A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1.

Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one. Two patients out of 41 (4.9%) experienced transplant-related mortality. CD34 selection was discontinued after subjects were enrolled due to serious viral illness. From the time of study enrollment, the overall 3-year EFS and OS were 44.8 ± 9.6% and 59.2 ± 9.2% (N=41). These results demonstrate that tandem transplantation in the cooperative group setting is feasible and support a randomized comparison of single vs tandem myeloablative consolidation with PBSC support for high-risk neuroblastoma.

Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma.

Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3-4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure - all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.

Desmoplastic small cell tumor: a report of three cases and a review of the literature.

PURPOSE: Desmoplastic round cell tumor (DSCT) is a highly malignant abdominal tumor first described in 1991, with subsequent cases predominantly noted in pathologic case reports. The authors evaluated response to alternating, intensive chemotherapy in three patients with DSCT, and reviewed the clinical experience with this newly described tumor as reported in the literature. PATIENTS AND METHODS: Three adolescent boys with DSCT were treated intravenously with vincristine 2 mg/m2, doxorubicin 75 mg/m2, cyclophosphamide 1.8 g/m2, alternating with 5-day cycles of etoposide 100 mg/m2/day, ifosfamide 1.8 g/m2/day for a total of 11-15 courses. RESULTS: Each patient showed initial tumor regression during chemotherapy, but developed progressive disease within 8-18 months. One patient subsequently showed a transient response to doxorubicin 45 mg/m2 plus 5-fluorouracil 500-600 mg/m2. All three patients died of disease within 20 months of diagnosis. A comprehensive literature review of clinical data on 101 reported cases of DSCT is presented. The median age was 21 years (range 6-38 years) with 78 male patients and 23 female patients. Ninety-nine cases involved tumor mass in the abdominal-pelvic cavity in proximity to the mesentery. Metastatic seeding to the omentum was most common, followed by spread of disease to liver, distant lymph nodes, lung, and occasionally to scrotum or to ovary. Tumor response to chemotherapy was noted in approximately 50% of 40 patients who received combinations of doxorubicin, cisplatin, cyclophosphamide, etoposide, and/or 5-fluorouracil. Four of 13 patients who received additional radiotherapy were alive at 24-48 months. Median survival was 17 months (range: 3-72 months), with only two patients reported disease free beyond 2 years at 40 and 48 months. CONCLUSION: DSCT should be included in the differential diagnosis of small round cell tumors in children and young adults. Tumor regression has been noted during multiagent chemotherapy, but prolonged survival is rare with current therapies.

Urological aspects of intra-abdominal desmoplastic small round cell tumor of childhood: a preliminary report.

To our knowledge intra-abdominal desmoplastic round cell tumor has not previously been described in the pediatric urological literature. This lesion has only recently been recognized as a clinicopathological entity with predilection for adolescent boys. We report on 2 patients who presented with urological symptoms and a large abdominal or pelvic tumor that was biopsied at exploratory laparotomy. Complete surgical excision was impossible in both patients, who subsequently underwent multiagent chemotherapy. Histological and immunohistochemical staining are distinctive in this condition. The tumor is associated with a poor prognosis, despite multidisciplinary, multimodal therapy.

Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the Pediatric Oncology Group, Protocol 8833.

BACKGROUND: Fewer than 20% of children with intrinsic brain stem tumors survive longer than 2 years. Although some improvement has been noted in recent trials using higher doses of hyperfractionated radiation therapy (HRT), the feasibility of pre-irradiation chemotherapy has not been explored in these patients with poor prognosis. METHODS: Between February 1988 and March 1989, 37 patients were entered onto a Phase II Pediatric Oncology Group study for evaluating the feasibility, response, and toxicity of treating children with high-risk brain stem tumors with chemotherapy followed by HRT (66 Gy). Chemotherapy consisted of four cycles of cisplatin (100 mg/m2) plus cyclophosphamide (3 g/m2). RESULTS: Of 32 eligible patients, 65% improved clinically during the first 2-3 cycles of chemotherapy; 75% of those improving were weaned from steroids. On neuroradiology review of scans before and after chemotherapy, 3 patients had partial responses (PR, > 50% shrinkage), 23 had stable disease (SD), and 6 had progressive disease (PD). The median survival was 9 months. The three patients who attained a PR on chemotherapy were among the longest survivors at 38 plus, 44 plus, and 40 months. Toxicities included profound but brief marrow suppression, transient electrolyte-renal dysfunction, and ototoxicity. Brain stem swelling from intravenous fluids caused transient deterioration in two patients. Six patients developed an unusual syndrome of transient marrow suppression after HRT. CONCLUSIONS: This study suggests that pre-irradiation chemotherapy can be successfully added to the treatment of patients with brain stem tumors with both clinical and objective responses noted, but that other agents must be identified to overcome the apparent development of drug resistance and to improve survival.

