Medical and Pediatric Oncology 6: 179-188 (1979)

Multiagent Chemotherapy for Children With Metastatic Neuroblastoma: A Report From Childrens Cancer Study Group J.Z. Finklestein, MD, M.R. Klemperer, MD, A. Evans, MD, I. Bernstein, MD, S. Leikin, MD, S. McCreadie, MD, J. Grosfeld, MD, R. Hittle, MD, J. Weiner, DrPH, H. Sather, P m , and D. Hammond, MD During the past 10-15 years there has not been a significant improvement in the overall survival of children with metastatic neuroblastoma. From 1971 through 1975, 104 eligible patients were entered on two clinical studies for newly diagnosed cases of stage IV neuroblastoma by the Childrens Cancer Study Group (CCSG). Patient data from both studies were evaluated for activity of cyclophosphamide, imidazole carboxamide, and vincristine and of these same agents plus adriamycin. Response was evaluated by serial measurements of tumor size. Eighty-four patients experienced a complete or partial response. The life-table estimate of median survival on both studies was 11-12 months for all patients and 13-18 months for responders, unchanged from the results of previous CCSG studies. Long-term survival, however, for patients on these studies demonstrates a significant increase compared with results reported from the three previous CCSG studies. Children less than 1 year or greater than 6 years of age at diagnosis showed a significantly improved survival pattern over the intermediate age group. It is suggested that there is a need t o consider the induction response pattern and age at diagnosis when planning a maintenance program so that nonresponders can be identified early and considered for treatment with new agents or aggressive multimodal therapy. Key words: cancer, neuroblastoma. children, chemotherapy

INTRODUCTION The overall survival of children with metastatic stage IV neuroblastoma has remained disappointing despite the introduction of new chemotherapeutic agents in the past 1015 years. Breslow and McCann [l] reported that of 118 children over the age of 1 year with stage IV disease, 2.5% survive tumor-free two years following diagnosis. Leikin and

Childrens Cancer Study Group investigators, institutions, and grant numbers are given in Appendix. Grant Support from Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health, Education and Welfare. Address reprint requests to Childrens Cancer Study Group Operations Office, 1721 Griffin Ave, Los Angeles, CA 90031.

0098-1532/79/0602-0179$02.00 0 1979 Alan

R. Liss, Inc.

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colleagues [2] compared previously published data with two Childrens Cancer Study Group (CCSC) studies and noted that the chemotherapeutic regimeris administered during the latter part of the 1960s had failed to improve overall survival. This paper reports the results of CCSG protocols that evaluated the activity of cyclophosphamide, imidazole carboxamide, and vincristine (CCG-331 conducted between 197 1-1974) and these three agents plus adriamycin (CCG-334 conducted between 1974- 1975) in previously untreated children with metastatic neuroblastoma. Imidazole carboxamide and adriamycin were included because each has been suggested as having antitumor effect in children with neuroblastoma [3-71. MATERIALS AND METHODS

