Chemotherapy-induced histologic changes in Wilms' tumors.

The nephrectomy specimens of 21 patients with Wilms' tumor who received preoperative chemotherapy consisting of vincristine and actinomycin D, alone or in combination, were studied pathologically; 1 patient also received radiation therapy. Pathological material from 20 randomly selected patients with Wilms' tumor who did not receive preoperative chemotherapy was reviewed and used as a control. Twenty tumors were of favorable histology, and one was unfavorable; all control tumors were of favorable histology. The histological changes were diffuse. The most marked changes occurred in the undifferentiated stroma of 18 tumors: the stroma was edematous; had a fibrovascular background, granulation tissue, and histiocytes; and lacked atypical cells. The blastematous nodules were reduced in size and necrotic or undergoing necrosis in 5 cases. Differentiated elements, including glomeruloid, tubular, and rhabdomyoblastic components, were unaffected. Vascular changes, consisting of fibrinoid necrosis, thrombosis, and acute inflammation were prominent in 15 instances. Two tumors of favorable histology, including one that was a rhabdomyomatous Wilms' tumor, and the tumor of unfavorable histology were unchanged by the therapy. In contrast, the histological changes present in only 4 of the control group, while similar, were rather minimal and focal. This evaluation helps to define the susceptibility of the different elements in Wilms' tumor to chemotherapy.

Renal cell carcinoma in children.

Data from four pediatric hospitals concerning 20 children treated for renal cell carcinoma (RCC) from 1964-1978 were reviewed. Median age of the patients (pts) was 11.8 years (range, 14 months-19 years). Twelve were male and eight female; 17 were white and three black. Most patients presented with pain and hematuria with or without a palpable mass. An intrarenal tumor was detected at IV urography (17 pts), arteriography (2 pts), or at surgery (1 pt). Treatment consisted of nephrectomy in 15 pts, renal biopsy (4 pts), or no surgery (1 pt), followed by chemotherapy (5 pts), radiation therapy (1 pt), or both (7 pts). Ten pts died of distant metastases at a median of one year (range, 0.2 to two years) after diagnosis. The other 10 pts (50%) survive free of relapse at a median of 4 years (range, two to ten years) from diagnosis. Proportions surviving free of recurrent disease two or more years by National Wilms' Tumor Study (NWTS) Group were 5/5 in Group I, 3/7 in Group II, 1/3 in Group III, and 1/5 in Group IV; by age at diagnosis, 6/6 in those under 11 years old and 4/14 in those 11 or older; and by type of surgery, 10/15 who had nephrectomy and 0/5 with limited or no surgery. The data indicate that radiation and chemotherapy had only minor if any influences on relapse-free survival. We conclude that (1) RCC in children is similar to its counterpart in adults; (2) RCC has a worse prognosis than Wilms' tumor except for the earliest stage; (3) nephrectomy alone is adequate treatment for Group I RCC, and (4) young age (less than 11 years old) may be prognostically favorable.

[Experimental study on pharmacokinetics of methotrexate and its metabolite (7-hydroxy-methotrexate) in tissue].

The metabolism of methotrexate was investigated in rabbits with six hours infusion of (3'5'7-3H) methotrexate (50mg/kg). Methotrexate and its metabolites were analyzed by reverse-phase high-pressure liquid chromatography and by counting of radioactivity. 7-Hydroxymethotrexate was found to be the major metabolite in the plasma, urine, bile and tissues of rabbits. Cumulative production of 7-Hydroxymethotrexate during the first six hours was 31.8% of the total dose. The 7-Hydroxymethotrexate concentration in plasma was reached to peak level in six hours after the initiation of the infusion, and was declined slower than that of methotrexate. The highest total radioactivity was found in the kidney after six hours, which was 7.24 times higher than that in plasma. Ratio of 7-Hydroxymethotrexate/methotrexate increased in the liver, small intestine, lung, kidney and testis. This data suggested that conversion of methotrexate to 7-hydroxymethotrexate took place in lung and kidney as well as in liver.

Prognosis in children with Wilms' tumor metastases prior to or following primary treatment: results from the first National Wilms' Tumor Study (NWTS-1).

Survival data from the first National Wilms' Tumor Study were analyzed on 101 patients who relapsed after primary therapy (group I-III) and on 82 patients who presented initially with metastases (group IV). The group I patients had significantly better 3-year survival rates than group II/III patients (64% vs 37%). Histology, relapse site, and time to relapse all showed strong independent effects on survival even in the presence of other variables. The survival curves were significantly better for patients with favorable histology, extraabdominal metastases, and late metastases. The overall survival (longer than 3 years) was 46% of group I-III patients who relapsed and 56% of group IV patients.

Three-year relapse-free survival rates in childhood rhabdomyosarcoma of the head and neck: report from the Intergroup Rhabdomyosarcoma Study.

