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Background The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. Methods This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803. Results For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively). Conclusions Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.

Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/mTherapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/mAmong 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02).The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.

BACKGROUND The purpose of the study was to determine the activity and toxicity of pulse dactinomycin as salvage treatment of patients with low-risk gestational trophoblastic neoplasia (GTN) who failed methotrexate therapy. METHODS Eligible patients had persistent/recurrent low-risk GTN defined by changes in serum human chorionic gonadotropin (hCG) levels ( 20% rise over the previous value, or a rise after attaining institutional normal [>5 mu/mL]); World Health Organization (WHO) score 2–6; Gynecologic Oncology Group (GOG) performance status 0–1; and previous treatment restricted to methotrexate. Dactinomycin administration was 1.25 mg/m2 intravenous (i.v.) every 2 weeks until documented complete response (CR) or treatment failure. CR was defined as an institutional normal serum hCG level sustained for ≥4 consecutive weeks; treatment failure was a 20% rise (over previous value) in hCG serum level. Levels were monitored biweekly × 8 weeks beyond the first normal value, then monthly × 10. RESULTS Five of 44 enrolled patients were ineligible due to choriocarcinoma and normal pretreatment serum hCG level (2 each), no history of methotrexate (1), and 1 patient with documented phantom hCG syndrome was unevaluable. In all, 28 of 38 (74%) evaluable patients attained CR. The median number of cycles was 4 (range, 2–10). Severe toxicity was minimal, causing no patient to discontinue therapy. All treatment failures achieved a CR after receiving subsequent chemotherapy; 3 patients also underwent hysterectomy. CONCLUSION Pulse dactinomycin is an active regimen for patients withlow-risk GTN who fail previous methotrexate therapy. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND It is believed that midkine (MK), a heparin-binding growth factor, plays an important role in carcinogenesis. However, the biologic mechanism of MK in hepatocellular carcinoma has not been clarified to date. The objective of the current study was to investigate the antiapoptotic role of MK in a human hepatoma cell line. METHODS The human hepatoma cell line HepG2 was used to study the antiapoptotic effect of MK. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)/actinomycin D (ActD)–induced apoptosis was detected using a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphophenyl)-2H-tetrazolium monosodium salt (WST-8) assay, a caspase-3 activity assay, a caspase-8 activity assay, and flow cytometric analysis. RESULTS TRAIL had a potent, dose-dependent inductive effect on cell death in HepG2 cells, for which viable cell counts decreased to 6.3% of the control count at a TRAIL concentration of 100 ng/mL in the presence of 500 ng/mL ActD. Flow cytometry was used to demonstrate that apoptosis induced by TRAIL/ActD was in fact the cause of cell death. According to the WST-8 assay, MK pretreatment resulted in the suppression of TRAIL/ActD-mediated apoptosis in HepG2 cells, although cell viability did not increase when HepG2 cells were treated with MK alone. Caspase-3 activity was down-regulated when MK was added, but caspase-8 activity was high in both the absence and presence of MK. CONCLUSIONS The results of the current study indicate that MK acts as an antiapoptotic factor in HepG2 cells through the down-regulation of caspase-3 activity. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND The objective of this study was to evaluate the efficacy and toxicity of a high-dose 5-fluorouracil and actinomycin D regimen (the FA regimen) as salvage chemotherapy for patients with high-risk gestational trophoblastic tumors (GTTs). METHODS From 1985 to 1997, 10 patients with refractory, high-risk GTTs were treated with the FA regimen at Chiba University Hospital. Of those 10 patients, 7 patients developed drug resistance to methotrexate, etoposide, and actinomycin D combination chemotherapy (the MEA regimen); 1 patient developed recurrent disease after receiving the MEA regimen; and 2 patients developed recurrent disease after receiving combination chemotherapy with etoposide, methotrexate, and actinomycin D alternating with cyclophosphamide and vincristine (the EMA/CO regimen). The hematologic toxicity of the FA regimen was graded at every chemotherapy course. RESULTS With the FA regimen, the survival rate was 80.0% (8 of 10 patients) for a mean follow-up of 10 years. Two patients died due to multidrug resistance, and two patients subsequently developed recurrent disease. The two patients with recurrent disease were successfully salvaged again with the MEA regimen. The toxicity of the FA regimen was evaluated in 78 cycles. Myelosuppression seemed to be the dose-limiting toxicity, and the incidences of World Health Organization Grade 4 leukocytopenia and thrombocytopenia were 6.4% and 3.8%, respectively, of 78 cycles. CONCLUSIONS Although etoposide-containing chemotherapy is currently the most effective and well-tolerated regimen for patients with high-risk GTTs, 20–30% of patients develop resistance to etoposide-containing regimens. Salvage combination chemotherapy with FA is effective for these patients with refractory disease, and the toxicity is predictable and manageable. Cancer 2002;95:1051–4. © 2002 American Cancer Society. DOI 10.1002/cncr.10790

BACKGROUND Ifosfamide (IF) alone or combined with etoposide (ET) was reported to be effective in the treatment of patients with Ewing's sarcoma who relapsed after treatment with the VACA regimen, which consisted of vincristine (VC), actinomycin (AC), cyclophosphamide (CP), and doxorubicin (AD). The purpose of this article is to report the results achieved in a new neoadjuvant protocol in which IF and ET were added to the conventional VACA regimen and administered to patients with localized disease. METHODS In this study, eighty-two patients were treated between May 1988 and October 1991. Chemotherapy consisted of two induction cycles of VC/CP/AD followed by alternating cycles of VC/AD/CP, VC/IF/AC, IF/ET, and VC/CP/AC after local treatment. Twenty-two patients (27%) were treated with surgery only, 22 (27%) underwent surgery followed by radiation therapy, and 38 (46%) received radiotherapy only. RESULTS At a median follow-up of 6.7 years (range, 4-9 years), 43 patients (52%) remained continuously disease free, and 39 relapsed (34 with metastases, 4 with local recurrence and metastases, and 1 with a local recurrence). These results were similar to those obtained at the same institute in a previous neoadjuvant study (March 1983 and April 1988) that included 108 patients treated with the conventional 4-drug regimen. The 5-year disease free and overall survival in the current study were 54% and 59%, respectively, and in the first study were 50% and 56%, respectively. CONCLUSIONS The comparison of these two sequential studies, although not randomized, referred to homogeneous groups of patients observed at the same institution who were treated by the same medical team. No advantage was observed when IF and ET were added to the VACA regimen. Cancer 1998;82:1174-83. © 1998 American Cancer Society.

Background. Wilms' tumor is rare in adults. The recommended treatments for patients with Stage II adult Wilms' tumor with favorable histology (FH) nephroblastomas are conflicting. Methods. Two patients with Stage II, favorable histology, adult nephroblastomas are described. Current treatment modalities are discussed and the literature is reviewed. Results. The first patient, a 52-year-old woman, probably had a late local relapse of a Wilms' tumor 21 years after nephrectomy because of a renal tumor originally diagnosed as reticular sarcoma. In this case, a recurring or an extrarenal Wilms' tumor should have been considered. After the tumor was removed, the patient received adjuvant chemotherapy with dactinomycin and vincristine and was disease free 44 months after diagnosis. The Wilms' tumor in the second patient, a 33-year-old woman, was discovered accidentally and classified as Stage II/FH based on preoperative biopsy. She was treated with radical nephrectomy and adjuvant chemotherapy with dactinomycin and vincristine. This patient was disease free 24 months after surgery. Conclusions. Surgery and two-drug chemotherapy with dactinomycin and vincristine is suggested for patients with Stage II adult Wilms' tumor with FH nephroblastomas. Cancer 1995;75:545-51.