All children in these studies had stage IV neuroblastoma, that is, disease remote from the primary site involving the skeleton, soft tissues, distant lymph nodes, marrow, etc. Patients with stage IV S disease [8] were not eligible for these studies. Diagnostic criteria included histologic verification of tumor-type cells and/or demonstration of clumps of tumor cells in the bone marrow in patients with documented elevation of urinary catecholamines. All children were newly diagnosed and none had received previous chemotherapy or radiation therapy. Wherever possible, one index lesion (ie, a nonirradiated area) was identified by the patient’s physician. When a nonirradiated area was not identified, bone marrow involvement with tumor cells was considered as measurable disease. Children were under 16 years of age at the time of diagnosis. Informed consent was obtained from the patient’s parents or legal guardian prior to the entry of the child into the study. History and physical examination with documentation of pretreatment extent of disease was required. Pathologic material was submitted to a review board and classified according to criteria suggested by Beckwith and Martin [9]. All children had blood counts, bone marrow aspirations, catecholamine determinations, and appropriate radiographs and biochemical studies. Patients entered into study CCG-331 received a combination of cyclophosphamide, vincristine, and imidazole carboxamide in the following doses: a) Cyclophosphamide 750 mg/mZ X 1 IV on day 1, b) imidazole carboxamide (DTIC) 250 mg/mZ daily IV, days 1-5, and c) vincristine 1.5 mg/mZ IV on day five (maximum dose 2.0 mg). The regimen was repeated every 22 days whenever possible (Fig. 1). Patients entered into CCG-334 received a) cyclophosphamide 750 mg/mZ X 1 1V on day 1, b) DTIC 200 mg/mZ daily IV, days 1-5, c) adriamycin 40 mg/mZ X 1 on day 3, and d) vincristine 1.5 mg/mZ on day 5 (maximum dose 2.0 mg). The regimen was to be repeated every 29 days (Fig. 1). Patient management recommendations and dose modification provisions were provided to enable dose escalations of cyclophosphamide and DTIC in patients in whom the absolute neutorphil count remained above 1,5OO/cu mm and the platelet count above 75,OOO/cu mm at the end of each cycle of therapy. In addition, specific recommendations were made for dose reduction and for the management of the common sideeffects caused by vincristine and cyclophosphamide. There was no limitation to support measures such as allopurinal, antibiotics, and the transfusion of blood products. Surgical excision and/or local X-ray therapy were permitted during the study, providing index lesions remained for evaluating the effect of chemotherapy. Seventy-two children received radiation therapy with a cumulative dose range of 200 rads to 5,000 rads. The irradiation was utilized to reduce bulk tumor or re-

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lieve symptomatic disease. There was no attempt to analyze the role of radiation therapy in the response rate and survival. During the course of the treatment, symptoms and physical findings were evaluated weekly for the first month and at the beginning of every cycle thereafter. Blood counts were obtained twice a week during the first cycle and at least weekly thereafter. Bone marrow aspirations were obtained every other cycle if tumor cells were observed at the pretreatment evaluation. Otherwise, bone marrow aspirations were performed to document either hematologic toxicity or recurrent disease. Liver function tests, urinalyses, radiologic surveys, and urine catecholamine studies were performed at 6- to 12-week intervals. Evaluation of response was based on serial measurements of tumor size. Complete tumor regression was defined as complete disappearance of all recognizable tumor masses. Partial tumor regression was defined as at least a 50% decrease of one or more lesions in the absence of progression or occurrence of new lesions elsewhere. A response: for patients with infiltration of the marrow with tumor was defined as complete elimination of observable tumor cells from the marrow sample. Progressive disease was defined as the occurrence of any new lesion or an increase of a previously measured lesion by 25%. RESULTS

Seventy-five children were entered into study CCG-331. Fifteen children were declared ineligible because of a) inappropiate age, ie, more than 16 years, b) inappropriate

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TABLE I. Multiagent Chemotherapy in Childhood Metastatic Neuroblastoma: Induction Response Evaluation Number of patients by stud? Degree of response Complete regression (> 1 mo) Partial regression (> 50%for > 1 mo) No regression Total evaluated for resuonse

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44

aSixty of 75 patients entered on CCG-331, and 44 of 5 1 entered on CCG-334 were evaluated for tumor response.

diagnosis, eg, pheochromocytoma, c) previous therapy, and d) error in staging. Sixty patients had a measurable index lesion. Fifty-one patients were entered into study CCG-334. Seven children were declared ineligible because of a) age, b) previous therapy, and c) error in staging. Forty-four patients had a measurable index lesion. Evaluation of Antitumor Effect

CCG-331. Fortyeight of 60 evaluable patients (80%)had either a complete or a partial response. Twenty-three patients experienced complete regression of all measurable disease (Table 1). CCG-334. Thirty-six of the 44 evaluable patients (82%)had either a complete or a partial response. In 19 patients complete regression of all measurable disease was observed (Table 1).