In 202 patients with rhabdomyosarcoma of the head and neck who registered in the first Intergroup Rhabdomyosarcoma Study, the primary lesions arose about the eye and orbit in 26%, in parameningeal sites in 46%, and in other head and neck areas in 28%. Histopathologically, 78% were embryonal-botryoid, 9% alveolar, 10% undifferentiated, and 3% extraosseous Ewing's types. Actual three-year relapse-free survival rates were calculated from data on 103 of these patients who were free of distant metastases at diagnosis and in whom follow-up had been completed for a three-year period. The actual relapse-free survival rates were 91% (21/23) for those with eye/orbit primaries, 46% (20/44) for those with parameningeal primaries, and 75% (27/36) for those with other head and neck sites affected. Among those with no clinical evidence of tumor activity at two years, 8% (6/75) had subsequent relapses.

Preoperative chemotherapy for Wilms tumor.

Preoperative chemotherapy was administered to 19 children with Wilms tumor judged clinically to be unresectable at M. D. Anderson Hospital between January 1, 1962, and September 1, 1980. After 2 to 4 doses of vincristine, marked reduction in tumor size occurred in 16 patients. After chemotherapy 16 tumors could be resected completely, another required irradiation to reduce the tumor, and only 2 tumors could not be excised. Pathologically the most dramatic changes occurred in the undifferentiated interstitial stroma, followed next by changes in the nodular blastema. Differentiated elements were apparently not affected. No serious complications were attributed to the preoperative drug treatment. This experience suggests that in selected instances preoperative chemotherapy can affectively facilitate the therapy of Wilms tumor.

Special considerations related to primary site in rhabdomyosarcoma: experience of the Intergroup Rhabdomyosarcoma Study, 1972--76.

Rhabdomyosarcomas (RMS) arising in the head and neck region, retroperitoneum, and perineum were considered together here because the usual surgical approach is incisional biopsy. Thus successful treatment of these neoplasms depends on effective radiation therapy and chemotherapy. From November 1972 through December 1976 the Intergroup Rhabdomyosarcoma Study accrued 127 patients with primary tumors in the head and neck, 34 with orbital tumors, 24 with sarcomas arising in the retroperitoneum-pelvis (no genitourinary), and 11 with perineal lesions. Results of treatment varied among these primary sites. Patients with orbital RMS had the best prognoses; 77% of them were free of disease, compared with a 51% disease-free rate in patients with nonorbital head and neck RMS. In this latter group, disease recurrence was evenly divided among local failure, distant metastases, and direct meningeal extension. Prognoses were similar for retroperitoneal tumors; 46% of such patients are currently free of disease. That the perineum was a rare site for RMS was fortunate because only 3 of 11 such patients (27%) are free of detectable disease now (January 1979). We concluded that the site of the primary tumor is an important prognostic variable in children with RMS.

Prognostic factors in children with rhabdomyosarcoma.

The characteristics of 554 evaluated patients entered into a clinical trial conducted by the Pediatric Intergroup Rhabdomyosarcoma Committee between November 1972 and September 1978 were examined for their relationship to prognosis. Prognosis was defined as disease-free time and overall survival time in clinical groups I and II and time on study and survival time in clinical groups III and IV; all times were measured from the start of treatment. The percentage of patients surviving 2 years differed significantly among the clinical groups: I, 92; II, 78; III, 64; and IV, 35. The percentage of patients free of disease at 2 years was significantly higher in group I than in group II (83 vs. 72%, respectively); P = 0.02. The patient characteristics of group I most related to disease-free and overall survival were histologic cell type (alveolar, unfavorable), lymphocyte count (low count, unfavorable), and primary site (disease in extremities, unfavorable). In group II, sex (male, favorable) and lymphocyte count (low count, unfavorable) were significantly related to disease-free and overall survival times. Patients in the clinical subgroup with both microscopic residual disease and lymph node metastasis had poorer survival than patients in other subgroups. Primary site of disease was the only characteristic of group III related to length of time on study and to survival. Orbit and the genitourinary system were favorable primary sites, whereas the retroperitoneal area and extremities were unfavorable. In group IV, primary site (genitourinary, favorable) was related to length of time on study and survival. Sex (male, favorable) was related to survival experience.

Survival after metastasis in osteosarcoma.