Patients aged10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions.AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years.In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P.0001), thrombocytopenia (OR, 0.41; P.0001), anemia (OR, 0.34; P.0001), and infection (OR, 0.41; P.0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged10 years (OR, 4.18; P.0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males.Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary.

Background. Synovial sarcoma is the third most common pediatric soft tissue tumor. It requires an aggressive approach to achieve a cure. However, optimal treatment modalities adapted to disease extension and histologic variants have not been determined because there is little information about prospectively treated patients. Methods. A multicenter trial for soft tissue sarcomas (Protocol CWS 81) was conducted in West Germany between 1981–1985, and 31 patients with synovial sarcoma were registered. Treatment included multiagent chemotherapy and irradiation after initial tumor excision or biopsy. The male–female ratio in this group was 1:1.6 with a median age of 14 years (range, 1–19 years). The median follow-up time after diagnosis was 101 months (range, 77–131 months). Results. The overall event-free survival (EFS) for patients with synovial sarcoma was 74.2% at 5 years. Group I–II tumors had a significantly better prognosis than those in Group III–IV (EFS at 5 years 84.4% and 58.3%, respectively; P = 0.024). Small tumors (< 5 cm) responded better than larger tumors (≥ 5 cm; EFS, 93% versus 58%; P = 0.029). Synovial sarcoma involved the extremities in 28 patients who had a better outcome compared with those with extremity rhabdomyosarcoma in this study (EFS for Group I–IV was 82% versus 24%, P = 0.001). Conclusions. The results appeared superior to previous experience using radical surgery alone and suggested that after initial, nonmutilating surgery, adjuvant chemotherapy, and irradiation contributed to the improved long-term survival.

Background In the first German soft tissue sarcoma (STS) study, CWS-81, 344 patients younger than 19 years of age who had previously untreated soft tissue sarcoma were studied. For this analysis, there were 218 patients with chemosensitive STS (Group A: rhabdomyosarcoma [RMS], synovial sarcoma, extraosseous Ewing sarcoma, leiomyosarcoma, undifferentiated sarcoma, and malignant peripheral neuroectodermal tumor) who could be studied for a minimum potential follow-up time of 6 years. Methods A staging system based on the postoperative extent of the disease was used. The chemotherapy for Stage I-III disease consisted of vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA). Patients with metastatic disease and patients with Stage III disease who failed to respond to VACA were given ifosfamide instead of cyclophosphamide. The definitive procedure for local tumor control (either no radiation exposure, 40 Gy, or 50 Gy) for patients with Stage II-III disease depended on the tumor status at second-look surgery after 16 weeks of chemotherapy. Results The rates of disease-free survival (DFS) and survival after 5 years was 61% +/- 4% and 57% +/- 4%, respectively, in group A; for patients with nonmetastatic tumors (Stages I-III), the rates were 69% +/- 4% and 72% +/- 4, respectively. Patients with nonmetastatic rhabdomyosarcoma had a similar prognosis: the survival rate was 73% +/- 4%, and the DFS rate was 68% +/- 4%. There was no difference in prognosis between patients with Stage I and and those with Stage II disease (DFS rate, 88% +/- 5% and 88% +/- 6%, respectively). The DFS rate for patients with Stage III disease was 54% +/- 5% and for those with Stage IV, 11% +/- 5%. Lack of local tumor control was the primary cause of therapy failure: 10% of patients with localized disease did not achieve complete remission, whereas 18% who were in complete remission experienced local relapse. The most important prognostic factors were tumor size (P = 0.005) and the degree of tumor regression after primary chemotherapy (P = 0.007). The prognosis also differed according to primary site: paratesticular tumors had the best prognosis, whereas tumors located in the parameningeal regions of the head and neck had the worst prognosis (DFS rate, 96% +/- 4% versus 49% +/- 7%, respectively). Conclusions The following conclusions were drawn from the CWS-81 study: (1) intensive chemotherapy (VACA for 35 weeks) provides long-term control for most patients with Stage I-II disease; (2) patients with primary unresectable tumors (i.e., Stage III) who achieve complete remission with chemotherapy alone have the same prognosis as patients with postoperative disease of Stages I and II; (3) tumor size and the degree of tumor regression after primary chemotherapy influence outcome and thus can be used as a basis for risk-adapted therapy.

Mammalian cells exposed to a single cytotoxic natural product drug, such as vincristine or dactinomycin, can develop resistance to the selective agent and cross-resistance to a broad spectrum of structurally and functionally distinct antibiotics and alkaloids. This phenomenon, termed multidrug resistance (MDR), has been widely studied experimentally. The most consistent feature of cells with high-level MDR is amplification and overexpression of genes encoding an integral plasma membrane protein known as P-glycoprotein. The MDR genes belong to a small family (two members in humans and three members in mouse and Chinese hamster)

BACKGROUND: Isolated limb infusion (ILI) is an effective and minimally invasive treatment option for delivering regional chemotherapy in patients with metastatic melanoma confined to a limb. Recurrent or progressive disease after an ILI, however, presents a challenge for further treatment. The value of repeat ILI in this situation has not been well documented. METHODS: Forty-eight patients were identified who had been treated with a repeat ILI. In all patients, a cytotoxic combination of melphalan and actinomycin D was used. RESULTS: The median time between the 2 procedures was 11 months. The complete response (CR) rate after repeat ILI was 23%, compared with 31% after the initial ILI (P = .36). The overall response was 83%, compared with 75% after the first procedure (P = .32). The median duration of response was 11 months (10 months for patients with CR; P = .80), and median survival was 38 months. In those patients achieving a CR, the median survival was 68 months (P = .003). Toxicity after repeat ILI was increased, with 20 patients experiencing Wieberdink grade III limb toxicity (considerable erythema and edema with blistering) and 5 patients experiencing grade IV toxicity (threatened or actual compartment syndrome), whereas after the initial ILI these toxicity grades occurred in 14 patients and 1 patient, respectively (P = .03). No patient experienced grade V toxicity (requiring amputation). CONCLUSIONS: Repeat ILI is an attractive treatment option to achieve limb salvage in patients with inoperable recurrent or progressive melanoma after a previous ILI. It can be associated with significant short-term regional toxicity, but is well tolerated by most patients, with satisfactory response rates. Cancer 2009. © 2009 American Cancer Society.

In the third National Wilms' Tumor Study (NWTS-3), patients with Stage II favorable histologic type (FH) or Stage III FH Wilms' tumor were randomized according to a factorial design for both radiation therapy (RT) and chemotherapy to be given after nephrectomy. Patients with Stage II FH disease were randomized between 2000 cGy and no postoperative RT; patients with Stage III FH disease were randomized between 2000 and 1000 cGy. No significant differences in survival were noticed. Although there were no significant differences in the rate of intraabdominal relapses, those patients with Stage III disease who received 1000 cGy and dactinomycin and vincristine (seven patients) experienced a relapse in the abdomen more frequently than those who received 2000 cGy and dactinomycin and vincristine (three patients), 1000 cGy and dactinomycin, vincristine, and doxorubicin (three patients), or 2000 cGy and dactinomycin, vincristine, and doxorubicin (two patients). This would suggest that doxorubicin might be a good substitute for the second 1000 cGy of RT. Boost doses of RT, although allowed, were rarely given and no assessment of the value of supplemental RT can be made. The dismal prognosis of abdominal relapse after RT is confirmed and delay of initiation of treatment beyond 10 days after surgery was a significant adverse factor as in NWTS-1 and NWTS-2.

