M etastatic N euroblastoma: Factors Influencing Survival By Jay L. Grosfeld, Michael Schatzlein, Thomas V. N. Ballantine, Robert M. Weetman, and Robert L. Baehner 9 Ninety of 1 4 2 patients (63%) with neuroblastoma had metastatic disease at the t i m e of diagnosis. Seventy-four (52%) patients had stage IV disease and 16 (11%) had stage IV-S. Survival in stage IV-S was 7 5 % ( 1 2 / 1 6 ) . Four deaths occurred in infants under 6 w k of age, three of w h o m had bone m a r r o w involvement. Deaths w e r e related to respiratory insufficiency and sepsis rather than progression of disease. All patients over 6 w k of age survived with resection of primary t u m o r and skin metastases. Survivors had slow, spontaneous regression of t u m o r over a 6 - 1 5 mo period regardless of treatment. Bone m a r r o w inv o l v e m e n t w i t h t u m o r reduces the otherwise favorable outlook for patients w i t h stage IV-S disease. This suggests that patients with bone m a r r o w metastases be excluded from stage IV-S classification. Of 7 4 patients w i t h stage IV disease, 4 9 w e r e boys and 2 5 w e r e girls, with a mean age of 3 7 too. Site of primary t u m o r was adrenal in 4 0 patients, paraspinal in 27, and mediastinal in seven. Prior to 1 9 6 5 , the mean survival w a s 3 too. S i n c e t h a t t i m e , w i t h chemotherapy programs, the mean survival is 2 0 mo with 18% of patients surviving more than 2 yr. W h i l e there is l i t t l e o b j e c t i v e e v i d e n c e t h a t c h e m o t h e r a p y increases the cure rate, it can reduce t u m o r size, cause histologic maturation of tumor, and result in considerable palliation. There are six survivors (8%) disease-free longer than 2 yr. T w o w e r e under 13 mo of age and three over 6 yr. All had delayed primary or second-look t u m o r resections, and five had bone marr o w involvement, but only t w o had bone cortex metastases. These observations suggest that resection of bulk t u m o r and histologic evidence of t u m o r maturation, particularly in patients with only bone m a r r o w involvement, may result in an occasional survival. These data further suggest a modification in the staging of metastatic cases into three groups: stage I V - M , bone m a r r o w involvement only; stage IV-B, metastatic disease including bone cortex; and stage IV-S, metastatic disease involving liver and skin only. IN D E X W O R D S : M e t a s t a t i c neuroblastomas.
LTHOUGH COMBINED modalities of cancer therapy have resulted in improved survival of children with certain embryonal neoplasms (e.g. Wilms' tumor, rhabdomyosarcoma), survival in neuroblastoma has remained essentially unchanged. 1,2 While spontaneous disappearance of tumor and maturation to benign histology occasionally occur, patients with
A
Journal of Pediatric Surgery, Vol. 13, No. I (February),1978
metastatic neuroblastoma continue to have dismal prognosis, especially when bone cortex is involved. This report evaluates the factors associated with survival in 90 infants and children with metastatic neuroblastoma treated at a single pediatric cancer center. MATERIALS AND METHODS One hundred and forty-two infants and children with neuroblastoma were treated at the J a m e s Whitcomb Riley Hospital for Children on the Indiana University Medical Center campus from 1946 to 1976. Fifty-two were localized (37%) (stages I, II, or III) and 90 patients (63%) had metastatic disease at the time of diagnosis. Seventy-four patients (52%) were classified as stage IV (distant m e t a s t a s e s including bone cortex, distant lymph nodes, bone marrow, etc.), and 16 (11%) as stage IV-S, according to the staging criteria of Evans et al? This latter group of patients are usually u n d e r 1 yr of age with m e t a s t a s e s to liver, skin (subcutaneous nodules), and/or bone marrow, but no involvement of bone cortex.
Stage IV-S Of the 16 patients classified as stage IV-S, 10 patients were boys and 6 girls. Mean age at diagnosis was 3 mo (newborn-7 too) and 6 patients were less than 6 wk of age, including 2 neonates, The site of primary tumor was adrenal in 10 patients (6 right, 4 left), retroperitoneal in 4, and could not be d e t e r m i n e d in 2. T h i r t e e n patients had liver metastases, with the liver involved alone in 3 patients, with skin m e t a s t a s e s in 5 patients, and with bone marrow m e t a s t a s e s in 5. T h r e e additional patients had skin m e t a s t a s e s alone. No patient with skin involvement had tumor cells noted in the bone marrow biopsy and/or aspirate.
From the Section of Pediatric Surgery, Department of Surgery, and the Section of Pediatric HematologyOncology, Department of Pediatrics, Indiana University School of Medicine and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Presented before the X X I V lnternational Congress of the British Association of Paediatric Surgeons, Oslo, Norway, August 2-6, 1977. Address reprint requests to Jay L. Grosfeld, M.D., Surgeon-in-Chief, James Whitcomb Riley Hospital for Children, 1100 West Michigan Street, Indianapolis, Ind. 46202. 9 1978 by Grune & Stratton, Inc. 0022-3468/78/1301 0014501.00/0
59
60
GROSFELO ET AL.
Table 1. IV-S Neuroblastoma--16 Cases Site of Metastases Patient
Age at Diagnosis
Sex
Site of Primary
1 2 3 4
4 wk newborn 4wk 5 me
F M M M
right adrenal left adrenal ? left adrenal
+ + +
M
right adrenal
+
5
6 me
Liver
Skin
Bone Marrow
Therapy Chemo
600 to liver 800 to liver
CYT, VNC
liver biopsy liver biopsy
6 days 1" 32 days 1"
P32
liver biopsy adrenalectomy skin biopsy adrenalectomy
2 me I" 5 yr
+
Surgery
Length of Survival
X-ray*
10 me
skin biopsy 6
7 me
M
right adrenal
7
newborn
F
?
+
21 O0 to liver
adrenalectomy liver biopsy skin biopsy
+
8
4 me
M
left adrenal
+
+
9
3 me
F
right adrenal
+
10
5 me
F
right adrenal
+
11 12 13
6 wk 11 wk 6 wk
F M F
left adrenal paraspinal right adrenal
+ + +
+ +
+ dose?
14
6 me
M
paraspinal
+
+
800 to liver
15 16
3 me 5 me
M M
paraspinal paraspinal
+
+ +
1200 to liver
1600 to liver
1200 to liver
P32 P32
no laparotomy adrenalectomy liver, skin biopsy adrenalectomy liver biopsy adrenalectomy liver biopsy none liver biopsy adrenalectomy kidney tumor resection none liver biopsy
5 yr 3 yr 3 yr
1 yr 3 yr 2 days t 20 yr 2 yr 18 yr 17 yr 16 yr
CYT, Cytoxan; VNC. vincristine; P32, radioactive phosphorus. "Measured in rads. I" Died.
