Experience with “second-look” operations in pediatric solid tumors

Experience With "Second-look" Operations in Pediatric Solid Tumors By Jay L. Grosfeld, Thomas V. N. Ballantine, and Robert L. Baehner 9 "Second-look" operations were performed in 32 infants and children with initially unresectable or recurrent solid t u m o r s treated with combination chemotherapy and/or irradiation. Tumors were resectable in 26 of 32 cases (81%). These procedures often yielded information affecting staging and treatment. Disease-free survival was achieved in 18 of 32 patients (56%). Mortality was related to progressive disease in seven cases and opportunistic infections due to immunosuppression in three. Four additional patients are alive with evidence of persistent tumor. Second-look procedures were beneficial in patients with Wilms" tumor previously operated upon by a flank approach and in children with bilateral tumors. These procedures were particularly useful in children with stage III localized neuroblastoma and cases of metastatic neuroblastoma that respond to chemotherapy, Second-look operations were also useful in selected cases of rhabdomyosarcoma, teratoma, and Ewing's sarcoma. These observations suggest that combination chemotherapy has increased the use of second-look operations in a variety of less favorable (e.g. initially unresectable or recurrent) pediatric solid tumors. I N D EX W O R DS : "Second-look" operations; pediatric solid tumors.

URING the past decade, utilization of combined modalities of cancer treatment has resulted in improved survival for children with embryonal tumors. Programs employing combination chemotherapy often based on cellcycle dynamics and accurate assessment of extent of disease have been instrumental in improving survival while obviating the need for irradiation in some instances and diminishing the extent of surgery in others. 1 Patients with localized disease who undergo complete resection of the primary embryonal tumor have the best survival. Following excision of the primary tumor, the addition of chemotherapy and/or irradiation will often contain and destroy microscopic residual disease and small foci of metastatic tumor. Unfortunately, there remains a significant number of patients in whom the primary tumor is considered unresectable at the initial operation or where tumor recurrence is observed despite prior therapy. The purpose of this report is to describe a favorable experience with "second-look" operations in patients with

Journal of Pediatric Surgery, Vol. 13, No. 3 (June), 1978

recurrent or initially unresectable pediatric solid tumors. CLINICAL MATERIAL

Thirty-two infants and children with recurrent or initially unresectable solid tumors were treated by second-look operations from 1972 to 1977. All procedures were carried out at the James Whitcomb Riley Hospital for Children on the Indiana University Medical Center Campus in Indianapolis. Many of these patients were managed according to protocols designed by the Children's Cancer Study Group. Twenty-one were girls and eleven boys. They ranged in age from 4 mo to 12 yr. The diagnosis was neuroblastoma in ten patients, rhabdomyosarcoma in eight, Wilms' tumor in eight, Ewing's sarcoma in three, and malignant teratoma in three (Fig. 1). NEUROBLASTOMA

T h r e e o f ten p a t i e n t s with n e u r o b l a s t o m a had localized disease. A 4-too-old girl with a s t a g e I I I left cervical n e u r o b l a s t o m a and a 7-yr-old girl with a s t a g e I I I right t h o r a c o a b d o m i n a l n e u r o b l a s t o m a w e r e initially c o n s i d e r e d to have u n r e s e c t a b l e p r i m a r y t u m o r s , which had been biopsied at local c o m m u n i t y hospitals. T h e s e p a t i e n t s w e r e then r e f e r r e d for f u r t h e r t r e a t m e n t . T h e infant with t h e n e c k lesion was reexp l o r e d and a 90% s u b t o t a l r e s e c t i o n was a c c o m plished. T h e p a t i e n t received i r r a d i a t i o n (1000 R) to the residual t u m o r and an excellent r e s p o n s e was o b t a i n e d ; t h e p a t i e n t is alive and free o f disease 4 y r l a t e r . T h e child with t h e thoracoabdominal lesion was initially biopsied t h r o u g h a small a b d o m i n a l incision. Following r e f e r r a l , a c o m p l e t e resection of a 16 x 10 • 10 c m t u m o r was a c c o m p l i s h e d using a t h o r a c o a b 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 26th Annual Meeting of the American Academy of Pediatrics, Surgical Section, New York, New York, November6-8, 1977. Address reprint requests to Jay L. Grosfeld, M.D., Professor of Children's Surgery, Surgeon in Chief James Whitcomb Riley Hospital for Children, Rm. K-21, 1100 West Michigan Street, Indianapolis, Ind. 46202. 9 1978 by Grune & Stratton, Inc. 0022-3468/78/1303-0013501.00/0