A clinical trial was conducted by the Brazilian Wilms' Tumor (WT) Study Group to compare the single-dose (60 micrograms/kg x 1 day) administration of dactinomycin (AMD) with the standard fractionated dose (15 micrograms/kg/d x 5 days) used in the US National WT Study. Except for the AMD administration, treatment for all patients followed that of the latter study. Patients were randomized to receive either of the two AMD regimens in the schedules most appropriate for their stage and histologic condition. One hundred seventy-six children with WT entered the study until December 1988. No significant differences in overall or relapse-free survival distributions were observed between treatment arms using data for all patients or data stratified by disease stage. Two-year survival rates were 83.0% and 85.3% for patients receiving the fractionated and single doses of AMD, respectively. Survival distributions could also be compared once patients with protocol violations were excluded. The overall 2-year survival rates were 89.7% and 88.6% and the relapse-free 2-year survival rates were 78.2% and 76.1% for the fractionated and single AMD doses, respectively. Altered liver function was seen in three patients who received fractionated dose and in four patients who received the single AMD dose. Acute toxicity was observed in only one patient of the fractionated-dose group and in zero of the patients of the single-dose group. At the closing date, patients assigned to the simplified AMD regimen had accumulated 1840 days less of hospital stay than those treated by the standard regimen.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

BACKGROUND The local management of Ewing sarcoma family of tumors (ESFT) often centers on the surgical resectability of the primary lesion and physician biases regarding differences in the morbidity between primary surgical and radiotherapeutic management. METHODS The authors retrospectively reviewed the records of 33 patients with localized ESFT who underwent surgery and received systemic chemotherapy at St. Jude Children's Research Hospital (Memphis, TN). Two multiagent systemic chemotherapy regimens were used: 14 patients received vincristine, doxorubicin, cyclophosphamide, and actinomycin D (VACA), and 19 received VACA in combination with ifosphamide and etoposide. The primary tumor was surgically resected via a wide, local excision (n = 32) or a marginal excision (n = 1)performed either at diagnosis or after 3–5 months of systemic chemotherapy. Clinical outcome and prognostic factors for disease control were reported in the current study. RESULTS The median follow-up for patients was 9.9 years. The 5-year and 10-year survival rates were 84.5% and 75.8%, respectively. At 5 years, the cumulative incidence of local disease recurrence was 12.5%, and the event-free survival (EFS) rate was 71.7%. The same values were found at 10 years. The site of tumor origin was a significant predictor of EFS. The survival rate of patients whose tumors arose in bone was 78.6%, and the survival rate of patients whose tumors originated in soft tissue was 25.0% (P = 0.028). No other factors investigated were predictive of outcome. CONCLUSIONS Local disease control and overall outcome for patients with ESFT managed by multiagent systemic therapy and surgery was excellent. Local disease control rates remained near 90% at 10-year follow-up. Patients with extraosseous primary sites of disease may fare less well with this approach to therapy. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND The role of doxorubicin (Doxo) as part of multidrug regimens used to treat children with soft tissue sarcoma (STS) is controversial. To evaluate the feasibility of combining Doxo with the well established ifosfamide, vincristine, and actinomycin D (IVA) regimen, the Italian STS Committee performed a pilot study on a series of children with metastatic STS. METHODS Between July 2002 and February 2004, 29 evaluable patients were enrolled in this study; 19 patients had rhabdomyosarcoma, 5 patients had peripheral neuroectodermal tumor, and 5 patients had other types of STS. The IVA-Doxo (IVADo) regimen included ifosfamide 3 g/m2 on Days 1 and 2, vincristine 1.5 mg/m2 on Day 1, actinomycin D 1.5 mg/m2 on Day 1, and Doxo 30 mg/m2 on Days 1 and 2. Three courses of IVADo were to be administered in the initial part of treatment and analyzed for toxicity and tumor response. RESULTS Overall, 92 cycles were delivered. Major regimen-related toxicity was myelosuppression, with Grade 4 neutropenia in 67% of cycles and fever and neutropenia in 37% of cycles. Nonhematologic toxicity included Grade 3–4 mucositis (6.5% of cycles), constipation (9.7%), and peripheral neuropathy (6.5%). Other manifestations of major toxicity were venoocclusive disease and seizures, which occurred in one patient each. All but 1 patient with a malignant schwannoma showed some degree of tumor volume reduction; however, considering only complete and partial remissions, the response rate was 76% (± 7.9%). CONCLUSIONS The intensive IVADo regimen was effective against pediatric STS with acceptable toxicity. This combination will be investigated in high-risk patients with rhabdomyosarcoma in a randomized trial launched by the European pediatric Soft tissue sarcoma Study Group. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND After randomized trials in the 1980s, doxorubicin (DOX) was added to dactinomycin plus vincristine as standard chemotherapy for patients who had Stage III Wilms tumor (WT) of favorable histology (FH). Double-agent chemotherapy was retained for patients with Stage II disease. In this study, the authors reevaluated the efficacy of DOX using extended follow-up and additional patients. METHODS The relative risks (RR) (DOX vs. no DOX) of disease recurrence and mortality were estimated for patients with Stage II–III/FH WT who were enrolled in the third and fourth National Wilms Tumor Studies (NWTS-3 and NWTS-4). The risk of congestive heart failure (CHF) was estimated for all patients who received DOX. RESULTS No statistically significant effects of DOX were found for patients with Stage II tumors. For patients with Stage III tumors, the 8 year recurrence-free survival (RFS) and overall survival (OS) rates for randomized patients on NWTS-3 were 84% and 89%, respectively, for patients who received DOX (n = 130) and 74% and 83%, respectively, for patients who did not receive DOX (n = 118). Including all patients with Stage III disease who received DOX (n = 678) and did not receive DOX (n = 138), the RRs of recurrence were 0.47 (P = 0.007) and 0.40 (P = 0.011), and local recurrence respectively, after adjustment for radiation therapy (RT) dose, whereas the RR of mortality adjusted for RT and study was 0.68 (P = 0.17). The 20-year risk of CHF after primary DOX treatment on NWTS-3 and NWTS-4 was 1.2%. CONCLUSIONS The inclusion of data from nonrandomized patients yielded estimates of DOX treatment effects for Stage III/FH WT that were stronger, albeit more susceptible to bias, than reported previously. Despite a lower reported risk of CHF, conclusive evidence that frontline therapy with DOX definitively improves survival remains elusive. Cancer 2004. © 2004 American Cancer Society.

Small cell carcinoma of the uterine cervix is an uncommon tumor associated with high mortality even among patients with early stage disease. The role of adjuvant chemotherapy after surgery has been suggested by regimens used for small cell lung carcinoma. During the years 1980-1997, 19 cases in which various adjuvant chemotherapies were given after hysterectomy were reported in the literature published in English.Adjuvant chemotherapy was administered consecutively to 23 patients with Stage Ib-II small cell cervical carcinoma who had been primarily treated with radical hysterectomy and had adequate bone marrow, renal, and hepatic functions. A combination of vincristine, doxorubicin, and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE) was administered to 14 patients during the years 1988-1996 according to a prospective study protocol. A combination of cisplatin, vinblastine, and bleomycin (PVB) was administered to 8 patients, and another regimen was administered to 1 patient during the years 1984-1988. Prognostic factors were evaluated by analyzing both the data on these 23 patients and the pooled data on the cases retrieved from the literature and our own files.Ten of the 14 patients who received VAC/PE had no evidence of disease during a median follow-up of 41 months, whereas 3 of the 9 who received PVB or another regimen survived. Of the 10 patients who died of their disease, all died of distant metastasis within 10 months after recurrence. Meta-analysis of the pooled data showed that 68% of patients who received regimens containing VAC or PE survived, whereas 33% of patients who received regimens not containing VAC/PE survived (P = 0.0078, log rank test). Seventy percent of patients with no lymph node metastasis at hysterectomy and 35% with lymph node metastasis survived (P = 0.05). All patients who died of disease had extrapelvic metastasis.Chemotherapies containing VAC or PE are favorable regimens for patients with early stage small cell cervical carcinoma after radical hysterectomy.