Laparotomy was performed in 13 patients, with resection of the primary tumor and liver biopsy in 8 cases and liver biopsy alone in 5. Three infants had no laparotomy. Radiation therapy, to the liver (600-2100 rad) was employed in 8 patients and chemotherapy (P32, vincristine, Cytoxan) in four (Table 1). The mortality rate was 25 % (4/16). All 4 deaths (2 boys, 2 girls) occurred in infants less than age 6 wk at diagnosis, including one neonate. Three had liver and bone marrow involvement and one had only liver involved by tumor. Two of these patients received radiation and 2 chemotherapy. Two patients developed respiratory insufficiency related to massive hepatomegaly and succumbed to pulmonary infection. Two other patients (one of whom had renal failure) died following septicemia. Two of these patients were given total parenteral nutrition and one newborn had a temporary ventral hernia created by insertion of a Dacron reinforced silastic sheet in an attempt to relieve respiratory distress. The overall survival rate was 75% (12/16) and was associated with a spontaneous slow regression and finally disappearance of tumor over a 6-15 me period. This coincided with a slow decrease in the elevated urinary excretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA). During this time, vomiting due to gastroesophageal reflux was a significant problem in 5 surviving patients with significant hepatomegaly. Three were treated with total parenteral nutrition. All 10 patients over 6 wk of age at the
time of diagnosis, with resection of the primary tumor and skin involvement, survived.
Stage IV o f 74 patients with stage IV metastatic neuroblastoma, 49 (67%) were boys and 25 (33%) were girls. The mean age of diagnosis was 37 me with a range of newborn-9~ yr. Age grouping at the time of diagnosis (Fig. 1) included 7 infants under 1 yr (9.4%), 20 between 12 and 24 me (27.6%), 27 from 2 to 4 yr (36.5%), six patients 4-5 yr (6.7%), and 14 patients over 6 yr (18.9%). The clinical manifestations were quite varied, but frequently included the presence of mass, weight loss, fever, bone or abdominal pain, weakness, anemia, proptosis, and a generalized failure to thrive. Most patients with abdominal neuroblastoma demonstrated a downward and/or outward displacement of the kidney by an extrarenal mass on pyelography. Abdominal radiograph showed calcification of the punctate form within the tumor in 50% of the cases. Diagnosis was usually established by tissue biopsy, elevated 24-hr urinary VMA or HVA levels, and the presence of neuroblastoma cells on bone marrow aspirate and/or biopsy. Skeletal radiographic survey was routinely obtained, and in recent years a radioactive pertechnetate diphosphanate bone scan was employed. Skeletal metastases most commonly occurred in the skull (including the orbit), femur, humerus, pelvis, ribs, vertebral
METASTATIC
u~
NEUROBLASTOMA
61
> 2 YEAR F R E E OF DISEASE
25
Z
~ 20
Q
15-
10--
5--
0----
0-1
1-2
AGE
2-4
4-5
> - 6
(Y E A R S)
Fig. 1. Bar graph illustrating the age at the time of diagnosis in 74 infants with stage IV neuroblastoma. There were six disease-free survivors (striped bar), three of whom were older than 6 yr.
column, and tibia. Distant lymph nodes, particularly in the mediastinum and neck, were frequently involved. The site of primary tumor occurrence was adrenal in 40 patients (54%) with a left-sided predominance, retroperitoneal (paraspinal) in 27 (36.6%), and mediastinal in 7 (9.4%). In 30 patients treated prior to 1965, therapy was limited in most to radiation treatment and the occasional use of P32 and nitrogen mustard. Few patients had resectional therapy. Since 1965, 44 patients with metastatic neuroblastoma have been treated under a number of protocols designed by the Children's Cancer Study Group (CCSG) of which the James Whitcomb Riley Hospital is a member institution. Treatment included utilization of chemotherapy programs using nitrogen mustard, Cytoxan, vincristine, adriamycin, and imidazole carboxamide (DTIC) as single agents and in combination. Radiation therapy was usually given to the primary tumor and occasionally to metastatic foci (orbit), especially to relieve symptoms of bone pain. Complete or partial operative resection of the primary tumor was attempted when possible. However, in most cases on initial operation, only a biopsy of a massive unresectable tumor was feasible (Figure 2). In recent years (1972 1976), 70% of patients treated with multidrug chemotherapy (Cytoxan, vincristine, DTIC) showed a response to therapy, while in 30% no response was observed. Eight patients who responded to therapy (5 with a complete response, e.g. no overt evidence of tumor, and 3 with a partial response) underwent a delayed primary or secondlook operation following significant reduction of tumor size on therapy. Residual tumor was found in each case. Complete resection was accomplished in 4 of 5 patients c o n s i d e r e d c o m p l e t e r e s p o n d e r s , and in one p a r t i a l responder, in 2 other patients who had a partial response to chemotherapy, resection was still not possible, Histologic examination of resected tissues following treatment showed maturation of tumor from a highly malignant grade IV neuroblastoma obtained at the initial biopsy to a less malignant ganglioneuroblastoma (grade II). The mean duration of survival for the 74 stage IV patients was 13 mo. Prior to 1965 the mean survival was only 3 mo, compared to 20 mo since that time. There were no survivors among 30 stage IV patients treated before 1965, while 9 of
Fig. 2. Abdominal radiograph in a 6-yr-old girl with a large, calcified n e u r o b l a s t o m a and bone m a r r o w metastases. The tumor was unresectable at the initial operation and only a biopsy was performed. Treatment with three drug chemotherapy (Cytoxan, Vincristine, DTIC) resulted in a significant reduction in the size of the tumor. Complete resection of the lesion was accomplished at a second-look laparotomy.
44 treated since then are presently alive. One patient, age 26 mo with multiple bone metastases, is alive with disease within 1 yr following diagnosis. Eight patients are surviving more than 2 yr, with 6 (8.1%) free of disease from 2 ~ to 11 yr following diagnosis (Table 2). Age at the time of diagnosis in these 6 patients was 4 too, 13 mo, 30 mo, and 3 patients over age 6. Three patients (ages 13 mo, 6 yr, 6 yr) had neuroblastoma in bone marrow but were without evidence of bone cortex involvement. All had second-look resections and are alive 3, 4, and 8 yr following treatment. One patient (age 30 mo) had mediastinal lymph node metastases treated by x-ray therapy and a delayed primary resection of a left adrenal tumor 6 mo following chemotherapy and is alive and well 7 yr later. Two patients ages 4 mo and 6 yr had both bone marrow and bone cortex involvement. The former had partial resection of a retroperitoneal mass followed by x-ray therapy, Cytoxan, and vincristine treatment. Eight yr later, a single metastatic focus was excised from the tibia and the patient has been free of disease for 3 additional y r - - a total of 11 yr from the time of initial diagnosis. The 6-yr-old boy had a delayed primary resection of a right adrenal tumor 5 mo following treatment with x-ray, vincristine, Cytoxan, and DTIC. He is alive and well and free of disease, 21~ yr later. Three patients with second-look operations had evi-
62
GROSFELD ET AL.