The relationships between presenting features and tumor response were investigated in both studies. Sufficient histologic material was available in 52 cases to analyze histologic grading and survival. There appeared to be a relationship between survival and the percentage of differentiated cells in the biopsy specimen, as suggested by Beckwith and Martini [9]. Exactly one-half of the children (26/52) had 5% or less differentiated cells; 35%of children with greater than 5% differentiated cells are living, whereas only 12%of children with 5% or less differentiated cells are alive. These data will be the subject of a separate report. The age distributions of patients in these studies were similar when groups were compared. There was no significant difference between response and sex of the patient, primary site of tumor, documented marrow infiltration, bone metastases, initial total leukocyte count, or absolute count. Analysis of results for children treated according to CCG-331 reveals that 14 (23%) are alive and free from tumor two years following diagnosis (Fig. 1). The life-table estimated median survival was 1 1 months for all patients, 4 months for nonresponders, and 13 months for responders (partial and complete). All patients who failed the study have expired. Survival in patients studied in CCG-334 was not significantly different from that in CCG-331 (Fig. 2). Eight of 44 patients (18%)are alive and tumor-free two years following diagnosis. The median survival was 12 months for all patients, 2 months for nonresponders, and 18 months for responders (partial or complete). Survival according to

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response in both studies is shown in Figure 3. In CCG-33 1, seven of the complete responses were in children under 1 year of age and 16 were in children 2 or more years old. In CCG-334, one of the complete responses was in a child under 1 year of age; 14 of the 18 others were in children 2 years old or older. In Figure 4, survival of the pooled CCG-33 1/334 studies is compared with CCSG predecessor studies reported by Leikin et a1 [2] (CCG-610 and 714) and a recent CCSG study that evaluated cyclophosphamide, vincristine, and cytosine arabinoside (CCG-9 13). The test for differences reveals a probability value of 0.005, suggesting that the increase in long-term survival (21% versus 6%) represents a very significant improvement over the earlier studies. The relationship between age and survival was evaluated and showed a significantly improved survival pattern for children under the age of 1 year and over the age of 6 years

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Fig. 4. Survival of children with stage IV neuroblastoma treated by Childrens Cancer Study Group since 1966. CCG-610 (vincristine and cyclophosphamide) 1966; CCC-714 (vincristine and cyclophosphamice) 1967; CCG-913 (vincristine, cyclophosphamide, cytosine arabinoside) 1969; CCC-331 and CCG-334, reported three- and fourdrug regimens.

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at the time of diagnosis (Fig. 5). Comparisons of survival experience by age at diagnosis within the CCSG predecessor studies is illustrated in Figure 6. In both groups of studies, it is apparent that the group of very young children had a better survival than the intermediate age range. However, in the earlier studies the older age group (age at diagnosis > 6) did not do as well as that observed in CCG-33 1/334. Additional analyses are given in Tables 11 and 111. Table I1 lists the age distribution in the two sets of studies. A formal statistical test for similarity in age distribution (chisquare test for homogeneity) results in a P value of 0.05 suggesting that there may be an important difference. However, this is due to proportionately more children in the < 1 and > 6 categories for CCG:331/334. When one adjusts for age categories, the survival results from CCG-331/334 are still superior. Table 111 gives the “long-term” survival at 36

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months after diagnosis within age categories for the studies. The survival results in the goodprognosis group of infants are similar in each set of studies. While there may have been a slightly different population of metastatic neuroblastoma patients treated in the studies, it does not appear that the difference in age distributions accounts for the better survival. Toxicity and Dose Escalation

Evaluable patients received the following percentages of recommended drug dosage: CCG331 : Cyclophosphamide 7 1.2%, vincristine 76.1%, vincristine 83.9%, DTIC 80.7%, and adriamycin 7 1.4%. There were no differences in the amounts of drugs received in the various age groups of children studied. Drug therapy in CCG-331 was delayed past 28 days in 10 / of 793 courses of therapy because of persistent leukopenia (13.5%). In addition, three children demonstrated enzyme changes consistent with drug-related hepatitis. In CCG-334, drug therapy was delayed past 35 days in 34 of the 496 courses (7.1%). Eighty-three courses of therapy were associated with neutropenia of less than 250/mm3 (16.7%).

