An evaluation of the role of surgery in disseminated neuroblastoma: A report from the Children's Cancer Study Group

An Evaluation of the Role of Surgery in Disseminated Neuroblastoma: A Report From the Children's Cancer Study Group By A. Sitarz, J. Finklestein, J. Grosfeld, S. Leikin, S. M c Creadie, M. Klemperer, I. Bernstein, H. Sather, and D. H a m m o n d

Children "s Cancer Study Group * 9 T h e role of surgery has been e v a l u a t e d in a group of patients w i t h m e t a s t a t i c neuroblastoma. Of 191 patients w i t h Stage IV neuroblastoma w h o w e r e enrolled on t w o c h e m o t h e r a p y protocols of t h e Children's Cancer Study Group, a t o t a l of 81 patients had major surgical procedures in addition t o receiving c h e m o t h e r a p y . In nine of these t h e r e had been c o m p l e t e removal of t h e p r i m a r y t u m o r at diagnosis. The remaining 72 patients had surgical e x p l o r a t i o n at t h e t i m e of a p p a r e n t l y c o m p l e t e remission. This w a s done to d e t e r m i n e w h e t h e r residual disease w a s still p r e s e n t at t h e p r i m a r y site and if present, w h e t h e r it w a s resectable, The p a t i e n t s w e r e divided into t h r e e groups according t o t h e t y p e of surgical p r o c e d u r e at diagnosis: (1) patients w i t h no surgery or a minimal procedure, (2) p a t i e n t s w i t h a major surgical procedure at diagnosis but w i t h only biopsy or p a r t i a l removal of t h e p r i m a r y t u m o r at t h e time, and (3) patients w i t h a p p a r e n t l y complete removal of t h e p r i m a r y t u m o r at diagnosis. Those p a t i e n t s in Group 1 w h o had a m a j o r surgical procedure later (N = 47) are referred to as delayed p r i m a r y s u r g e r y (DPS) and those patients in Group 2 w h o had later s u r g e r y (N = 25) are considered to have had a t r u e second look surgical p r o c e d u r e (SLS}. All p a t i e n t s received c h e m o t h e r a p y w i t h c y c l o p h o s p h a m i d e (Cytoxan| DTIC, and vincristine. Of m a j o r i n t e r e s t w a s t h e fact that even in patients w h o a p p e a r e d on clinical and radiologic grounds t o have achieved a c o m p l e t e remission f o l l o w i n g about 6 mo of c h e m o t h e r a p y , t h e m a j o r i t y w e r e found t o have residual t u m o r at the p r i m a r y site at late surgery. A r e t r o s p e c t i v e analysis of this limited series of patients w a s a t t e m p t e d t o d e t e r m i n e w h e t h e r resection of t h e p r i m a r y t u m o r influenced survival. The median survival for t h e DPS patients w a s 13 mo and for t h e SLS patients 8 mo. Despite this difference, h o w e v e r , t h e e s t i m a t e d l o n g - t e r m survival rate is a b o u t t h e same for both groups and not b e t t e r than t h a t published h e r e t o f o r e . While surgical i n t e r v e n t i o n as described here has n o t changed t h e overall remission rate, it m a y be helpful in directing f u r t h e r t h e r a p y in light of t h e finding of residual disease in so m a n y patients thought to be c o m p l e t e responders.

INDEX WORDS: Metastatic neuroblastoma.

E S E N T L Y , one-third to two-thirds of p Rpatients with metastatic neuroblastoma achieve an apparently complete clinical response after chemotherapy. ~'2 To evaluate further the Journal of Pediatric Surgery, Vol. 18, No. 2 (April), 1983

nature of this response, surgical exploration was undertaken in a series of patients with Stage IV disease at the time of apparently complete remission. This was done to determine (a) whether residual disease was still present at the primary site, and (b) if present, whether it was resectable. In addition a retrospective analysis of this limited series of patients was attempted to determine whether resection of the primary tumor influenced survival. Data from previous studies have indicated that clinical responses were usually achieved after 7-9 courses of chemotherapy or approximately 5 mo of treatment, and that relapse often occurred shortly thereafter? For this reason operative resection of the primary tumor was attempted by 6 mo of therapy in those patients who on clinical and radiologic grounds had attained an apparently complete or at least a good partial response to chemotherapy. Surgical procedures done at that time were considered delayed primary surgery (DPS), if none had been attempted previously, or true second look surgery (SLS), if a previous major procedure had been performed. All patients continued on chemotherapy following the 6-mo evaluation, but those who had not yet attained an apparently complete response on clinical grounds or were found to have u n r e sectable residual disease at surgery were also

