Chemotherapy

The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]

The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]

The 3-year OS rate was 81.4%.

The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]

Eight of the nine deaths occurred in patients younger than 2 months at diagnosis. Five deaths were related to acute complications of rapidly progressing hepatomegaly (i.e., abdominal compartment syndrome, renal failure, respiratory failure, coagulopathy, and infection). Patients younger than 40 days at diagnosis had more than 13 times the risk of dying compared with patients older than 47 days. The study was amended after the five deaths to mandate immediate chemotherapy for patients with 4S disease younger than 2 months at diagnosis with evolving hepatomegaly. No deaths related to complications of hepatomegaly occurred in the subsequent infants enrolled, including 18 infants who were younger than 2 months.

The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]

This study confirmed the inferior outcome of patients with unfavorable biology (DI = 1, segmental chromosome aberrations [1p and/or 11p loss of heterozygosity, unfavorable histology] without MYCN amplification) compared with symptomatic patients with favorable biology.

The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]

Both of the patients with late death died of metastatic disease and had unfavorable biology.

Eighty patients with stage 4S disease were enrolled on the COG-P9641 (NCT00003119) trial. Forty-one patients with asymptomatic stage 4S neuroblastoma were treated with surgery or biopsy alone, and 39 patients were treated with surgery and chemotherapy.[12]

Eighty patients with stage 4S disease were enrolled on the COG-P9641 (NCT00003119) trial. Forty-one patients with asymptomatic stage 4S neuroblastoma were treated with surgery or biopsy alone, and 39 patients were treated with surgery and chemotherapy.[12]

Overall, the 5-year EFS rate was 77%, and the OS rate was 91%.

Eighty patients with stage 4S disease were enrolled on the COG-P9641 (NCT00003119) trial. Forty-one patients with asymptomatic stage 4S neuroblastoma were treated with surgery or biopsy alone, and 39 patients were treated with surgery and chemotherapy.[12]

The 5-year EFS rate was 63% for patients treated with surgery or biopsy alone and 95% for patients treated with surgery and chemotherapy (P = .0016).

Eighty patients with stage 4S disease were enrolled on the COG-P9641 (NCT00003119) trial. Forty-one patients with asymptomatic stage 4S neuroblastoma were treated with surgery or biopsy alone, and 39 patients were treated with surgery and chemotherapy.[12]

The 5-year OS rate was 84% for patients treated with surgery or biopsy alone and 97% for patients treated with surgery and chemotherapy (P = .1302).Previously, chemotherapy toxicity was thought to be responsible for the poorer survival of patients with stage 4S disease. However, the use of chemotherapy on the COG-P9641 trial was restricted to specific clinical situations with a recommended number of cycles.

Also, on the COG-P9641 trial, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[12]

Also, on the COG-P9641 trial, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[12]

Infants who became symptomatic had disease-related organ failure and infectious complications, resulting in an inferior OS compared with those who received immediate chemotherapy (4–8 cycles of therapy). The 3-year OS rate was 84% for infants who did not receive chemotherapy versus 97% for infants who received chemotherapy (P = .1321).

For the COG-ANBL0531 trial, treatment was allocated based on symptoms, patient age, and tumor biology.[9]

For the COG-ANBL0531 trial, treatment was allocated based on symptoms, patient age, and tumor biology.[9]

The 2-year OS rate was 81% for patients with INSS stage 4S disease, which is lower than that reported in other cooperative trials such as COG-P9641.

For the COG-ANBL0531 trial, treatment was allocated based on symptoms, patient age, and tumor biology.[9]

Many patients enrolled in the ANBL0531 study were more ill than patients entered in previous trials, in part because tumor biopsy was not required in symptomatic infants. Previous trials mainly included asymptomatic patients, most with favorable tumor biology.

A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.

A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.

There was no difference in the 2-year EFS and OS between asymptomatic and symptomatic patients (EFS rate, 87% vs. 88%; OS rate, 98% vs. 97%), although many of the investigators preferred to give chemotherapy in the presence of a low symptom score.

A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.

For infants with low symptom scores, there was no difference in the outcome between the initially untreated infants (n = 56; OS rate, 93%) and treated infants (n = 30; OS rate, 86%).

A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.

The OS rate was 90% for infants presenting with high symptom scores.

A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.

There was no significant difference in 2-year OS rates between patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and between patients with negative and positive skeletal scintigraphy without radiological abnormalities (100% vs. 97%).