Charlotte Tan

Adriamycin—an antitumor antibiotic in the treatment of neoplastic diseases

Adriamycin was given to 234 patients with leukemia and other types of neoplastic diseases. In children with acute leukemia previously treated, adriamycin produced complete remissions (12%) and good partial remissions (26%). Tumor regressions were seen in 60% of the patients with solid tumors. These included lymphoma, embryonal rhabdomyosarcoma, neuroblastoma, Ewings sarcoma, Wilms tumor, ovarian tumor, hepatoma, embryonal carcinoma, malignant teratoma, and retinoblastoma. The therapeutic responses in adults have been less consistent and were confined to lymphomas and soft tissue sarcomas. The dose in children was 0.5 mg/kg daily to a total of 2‐4 mg/kg per course. In adults, the single dose was 0.4 mg/kg to a total of about 2.5 mg/kg in 10 days. Adriamycin at half the dose of daunomycin produced comparable toxicities, except for earlier and more frequent oral ulcers and alopecia. Varying degrees of transient electrocardiographic changes have been seen in children. Adriamycin may have contributed to cardiac failure and death in one child, who had recurrent pulmonary metastases.

Carboplatin and recurrent childhood brain tumors.

Carboplatin, a cisplatin analogue, was administered as an intravenous (IV) one-hour infusion in a 4-consecutive weekly dose schedule to 44 patients with recurrent childhood brain tumors. Twenty-four patients were registered on our phase I, and 20 on our phase II studies. The maximum tolerable dose derived from our phase I study was 210 mg/m2/wk in patients with solid tumors, and the recommended dose for subsequent pediatric phase II studies was 175 mg/m2/wk. This dose was administered to 14 patients in the phase I and all 20 patients in the phase II study. Nine of 36 (25%) evaluable patients in the combined studies experienced objective responses for a median duration of 10+ months. Seven of nine responders had received prior cisplatin. Disease-specific response rates were as follows: medulloblastoma, six of 14 (43%) with three complete (CR) and three partial responses (PR); pineoblastoma, one of one (PR); germinoma, one of two (CR); and brainstem glioma, one of eight (13%) (PR). Carboplatin had mild emetic effects but no significant auditory or renal toxicity. Thrombocytopenia (less than 49,000) was encountered in nine of 28 (32%) evaluable trials at a dose of 175 mg/m2/wk. Because of its low potential for auditory, renal, and emetic toxicity, ease of administration, and high disease-specific activity, carboplatin deserves further study in multiagent phase II and III trials, especially in chemotherapy-sensitive diseases such as medulloblastoma.

The cardiotoxicity of adriamycin and daunomycin in children.

Eight (16%) of 50 children receiving adriamycin and 2 (3%) of 60 receiving daunomycin had severe cardiomyopathy with congestive heart failure. All 110 patients received cumulative doses of over 500 mg/m2. The incidence was significantly higher in those who also had incidental cardiac radiation. The electrocardiogram, with few exceptions, provided the first indication of cardiac abnormality. There were no deaths from heart failure. Two had thromboembolic episodes. Recommendations are discussed.

The rationale for multiple drug chemotherapy in the treatment of osteogenic sarcoma

Based on our prior experience in treating children with metastatic osteogenic sarcoma, a multidrug regimen was developed. Nine children with evaluable osteogenic sarcoma were treated with vincristine 1.5 mg/m2 on day 1, high‐dose methotrexate 200‐300 mg/kg i.v. on day 2, with p.o. citrovorum factor “rescue” 9 mg every 6 hours × 12, followed in 2 weeks by cyclophosphamide 40 mg/kg i.v., then 2 weeks later Adriamycin 1.5 mg/kg/day × 2; in 2 weeks cyclophosphamide was repeated. After a 2‐week rest, the 56‐day cycle was repeated for a total period of 1 year. Oropharyngeal mucositis was the most frequent severe manifestation of gastrointestinal toxicity. Hematologic depression was mild to severe. Nine patients with clinically evaluable osteogenic sarcoma and no previous chemotherapeutic treatment were treated with this regimen. One patient had only a transient shrinkage in tumor mass, and one patient had no progression of multiple pulmonary and bone metastases for 16 months while on therapy. Of the remaining seven patients, all had clinically significant responses with tumor regression demonstrated for from 5 to 20+ months. Four of these patients (three presenting with primary tumor and pulmonary metastases) demonstrated regression of their primary tumor. In an attempt to increase the cure rate in osteogenic sarcoma, chemotherapy that has proven to be effective against metastatic osteogenic sarcoma should now be employed as prophylactic therapy, after amputation, at cancer treatment centers where it can be safely and effectively administered.