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instances. Seven of the ten patients with neuroblastoma survived and benefited from secondlook procedures.

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Fig. 1. Second-look procedures were performed for initially unresectable or recurrent neuroblastoma (10), rhabdomyosarcoma (8), Wilm's tumor (8), Ewing's sarcoma (3), and teratoma (3).

dominal approach. No further treatment was given. This patient is alive and free of disease 4 yr later. Four of seven initially unresectable retroperitoneal stage IV tumors and an unresectable stage III lesion survived and are disease-free more than 2 yr following successful second-look excisions. Following initial biopsy, three children were managed by irradiation and three drug chemotheray (Cytoxan, vincristine, and imidazole carboximide) and two by chemotherapy alone. Chemotherapy significantly reduced tumor size and in most cases resulted in histologic maturation of the lesion from neuroblastoma to ganglioneuroblastoma. Two stage IV survivors were more than 6 yr of age at diagnosis, one was 2 yr, and one 13 mo. Three had bone marrow involvement alone while one had both bone marrow and bone cortex metatases. Two of the three unsuccessful stage IV cases involved patients with bone cortex metastases who were poor responders to chemotherapy and had known residual disease. Resection was still not feasible at the second-look operation in these cases and both patients died shortly thereafter. The third patient showed a good response to chemotherapy and had a successful resection of a small unsuspected tumor of the right adrenal gland at second-look. Multiple bone metastases, significant bone marrow involvement, and mediastinal and lung spread occurred 5 mo later and the patient succumbed. Overall, at second-look in patients with neuroblastoma, complete resection of tumor was possible in seven cases and subtotal resection in one, while the tumor remained unresectable in two

Second-looks were a t t e m p t e d in three children with retroperitoneal rhabdomyosarcoma. Two patients, aged 21~ and 9 yr, respectively, were initially unresectable (stage III) and received adjunctive treatment including irradiation (3500-4000 R) and four drug chemotherapy employing Cytoxan, actinomycin-D, vincristine, and adriamycin. At second look, the tumor remained unresectable in one case (9-yr-old) but there was no remaining evidence of tumor in the other. Despite this latter finding, a pathologic fracture of the humerus occurred 6 mo later due to bone metastases. The third patient, a 3-yr-old boy with a stage III right paraspinal tumor (incompletely resected elsewhere), developed a retroperitoneal recurrence 9 mo later despite irradiation and four drug chemotherapy. At second look, a near-total resection of this tumor was possible; however, direct extension of tumor into the iliac bone could not be removed. The boy had progressive disease and died 6 mo later despite intensive treatment. Four of five additional patients with rhabdomyosarcoma involving other sites survived second-look procedures. A 22-mo-old boy with a left paratesticular lesion was operated on elsewhere for "hydrocele" prior to transfer. At initial operation, high ligation of the spermatic cord and vessels was done tbr a paratesticular tumor. The pathology report documented an incomplete resection. At a second operation, a hemiscrotectomy was performed removing residual gross tumor. Retroperitoneal lymph node dissection was also performed and a single lymph node positive for tumor was found below the left renal vein. The right testis was temporarily relocated in the right thigh and the patient received both scrotal and retroperitoneal irradiation and three drug chemotherapy (actinomycin-D, Cytoxan, and vincristine) for 18 mo. The right testis was returned to its normal scrotal location following radiation therapy by an orchiopexy procedure. The patient is alive and free of disease 3 yr later. A 9-yr-old girl had an en bloc resection of an anterior chest wall rhabdomyosarcoma that involved the intercostal muscles and ribs, and

