 2400 to 1800 rads. Maintenance intrathecal chemotherapy has had a marginal effect among patients randomized to receive this additional therapy (p = 0.06). The overall outcome has been an increase in the continuous complete remission rate (p = 0.04) but not in the estimated 3-yr continuous hematologic remission or survival rates.

Lymphomatous presentation of childhood acute lymphoblastic leukemia a subgroup at high risk of early treatment failure

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, Erosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/μl, male predominance, and older age. This type of presentation of ALL is referred to as the “lymphoma syndrome” (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E‐rosette‐positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease‐free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Modified BFM therapy for children with previously untreated acute lymphoblastic leukemia and unfavorable prognostic features. Report of Children's Cancer Study Group Study CCG-193P.

The Childrens Cancer Study Groups (CCG) clinical trials in acute lymphoblastic leukemia (ALL) prior to 1981 consistently demonstrated that patients presenting with a white blood cell count (WBC) greater than or equal to 50,000/microliter or the lymphoma syndrome had a less than 40% 3-year event-free survival (EFS). The Berlin Frankfurt Munster (BFM) 76/79 study suggested that the prognosis of these patients could be improved. Before testing this therapy in a randomized setting, 29 CCG institutions used it for treatment of 209 newly diagnosed children with ALL and an initial WBC greater than or equal to 50,000/microliter or the lymphoma syndrome. In the intensive phases of therapy, 77% of cumulative parenteral doses and 55% of cumulative oral doses were within 10% of protocol requirements or were modified appropriately for reported toxicity. One hundred ninety-five patients achieved remission (93.3%). Eleven patients died in remission (5.6%)--10 during the intensive reinduction/reconsolidation phase. The 4-year EFS (+/- 1 SD) was 62% (+/- 3.7%) with a median follow-up of 40 months. Only one patient has had an isolated CNS relapse. These results appear superior to past CCG studies for high-risk patients and extend observations made from studies of similar therapy.

Influenza immunization of children with neoplastic diseases.

During the National Influenza Immunization Program in 1976, 147 children with neoplastic diseases received Wyeth split‐product bivalent influenza vaccine: A/New Jersey/8/76 (Hsw1N1), A/Victoria/3/75 (H3N2). Thirteen normal siblings served as controls. Seventy‐one patients received two doses of the vaccine four weeks apart. After the second injection of A/NJ/8/76, there was a difference between the response of the patients on chemotherapy and those off therapy ⩾30 days—38% vs. 76%, P < 0.01 for four‐fold rise and 26% vs. 57%, P < 0.05 for the attainment of protective (⩾32) hemagglutination inhibition (HI) titers. These differences were observed in both leukemia‐lymphoma and solid tumor patients. There was a difference in HI titers to A/Vic/75 between patients on and off chemotherapy after a single injection, 34% vs. 71%, P < 0.001 for a four‐fold rise. After the second immunization, only 52% on, and 86% off therapy (P < 0.05) had a four‐fold rise in titers. Thirty‐two percent of the patients on treatment who achieved “protective” titers did so only after the second immunization. Immunoglobulin levels and neutropenia did not correlate with the inability to obtain a four‐fold rise in titers. Our findings suggest that patients on chemotherapy cannot be effectively vaccinated by a new antigen, and that single yearly boosters may be insufficient for recall of old antigens. Patients off chemotherapy ⩾30 days respond as normal controls. Cancer 45:750‐756, 1980.

Three Versus Five Years of Maintenance Therapy Are Equivalent in Childhood Acute Lymphoblastic Leukemia: A Report From the Childrens Cancer Study Group

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.

The prognostic value of testicular biopsy in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

One of the objectives of Childrens Cancer Study Group (CCSG) study 141 (CCG-141) was to determine the frequency of occult testicular leukemia (TL) after 3 years of disease-free survival (DFS) and to retreat boys with occult TL to prolong their subsequent DFS. Of the 494 boys entered on study, 255 (51.6%) were in complete continuous remission (CCR) 3 years after entering remission and an additional eight were in CCR 3 years after localized extramedullary relapse and retreatment; 263 boys were eligible for testicular biopsy. Elective testicular biopsy was performed on 235 (89.4%) boys. Of the 204 (86.8%) boys with negative biopsies, 175 (85.8%) remained in CCR 10 to 12 years after diagnosis and 25 (12.3%) relapsed, 11 (44%) of whom died. Isolated overt TL occurred in four (2.0%) and all remained in CCR 22+ to 60+ months after re-treatment. Of the 26 boys with occult TL, 16 (62%) remained in CCR. Ten (38%) relapsed despite local testicular irradiation and systemic re-treatment; six of the 10 died. Of the 26 boys who did not undergo biopsy, 21 (80.8%) remained in CCR; two (7.7%) developed isolated overt TL. DFS after testicular biopsy was significantly better in boys without occult TL (P = .001). Occult TL after 3 years of CCR represents aggressive minimal-residual disease and carries a worse prognosis than absence of TL. Initial treatment should be directed at obviating occult and overt testicular relapse. Conventional therapy as used in this study was suboptimal in preventing subsequent bone marrow (BM) relapse and death. If occult TR is identified during or at the end of planned therapy, a higher salvage rate may require intensified alternate therapy. As such, testicular biopsies may be clinically useful. Further investigation is limited by the relative rarity of, and the lack of identifying features in boys with occult TL.

Hepatocellular carcinoma, transfusion-induced hemochromatosis and congenital hypoplastic anemia (Blackfan-Diamond syndrome)

A 25 year old patient with congenital hypoplastic anemia (Black-fan-Diamond syndrome) is described. This patient was hepatitis-antigen negative, had not received androgens and had a hepatoma develop in a transfusional hemochromatotic liver. Since androgens have been associated with hepatocellular carcinoma, the use of androgenic steroids for other than life-threatening symptoms in this disease should be avoided.