A long-term clinical follow-up of children with acute lymphoblastic leukemia treated with intensive chemotherapy regimens

One hundred and thirty‐three children 15 years old and younger with acute lymphoblastic leukemia were treated with two different protocols. Both regimens consist of a multi‐drug program, without CNS irradiation, administered for three years. Seventy‐five children were enrolled on the first protocol, L‐2; and 58 were treated on the subsequent regimen, L‐10. Of the 70 evaluable patients on the L‐2 program, 40 continue in complete remission from 72–111 months. Seventy‐four percent of the children qualified for treatment cessation, and 59% have remained in continuous remission for six years. The estimated seven year disease‐free survival for the 70 evaluable children on the L‐2 protocol is 57% and for all entries is 53%. Of the 57 evaluable patients on the L‐10 program, 35 are in complete remission from 15–67 months. The combined frequency of primary CNS leukemia for the two regimens is 7%. The off‐therapy results of the L‐2 protocol cannot be compared to the L‐10 at present, but the on‐therapy outcomes, despite the modifications that were designed to improve the L‐10 regimen, are comparable.

Gonadal function in young patients successfully treated for Hodgkin disease

BACKGROUNDnGonadal function in pediatric and young adult survivors of Hodgkin disease is not very well defined. This study evaluates the outcome following the Multiple Drug Protocol (MDP) and the results are compared to the published experience.nnnPROCEDUREnOvarian and testicular function was assessed in 65 patients (36 males) with Hodgkin disease in first or second complete remission after treatment with either radiation (RT, n = 13), chemotherapy (CT, n = 9), or both (n = 43). Chemotherapy consisted of six cycles of the MDP (doxorubicin, procarbazine, prednisone, vincristine, and cyclophosphamide). Median age at diagnosis was 13.1 years (range, 2.4-22.6) and median age at evaluation was 22.6 years (range, 15.1-33.7), which was 6.7 years (range, 2.0-19.8) after the completion of all treatments. For the purpose of analysis, patients were divided into three groups: group A, patients who received only RT that did not include the pelvis (8 females, 5 males); group B, patients who received CT but no pelvic RT (15 females, 25 males); and group C, patients who received CT plus pelvic RT (6 females, 6 males).nnnRESULTSnAll patients progressed spontaneously through puberty and evaluable patients were found to be sexually mature (Tanner stage IV and V). Serum follicle stimulating hormone (FSH) was increased in 0/5, 13/25, and 5/6 and testicular volume was decreased in 1/3, 4/11, and 2/3 group A, B, and C male patients, respectively. Leydig cell dysfunction was uncommon; 91% and 88% of males had normal serum concentrations of luteinizing hormone (LH) and testosterone, respectively. FSH and LH were increased in 0/8, 3/15, and 2/6 group A, B, and C female patients, respectively, at last follow-up, indicating a 17% prevalence of ovarian dysfunction. Serial data in seven females whose initial levels of FSH/LH were elevated revealed normalization in four. Six females delivered eight normal children.nnnCONCLUSIONSnThe majority of males who received CT +/- RT have evidence of germ cell dysfunction, while Leydig cell function is unaffected in most. In females, although abnormal function early after the end of treatment was observed, ovarian function remained or returned to normal in most young women. Thus, in females the results of hormone testing performed early after treatment may not be predictive of their eventual reproductive potential.

Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia

The basis of intrinsic resistance of blasts from patients with acute non-lymphocytic leukemia (ANLL) to methotrexate was studied. MTX polyglutamate formation was measured in blast cells from 19 patients with ANLL and in 7 pediatric patients with acute lymphocytic leukemia (ALL), after in vitro incubation for 24 h with 3H-methotrexate. There was no significant differences seen in the total amount of MTX plus polyglutamates measured between ANLL and ALL blasts, indicating that transport defects do not account for intrinsic MTX resistance in ANLL. However, there were significant differences between the amounts of long chain MTX polyglutamates found in ANLL cells as compared to ALL cells. Most, but not all, ANLL blasts were unable to form long chain polyglutamates. In as much as the level of MTX polyglutamates found in blast cells after MTX administration allows for retention of this drug, this property may explain, at least in part, the refractoriness of most patients with ANLL to methotrexate.

Second malignancies after childhood Hodgkin's disease: the memorial Sloan-Kettering cancer center experience

A review of the Memorial Sloan‐Kettering Cancer Center experience with second malignancies (SM) after childhood Hodgkins Disease (HD) identified 17 SM in 320 patients who survived more than 1 year from, and were 15 years old or younger at the time of, HD diagnosis (1949 to 1983). Of 254 previously untreated patients, 12 SM were noticed as compared with 0.606 expected on the basis of rates in the general pediatric population (relative risk, 19.8; 95% confidence interval, 10.2 to 34.6). For patients who received multi‐agent chemotherapy, the cumulative probability of developing acute nonlymphocytic leukemia (ANLL) or bone sarcoma was 6.2% and 5.5%, respectively, at 10 years from the initiation of therapy; the cumulative risk of all SM in this group reached 18.7% at 15 years. For patients who received radiation alone or with single‐agent chemotherapy, the cumulative risk of SM rose from 0% at 10 years and 2% at 15 years, to 10.7% at 25 years from the initiation of treatment. The risk of ANLL after childhood HD was highest in the first 5 to 10 years after combined modality treatment, and aggressive forms of NHL associated with excessive immunosuppression. Bone sarcomas predominated in solid SM in the first decade after HD treatment, whereas “adult‐type” cancers, for example, breast and colon carcinomas, were more delayed. Our findings, supported by a literature review, point to a therapy‐related enhanced risk of approximately age‐appropriate solid SM. This possibility mandates careful surveillance of long‐term survivors of childhood HD.

Alterations in Self-Perceptions Among Adolescent Cancer Survivors

Psychosocial adjustment in adolescent cancer survivors has been documented to be quite variable. Factors mediating adjustment need to be identified. The current study is an exploration of the impact that cancer diagnosis and treatment has on adolescents self-perceptions and the role this has in mediating adjustment in this group. Fifty-eight adolescent survivors of hematologic malignancies were interviewed about alterations in self-perceptions related to their cancer experience and completed a cancer-specific social problem-solving task. Initial findings suggest that cancer universally alters the way adolescent survivors view themselves, but that the alteration can be both positive or negative depending on the meaning ascribed to it.

The changing management of childhood Hodgkin's disease.

Between 1929 and September 1974,211 children under 15 years of age with biopsy‐proven Hodgkins disease were treated at Memorial Sloan‐Kettering Cancer Center. For analysis these patients were placed into three historical groups which displayed the most marked changes in diagnostic workup and therapy. They are as follows: Pre‐1959—80 patients with “clinical” staging, local field radiation therapy, palliative chemotherapy; 1960–1969—86 patients with lymphangiographic staging, extended field radiation therapy, palliative chemotherapy; 1970‐September 1974—45 patients with “contemporary” staging, including laparotomy, involved field radiation therapy, and/or multiple drug chemotherapy. Twenty‐seven children with Stage IV disease at diagnosis or those with recurrent disease received this multiple drug regimen. This consisted of Adriamycin, followed by combined prednisone, procarbazine, and vincristine, then cyclophosphamide. Drug cycles were repeated every 3–4 months for a period of about 24 months. Twenty‐five achieved remission, 20 complete and 5 partial. The median duration of complete remission was 18+ months. This multidisciplinary management of Hodgkins disease has shown early, encouraging results. Longer followup is needed to determine that this improvement in survival will persist into adulthood.