The desmoplastic round cell tumor: a new solid tumor of childhood.

Three patients with a new, pathologically distinct solid tumor of childhood have been treated recently. The disease is characterized by male predominance, adolescent onset, an extensive abdominal primary tumor, and aggressive metastases to regional lymph nodes, liver, and lung. Two patients presented with vague abdominal pain and the third with testicular pain. All three noted fatigue and malaise of less than two months' duration with minimal associated weight loss. Computed tomography (CT) scans of the abdomen and chest were obtained for initial preoperative staging, and then all three underwent surgical exploration. Widespread disease was found in each case. In no instance was complete tumor extirpation possible because of extensive peritoneal spread and lymphatic and hepatic metastases. Histologically, all three tumors consisted of round blue cells with a dense desmoplastic reaction and focal rhabdoid features. Immunohistochemical markers for epithelial, neural, and muscle elements were positive. Aggressive multidrug chemotherapeutic regimens were used in each case, and all three patients are alive and well but with known residual disease. We conclude that in cases of the desmoplastic round cell tumor of childhood, CT scans underestimate the extent of disease, and exploratory laparotomy is necessary for diagnosis and appropriate staging. Surgery is usually palliative because of extensive spread. Awareness of this newly recognized aggressive solid tumor of childhood is essential to define its natural history and guide the development of effective multidisciplinary therapeutic regimens.

Chemotherapeutic treatment of extensive optic pathway tumors in infants.

Two infants, ages 14 and 4 months, with extensive optic pathway tumors were treated with intensive chemotherapy called MADDOC: nitrogen mustard, doxorubicin, cis-platinum, dacarbazine, vincristine, and cyclophosphamide. The first child had hydrocephalus with an enhancing mass at the hypothalamus which followed the optic radiation to include the lateral geniculate body and medial temporal lobe. A v-p shunt was placed, and biopsy revealed a Grade II astrocytoma. One month later, the child developed malignant ascites. Intensive induction chemotherapy was then begun with cis-platinum 100 mg/m2 and cyclophosphamide 3 g/m2 for two initial cycles. The ascites resolved within one week, and chemotherapy was continued for 10 courses of the 6-drug MADDOC regimen. CT scans showed a gradual shrinkage of the tumor mass by approximately 70%. The enhancing areas continued to decrease in size through 20 months after completing MADDOC. The child has not received radiation and is well 4 years 7 months post diagnosis. The second infant had massive enlargement of the right optic nerve with an enhancing chiasmatic mass extending into the suprasellar space, hypothalamus, and brain stem. This infant was not biopsied; she also received induction MADDOC chemotherapy for 12 cycles. CT scans showed a definite decrease in the chiasmatic mass by the fifth cycle, with continued reduction by approximately 40% after 10 months. Twenty-three months from diagnosis there was asymptomatic evidence of tumor growth. The child is being treated with carboplatinum and remains ophthalmologically and radiographically stable 43 months from diagnosis.

Stage IV neuroblastoma in infants. Long-term survival.

Before the advent of multiagent chemotherapy, the prognosis for patients with Stage IV neuroblastoma of all ages was dismal. More recently, marked improvement in infants with Stage IV neuroblastoma has been reported. Twenty-four infants with Stage IV neuroblastoma have been treated at the Dana-Farber Cancer Institute/The Children's Hospital, and the Joint Center For Radiation Therapy, Boston, Massachusetts, between 1970 and 1988. Twenty-three of these patients were treated with multiagent chemotherapy and one with a single drug. In the initial report, ten of 11 patients were alive without evidence of disease after intensive therapy. In this report the authors update their initial series of patients and include 13 additional patients who subsequently presented to our institutions with Stage IV neuroblastoma younger than 1 year of age. The 5-year actuarial event-free survival for the 24 patients is 75%. No patient without bone metastases died from neuroblastoma, and 12 of 16 patients with bone metastases remained disease free. These results confirm that infants with Stage IV neuroblastoma have a very good prognosis when treated with intensive multiagent chemotherapy.