Venoocclusive disease (VOD) of the liver is a common complication after allogenic and autologous bone marrow transplantation for malignant disease. The authors report the unusual and unexpected complication of VOD of the liver occurring in children with rhabdomyosarcoma who were receiving vincristine, actinomycin D, and cyclophosphamide (VAC) according to the chemotherapy regimens of the Intergroup Rhabdomyosarcoma Study (IRS) IV.The authors evaluated 821 patients with newly diagnosed rhabdomyosarcoma receiving treatment according to IRS IV who were considered at risk for VOD.Ten patients developed VOD of the liver for an overall incidence of 1.2%. VOD was found only after the administration of VAC chemotherapy. The highest incidence of VOD was observed among patients who had previously received vincristine and melphalan (Regimen 48). None of the patients receiving the chemotherapy regimen of vincristine and actinomycin D (Regimen 44) developed VOD.Patients receiving VAC-containing regimens on the IRS IV were found to be at risk for VOD. The VAC combination was used extensively in previous IRS studies (I, II, and III) and VOD was not reported during these studies, strongly suggesting that the escalation of the cyclophosphamide dose to 2.2 g/m2 (with the vincristine and actinomycin D doses and schedule remaining unchanged) triggered the development of VOD. The contributing role of previous therapy or events is unknown. At last follow-up, none of the nine surviving patients had developed recurrent VOD on continuation of chemotherapy.

Complete maturation (cytodifferentiation) of treated metastatic Wilms' tumor is an infrequent occurrence. In a large series of reports, Wilms' metastases have generally contained malignant blastemic elements admixed with lesser amounts of cytodifferentiated mesenchyme. The authors describe a patient in whom complete maturation of a pulmonary metastasis was documented after intensive chemoradiotherapy.A MEDLINE search was employed to identify pertinent cases from 1966 to the present. Key words used in the search included Wilms' tumor, relapse, therapy, metastasis, maturation, and cytodifferentiation. Four patients were identified as having completely mature cytodifferentiated pulmonary metastases of Wilms' tumor after chemotherapy; one had also undergone irradiation of the pulmonary metastasis.The primary tumor was an extremely necrotic blastemic Wilms' tumor devoid of maturation, as studied after irradiation and chemotherapy. The lung metastases (examined 13 years later) were represented by a scar and a nodule comprised of bland epithelium and tubules admixed with mature smooth muscle. Immunohistochemical stains, used to assess the proliferative rate of these cells, revealed a nearly negligible proliferation index.This report suggests that therapy (chemotherapy and/or irradiation) may effect, on occasion, complete cytodifferentiation of Wilms' tumor pulmonary metastasis. Although this would appear to be an uncommon event, its true incidence is unknown, because few patients with metastatic pulmonary Wilms' tumor are subjected to biopsy. The findings of this study suggest that for children with radiologically stable Wilms' lung metastases (as determined by imaging studies) who are yet undergoing intensive chemoradiotherapy, the notion of a surgical biopsy should be entertained to determine the true nature of the radiologic images. For some, this might result in the cessation of further therapy that would be unnecessary and not without complications.

The purpose of this study was to evaluate the use of two cycles of high dose chemotherapy with autologous bone marrow transplantation (ABMT) in the treatment of patients having a first relapse of testicular germ cell cancer.Twenty-five patients whose disease had relapsed after 1 platinum-based regimen received 1-2 cycles of conventional dose salvage therapy, followed by a planned 2 consecutive cycles of carboplatin 2100 mg/m2 and etoposide 2250 mg/m2 with ABMT. Patients were required to have testicular germ cell cancer, adequate organ function, and performance status. The median patient age was 32 years; 3 cisplatin refractory.Conventional dose salvage therapy consisted of vinblastine, ifosfamide, and cisplatin (for 16 patients); etoposide, cisplatin, and ifosfamide (for 3 patients); cisplatin, vinblastine, and bleomycin (for 2 patients); or none (for 4 patients). Twenty-five patients received high dose therapy; of these, 19 (76%) received two cycles. The median time to an absolute neutrophil count of 500 was 12 days (range, 8-20 days) for the first cycle and and 11 days (range, 8-18 days) for the second. The median time to a platelet count of 20,000/microL, independent of transfusions, was 15 days (range, 8-60 days) for the first cycle and 14 days (range, 8-22 days) for the second. Extramyeloid toxicities were as follows: Grade 3-4 stomatitis in 17 of 25 patients, Grade 3-4 nausea/emesis in 12 of 25 patients, and Grade 3 ototoxicity in 3 of 25 patients. At the completion of therapy, nine patients were in complete remission, six had only teratoma found at resection, one had carcinoma resected, six were in partial remission, two had stable disease, and one had progressive disease. With a median follow-up period of 26 months (range, 14-36 months), 13 of 25 patients (52%) had been continuously progression free at last follow-up, 11 of 25 (44%) progressed, and 1 patient died in treatment.Salvage treatment incorporating brief conventional dose therapy followed by two cycles of high dose therapy resulted in prolonged disease free survival in a proportion of patients with relapsed testicular germ cell cancer.

Background. Estrogen receptor (ER) has been found in human pancreatic carcinoma, but the potential benefit of endocrine therapy never has been assessed adequately. The aim of this study was to determine whether the presence of ER can be used as an indicator of hormone responsiveness, and whether modulation of tissue-type plasminogen activator (t-PA) by ER can identify hormone-responsive pancreatic carcinomas. Methods. The authors investigated ER status and hormonal regulation of t-PA in nine human pancreatic carcinoma cell lines, AsPC-1, BxPC-3, Capan-1, Capan-2, Hs-700T, Hs-766T, MiaPaCa-2, PANC-1, and SUIT-2. Furthermore, to examine whether estrogen dependency of t-PA production in pancreatic carcinoma cells correlated with responsiveness to endocrine therapy, the in vivo effects of various endocrine agents on the growth of the nine pancreatic cell lines transplanted into nude mice were examined. Results. In a 17beta-estradiol (E2)-binding assay, three of the nine pancreatic carcinoma cell lines (BxPC-3, Capan-2, and MiaPaCa-2) contained measurable levels of estradiol binding sites in vitro and in vivo using tumors; transplanted into nude mice. Although t-PA was present in the culture medium in eight of the nine pancreatic carcinoma cell lines (not in Hs-700T), t-PA production was regulated by estrogen via an ER system in vitro only in the Capan-2 cell line. E2 injection into tumor-bearing, mice showed acceleration of tumor growth only in Capan-2 tumors. Administration of a competitive ER antagonist, toremifene, and a luteinizing hormone-releasing hormone analogue, leuprorelin acetate (LEU), to Capan 2-bearing mice significantly reduced the rate of tumor growth, although there was no actual shrinkage of tumor mass. These agents failed to exert any antitumor effect on the other eight pancreatic cell lines. Although aromatase inhibitors, CGS 20267 and vorozole did not modify the in vivo growth of the nine pancreatic carcinoma cell lines significantly, the combined use of aromatase inhibitors with LEU exhibited a synergistic antitumor effect on Ca-pan-2-bearing mice. Medroxyprogesterone acetate treatment significantly reduced the tumor volume of Capan-2 and also caused delayed growth in two other cell lines, AsPC-1 and MiaPaCa-2. Conclusions. The estrogen dependency of t-PA production may clarify the functional state of ER in human pancreatic carcinoma cells. This finding may aid in planning endocrine therapy for patients with this lethal cancer. Cancer 1995;75:1263-72.