*Contributing Children's Cancer Group investigators, institutions, and grant numbers are given in the appendix at the end of the paper. From the Children's Cancer Study Group, Los Angeles, Calif Supported by grants from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md. Address reprint requests to Children's Cancer Study Group, Operations Office, 1721 Griffin Avenue, Los Angeles, Calif. 90031. 9 1983 by Grune & Stratton, Inc. 0022-3468/83/1802-0010501.00/0 147

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given standard radiotherapy at that time to the residual tumor. This report will describe the operative findings at the time of late surgery and the subsequent outcome of patients having either DPS or SLS. MATERIALS AND

METHODS

The patients reported here were entered on the CCG 352-Pilot and CCG 352 studies of the Children's Cancer Study Group. Patients less than 16 yr of age with newly diagnosed metastatic (Stage IV) neuroblastoma were eligible for these studies. Those with Stage IV-S disease were excluded. Diagnosis was confirmed by biopsy of tumor or distant lymph nodes, or by demonstration of clumps of tumor cells in the bone marrow aspirate or biopsy with concurrent elevation of urinary catecholamines or their degradation products. In both studies initial treatment consisted of triple drug therapy repeated at 21-day intervals. The drugs and doses were as follows: cyclophosphamide imidazole carhoxamide vincristine

750 g / m 2 i.v. day 1 250 m g / m 2 i.v. day 1-5 1.5 m g / m 2 i.v. day 5

This regimen had produced a complete or good partial response in approximately 80% of patients so treated in a previous study? Course and dose adjustment were made at the time of each course for absolute neutrophil counts of less than 1,000/mm 3 and platelet counts of less than 75,000/mm 3, unless there was extensive bone marrow replacement with tumor cells. A total of 191 eligible patients with Stage IV neuroblastoma were entered on the two studies between January 1975 and June 1978 (78 in CCG 352-P and 113 in CCG 352). There were 84 females and 107 males. Of the 191 patients, 24 (12.6%) were under 1 yr of age, 142 (74.3%) between 1 and 6 yr, and 25 (13.1%) over 6 yr of age (Table 1). In order to assess the effects of late surgery on subsequent survival, an attempt was made to group patients so that they would be comparable for analysis. Thus, the following groups were established according to the type of surgical procedure at diagnosis: (1) Patients with no surgery or a minimal procedure at diagnosis, i.e., peripheral node biopsy or marrow aspiration and/or biopsy (N = 113). (2) Patients with a major surgical procedure performed at diagnosis, but without complete removal of the primary tumor, i.e., laparotomy or thoracotomy with partial removal or biopsy only of the main tumor (N = 69).

(3) Patients with an apparently complete removal of the primary tumor at diagnosis (N = 9). Patients in Group 1 who then had a major surgical procedure later (N = 47) are referred to as having had DPS. Those patients who were in Group 2 and had a later major surgical procedure (N = 25) are considered to have had a SLS procedure. The ages of the patients in these groups are given in Table 1. The age distribution in the subgroups is comparable to the overall distribution for all patients in these two studies. All patients had Stage IV disease, but the extent of the metastic involvement did vary from minimal (small primaries and one or two bone metastases) to extensive (large masses, total marrow replacement, and multiple bone or node involvement). RESULTS

Nine patients had complete removal of the primary tumor at diagnosis (Group 3) and were not subjected to further surgery. Eight of these children subsequently have had progression of disease and have died with a median survival of lOl/z mo from their surgery (Fig. 1). The longterm outcome in these patients is not better than the results for all other Stage IV patients in these studies. Seventy-two patients (from Groups 1 and 2) who attained a complete or good partial response to therapy underwent a later major surgical procedure. For these children with late surgery, the median time to DPS was 186 days (range 58-527 days) and to SLS was 177 days (range 38-357 days). Although these median times were in accord with the protocol-specified time for the procedures, the ranges show that some patients had late surgery at times that differed substantially from the protocol specifications. Of the 72 patients having late surgical procedures, 22 were considered to be in a complete remission on clinical and radiologic grounds at the time of the late surgery. Despite this clinical impression, residual tumor was found in 12 of the 22 children at exploration. Of these 12 children,

Tabte 1. Age of Patients at Diagnosis < 1 Yr Patients with primary tumor removed at diagnosis Patients with DPS* Patients with SLS t Total patients * DPS - - Delayedprimary surgery. tSLS--True second look surgery.