Table 2. Survival in Stage IV Metastatic N e u r o b l a s t o m a - - 6 / 7 4 Cases (8.1%) Site of Metastases Patient 1
Age at Diagnosis 4 mo
Sex M
Site of Primary retroperitoneal
Bone
Bone Marrow
+
+
Other lymph nodes
X-ray +
Therapy Chemo CYT
Surgery
delayed
Length of Survival 11 yr
incomplete resection 2
13 mo
F
paraspinal
--
+
lymph nodes
+
CYT, VNC
second-look
8 yr
resection 3
3 0 mo
M
left adrenal
--
--
mediastinal
+
CYT, VNC
lymph nodes 4 5 6
6 yr 6 yr 11 mo 6 yr
F M M
left adrenal right adrenal left adrenal
--+
+ + +
lymph nodes lymph nodes lymph nodes
delayed primary
8 yr
resection +
CYT, VNC,
second-look
3 yr
+
DTIC CYT, VNC,
resection second-look
4 yr
+
DTIC CYT, VNC,
resection delayed primary
2 ~,5 yr
DTIC
resection
CYT, Cytoxan; VNC, vincristine; DTIC, imidizole carboxamide.
dence of maturation of tumor tissues from neuroblastomato ganglioneuroblastoma with areas of benign ganglioneuroma in one. The mean total lymphocyte count in this group of survivors was 1344/mm3 with a range of 945-2232/mm3 that was similar to counts in nonsurvivors. DISCUSSION
Neuroblastoma is an example of a malignant tumor with the potential to undergo spontaneous regression and mature to a benign form. Spontaneous regression of neuroblastoma in patients who recover after no therapy or unconventional therapy usually considered inadequate for cure (e.g. irradiation of liver) is commonly observed in stage IV-S and occasionally in stage II patients. The favorable prognosis for this variant of metastatic neuroblastoma (stage IV-S) was confirmed in the present study where the survival rate was 75% (12/16). D'Angio et al? and Evans et al. 2 similarly recorded survival rates of 84% (21/25) and 75% (12/16)in infants with IV-S disease. Deaths in these infants are rarely due to progression of malignant disease, being more often related to complications such as respiratory insufficiency and sepsis. Respirat o r y e m b a r r a s s m e n t m a y o c c u r due to diaphragmatic elevation from an enlarged liver filled with tumor. Attempts to decrease the rapidly increasing liver size with radiation therapy was attempted in 8 patients in the present study including two who died. Although a few patients experienced some decrease in liver size, the response was not uniform. In general, t u m o r regression in the liver was characterized by a slow, spontaneous disapp e a r a n c e over a 6 - i 5 mo period of time.
Schnaufer and Koop reported the use of a temporary ventral hernia created by inserting a Dacron reinforced silastic sheet (much like treatment of neonates with abdominal wall defects) to relieve intraabdominal pressure in two IV-S cases, one of whom survived? This technique was unsuccessfully employed in one infant in the present study who eviscerated when the silastic sheeting separated from the skin edge, and the child subsequently succumbed from sepsis. Koop and Schnaufer suggested individualizing decisions regarding the most appropriate management of IV-S cases? They suggest no therapy other than removal of the primary tumor for infants with small primary lesion and liver metastases. There is no strong evidence to confirm primary tumor resection as beneficial in instances of Stage IV-S (as the primary site may not be determinable). In the present study, however, all eight of the infants with IV-S disease who had the primary tumor resected survived. It is of interest that three of the four patients with IV-S disease that died had tumor clumps in the bone marrow. All were under 6 wk of age at the time of diagnosis. The relatively poor survival of IV-S patients with bone marrow involvement (3/5 died) suggest that this presentation may not yield the same favorable prognosis as those infants with liver disease and/or skin involvement alone. D'Angio et al. described two IV-S patients with positive bone marrow aspirates who died of progressive disease? These observations question the advisability of including patients with positive bone marrow in stage
METASTATIC NEUROBLASTOMA
IV-S. Perhaps it would be more useful to group these patients as stage IV-M (marrow) and treat them with chemotherapy. Koop et al. and D'Angio et al. have similarly suggested using chemotherapy for infants with IV-S disease and a positive bone marrow? ,5 They stress the theoretic dangers of simply observing clumps of tumor cells in the marrow that may progress to bone cortex metastases. Treatment with chemotherapy, however, does not guarantee survival, as two infants with stage IV-S and marrow involvement who died in the present review received chemotherapy. The best prognosis in patients with neuroblastoma is observed in the youngest patients, who usually are those with the highest total lymphocyte counts. ~ Tumor involvement of the bone marrow inhibits both lymphocyte and g r a n u l o c y t e (phagocytic) cell production, reduces immunocompetence, and makes the patient more susceptible to tumor spread and sepsis. A comparison can be made to the increased incidence of infection seen in infants and children with lymphocytic leukemia who have bone marrow replacement by tumor cells and absolute g r a n u l o c y t e counts below 200/mm3. r This may be of considerable importance in the newborn period, when the infant has relative deficiencies of IgM, of factor B of the alternative complement pathway leading to a decrease in the C3 component of complement, and opsonin production. These factors may explain in part the occurrence of fatal instances of sepsis in the present report: all deaths occurred in young infants under 6 wk of age. In addition, the greatly enlarged liver in IV-S cases c o m p r e s s e s the viscera and elevates the diaphragm resulting in a change in the gastroesophageal angle. This results in significant gastroesophageal reflux, vomiting, aspiration, and poor nutrition that further affects the immune response, making the infant even more susceptible to infection. Total parenteral nutrition was used in five patients in this review for nutritional support in attempts to improve caloric intake and immune competence. The fact that all infants with IV-S disease and skin (subcutaneous nodules) involvement uniforreally survived is most unique. This occurrence strongly implicates an unusual tumor-host relationship probably based on immune factors. A detailed description of all the immune factors
63