Wilms' tumor is rare in adults. The recommended treatments for patients with Stage II adult Wilms' tumor with favorable histology (FH) nephroblastomas are conflicting.Two patients with Stage II, favorable histology, adult nephroblastomas are described. Current treatment modalities are discussed and the literature is reviewed.The first patient, a 52-year-old woman, probably had a late local relapse of a Wilms' tumor 21 years after nephrectomy because of a renal tumor originally diagnosed as reticular sarcoma. In this case, a recurring or an extrarenal Wilms' tumor should have been considered. After the tumor was removed, the patient received adjuvant chemotherapy with dactinomycin and vincristine and was disease free 44 months after diagnosis. The Wilms' tumor in the second patient, a 33-year-old woman, was discovered accidentally and classified as Stage II/FH based on preoperative biopsy. She was treated with radical nephrectomy and adjuvant chemotherapy with dactinomycin and vincristine. This patient was disease free 24 months after surgery.Surgery and two-drug chemotherapy with dactinomycin and vincristine is suggested for patients with Stage II adult Wilms' tumor with FH nephroblastomas.

The purpose of this study was to determine the relationship between histologic microsubstaging variables, patient age, and tumor specimen weight in patients with Stage I/favorable histology Wilms' tumors.The authors reviewed all randomized patients from the Fourth National Wilms' Tumor Study, who had Stage I/favorable histology Wilms' tumors evaluated for one or more of the microsubstaging variables: (1) the presence of an inflammatory pseudocapsule, (2) renal sinus invasion, (3) tumor in the intrarenal vessels, and (4) tumor capsule invasion. The authors determined the correlation between microsubstaging variables and age at diagnosis or tumor specimen weight.Patients who were younger than 2 years of age at diagnosis were significantly more likely to have all negative microsubstaging variables. Patients who had tumors weighing less than 550 g were more likely to have all negative microsubstaging variables. However, neither renal sinus invasion nor tumor in the intrarenal vessels was more frequent in tumors weighing more than 550 g.An age at diagnosis of younger than 2 years and a tumor specimen weight of less than 550 g are highly correlated with the absence of adverse microsubstaging variables. The clinical variables of age at diagnosis and tumor specimen weight, compared with the assessment of microsubstaging variables, have the practical advantage of being more objectively determined and not requiring a central pathologic review for confirmation.

Angiomatoid malignant fibrous histiocytoma (AMFH) is a low grade soft tissue sarcoma usually treated with surgery alone. Only one adult patient has been treated with systemic chemotherapy. The authors report a case of unresectable, metastatic AMFH treated initially with vincristine, doxorubicin, dactinomycin, and cyclophosphamide. A complete response at the metastatic site and a marked reduction in the size of the primary tumor allowed complete surgical excision 7 months after treatment was initiated. The patient remains disease free 19 months after being diagnosed. It was concluded that systemic chemotherapy may be effective in patients with AMFH.

To verify the adequacy of a simplified chemotherapeutic regimen for the treatment of Wilms' tumor (WT), the authors conducted a clinical trial to compare the standard fractionated dose (15 mcg/kg x 5 days) of dactinomycin (AMD) with a single dose (60 mcg/kg x 1 day) administration of the drug.From October 1986 to December 1988, 176 WT patients were enrolled in a randomized, multicentric clinical trial conducted by the Brazilian WT Study Group in 38 institutions from 8 states. Patients were randomly assigned to treatment arm A (standard 5-day fractionated AMD administration) or arm B (single high dose AMD administration) in the schedules most appropriate for their stage and histology. Except for the differences in AMD administration, patients were managed by the Third U.S. National WT Study protocol. The endpoints of interest were relapse free and overall survival. Complete follow-up information was obtained until December 1992.After a median follow-up of 47 months, there were no significant differences in survival distributions between treatment arms, using data for all patients or data stratified by disease stage. Relapse free and overall 4-year rates were similar in both groups: 67% and 72%, respectively, in arm A, and 67% and 75%, respectively, in arm B (P = 0.839 and 0.710, respectively). Patients assigned to the simplified arm had cumulatively 1921 fewer hospital days as compared with those receiving the fractionated dose. Hepatic toxicity was observed in only one patient assigned to the divided dose regimen and in none of the single dose group.WT can be treated using a single dose regimen for AMD administration, thus minimizing the inconvenience for the children and their parents and reducing considerably health care delivery costs.

Platinum-DNA adducts can be measured in peripheral blood cells, and high adduct levels have previously been correlated with favorable clinical response to platinum-based therapy in patients with germ cell tumors and ovarian cancer.To evaluate the relationship between platinum-DNA adducts and clinical response to chemotherapy, 36 patients with germ cell tumors treated with cisplatin-based chemotherapy had platinum-DNA adducts assayed in leukocytes by atomic absorption spectrometry (AAS) and cisplatin-DNA enzyme-linked immunosorbent assay (ELISA). Three chemotherapy regimens were involved: cisplatin and etoposide (Regimen A); carboplatin and etoposide (Regimen B); and cyclophosphamide, vinblastine, dactinomycin, bleomycin, and cisplatin [VAB-6] with or without high dose carboplatin plus etoposide plus autologous bone marrow rescue (Regimen C). Blood samples were drawn before and after each cycle of chemotherapy.One hundred ninety-two blood samples were assayed by AAS and 137 by ELISA: DNA adducts measured by AAS and ELISA increased immediately after treatment and decreased during the intervening time before the next treatment. DNA adducts were measurable by both methods 4-8 weeks after the last cycle of therapy. The peak and mean adduct levels measured in samples drawn immediately after Cycles 1 and 2 and after all cycles were analyzed in terms of their relationship to clinical response. In contrast to numerous prior studies, a positive correlation was not observed between DNA adduct formation as determined by either AAS or ELISA and favorable clinical responses.This study demonstrated that peak and mean platinum-DNA adduct levels were influenced by the dose and schedule of the platinum analogue. For example, treatment with VAB-6 with or without high dose carboplatin and etoposide (Regimen C) resulted in significantly higher adduct levels when measured by AAS compared with Regimen A or B. Inconsistencies between studies regarding observed correlations of DNA adducts and treatment outcome may be attributable to differences in platinum analogue, dose, schedule, and timing of sample procurement. These factors must be considered in future studies.