We analyzed survival patterns of 106 patients with metastatic osteosarcoma treated at the M. D. Anderson Hospital from 1954 to 1975. All were 20 years of age or less, had a confirmed diagnosis of medullary osteosarcoma (excluding mandibular and radiogenic osteosarcoma), and had developed evidence of metastasis at diagnosis or during treatment. Clinical characteristics evaluated statistically as possible prognostic factors in postmetastatic survival were: age at diagnosis, sex, race, site or primary, site of first metastasis, year of diagnosis, and time from diagnosis to metastasis. Two factors, year of diagnosis and time to metastasis, showed statistically significant association with postmetastastic survival. Those patients treated in 1971 or later (62) had significantly longer postmetastatic survival times than those (44) treated in 1970 or earlier (P = 0.002). Also, 14 patients who developed metastasis 1 year or more after diagnosis had significantly longer postmetastatic survival times than the 19 with metastasis at diagnosis (P = 0.002) or the 73 who developed metastasis during the 1st year after diagnosis (P = 0.005). Analysis also indicated a statistically significant interaction effect between the two factors (P = 0.093) that suggested the time to metastasis had a greater influence on postmetastatic survival time in those diagnosed in 1971 or later than in those diagnosed earlier.

Multidrug chemotherapy in osteosarcoma.

A review of the steps by which the current adjuvant chemotherapy programs for osteosarcoma (COMPADRI-V) evolved over the past 19 years indicates that among the important concepts incorporated into the program are demonstration of antitumor activity of each component, adequate evaluation of patient tolerance of the treatment regimen, progressive improvement in documented treatment results, and concomitant utilization of pharmacokinetic information. The current program utilizes intensified high-dose methotrexate and Adriamycin courses and preoperative chemotherapy. The regimen has permitted ready amalgamation of limb-salvage programs. The success of these approaches is emphasized by the overall survival rate of 79% at three years for the patients with osteosarcoma treated at M. D. Anderson Hospital.

Radiation to regional nodes for rhabdomyosarcoma of the genitourinary tract in children: is it necessary? A report from the Intergroup Rhabdomyosarcoma Study No. 1 (IRS-1).

Fifty-eight children with genitourinary rhabdomyosarcoma are reported. Lesions involved the bladder (22), prostate (14), vagina/uterus (6), and paratesticular tissues (16). Fifteen of 58 had positive sampling of regional lymph nodes. Eleven of 15 received radiation to no more than 4500 rad in most cases, and 9 of 11 are diseases free. Two of 15 had no radiation and are disease free also. Twenty-three of 58 had negative nodes. Six of 23 had radiation to these nodal areas and 4 of 6 are disease free. Fifteen of 17 patients had no radiation and are disease free also. Sixteen of 20 patients with no node sampling are disease free; 9 of 16 had radiation but 7 of 16 did not. All patients in the Study had intensive systemic maintenance chemotherapy. One 1 patient failed in regional nodes despite 4500 rad to these node echelons. We suggest chemotherapy and radiotherapy, not to exceed 3500 rad in four weeks, to known residual disease including regions from which positive nodes have been obtained.

Plasma methotrexate as determined by liquid chromatography, enzyme-inhibition assay, and radioimmunoassay after high-dose infusion.

Three techniques for measuring methotrexate show various cross reactivities with methotrexate-related compounds: "high-pressure" liquid chromatography, by principle, is virtually specific for methotrexate; the enzyme-inhibition assay quantitates methotrexate, methotrexate diglutamate, and methotrexate triglutamate equally well, but has a 10% cross reactivity with 4-amino-4-deoxy-N10-methylpteroic acid and 1% with 7-hydroxymethotrexate; radioimmunoassay shows an equal cross reactivity with methotrexate, 4-amino-4-deoxy-N10-methylpteroic acid, methotrexate diglutamate and triglutamate, and a 5 to 10% cross reactivity with 7-hydroxymethotrexate. Radioimmunoassay almost always yielded the highest values for methotrexate, followed by enzyme-inhibition assay then liquid chromatography. The presence of two methotrexate-related compounds, 7-hydroxymethotrexate and 4-amino-4-deoxy-N10-methylpteroic acid, was confirmed in human urine samples and quantitated in patients' plasma by liquid chromatography, the respective maximum plasma concentrations being 250 and 16 mumol/L. Materials cross reacting with methotrexate in radioimmunoassay of chromatographic fractions from plasma were also noted in fractions corresponding to methotrexate diglutamate and triglutamate peaks, in quantities estimated to be 47 and 30 nmol/L methotrexate equivalents, respectively. 7-Hydroxymethotrexate is eliminated more slowly than methotrexate and its production increases with dosages of methotrexate.

Adjuvant chemotherapy in nonmetastatic osteosarcoma: a Southwest Oncology Group Study.

This report updates experience with the CONPADRI-I, COMPADRI-II, and COMPADRI-III adjuvant chemotherapy programs for the treatment of nonmetastatic osteosarcoma. A total of 200 patients received one of the three regimens. The analysis of response to treatment is based on disease-free survival time (DFS time). The effect of treatment, age, sex, site of disease involvement, and race on DFS time were investigated. Cox's life-table regression analysis found only sex to have a significant effect on DFS time with males having 1.8 times the risk of recurrence or death per unit time as female patients (P = 0.004). An analysis of the 81 patients still alive and disease-free 18 months after the start of treatment shows significantly longer DFS time for CONPADRI-I than COMPADRI-II patients (P = 0.01). This trend is true for both male (P = 0.12) and female (P = 0.08) patients.