associated with neuroblastoma is beyond the scope of this report. The most dismal survival data in instances of neuroblastoma has been noted in cases of Stage IV disease. Unfortunately, these patients account for more than half of all the cases of neuroblastoma seen at the time of diagnosis. Breslow and McCann reported a 2.5% 2-yr survival in cases of stage IV disease. 8 Unlike other embryonal tumors (e.g. Wilms', rhabdomyosarcoma), there has been no objective evidence that chemotherapy has improved the cure rate of neuroblastoma over the past decade. 1,2,5,8,9 Although chemotherapy has not prolonged the median survival time in patients with metastatic neuroblastoma in some reports, ~ we have observed an increase in the mean survival time from 3 mo to 20 mo since 1965, using chemotherapy programs according to the CCSG protocols. It is apparent, therefore, that chemotherapy can reduce tumor size and result in appreciable palliation. Unfortunately, only 40% of patients with metastatic neuroblastoma (stage IV) had a complete response, while 30% did not respond at all to chemotherapy programs. On the other hand, in the present report, 18% (8/44) of patients survive for more than 2 yr, some, of course, with evidence of disease. While complete excision of neuroblastoma in patients with localized disease results in a higher survival rate, the efficacy of resection of the primary tumor in instances of metastatic neuroblastoma has not yet been clearly established. Koop and Schnaufer suggest resection of the primary tumor in stage IV cases only when the operative risk is small and the patient's general condition is not severely undermined by the disseminated process? In the presence of distant metastases, the use of wide enbloc resection of viscera contiguous to the tumor is obviously unwarranted. It has been our experience that in most cases of stage IV disease, the tumor is usually excessively large and often initially unresectable. The six longterm survivors in the present report all had their primary tumor resected. Operative resection, however, was carried out at a delayed primary operation or a second-look procedure, following a significant decrease in the size of the primary lesion related to irradiation and/or chemotherapy. All patients with delayed primary or second-look operations had residual tumor,
64
even those patients who were considered to be complete responders without obvious clinical evidence of persistent disease. The histologic evaluation of residual tumor obtained in the second-look cases demonstrated that treatment with chemotherapy resulted in maturation of the tumor from neuroblastoma to ganglioneuroblastoma in each instance, with areas of benign ganglioneuroma observed in one instance. Similar observations had been made in a recent CCSG metastatic neuroblastoma study, where 22 of 23 patients with delayed primary or second-look resections had residual tumor, and tumor m a t u r a t i o n to ganglioneuroblastoma usually followed c h e m o t h e r a p e u t i c management. ~o Although Evans and Hummeler suggest that a high total lymphocyte count (greater than 3000/mm 3) is associated with improved survival, 6 the mean total lymphocyte counts of the six stage IV survivors in the present report was 1344/mm 3. This was not significantly different from patients who died. Although age is an independent variable that directly affects survival in neuroblastoma, only two of six stage IV survivors in the present study were under 13 mo at diagnosis. Of great interest is the fact that three of six survivors were over the age of 6 yr at the time of diagnosis. The explanation for this latter finding is not clear. Five of six survivors in the present report had neuroblastoma in the bone marrow, whereas only two had bone cortex involvement. These observations support the view of Evans et al. 2 and Priebe and Clatworthy, 9 that identification of tumor cells in the bone marrow does not have the same grave prognosis as bone cortex metastases. This further implies that a modification in the staging of metastatic neuroblastoma seems indicated. We propose the following change: stage IV-M metastatic disease involving bone marrow only; stage IV-B metastatic disease including bone cortex and other sites: and stage IV-S metastatic disease involving liver and skin (subcutaneous tissue) only. With these considerations it is important that at the time of diagnosis, the tumor cell invasion of the bone m a r r o w m u s t be c a r e f u l l y differentiated from lymphoblasts. Although radioactive bone scans ( p e r t e c h n e t a t e diphosphanate) seem more sensitive than the long
GROSFELD ET AL.
bone survey in detecting early cortical bone metastasis, false positives can be observed in instances of recent bone trauma or inflammation. While bone scans may be highly suggestive of metastatic disease, the radiographic bone survey still appears to be the most reliable clinical determinant of this type of metastatic process. Long-term disease-free survival with bone metastases is uncommon, although one patient in the present review went 8 yr following initial diagnosis until a late recurrence of neuroblastoma in a single metastatic focus occurred in the distal tibia. This was biopsied and treated with radiation and chemotherapy. The child has been free of disease for 3 yr, or 11 years since the time of initial diagnosis. Konrad et al. noted two late recurrences 6 and 10 yr following treatment. 11 These instances indicate that although 2-yr survival without evidence of r e c u r r e n t disease usually indicates a "cure," occasional patients also have late recurrences. These cases further imply that long-term tumor clinic follow-up is required in patients with metastatic disease who are presumably free of recurrence. Ogle et al. and Versfeldt followed patients with recurring metastases for 17 and 21 yr, respectively, who finally died at ages 21 and 22 yr. 12'13 Other reports concerning long-term survivors with stage IV disease indicate most patients with extraadrenal primary tumors that have been resected are under 1 yr of age at diagnosis. 14--17 Although our six long-term survivors with stage IV disease give rise to some hope for " c u r e " in metastatic neuroblastoma, such cases are unusual. The major problems associated with therapy in cases of metastatic disease include the advanced extent of disease with a large tumor volume that results in suppression of lymphocytes and the immune response. Present studies at some centers attempting to overcome inadequate initial cell kill by employing aggressive high dose Cytoxan therapy (given to toxicity) in conjunction with papaverine (to c a u s e t u m o r m a t u r a t i o n ) do not c l e a r l y demonstrate improved results. 18 Future treatment programs should be directed towards operative reduction of tumor bulk, enhancement of the immune response (such as the use of BCG-injection directly into unresectable tu-
METASTATIC NEUROBLASTOMA
65
mors), stimulation of tumor maturation (neuroblastoma ~ ganglioneuroblastoma --- ganglioneuroma), and delivery of more effective sequentially administered cell-cycle oriented chemotherapy. Unfortunately, at the present time there is no specific drug that has a curative
effect on this tumor. In addition, there are still many unknown factors, especially those affecting the host-tumor relationship that probably play a significant role in the survival of occasional patients with metastatic neuroblastoma,
REFERENCES
1. Grosfeld JL, Ballantine TVN, Baehner RL: Current management of childhood solid tumors. Surg Clin North Am 56:513-535, 1976 2. Evans AE, D'Angio G J, Randolph JG: A proposed staging for children with n e u r o b l a s t o m a . C a n c e r 27:374-378, 1971 3. D'Angio G J, Evans AE, Koop CE: Special pattern of widespread neuroblastoma with a favorable prognosis. Lancet 1; 1046-1049, 1971 4. Schnaufer L, Koop CE: Silastic abdominal pouch for temporary hepatomegaly in stage IV-S neuroblastoma. J Pediatr Surg 10:73-75, 1965 5. Koop CE, Schnaufer L: The management of abdominal neuroblastoma, Cancer 35:905-909, 1975 6. Evans AE, Hummeler K: The significance of primitive cells in marrow aspirates of children with neuroblastoma. Cancer 32:906-912, 1973 7. Chilcote RR, Baehner RL: Infection in childhood cancer: Experience in the management of infections in acute leukemia. Pediatr Ann 3:71 88, 1974 8. Breslow N, McCann B: Statistical estimation of prognosis for children with n e u r o b l a s t o m a . Cancer Res 31:2098-2103, 1971 9. Priebe CR, Clatworthy HW Jr: Neurobtastoma: An evaluation of 90 children. Arch Surg 95:538-545, 1967 10. Grosfeld JL, Bernstein I, Sitarz A, et al: The effect of primary tumor resection on survival in metastatic neuroblastoma. Proc Am Soc Clin Oncol 18:308 (C-167), 1977