Patients with relapsed germ cell cancer (GCT) have a poor prognosis when treated solely with conventional chemotherapy; high dose chemotherapy with autologous bone marrow rescue (ABMR) has shown curative potential in patients with relapsed and refractory GCT. This protocol was designed to incorporate high dose therapy with initial salvage therapy.Twenty-three patients in the first relapse of GCT received two cycles of conventional dose cisplatin-based therapy (either vinblastine, ifosfamide and cisplatin [VeIP] or cisplatin, vinblastine, and bleomycin) followed by carboplatin (1500-2100 mg/m2) and etoposide (1200-2250 mg/m2) given in divided doses with ABMR.Eighteen of 23 patients completed protocol therapy including high dose therapy. Five of 23 did not undergo high dose therapy due to: insurance refusal (1); patient refusal (1); active infection (1); central nervous system metastasis (1); death on induction therapy (1). Response to two courses of conventional dose induction therapy (N = 23) was complete response (CR), 8; partial response (PR), 12; stable disease (SD), 2; and toxic death, 1. Two of five individuals who did not continue with high dose therapy are alive and progression free after conventional salvage therapy and surgery with at least 24 months of follow-up. Outcome after high dose therapy (N = 18) was CR, 9, PR, 6, SD, 1, and PD, 2. Two patients who were in PR after receiving two cycles of conventional dose therapy were converted to CR using high dose therapy. There was only one treatment-related death in this cohort, a septic death during VeIP induction therapy. There were no transplant related deaths. Of those patients completing high dose therapy, 7 of 18 (39%) survived, progression free with a median follow-up of 26 months, 2 of 18 are alive with active disease, and 9 of 18 died of recurrent disease.Conventional dose induction therapy followed by consolidation with high dose therapy and ABMR is well tolerated and provides prolonged disease-free survival in some patients with chemosensitive relapsed germ cell cancer.

Metastatic carcinoma of uncertain primary site (CUPS) is a common problem and has a poor prognosis. The intention of this study was to determine whether the addition of cisplatin and etoposide (PE) to vincristine, doxorubicin and cyclophosphamide (VAC) chemotherapy improves outcome.Fifty-seven consecutive patients with an initial diagnosis of CUPS were studied. The first 40 patients had received six or 10 cycles of VAC and 17 patients VAC alternating with PE for six cycles. Review of histology using immunohistochemical techniques where appropriate was performed in all cases.Histologic review resulted in six tumors reclassified as non-Hodgkin's lymphoma (NHL), one as hepatocarcinoma, and one as adenocarcinoma. Six of the 11 responses occurred in patients with a review diagnosis of NHL. If the six cases of NHL and the case of hepatocarcinoma were excluded, there was no difference in survival between VAC and VAC/PE treated patients. Five patients with true CUPS who responded to VAC or VAC/PE had poorly differentiated histology, and this group (n = 24) also had a significantly longer survival.Some patients thought to have CUPS actually have NHL, and it is this group which responds well to chemotherapy. True CUPS patients respond to chemotherapy only if the tumor is poorly differentiated; survival is significantly longer for this group of patients. An advantage for VAC/PE over VAC chemotherapy was not identified.

Intergroup Rhabdomyosarcoma Study (IRS)-II, (1978-1984) had the general goals of improving the survival and treatment of children with rhabdomyosarcoma (RMS).Nine hundred ninety-nine previously untreated eligible patients entered the study after surgery and were randomized or assigned to therapy by IRS Clinical Group (I-IV), tumor site, and histologic type. Outcomes were compared between treatments and with results of IRS-I (1972-1978).Patients in Group I, excluding extremity alveolar (EA) RMS, were randomized to standard vincristine (V), dactinomycin (A), and cyclophosphamide (C) or standard VA. At 5 years, disease-free survival (DFS) and survival (S) rates were similar between VAC and VA (DFS: 80%, 70%, P = 0.47; S: 85%, 84%, P = 0.73). Patients in Group II, excluding EA RMS, received radiation and were randomized to intensive VA or repetitive-pulse VAC. Outcomes were similar for rates of DFS (69%, 74%, P = 0.83) and S (88%, 79%, P = 0.17). Patients in Group III, excluding certain pelvic tumors, received radiation and were randomized to repetitive-pulse VAC or repetitive-pulse VAdrC-VAC (Adr, Adriamycin [doxorubicin]). Complete remission (CR) rates were close at 74%, 78%, respectively (P = 0.32), as were percentages in CR (73%) and S (66%) rates; the latter outcomes were significantly better than IRS-I (CR: 56%, P0.001; S: 50%, P0.001). Central nervous system prophylaxis for Group III patients with cranial parameningeal sarcoma increased S rate to 67% from 45% in IRS-I (P0.001). Patients in Group IV received the same regimens as Group III; the CR rate was 53%, 38% remained in CR and S rate was 27% with and 26% without Adr (P = 0.90). At 5 years, S rate for IRS-II, including EA and all pelvic tumors, was 63%: an 8% increase over IRS-I (P0.001). Outcomes by primary site were as good as, or better than, the IRS-I experience.Combining all Groups and treatments in IRS-II, the major improvement in S rate at 5 years between studies was in nonmetastatic patients (71% for IRS-II versus 63% for IRS-I, P = 0.01).

The outlook for patients with germ cell tumors was poor before the advent of effective chemotherapy. The authors assessed the outcome of treatment with multiagent chemotherapy (with or without radiation therapy) in children treated for germ cell tumors at St. Jude Children's Research Hospital (SJCRH).Sixty children with germ cell tumors were treated between January 1979 and June 1988. Postsurgical treatment was based on tumor site, stage, and histology. Most patients received chemotherapy with vincristine, actinomycin-D, and cyclophosphamide (VAC), or a modified Einhorn regimen (cisplatin, bleomycin, and vinblastine [PVB]); in the absence of response to initial therapy, patients received alternating courses of VAC and PVB (VAC/PVB regimen). Exceptions were patients with Stage I testicular tumors (observation only) and ovarian germinomas (Stage I tumors measuring less than 10 cm, observation only; tumors larger than 10 cm or Stage II-III disease, radiation only; and Stage IV disease, VAC plus radiation).The estimated 5-year survival is 100% for patients with Stage I disease (n = 18), 87% for patients with Stage II (n = 8), 72% for Stage III (n = 25), and 56% for Stage IV (n = 9). Patients with testicular tumors of any stage or with Stage I-II ovarian tumors had 100% 5-year survival. Extragonadal tumors responded poorly to VAC alone with recurrent or progressive disease in eight of nine patients. Treatment for those tumors was changed to alternating courses of VAC and PVB, which failed in only one of seven patients. Nine of 19 patients with advanced ovarian tumors had disease recurrence with VAC; these patients then received PVB, which was effective in four cases.For patients with advanced germ cell cancers, intensification of therapy or the development of new approaches is necessary. In contrast, future trials in children with limited stage should focus on reducing acute and long-term toxicities.

A 27-year-old woman had a large hepatic tumor and a markedly increased serum alpha-fetoprotein (AFP) level. A diagnosis of endodermal sinus tumor was made after a needle biopsy was performed on the liver. Clinical and radiologic examinations did not show an alternative primary site. Treatment with cisplatin, etoposide, and bleomycin was started, but, after three cycles, was changed to cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide because the serum AFP level was decreasing too slowly. After additional chemotherapy was given, the patient was well but had an increased AFP level and a large residual mass in the liver. A right hemihepatectomy was performed, but no viable tumor was present. The patient is alive and disease-free 5 years later. Thus, AFP levels may be misleading in the presence of large necrotic tumors. The authors stress the need to make a diagnosis of these rare tumors early because aggressive treatment with combination chemotherapy may result in cure.

The International Society of Pediatric Oncology (SIOP) recommends preoperative treatment in the management of eligible patients with Wilms' tumor. Until 1980, children younger than 12 months of age (infants) at diagnosis had been excluded from the SIOP trials. SIOP 6, conducted from 1980 to 1987, was the first SIOP study to include infants older than 6 months of age. This retrospective analysis of 145 infants registered to SIOP 6 demonstrates that in infants older than 6 months and having favorable histology (FH), a two-drug preoperative chemotherapy (CT) regimen of 4 weeks significantly ameliorated stage distribution as determined at delayed surgery but did not affect a good outcome. However, the CT dose utilized in SIOP 6 resulted in an unacceptable toxicity in this age group, and SIOP 9, the new SIOP study of Wilms' tumor, recommends a reduced dose of CT in infants. Preoperative CT is not recommended in infants younger than 6 months of age. Specifically, the high incidence (29%) of mesoblastic nephroma in this age group does not justify such an approach. Histopathologic diagnosis should be obtained in these patients before any treatment.