Risk of radiation-related subsequent malignant tumors in survivors of Ewing's sarcoma.

Twenty-four long-term survivors of Ewing's sarcoma were identified as being at risk for a second primary tumor. Among this group of patients followed from 3 to 22 years, 4 new bone tumors were observed, whereas 1.2 x 10(-3) were expected. All new tumors arose in heavily irradiated areas. The risk associated with radiation after 3 years was 7.2 cases/million person-years per rad. The cumulative cancer risk over 10 years for irradiated patients was 35% (SE, 15.1%). Intensive chemotherapy (cyclophosphamide and vincristine administered in five or more courses) seemed to exert an enhancing effect, increasing the rate of development of new tumors.

Parameningeal rhabdomyosarcoma.

The records of 27 patients with rhabdomyosarcoma involving the parameningeal area (nasopharynx, paranasal sinus, and middle ear) treated from 1961 to 1976 were reviewed. Due to the location of the primary tumor, radiation and chemotherapy were used but surgery was limited to simple biopsy. In the literature, spread of tumor from these primary sites to the meninges has been as high as 26-35%. In this series, meningeal disease developed in only 2 of the 27 patients (7%).

Management and results of localized Ewing's sarcoma.

Seventy-six patients with localized Ewing's sarcoma who received primary treatment at M.D. Anderson Hospital from 1948 through December 1975 were reviewed. Patients have been divided into four groups according to the different treatment regimens they received: Group I, moderate dose radiotherapy alone; Group II, high dose radiotherapy alone; Group III, radiotherapy plus vincristine and cytoxan; and Group IV, radiotherapy plus vincristine, Adriamycin, cytoxan and actinomycin. The problem of local recurrence appears to be solved with combined chemotherapy and radiation therapy with only one of 36 patients having a recurrence at the primary site in Groups III and IV. Multimodal therapy is the preferred treatment to obtain control of the primary lesion by radiation therapy while preserving good function. However, the major cause of failure remains distant metastases, 19 of 36 (53%) in Groups III and IV. In addition, 4 of 10 patients who have survived over 5 years have developed osteogenic sarcoma.

Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma.

Plasma methotrexate (MTX) concentrations were determined in 52 patients after 409 infusions of high-dose (HD) (50-250 mg/kg) MTX with citrovorum factor (CF) rescue. In addition, detailed pharmacokinetic studies were conducted in nine of these patients. Plasma drug levels were compared at 6, 24, 48, and 72 hours from the start of MTX infusions in four different age groups (less than or equal to 10, 11-14, 15-17, and greater than or equal to 18 years of age). At the same drug dose, the younger patients had lower plasma MTX levels than the older patients at 6 and 24 hours. This difference increased in significance with increasing MTX dose. However, MTX plasma levels became similar at 48 and 72 hours, regardless of age. The half-life for the first phase of biphasic MTX clearance in children was shorter than that in adults. In addition, the urinary excretion of MTX was faster in younger children at all doses. The younger patients had a greater apparent volume of distribution of MTX after HD infusion. These results indicate that the age-dependent pharmacokinetics can be attributed to greater distribution and elimination of MTX in the younger patients. The potential difference in the metabolism of MTX between children and adults is currently under investigation. Our observations suggest that age exerts a dominant effect on the pharmacokinetics of HD-MTX.

Evaluation of overall toxicity of high-dosage methotrexate regimens.

The occurrence of overall toxicity was analyzed for 43 patients with osteosarcoma who received 349 high-dosage courses of methotrexate (HD-MTX) with citrovorum factor (Leukovorin) "rescue" (CF). The dosages of HD-MTX ranged from 50 to 350 mg/kg. Overall toxicity was assessed on the basis of five manifestations of toxicity: stomatitis, dermatitis, myelosuppression, liver dysfunction, and kidney function abnormalities. The great majority (91.4%) of the infusions were well tolerated, but 8.6% were associated with moderate or severe toxicity. Stomatitis and serum glutamic-oxaloacetic transaminase (SGOT) changes were the most frequent postinfusion findings. Three patients died from causes related to MTX toxicity. Dose, age, sex, and number of prior infusions were investigated by logistic regression analysis for prognostic effect on frequency of moderate to severe overall toxicity. Age and number of prior infusions had significant (P less than 0.06) effects on overall toxicity. Patients older than 15 years with greater than 10 prior infusions constituted the "high risk" group with a risk of moderate to severe toxicity 6.3 times that of the younger patients with fewer than 10 infusions.