11, Konrad PN, Singher L J, Neerhout RC; Late death from neuroblastoma. J Pediatr 82;80-81, 1973 12. Vogel JM, Coddon DR, Simon N, et al: Osseous metastases in neuroblastoma: A 17 year survival, Cancer 26:1354-1360, 1970 13. Versfeldt J: Transformation of sympathicoblastoma to ganglioneuroma with a case report. Acta Pathol Microbiol Scand 58:414-428, 1963 14. Reilly D, Nesbit ME, Krivit W: Cure of three patients who had skeletal metastases in disseminated neuroblastoma. Pediatrics 41:47 51, 1968 15. McGoldrick KE, Lanzkansky P: Prolonged survival in neuroblastoma with multiple skeletal metastases and bone marrow infiltration. Acta Paediatr Stand 59:711 714, 1970 16. King RL, Storaasli JP, Dolande RP: Neuroblastoma: Review of 28 cases and presentation of two cases with metastases and long term survival. Am J Roentgenol 85:733-747, 1961 17. Goldman RL, Winterling AN, Winterling CC: Maturation of tumors of the sympathetic nervous system: Report of long term survival in two patients, Cancer 18:1510-15 !5, 1965 18. Murphy ML, Helson L: Chemotherapy of Stage IV metastatic neuroblastoma. Proc Am Soc Clin Oncol 18;338, 1977
LTHOUGH COMBINED modalities of cancer therapy have resulted in improved survival of children with certain embryonal neoplasms (e.g. Wilms' tumor, rhabdomyosarcoma), survival in neuroblastoma has remained essentially unchanged. 1,2 While spontaneous disappearance of tumor and maturation to benign histology occasionally occur, patients with
A
Journal of Pediatric Surgery, Vol. 13, No. I (February),1978
metastatic neuroblastoma continue to have dismal prognosis, especially when bone cortex is involved. This report evaluates the factors associated with survival in 90 infants and children with metastatic neuroblastoma treated at a single pediatric cancer center. MATERIALS AND METHODS One hundred and forty-two infants and children with neuroblastoma were treated at the J a m e s Whitcomb Riley Hospital for Children on the Indiana University Medical Center campus from 1946 to 1976. Fifty-two were localized (37%) (stages I, II, or III) and 90 patients (63%) had metastatic disease at the time of diagnosis. Seventy-four patients (52%) were classified as stage IV (distant m e t a s t a s e s including bone cortex, distant lymph nodes, bone marrow, etc.), and 16 (11%) as stage IV-S, according to the staging criteria of Evans et al? This latter group of patients are usually u n d e r 1 yr of age with m e t a s t a s e s to liver, skin (subcutaneous nodules), and/or bone marrow, but no involvement of bone cortex.
Stage IV-S Of the 16 patients classified as stage IV-S, 10 patients were boys and 6 girls. Mean age at diagnosis was 3 mo (newborn-7 too) and 6 patients were less than 6 wk of age, including 2 neonates, The site of primary tumor was adrenal in 10 patients (6 right, 4 left), retroperitoneal in 4, and could not be d e t e r m i n e d in 2. T h i r t e e n patients had liver metastases, with the liver involved alone in 3 patients, with skin m e t a s t a s e s in 5 patients, and with bone marrow m e t a s t a s e s in 5. T h r e e additional patients had skin m e t a s t a s e s alone. No patient with skin involvement had tumor cells noted in the bone marrow biopsy and/or aspirate.
From the Section of Pediatric Surgery, Department of Surgery, and the Section of Pediatric HematologyOncology, Department of Pediatrics, Indiana University School of Medicine and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Presented before the X X I V lnternational Congress of the British Association of Paediatric Surgeons, Oslo, Norway, August 2-6, 1977. Address reprint requests to Jay L. Grosfeld, M.D., Surgeon-in-Chief, James Whitcomb Riley Hospital for Children, 1100 West Michigan Street, Indianapolis, Ind. 46202. 9 1978 by Grune & Stratton, Inc. 0022-3468/78/1301 0014501.00/0
59
60
GROSFELO ET AL.
Table 1. IV-S Neuroblastoma--16 Cases Site of Metastases Patient
Age at Diagnosis
Sex
Site of Primary
1 2 3 4
4 wk newborn 4wk 5 me
F M M M
right adrenal left adrenal ? left adrenal
+ + +
M
right adrenal
+
5
6 me
Liver
Skin
Bone Marrow
Therapy Chemo
600 to liver 800 to liver
CYT, VNC
liver biopsy liver biopsy
6 days 1" 32 days 1"
P32
liver biopsy adrenalectomy skin biopsy adrenalectomy
2 me I" 5 yr
+
Surgery
Length of Survival
X-ray*
10 me
skin biopsy 6
7 me
M
right adrenal
7
newborn
F
?
+
21 O0 to liver
adrenalectomy liver biopsy skin biopsy
+
8
4 me
M
left adrenal
+
+
9
3 me
F
right adrenal
+
10
5 me
F
right adrenal
+
11 12 13
6 wk 11 wk 6 wk
F M F
left adrenal paraspinal right adrenal
+ + +
+ +
+ dose?
14
6 me
M
paraspinal
+
+
800 to liver
15 16
3 me 5 me
M M
paraspinal paraspinal
+
+ +
1200 to liver
1600 to liver
1200 to liver
P32 P32
no laparotomy adrenalectomy liver, skin biopsy adrenalectomy liver biopsy adrenalectomy liver biopsy none liver biopsy adrenalectomy kidney tumor resection none liver biopsy
5 yr 3 yr 3 yr
1 yr 3 yr 2 days t 20 yr 2 yr 18 yr 17 yr 16 yr
CYT, Cytoxan; VNC. vincristine; P32, radioactive phosphorus. "Measured in rads. I" Died.
Laparotomy was performed in 13 patients, with resection of the primary tumor and liver biopsy in 8 cases and liver biopsy alone in 5. Three infants had no laparotomy. Radiation therapy, to the liver (600-2100 rad) was employed in 8 patients and chemotherapy (P32, vincristine, Cytoxan) in four (Table 1). The mortality rate was 25 % (4/16). All 4 deaths (2 boys, 2 girls) occurred in infants less than age 6 wk at diagnosis, including one neonate. Three had liver and bone marrow involvement and one had only liver involved by tumor. Two of these patients received radiation and 2 chemotherapy. Two patients developed respiratory insufficiency related to massive hepatomegaly and succumbed to pulmonary infection. Two other patients (one of whom had renal failure) died following septicemia. Two of these patients were given total parenteral nutrition and one newborn had a temporary ventral hernia created by insertion of a Dacron reinforced silastic sheet in an attempt to relieve respiratory distress. The overall survival rate was 75% (12/16) and was associated with a spontaneous slow regression and finally disappearance of tumor over a 6-15 me period. This coincided with a slow decrease in the elevated urinary excretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA). During this time, vomiting due to gastroesophageal reflux was a significant problem in 5 surviving patients with significant hepatomegaly. Three were treated with total parenteral nutrition. All 10 patients over 6 wk of age at the
time of diagnosis, with resection of the primary tumor and skin involvement, survived.