In the third National Wilms' Tumor Study (NWTS-3), patients with Stage II favorable histologic type (FH) or Stage III FH Wilms' tumor were randomized according to a factorial design for both radiation therapy (RT) and chemotherapy to be given after nephrectomy. Patients with Stage II FH disease were randomized between 2000 cGy and no postoperative RT; patients with Stage III FH disease were randomized between 2000 and 1000 cGy. No significant differences in survival were noticed. Although there were no significant differences in the rate of intraabdominal relapses, those patients with Stage III disease who received 1000 cGy and dactinomycin and vincristine (seven patients) experienced a relapse in the abdomen more frequently than those who received 2000 cGy and dactinomycin and vincristine (three patients), 1000 cGy and dactinomycin, vincristine, and doxorubicin (three patients), or 2000 cGy and dactinomycin, vincristine, and doxorubicin (two patients). This would suggest that doxorubicin might be a good substitute for the second 1000 cGy of RT. Boost doses of RT, although allowed, were rarely given and no assessment of the value of supplemental RT can be made. The dismal prognosis of abdominal relapse after RT is confirmed and delay of initiation of treatment beyond 10 days after surgery was a significant adverse factor as in NWTS-1 and NWTS-2.

A 12-year-old girl with nonmetastatic osteogenic sarcoma received treatment with doxorubicin, methotrexate, cisplatin, cyclophosphamide, bleomycin, and dactinomycin. She developed unexplained persistent pancytopenia after completion of chemotherapy. Twenty-three months after the initial diagnosis of osteosarcoma an evaluation revealed a bone marrow pattern consistent with the diagnosis of refractory anemia with excess blasts, and karyotype analysis showed characteristic findings of therapy-related myelodysplasia (loss of chromosomes 5 and 7, as well as 12p and 17p deletions). Bone marrow transplantation from an human leukocyte antigen (HLA)-compatible sibling donor was performed 26 months after the diagnosis of the primary malignancy. Although it is unproven that the alkylating agents administered to this patient were responsible for the myelodysplastic syndrome, careful follow-up of osteosarcoma patients who receive alkylating agents is warranted.

The disposition of many drugs in obesity is altered, although little is known of the effect of obesity on the pharmacokinetics of anti-cancer drugs. In this report the authors describe the pharmacokinetics of high-dose methotrexate in an obese woman (184% ideal body weight) with osteosarcoma. For this patient, both the volume of distribution at steady-state (0.398 l/kg) and systemic clearance (0.0956 l/h/kg) of methotrexate were increased compared with values observed in adult patients with osteosarcoma. The terminal elimination half-life (9.29 hours) of methotrexate was similar to other reported values in adult patients, thus indicating that increases in methotrexate volume of distribution and clearance may offset each other in obesity. Based on the experience gained from this patient, the authors suggest that renal function and methotrexate serum concentrations should be monitored in obese patients receiving high-dose methotrexate with leucovorin rescue.

A clinical trial was conducted by the Brazilian Wilms' Tumor (WT) Study Group to compare the single-dose (60 micrograms/kg x 1 day) administration of dactinomycin (AMD) with the standard fractionated dose (15 micrograms/kg/d x 5 days) used in the US National WT Study. Except for the AMD administration, treatment for all patients followed that of the latter study. Patients were randomized to receive either of the two AMD regimens in the schedules most appropriate for their stage and histologic condition. One hundred seventy-six children with WT entered the study until December 1988. No significant differences in overall or relapse-free survival distributions were observed between treatment arms using data for all patients or data stratified by disease stage. Two-year survival rates were 83.0% and 85.3% for patients receiving the fractionated and single doses of AMD, respectively. Survival distributions could also be compared once patients with protocol violations were excluded. The overall 2-year survival rates were 89.7% and 88.6% and the relapse-free 2-year survival rates were 78.2% and 76.1% for the fractionated and single AMD doses, respectively. Altered liver function was seen in three patients who received fractionated dose and in four patients who received the single AMD dose. Acute toxicity was observed in only one patient of the fractionated-dose group and in zero of the patients of the single-dose group. At the closing date, patients assigned to the simplified AMD regimen had accumulated 1840 days less of hospital stay than those treated by the standard regimen.

The Cooperative Ewing's Sarcoma Studies, CESS 81 and CESS 86, are multiinstitutional trials with more than 80 participating institutions from Germany, the Netherlands, Austria, and Switzerland. Treatment consists of four courses of multiagent chemotherapy and local therapy. Local therapy was not randomized and was either radical surgery or resection plus postoperative irradiation or definitive radiation therapy. Here results according to local therapy have been analyzed for 93 protocol patients with localized Ewing's sarcoma (ES) who have been recruited in CESS 81 from January 1981 to February 1985 and 122 protocol patients recruited in CESS 86 from January 1986 to November 1989. The 3-year relapse-free survival (RFS) was 55% in CESS 81 and 62% in CESS 86. In CESS 81, the RFS was better for surgically treated than for irradiated patients. In this study there was an extremely high incidence of local failures (50%) after definitive irradiation. In CESS 86, however, the results after radiation therapy have been improved markedly (3-year RFS 67% after radiation therapy, 65% after surgery, and 62% after resection plus irradiation). Possible explanations for the improvement of radiotherapeutic results are as follows: selections for patients for radiation therapy, start of local therapy, and quality of radiation therapy. In CESS 86, irradiated patients were randomized to receive either conventionally fractionated irradiation with less intense chemotherapy or hyperfractionated irradiation with simultaneous chemotherapy. There was no difference in treatment results at the time of analysis. The authors conclude that selection of patients for local treatment modalities and quality of treatment performance has an impact on local and overall treatment results in ES.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

This report illustrates the use of cardiac magnetic resonance imaging (MRI) to quantify the initial extent of a cardiac rhabdomyosarcoma and, more importantly, its response to chemotherapy. Image slices spanning the heart and adjacent structures were analyzed using Simpson's rule applied to the image slices to estimate the tumor volume initially, then after 5 weeks, and again after 4 months of chemotherapy. A substantial, progressive reduction in tumor volume during chemotherapy was shown. After chemotherapy was discontinued, an increase in tumor volume was shown. It is suggested that, in addition to being useful in patient care, the technique may be useful in clinical investigations by providing an objective, quantitative measure of tumor response to therapy.

Twenty-eight of 124 (23%) advanced germ cell tumor (GCT) patients who were treated on four successive platin-based induction regimens and who failed to achieve a durable complete response (CR) remain alive (median follow-up, 50 months). An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy. Survival and/or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy, treatment with a cisplatin-based salvage regimen, a testis primary site, a normal serum human chorionic gonadotropin level, a normal serum lactate dehydrogenase level, one site of metastasis, and an Indiana Class of 6 or less. Patients with a prior incomplete response (IR) had a particularly poor prognosis (P = 0.00007) with only 4 of 52 (9%) patients alive (median follow-up, 37 months) compared with 15 of 42 (36%) patients with a prior best response of a CR (median follow-up, 35 months). The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy. The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens.