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Nineteen patients in the CCG-331 study experienced 23 episodies of pneumonitis. The total granulocyte count at the time of lung disease was below 1 ,000/mm3 in only four cases. Three of the four children recovered without sequelae. Seven children died during an episode of pulmonary infiltration. Etiologic factors included Pneumocystis carinii (two cases), one case each of cytomegalic inclusion disease, staphylococcal pneumonia, interstitial infiltration, possible pulmonary hemorrhage, and possible combined viral infection and bacterial septicemia. Three other children with P carinii infection proved by lung biopsy recovered. Postmortem examination revealed that five of the seven children who died had evidence of tumor in the lung. Infectious complications were significant in CCG-334 also, being the immediate cause of death in four patients: Sepsis in two, pneumonia and sepsis in one, and P carinii pneumonia and sepsis in one. Significant, nonfatal infections in ten patients were as follows: Sepsis (two cases), pneumonia (five cases), pneumonia and sepsis (two cases), and salmonella 0 enteritis (one case). Toxicities reported in these studies included emesis, which was considered t o be severe for 13 children. One child developed autoimmune hemolytic anemia and expired “tumor-free.” Other complications that may have been related to chemotherapy included: Hemorrhagic cystitis (2), marked pancytopenia (3), flu-like syndrome (3), diarrhea (2), varicella ( l ) , staphylococcal septicemia (l), and neurotoxicity (1). The incidence of alopecia is unknown because of the general acceptance of this complication as a consequence of chemotherapy. In CCG-331,20 patients appear to have met the eligibility requirements for dosage escalation. Eleven actually received higher dosages. In addition, 11 children had the dosage reduced. Survival for patients receiving an increased dosgage ranged from 5 to 27+ months. Four patients are alive and seven have expired from this group. Survival of 11 patients receiving decreased dosages because of toxicity ranged from 8 to 29+ months. Four are alive and seven are dead. Nine children who were eligible for increased dosages but did not receive them survived for 1 t o 2 7 t months. Of these, two are alive and seven have expired. No patients in CCG-334 had their drug dosages escalated. DISCUSSION

These data suggest that the triple-drug regimen of cyclophosphamide, imidazole carboxamide, and vincristine, and a similar regimen plus adriamycin, did not significantly alter the median survival seen in children with stage IV metastatic neuroblastoma. However, the overall survival has significantly improved and 2 1% of children with stage IV disease may be potentially curable. One must recognize that these curves are presented for comparison purposes, and the criteria for stage IV disease were only published in 1971 [8]. Thus, the patient population might not be entirely homogeneous. In addition, management approaches undoubtedly changed in a subtle fashion over the ten years included in this retrospective study. Analysis of the data from studies CCG-331 and CCG-334 does identify the improved survival in recently treated children over the age of 6 years at the time of diagnosis. This finding has not been demonstrated previously. It appears that children with stage IV disease under the age of 1 and over the age of 6 years at the time of diagnosis have more than a 40% greater chance of enjoying prolonged tumor-free survival and perhaps a cure. An extensive analysis was performed to determine any relationship between survival and type of operative procedure (partial or complete removal, biopsy, laparotomy , or