Stage IV o f 74 patients with stage IV metastatic neuroblastoma, 49 (67%) were boys and 25 (33%) were girls. The mean age of diagnosis was 37 me with a range of newborn-9~ yr. Age grouping at the time of diagnosis (Fig. 1) included 7 infants under 1 yr (9.4%), 20 between 12 and 24 me (27.6%), 27 from 2 to 4 yr (36.5%), six patients 4-5 yr (6.7%), and 14 patients over 6 yr (18.9%). The clinical manifestations were quite varied, but frequently included the presence of mass, weight loss, fever, bone or abdominal pain, weakness, anemia, proptosis, and a generalized failure to thrive. Most patients with abdominal neuroblastoma demonstrated a downward and/or outward displacement of the kidney by an extrarenal mass on pyelography. Abdominal radiograph showed calcification of the punctate form within the tumor in 50% of the cases. Diagnosis was usually established by tissue biopsy, elevated 24-hr urinary VMA or HVA levels, and the presence of neuroblastoma cells on bone marrow aspirate and/or biopsy. Skeletal radiographic survey was routinely obtained, and in recent years a radioactive pertechnetate diphosphanate bone scan was employed. Skeletal metastases most commonly occurred in the skull (including the orbit), femur, humerus, pelvis, ribs, vertebral
METASTATIC
u~
NEUROBLASTOMA
61
> 2 YEAR F R E E OF DISEASE
25
Z
~ 20
Q
15-
10--
5--
0----
0-1
1-2
AGE
2-4
4-5
> - 6
(Y E A R S)
Fig. 1. Bar graph illustrating the age at the time of diagnosis in 74 infants with stage IV neuroblastoma. There were six disease-free survivors (striped bar), three of whom were older than 6 yr.
column, and tibia. Distant lymph nodes, particularly in the mediastinum and neck, were frequently involved. The site of primary tumor occurrence was adrenal in 40 patients (54%) with a left-sided predominance, retroperitoneal (paraspinal) in 27 (36.6%), and mediastinal in 7 (9.4%). In 30 patients treated prior to 1965, therapy was limited in most to radiation treatment and the occasional use of P32 and nitrogen mustard. Few patients had resectional therapy. Since 1965, 44 patients with metastatic neuroblastoma have been treated under a number of protocols designed by the Children's Cancer Study Group (CCSG) of which the James Whitcomb Riley Hospital is a member institution. Treatment included utilization of chemotherapy programs using nitrogen mustard, Cytoxan, vincristine, adriamycin, and imidazole carboxamide (DTIC) as single agents and in combination. Radiation therapy was usually given to the primary tumor and occasionally to metastatic foci (orbit), especially to relieve symptoms of bone pain. Complete or partial operative resection of the primary tumor was attempted when possible. However, in most cases on initial operation, only a biopsy of a massive unresectable tumor was feasible (Figure 2). In recent years (1972 1976), 70% of patients treated with multidrug chemotherapy (Cytoxan, vincristine, DTIC) showed a response to therapy, while in 30% no response was observed. Eight patients who responded to therapy (5 with a complete response, e.g. no overt evidence of tumor, and 3 with a partial response) underwent a delayed primary or secondlook operation following significant reduction of tumor size on therapy. Residual tumor was found in each case. Complete resection was accomplished in 4 of 5 patients c o n s i d e r e d c o m p l e t e r e s p o n d e r s , and in one p a r t i a l responder, in 2 other patients who had a partial response to chemotherapy, resection was still not possible, Histologic examination of resected tissues following treatment showed maturation of tumor from a highly malignant grade IV neuroblastoma obtained at the initial biopsy to a less malignant ganglioneuroblastoma (grade II). The mean duration of survival for the 74 stage IV patients was 13 mo. Prior to 1965 the mean survival was only 3 mo, compared to 20 mo since that time. There were no survivors among 30 stage IV patients treated before 1965, while 9 of
Fig. 2. Abdominal radiograph in a 6-yr-old girl with a large, calcified n e u r o b l a s t o m a and bone m a r r o w metastases. The tumor was unresectable at the initial operation and only a biopsy was performed. Treatment with three drug chemotherapy (Cytoxan, Vincristine, DTIC) resulted in a significant reduction in the size of the tumor. Complete resection of the lesion was accomplished at a second-look laparotomy.
44 treated since then are presently alive. One patient, age 26 mo with multiple bone metastases, is alive with disease within 1 yr following diagnosis. Eight patients are surviving more than 2 yr, with 6 (8.1%) free of disease from 2 ~ to 11 yr following diagnosis (Table 2). Age at the time of diagnosis in these 6 patients was 4 too, 13 mo, 30 mo, and 3 patients over age 6. Three patients (ages 13 mo, 6 yr, 6 yr) had neuroblastoma in bone marrow but were without evidence of bone cortex involvement. All had second-look resections and are alive 3, 4, and 8 yr following treatment. One patient (age 30 mo) had mediastinal lymph node metastases treated by x-ray therapy and a delayed primary resection of a left adrenal tumor 6 mo following chemotherapy and is alive and well 7 yr later. Two patients ages 4 mo and 6 yr had both bone marrow and bone cortex involvement. The former had partial resection of a retroperitoneal mass followed by x-ray therapy, Cytoxan, and vincristine treatment. Eight yr later, a single metastatic focus was excised from the tibia and the patient has been free of disease for 3 additional y r - - a total of 11 yr from the time of initial diagnosis. The 6-yr-old boy had a delayed primary resection of a right adrenal tumor 5 mo following treatment with x-ray, vincristine, Cytoxan, and DTIC. He is alive and well and free of disease, 21~ yr later. Three patients with second-look operations had evi-
62
GROSFELD ET AL.
Table 2. Survival in Stage IV Metastatic N e u r o b l a s t o m a - - 6 / 7 4 Cases (8.1%) Site of Metastases Patient 1
Age at Diagnosis 4 mo
Sex M
Site of Primary retroperitoneal
Bone
Bone Marrow
+
+
Other lymph nodes
X-ray +
Therapy Chemo CYT
Surgery
delayed
Length of Survival 11 yr
incomplete resection 2
13 mo
F
paraspinal
--
+
lymph nodes
+
CYT, VNC
second-look
8 yr
resection 3
3 0 mo
M
left adrenal
--
--
mediastinal
+
CYT, VNC
lymph nodes 4 5 6
6 yr 6 yr 11 mo 6 yr
F M M
left adrenal right adrenal left adrenal
--+
+ + +
lymph nodes lymph nodes lymph nodes
delayed primary
8 yr
resection +
CYT, VNC,
second-look
3 yr
+
DTIC CYT, VNC,
resection second-look
4 yr
+
DTIC CYT, VNC,
resection delayed primary
2 ~,5 yr
DTIC
resection
CYT, Cytoxan; VNC, vincristine; DTIC, imidizole carboxamide.