Adults with Wilms' tumor (WT) have had a poor prognosis. More recently, therapies used in children, who have a better outlook, are also being employed for adults. This study was undertaken to see whether adults with WT have benefited. The results of treatment of 27 adults with WT were reported to the National Wilms' Tumor Study (NWTS) from 1979 to 1987. The ages of the 27 adults ranged from 16 to 74 years (median, 24 years). Four had anaplastic WT, and 23 had favorable histology (FH) WT. All but one patient underwent nephrectomy, 21 were given postoperative radiation therapy, and 25 received chemotherapy. The agents used most often included actinomycin D (AMD), vincristine (VCR), and doxorubicin (Adriamycin; ADR). There were six Stage I, five Stage II, four Stage III, 11 Stage IV, and one Stage V patients. The 3-year survival rate is 67%. These results are better than the 24% reported by the NWTS in the past for adults with WT. Analyses of the therapies given to the 27 adults lead to the following recommendations: for Stage I/FH patients, 6 months of postoperative chemotherapy using AMD + VCR without postoperative radiation therapy; and for Stage II, III, and IV/FH, VCR + AMD + ADR for 15 months + 2000 cGy to the tumor bed, 1200 to 1500 cGy to the lungs, 2000 cGy to the liver, and 3000 cGy to other sites as appropriate in patients with metastases at diagnosis.

The effect of duration of induction treatment on complete response (CR) and event-free survival (EFS) (time to death or relapse) was evaluated in 162 "good-risk" germ cell tumor (GCT) patients treated from November 1982 to July 1986 in a randomized prospective trial with VAB-6 (cyclophosphamide + vinblastine + bleomycin + dactinomycin + cisplatin; 81 patients) versus etoposide + cisplatin (EP; 81 patients). Patients received three cycles of VAB-6 every 28 days or four cycles of EP every 21 days. Treatment cycle with either regimen was routinely postponed for 7 days for leukocytes less than 3000/mm3 or platelets less than 100,000/mm3 and then administered regardless of blood count. The number of treatment days was calculated for each patient from initial treatment day to final induction date plus 28 days for VAB-6 and plus 21 days for EP. The proportion of CR and the EFS for good-risk GCT patients treated with cisplatin-based chemotherapy were not influenced by a less than or equal to 7-day delay resulting from chemotherapy-induced myelosuppression. Short, planned delays in chemotherapy for good-risk GCT patients (less than or equal to 7 days per cycle) appear to be acceptable since they may prevent serious toxicity in this curable patient population. Delays of longer than 7 days are strongly discouraged except in extraordinary life-threatening circumstances.

Bleomycin is well recognized as an active antineoplastic agent in the treatment of germ cell tumors. Pulmonary toxicity is the most significant complication of bleomycin administration. In this report, an attempt is made to modify both the incidence and severity of this side effect. One hundred eleven patients with advanced germ cell tumors were treated with a combination chemotherapy program that included the administration of 30 units (U) of bleomycin as a continuous infusion daily for 3 days every 3 weeks rather than a weekly bolus injection of a total of 360 U (mean dose received, 307 U). Also, 31 patients received high-dose steroids, which have been shown to modify bleomycin-induced pulmonary toxicity, for the treatment of chemotherapy-induced emesis. Changes in carbon monoxide diffusion capacity (DLCO) prompting cessation of bleomycin therapy occurred in 15 cases (bleomycin was stopped in one case due to dyspnea and lung infiltrates, and one patient suffered fatal respiratory failure probably due to bleomycin lung toxicity). Thus, probable bleomycin pulmonary toxicity changed the clinical treatment in 15.3% of the cases. On long-term follow-up, only two patients have demonstrated a residual decrease in DLCO. The incidence of a greater than 25% decrease in DLCO was 34% and was not significantly altered by the administration of steroids (P = 0.96). It is possible, however, that the low incidence of clinically significant and fatal pulmonary toxicity, as experienced in this group of patients, may be related to the infusion of bleomycin. It also is possible that the reversibility of the decrease in DLCO in 95% of the patients may be related to the duration and schedule of bleomycin administration. As bleomycin continues to be an important drug in the treatment of advanced germ cell tumors, further studies are warranted to evaluate the role of the continuous infusion of bleomycin as opposed to bolus therapy.

The prognosis for patients with adult Wilms' tumor is poor in contrast to pediatric Wilms' tumor. A 23-year-old patient with Wilms' tumor is described who relapsed twice; initially after adjuvant treatment with abdominal irradiation, vincristine, and actinomycin and again after treatment with high dose doxorubicin. The patient was treated with cisplatin and etoposide and is clear of disease 75 months after presentation. She has given birth to a healthy baby.

Twenty previously untreated children with primary Ewing's sarcoma and 8 children with primary tumor and metastatic disease were treated with surgery or radiation therapy (6,000-7,000 rads) for their primary tumor and T-2 chemotherapy. Of the 20 children with primary Ewing's sarcoma treated with T-2 "adjuvant" chemotherapy, 15 had no evidence of recurrent disease for from 31+-82+ months (median 46+ months) from the start of treatment. The actuarial 5-year disease-free survival rate for this group of patients was 75%. Eight patients presenting with metastatic disease had complete responses to T-2 chemotherapy, but 7/8 with metastatic disease eventually had tumor recurrence. Examination of the treatment failures, both those patients relapsing after adjuvant chemotherapy for primary Ewing's sarcoma (5), and those relapsing after having a complete response of metastatic disease (7) to T-2 chemotherapy, revealed that all relapses occurred at the end of the second year of T-2 chemotherapy or after chemotherapy was stopped. In addition, of 23 patients receiving "curative" radiation therapy to their primary tumor, 5 had local recurrence (22%) and 6 (26%) had severe functional debility secondary to combined radiation therapy and T-2 chemotherapy. The conclusions drawn from this experience have led us to consider a new approach to the treatment of Ewing's sarcoma, namely: 1) more aggressive initial or "induction" chemotherapy with subsequent T-2 "maintenance" chemotherapy to eradicate more completely all metastatic microfoci of disease presumed to be present in patients with primary tumor at the time of diagnosis, and ostensively present in patients with metastatic disease; 2) the use of surgery alone or in combination with moderate doses of radiation therapy in those patients in whom we can predict a high frequency of local recurrence (pelvic lesions) or a high percentage of "functional failures" (young children with lower extremity lesions). Preliminary results with this latter approach are encouraging with 11/13 patients with primary Ewing's sarcoma free of disease at 12+-26+ months. A longer follow-up of this more aggressive treatment is needed to determine the superiority of this approach for both increased survival and improved late physical rehabilitation.

Thirteen patients with osteogenic sarcoma were treated with multiple drug chemotherapy consisting of bleomycin, cyclophosphamide and dactinomycin. The dosage schedule used was: bleomycin 12 mg/m2/day, cyclophosphamide 600 mg/m2/day, and dactinomycin 450 microgram/m2/day. All drugs were given intravenously for two consecutive days. Treatment was repeated every 2 weeks. Toxicity included severe nausea and vomiting (managed with antiemetics and intravenous hydration) and manifestations of bone marrow depression. Of 13 patients, eight were previously treated with high dose methotrexate with citrovorum factor rescue, cyclophosphamide and Adriamycin. Of these eight, three patients had objective evidence of tumor regression (37.5%). Five of five previously untreated patients had objective evidence of tumor regression. The overall response rate in osteogenic sarcoma patients to BCD was 61.5%. The combination of BCD appears to be more active against osteogenic sarcoma than cyclophosphamide alone or Adriamycin alone. The relative safety with which BCD can be administered makes this combination a valuable adjunct to high dose methotrexate with citrovorum factor rescue and Adriamycin in the treatment of osteogenic sarcoma.