2 8 4 24

Percentage 22.0 17.0 16.0 12.6

1-6 Yr 7 31 18 142

Percentage 78.0 66.0 72.0 74.3

>6 Yr

Percentage

Total

0 8 3 25

0 17.0 12.0 13.1

9 47 25 191

S U R G E R Y IN D I S S E M I N A T E D

NEUROBLASTOMA

149

100~

75%

IS:,'. LL ~

25%

L....... t 10

i

) ~ l

(N=47)

"(. ==5"-) L

20 30 4o TIME (IN MONTI~} FROM SURGERY

J

5o

Survival subsequent to surgery. Patient groups Fig. 1. are: delayed primary surgery (- 9 -), second look surgery ( ), and complete surgical removal at diagnosis (---).

nine have died of their disease, one is alive but with disease after 4J/2 yr, and two appear disease free at 4 and 5 yr, respectively, after diagnosis. Of the 10 children in whom no residual tumor was found, five have died of progressive disease, one of infection, and four are alive and free of disease 31/z-5 yr after diagnosis. Of the 62 patients with residual tumor at the time of late surgery, grossly complete removal of the residual tumor was reported by the operating surgeons in 34 patients. Of these 34 patients, eight are alive 3-5 yr after diagnosis, although two of these have disease at the time of this report. Multiple node biopsies at the time of surgery were not prescribed by protocol. It appeared, however, that in those patients with apparently complete removal of residual tumor in whom nodes were sampled ( 15 of the 34), the finding of tumor in the nodes at the time of late surgery, which occurred in 11 of the 15, was a sign of poor prognosis even if gross total resection was achieved. Only two of these 11 patients are alive 5 yr after diagnosis. Although the numbers are small, of four children in whom the sampled nodes were found to be free of tumor, two are alive 3 and 41/2 yr after diagnosis, although only one of these is free of disease. Outcome of children with DPS and SLS is also shown in Fig. 1. The median survival subsequent to DPS was 13 mo and that following SLS was 8 too. Despite this difference the estimated longterm survival rate is about the same for both groups, namely 15%. An analysis of the possible prognostic effects of late surgery was limited by the fact that the

decision for a patient to have surgery was made in a nonrandomized fashion. Those patients who did not have late surgery were utilized as a retrospective comparison group in an attempt to establish "control" patients for the purpose of analysis. This was done separately for both the DPS and SLS groups, involving the use of patients who at diagnosis had comparable evaluative procedures as did those in the DPS and SLS groups, respectively (i.e., patients in Groups 1 and 2), but who then had no later surgical procedure. These "control" patients were further selected on the basis of having successfully remained on study until at least the median times to SLS or DPS, so that a negative bias would not be introduced through the use of nonsurgery patients who were unlikely to have been true potential candidates for late surgical procedures. The age distribution of the "control," SLS and DPS groups were comparable. Basic life-table 3 and other methods more specifically designed for these types of data ~ were used for analyses. The results suggested that the DPS patients had a longer time to disease progression and death than their "control" group (p = 0.002), while the SLS patients did not do as well as their "controls" (p = 0.15). DISCUSSION

This study has provided further evidence 5 that residual disease is found in most patients with Stage IV neuroblastoma in whom complete remissions are ostensibly achieved by clinical and radiologic studies. Thus, one must conclude that chemotherapy as given to these patients was ineffective in eradicating all evidence of disease even in those thought to be in complete remission. Of the 62 patients in whom residual tumor was found, total resection was achieved in 34 (55%) of them. Of these 34 patients only six remain free of disease at this time. In the analysis of these studies, the delayed primary surgery results are suggestively better in terms of longer time to disease progression and death when compared to those of patients who did not have such a procedure, i.e., the "controis." Second look surgery did not appear to improve the outcome for patients with a surgical procedure at diagnosis. In fact, the "control" group with no second look surgery did better. However, one must acknowledge the possibility