dence of maturation of tumor tissues from neuroblastomato ganglioneuroblastoma with areas of benign ganglioneuroma in one. The mean total lymphocyte count in this group of survivors was 1344/mm3 with a range of 945-2232/mm3 that was similar to counts in nonsurvivors. DISCUSSION
Neuroblastoma is an example of a malignant tumor with the potential to undergo spontaneous regression and mature to a benign form. Spontaneous regression of neuroblastoma in patients who recover after no therapy or unconventional therapy usually considered inadequate for cure (e.g. irradiation of liver) is commonly observed in stage IV-S and occasionally in stage II patients. The favorable prognosis for this variant of metastatic neuroblastoma (stage IV-S) was confirmed in the present study where the survival rate was 75% (12/16). D'Angio et al? and Evans et al. 2 similarly recorded survival rates of 84% (21/25) and 75% (12/16)in infants with IV-S disease. Deaths in these infants are rarely due to progression of malignant disease, being more often related to complications such as respiratory insufficiency and sepsis. Respirat o r y e m b a r r a s s m e n t m a y o c c u r due to diaphragmatic elevation from an enlarged liver filled with tumor. Attempts to decrease the rapidly increasing liver size with radiation therapy was attempted in 8 patients in the present study including two who died. Although a few patients experienced some decrease in liver size, the response was not uniform. In general, t u m o r regression in the liver was characterized by a slow, spontaneous disapp e a r a n c e over a 6 - i 5 mo period of time.
Schnaufer and Koop reported the use of a temporary ventral hernia created by inserting a Dacron reinforced silastic sheet (much like treatment of neonates with abdominal wall defects) to relieve intraabdominal pressure in two IV-S cases, one of whom survived? This technique was unsuccessfully employed in one infant in the present study who eviscerated when the silastic sheeting separated from the skin edge, and the child subsequently succumbed from sepsis. Koop and Schnaufer suggested individualizing decisions regarding the most appropriate management of IV-S cases? They suggest no therapy other than removal of the primary tumor for infants with small primary lesion and liver metastases. There is no strong evidence to confirm primary tumor resection as beneficial in instances of Stage IV-S (as the primary site may not be determinable). In the present study, however, all eight of the infants with IV-S disease who had the primary tumor resected survived. It is of interest that three of the four patients with IV-S disease that died had tumor clumps in the bone marrow. All were under 6 wk of age at the time of diagnosis. The relatively poor survival of IV-S patients with bone marrow involvement (3/5 died) suggest that this presentation may not yield the same favorable prognosis as those infants with liver disease and/or skin involvement alone. D'Angio et al. described two IV-S patients with positive bone marrow aspirates who died of progressive disease? These observations question the advisability of including patients with positive bone marrow in stage
METASTATIC NEUROBLASTOMA
IV-S. Perhaps it would be more useful to group these patients as stage IV-M (marrow) and treat them with chemotherapy. Koop et al. and D'Angio et al. have similarly suggested using chemotherapy for infants with IV-S disease and a positive bone marrow? ,5 They stress the theoretic dangers of simply observing clumps of tumor cells in the marrow that may progress to bone cortex metastases. Treatment with chemotherapy, however, does not guarantee survival, as two infants with stage IV-S and marrow involvement who died in the present review received chemotherapy. The best prognosis in patients with neuroblastoma is observed in the youngest patients, who usually are those with the highest total lymphocyte counts. ~ Tumor involvement of the bone marrow inhibits both lymphocyte and g r a n u l o c y t e (phagocytic) cell production, reduces immunocompetence, and makes the patient more susceptible to tumor spread and sepsis. A comparison can be made to the increased incidence of infection seen in infants and children with lymphocytic leukemia who have bone marrow replacement by tumor cells and absolute g r a n u l o c y t e counts below 200/mm3. r This may be of considerable importance in the newborn period, when the infant has relative deficiencies of IgM, of factor B of the alternative complement pathway leading to a decrease in the C3 component of complement, and opsonin production. These factors may explain in part the occurrence of fatal instances of sepsis in the present report: all deaths occurred in young infants under 6 wk of age. In addition, the greatly enlarged liver in IV-S cases c o m p r e s s e s the viscera and elevates the diaphragm resulting in a change in the gastroesophageal angle. This results in significant gastroesophageal reflux, vomiting, aspiration, and poor nutrition that further affects the immune response, making the infant even more susceptible to infection. Total parenteral nutrition was used in five patients in this review for nutritional support in attempts to improve caloric intake and immune competence. The fact that all infants with IV-S disease and skin (subcutaneous nodules) involvement uniforreally survived is most unique. This occurrence strongly implicates an unusual tumor-host relationship probably based on immune factors. A detailed description of all the immune factors
63
associated with neuroblastoma is beyond the scope of this report. The most dismal survival data in instances of neuroblastoma has been noted in cases of Stage IV disease. Unfortunately, these patients account for more than half of all the cases of neuroblastoma seen at the time of diagnosis. Breslow and McCann reported a 2.5% 2-yr survival in cases of stage IV disease. 8 Unlike other embryonal tumors (e.g. Wilms', rhabdomyosarcoma), there has been no objective evidence that chemotherapy has improved the cure rate of neuroblastoma over the past decade. 1,2,5,8,9 Although chemotherapy has not prolonged the median survival time in patients with metastatic neuroblastoma in some reports, ~ we have observed an increase in the mean survival time from 3 mo to 20 mo since 1965, using chemotherapy programs according to the CCSG protocols. It is apparent, therefore, that chemotherapy can reduce tumor size and result in appreciable palliation. Unfortunately, only 40% of patients with metastatic neuroblastoma (stage IV) had a complete response, while 30% did not respond at all to chemotherapy programs. On the other hand, in the present report, 18% (8/44) of patients survive for more than 2 yr, some, of course, with evidence of disease. While complete excision of neuroblastoma in patients with localized disease results in a higher survival rate, the efficacy of resection of the primary tumor in instances of metastatic neuroblastoma has not yet been clearly established. Koop and Schnaufer suggest resection of the primary tumor in stage IV cases only when the operative risk is small and the patient's general condition is not severely undermined by the disseminated process? In the presence of distant metastases, the use of wide enbloc resection of viscera contiguous to the tumor is obviously unwarranted. It has been our experience that in most cases of stage IV disease, the tumor is usually excessively large and often initially unresectable. The six longterm survivors in the present report all had their primary tumor resected. Operative resection, however, was carried out at a delayed primary operation or a second-look procedure, following a significant decrease in the size of the primary lesion related to irradiation and/or chemotherapy. All patients with delayed primary or second-look operations had residual tumor,
64
even those patients who were considered to be complete responders without obvious clinical evidence of persistent disease. The histologic evaluation of residual tumor obtained in the second-look cases demonstrated that treatment with chemotherapy resulted in maturation of the tumor from neuroblastoma to ganglioneuroblastoma in each instance, with areas of benign ganglioneuroma observed in one instance. Similar observations had been made in a recent CCSG metastatic neuroblastoma study, where 22 of 23 patients with delayed primary or second-look resections had residual tumor, and tumor m a t u r a t i o n to ganglioneuroblastoma usually followed c h e m o t h e r a p e u t i c management. ~o Although Evans and Hummeler suggest that a high total lymphocyte count (greater than 3000/mm 3) is associated with improved survival, 6 the mean total lymphocyte counts of the six stage IV survivors in the present report was 1344/mm 3. This was not significantly different from patients who died. Although age is an independent variable that directly affects survival in neuroblastoma, only two of six stage IV survivors in the present study were under 13 mo at diagnosis. Of great interest is the fact that three of six survivors were over the age of 6 yr at the time of diagnosis. The explanation for this latter finding is not clear. Five of six survivors in the present report had neuroblastoma in the bone marrow, whereas only two had bone cortex involvement. These observations support the view of Evans et al. 2 and Priebe and Clatworthy, 9 that identification of tumor cells in the bone marrow does not have the same grave prognosis as bone cortex metastases. This further implies that a modification in the staging of metastatic neuroblastoma seems indicated. We propose the following change: stage IV-M metastatic disease involving bone marrow only; stage IV-B metastatic disease including bone cortex and other sites: and stage IV-S metastatic disease involving liver and skin (subcutaneous tissue) only. With these considerations it is important that at the time of diagnosis, the tumor cell invasion of the bone m a r r o w m u s t be c a r e f u l l y differentiated from lymphoblasts. Although radioactive bone scans ( p e r t e c h n e t a t e diphosphanate) seem more sensitive than the long
GROSFELD ET AL.