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no operation of any kind). In any retrospective evaluation of this type, it must be realized that the extent of the initial operative procedure may be related to the patient’s disease status at the time of diagnosis. Thus, although a trend was observed that suggested that children who underwent more extensive surgery had an improved survival, little significance can be attributed to this finding without a prospective analysis. These data further suggest the need to consider response patterns and age at time of diagnosis when planning and judging the efficacy of maintenance programs. The addition of another agent, adriamycin, through the entire period of chemotherapy influenced neither the response rate nor the duration of response. Criteria for establishing the degree of response may have to be revised, since most children with intraabdominal neuroblastoma who appear clinically to be “complete responders” are found to have residual disease when they are explored surgically [ 101 . REFER ENCES 1. Breslow N, McCann B: Statistical estimation of prognosis for children with neuroblastoma. Cancer Res 31:2098,1972. 2. Leikin S, Evans A, Heyn R, Newton W: The impact of chemotherapy on advanced neuroblastoma. Survival of patients diagnosed in 1956, 1962, and 1966-1968 in Children’s Cancer Study Group A. J Pediatr 84: 131, 1974. 3. Finklestein JZ, Albo V, Ertel 1, Hammond GD: 5-(3,3-Dimethyl-l-l Triazeno) imidazole-4carboxamide (NSC-45388) in the treatment of solid tumors in children. Cancer Chemother Rep 59:351-357, 1975. 4. Tan C et al: Adriamycin - An anti-tumor antibiotic in the treatment of neoplastic diseases. Cancer 32:9, 1973. 5. Evans AE et al: Comparison of daunorubicin (NSC-83142) with adriamycin (NSC-123127) in the treatment of late-stage childhood solid tumors. Cancer Chemother Rep 58:671-676, 1974. 6. Blum RH, Carter SK: Adriamycin. A new anti-cancer drug with significant clinical activity. Ann Int Med 80(2):249,1974. 7. Donaldson MH: Proceedings: Treatment of neuroblastoma - 1972. Proc Natl Cancer Conf 7:605, 1973. 8. Evans AE, D’Angio GJ, Randolph J: A proposed staging for children with neuroblastoma. Cancer 27:374, 1971. 9. Beckwith J, Martin R: Observations on the histopathology of neuroblastomas. J Pediatr Surg . 3 (Part 11):106, 1968. 10. Grosfeld J, Sitarz A, Finklestein J, Leikin S: The effect of primary tumor resection on survival in metastatic neuroblastoma. Proc Am Assoc Cancer Res Am SOCClin Oncol 18:308, 1977.

APPENDIX: PRINCIPAL INVESTIGATORS IN CHILDRENS CANCER STUDY GROUP

Institution University of Southern California at Los Angeles

University of Michigan, Ann Arbor Childrens Hospital of the District of Columbia Cornell Medical Center, New York

Investigator

Grant No.

Denman Hammond, MD John Weiner, DrPh Richard Honour, PhD Harland Sather, PhD James Anderson, PhD Ruth Heyn, MD Sanford Leikin, MD

CA 13539

Denis R. Miller, MD

CA 14557

CA 0297 1 CA 03888

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Institution

Investigator

Grant No.

Childrens Hospital of Los Angeles Babies Hospital, New York Childrens Hospital of Pittsburgh Childrens Hospital of Columbus Childrens Orthopedic Hospital, Seattle University of Wisconsin, Madison University of Minnesota, Minneapolis Childrens Memorial Hospital, Chicago University of Utah Medical Center, Salt Lake City Princess Margaret Hospital, Toronto

Gussie Higgins, MD James Wolff, MD Vincent Albo, MD William Newton, MD Ronald Chard, MD N. Shahidi, MD Mark Nesbit, MD George Honig, MD Eugene Lahey, MD

CA 02649 CA 03526 CA 07439 CA 03750 CA 10382 CA 05436 CA 07306 CA 0743 1 CA 10198

Marilyn Sonley, MD

University of Rochester, New York Childrens Hospital of Louisville University of British Columbia, Vancouver Childrens Hospital of Philadelphia Indiana University, Indianapolis New Jersey College of Medicine, Newark Harbor General Hospital Torrance, California University of California at San Francisco Rainbow Babies & Childrens Hospital Cleveland

Martin Klemperer, MD Donald R. Kmetz, MD Mavis Teasdale, MD

Ontario Cancer Treatment and Research Foundation Grant No. 41-17 CA 11 174

Audrey Evans, MD Robert Baehner, MD Leonard Vitale, MD

Vancouver Foundation CA 11796 CA 13809 CA 12637

Jerry Finklestein, MD

CA 14560

Arthur Albin, MD Samuel Gross, MD

CA 17829 CA 20320