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o f bias in the " c o n t r o l s " in t h a t second look surgery was not always p e r f o r m e d on patients who h a d n e a r l y complete r e m o v a l of t u m o r at initial surgery with only microscopic residual disease. In c o m p a r i n g the results of patients having the late surgical p r o c e d u r e s with those of patients not having these procedures, one c a n n o t exclude the possibility t h a t the selection of the p a t i e n t s to have surgery m i g h t have h a d a relationship to the p a t i e n t s ' prognosis. O n l y a prospectively rand o m i z e d study assigning patients to s u r g e r y or no s u r g e r y would e l i m i n a t e this possible bias. A t t e m p t s were m a d e to a d j u s t for two potentially i m p o r t a n t prognostic variables in analysis, i.e., age at the time of diagnosis a n d extent of the disease. T h e p a t i e n t groups were c o m p a r a b l e r e g a r d i n g age at diagnosis, the m a j o r i t y being between ages 1 a n d 6 yr, the a g e group known to have the worst prognosis. 6 A l t h o u g h all patients had S t a g e IV disease, comparisons of extent o f the m e t a s t a t i c disease suggested t h a t there m a y have been some selection of the patients who had late surgery. T h e analysis of these d a t a leads one to conclude t h a t the role of late s u r g e r y for children with w i d e s p r e a d n e u r o b l a s t o m a is still unclear. C o n t r a r y to d a t a reported previously, 5 surgical removal of the p r i m a r y t u m o r in the patients reported here did not confer a significant advant a g e in terms of the long-term survival rate. T h e overall outcome o f all patients e n t e r e d into these studies has not c h a n g e d from t h a t of previous studies. Nevertheless, the fact t h a t so m a n y patients who a p p e a r to have achieved a c o m p l e t e remission do in fact, at surgical exploration, still have residual disease suggests t h a t a late surgical p r o c e d u r e m a y be helpful in directing f u r t h e r t h e r a p y . A d d i t i o n a l l y , the s a m p l i n g of l y m p h nodes at the t i m e of surgery should be encouraged and m a y be prognostically signficant. APPENDIX: PRINCIPAL INVESTIGATORS OF THE CHILDREN'S CANCER STUDY GROUP

Group Operations Office, University of Southern California, Comprehensive Cancer Center, Los Angeles, Ca, Denman Hammond, M.D., Richard Honour, Ph.D., Harland

Sather, Ph.D., James Anderson, Ph.D., John Weiner, Dr. PH., Grant Number CA 13539. University of Michigan Medical Center, Ann Arbor, Mi, Ruth Heyn, M.D., Grant Number CA 02971. Children's Hospital National Medical Center, George Washington University, Washington, DC, Sanford Leikin, M.D., Grant Number, CA 03888. Memorial Sloan-Kettering Cancer Center-Cornell University, New York, NY, Denis R. Miller, M.D., Grant Number CA 14557. Children's Hospital of Los Angeles, University of Southern California, Los Angeles, Ca, Jorge Ortega, M.D., Grant Number CA 02649. Babies Hospital, Columbia University, New York, NY, James A. Wolff, M.D., Grant Number CA 03526. Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa, Vincent Albo, M.D., Grant Number CA 07439. Children's Hospital of Columbus, Ohio State University, Columbus, Oh, William Newton, M.D., Grant Number CA 03750. Children's Orthopedic Hospital and Medical Center, University of Washington, Seattle, Wa. Ronald Chard, M.D., Grant Number CA 10382. University of Wisconsin Hospitals, Madison, Wi. N. Shahidi, M.D., Grant Number CA 05436. University of Minnesota Health Sciences Center, Minneapolis, Mn, Mark Nesbit, M.D., Grant Number CA 07306. Children's Memorial Hospital, Northwestern University, Chicago, I1, George Honig, M.D., Grant Number CA 07431. University of Utah Medical Center, Salt Lake City, Ut, Eugene Lohey, M.D., Grant Number CA 10198. Strong Memorial Hospital, University of Rochester, Rochester, NY, Martin Klemperer, M.D., Grant Number CA 11174. University of British Columbia, Vancouver, BC, Canada, Mavis Teasdale, M.D., Vancouver Foundation Grant. Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pa, Audrey Evans, M.D., Grant Number CA 11796. James Whitcomb Riley Hospital for Children, Indiana University, Indianapolis, In, Robert Baehner, M.D., Grant Number CA 13809. Harbor General Hospital, University of California, Los Angeles, Torrance, Ca, Jerry Finklestein, M.D., Grant Number CA 14560. University of California Medical Center, San Francisco, Ca, Arthur Ablin, M.D., Grant Number CA 17829. Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Oh, Peter Coccia, M.D., Grant Number CA 20320. University of Texas Health Science Center, San Antonio, Tex, Paul Zeltzer, M.D. Izaak Walton Killam Hospital For Children, Halifax, Nova Scotia, Canada, Allan Pyesomany, M.D.

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SURGERY IN DISSEMINATED NEUROBLASTOMA

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