bone survey in detecting early cortical bone metastasis, false positives can be observed in instances of recent bone trauma or inflammation. While bone scans may be highly suggestive of metastatic disease, the radiographic bone survey still appears to be the most reliable clinical determinant of this type of metastatic process. Long-term disease-free survival with bone metastases is uncommon, although one patient in the present review went 8 yr following initial diagnosis until a late recurrence of neuroblastoma in a single metastatic focus occurred in the distal tibia. This was biopsied and treated with radiation and chemotherapy. The child has been free of disease for 3 yr, or 11 years since the time of initial diagnosis. Konrad et al. noted two late recurrences 6 and 10 yr following treatment. 11 These instances indicate that although 2-yr survival without evidence of r e c u r r e n t disease usually indicates a "cure," occasional patients also have late recurrences. These cases further imply that long-term tumor clinic follow-up is required in patients with metastatic disease who are presumably free of recurrence. Ogle et al. and Versfeldt followed patients with recurring metastases for 17 and 21 yr, respectively, who finally died at ages 21 and 22 yr. 12'13 Other reports concerning long-term survivors with stage IV disease indicate most patients with extraadrenal primary tumors that have been resected are under 1 yr of age at diagnosis. 14--17 Although our six long-term survivors with stage IV disease give rise to some hope for " c u r e " in metastatic neuroblastoma, such cases are unusual. The major problems associated with therapy in cases of metastatic disease include the advanced extent of disease with a large tumor volume that results in suppression of lymphocytes and the immune response. Present studies at some centers attempting to overcome inadequate initial cell kill by employing aggressive high dose Cytoxan therapy (given to toxicity) in conjunction with papaverine (to c a u s e t u m o r m a t u r a t i o n ) do not c l e a r l y demonstrate improved results. 18 Future treatment programs should be directed towards operative reduction of tumor bulk, enhancement of the immune response (such as the use of BCG-injection directly into unresectable tu-
METASTATIC NEUROBLASTOMA
65
mors), stimulation of tumor maturation (neuroblastoma ~ ganglioneuroblastoma --- ganglioneuroma), and delivery of more effective sequentially administered cell-cycle oriented chemotherapy. Unfortunately, at the present time there is no specific drug that has a curative
effect on this tumor. In addition, there are still many unknown factors, especially those affecting the host-tumor relationship that probably play a significant role in the survival of occasional patients with metastatic neuroblastoma,
REFERENCES
1. Grosfeld JL, Ballantine TVN, Baehner RL: Current management of childhood solid tumors. Surg Clin North Am 56:513-535, 1976 2. Evans AE, D'Angio G J, Randolph JG: A proposed staging for children with n e u r o b l a s t o m a . C a n c e r 27:374-378, 1971 3. D'Angio G J, Evans AE, Koop CE: Special pattern of widespread neuroblastoma with a favorable prognosis. Lancet 1; 1046-1049, 1971 4. Schnaufer L, Koop CE: Silastic abdominal pouch for temporary hepatomegaly in stage IV-S neuroblastoma. J Pediatr Surg 10:73-75, 1965 5. Koop CE, Schnaufer L: The management of abdominal neuroblastoma, Cancer 35:905-909, 1975 6. Evans AE, Hummeler K: The significance of primitive cells in marrow aspirates of children with neuroblastoma. Cancer 32:906-912, 1973 7. Chilcote RR, Baehner RL: Infection in childhood cancer: Experience in the management of infections in acute leukemia. Pediatr Ann 3:71 88, 1974 8. Breslow N, McCann B: Statistical estimation of prognosis for children with n e u r o b l a s t o m a . Cancer Res 31:2098-2103, 1971 9. Priebe CR, Clatworthy HW Jr: Neurobtastoma: An evaluation of 90 children. Arch Surg 95:538-545, 1967 10. Grosfeld JL, Bernstein I, Sitarz A, et al: The effect of primary tumor resection on survival in metastatic neuroblastoma. Proc Am Soc Clin Oncol 18:308 (C-167), 1977
11, Konrad PN, Singher L J, Neerhout RC; Late death from neuroblastoma. J Pediatr 82;80-81, 1973 12. Vogel JM, Coddon DR, Simon N, et al: Osseous metastases in neuroblastoma: A 17 year survival, Cancer 26:1354-1360, 1970 13. Versfeldt J: Transformation of sympathicoblastoma to ganglioneuroma with a case report. Acta Pathol Microbiol Scand 58:414-428, 1963 14. Reilly D, Nesbit ME, Krivit W: Cure of three patients who had skeletal metastases in disseminated neuroblastoma. Pediatrics 41:47 51, 1968 15. McGoldrick KE, Lanzkansky P: Prolonged survival in neuroblastoma with multiple skeletal metastases and bone marrow infiltration. Acta Paediatr Stand 59:711 714, 1970 16. King RL, Storaasli JP, Dolande RP: Neuroblastoma: Review of 28 cases and presentation of two cases with metastases and long term survival. Am J Roentgenol 85:733-747, 1961 17. Goldman RL, Winterling AN, Winterling CC: Maturation of tumors of the sympathetic nervous system: Report of long term survival in two patients, Cancer 18:1510-15 !5, 1965 18. Murphy ML, Helson L: Chemotherapy of Stage IV metastatic neuroblastoma. Proc Am Soc Clin Oncol 18;338, 1977