PEDIATRIC SOLID TUMORS

extended into the mediastinum with contiguous involvement of the right upper and middle lobe. She was treated by local irradiation and three drug chemotherapy (actinomycin-D, vincristine, and Cytoxan). Eighteen months later, a density consistent with an extrapleural recurrence was observed posteriorly on chest x-ray along the stump of the fifth rib. A second-look thoracotomy was done with apparent complete excision of recurrent tumor. Six months later, however, the patient developed paraeosphageal and mediastinal recurrence and died shortly thereafter. A 13-yr-old boy had a subtotal excision of a stage III rhabdomyosarcoma of the right thigh at a local hospital. Following referral, he was treated with irradiation (4500 R) and three drug chemotherapy. Fourteen months later, a recurrence was noted in the soft tissues above the right knee and below the radiation field. A disarticulation was performed at second-look with the proximal margin free of tumor. The boy was managed by chemotherapy and is now 18 mo post-resection and free of disease. A 3-yr-old girl with tumor involving the left round ligament and a 7-year-old girl with tumor involving the rectus muscle at the umbilical level were initially operated upon elsewhere with local excision. In both instances, the margins of resection were questionable in regard to persistent tumor. Both children underwent second-look wide resection of the involved fields and were treated by radiation and chemotherapy (actinomycin-D, vincristine, and Cytoxan) for 15 mo and are presently diseasefree 3 and 4 yr, respectively, following therapy. WILMS' TUMOR

Four of eight patients with Wilms' tumor were originally explored at other hospitals through a retroperitoneal flank incision. Three patients (aged 28 mo, 9 yr, and 12 yr) were considered group I patients with completely resected tumors, while a 13-mo-old boy was considered unresectable (group III). Upon referral, all four patients had a transperitoneal second-look exploration. Two of the three patients considered group I had perirenal and paraaortic lymph nodes that were positive for tumor, changing their stage of disease and treatment protocol. In the third patient, most of the left renal vein, perirenal tissues, lymph

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nodes, and most of the ureter had not been excised at the previous operation. Fortunately, none of these tissues was involved by tumor. The 13-mo-old boy considered unresectable was reexplored by the transperitoneal route. A large right-sided Wilms' tumor with extension into the vena cava and ureter was observed. Radical nephrectomy, adrenalectomy, ureterectomy, and lymph node dissection was done and the tumor bolus in the renal vein and vena cava were controlled by vascular clamps, allowing its extraction. The 12-yr-old boy downstaged to group II had relapse in the form of bone metastases. The other three patients all survived following irradiation and chemotherapy employing actinomycin-D and vincristine. A 12-yr-old girl with a right-sided Wilms' tumor and bilobar liver metastases was considered unresectable at initial operation. Following 6 mo of intensive treatment with chemotherapy and irradiation, a second-look procedure was attempted but, unfortunately, there was no improvement. The child gradually succumbed despite all efforts and treatment. A 6-yr-old girl who had resection of a group II right-sided Wilms' tumor was treated by irradiation and chemotherapy (actinomycin-D and vincristine). Two years later, she presented with abdominal pain and an elevated right diaphragm. Liver scan demonstrated a cold nodule occupying the right lobe. At reoperation, a friable recurrent tumor was noted on the right lobe of the liver that was adherent to the diaphragm and extended across the falciform ligament into the left lobe. Following irradiation and chemotherapy, the abdomen was reexplored and a necrotic cystic lesion was dissected free from the right lobe capsule and diaphragm. Unfortunately, this patient recently developed recurrence of disease. Two additional children with bilateral Wilms' tumor (group V) had second-look procedures. A 4-yr-old girl had synchronous bilateral Wilms' tumors. Complete left nephrectomy and biopsy of the right kidney were performed. The patient was treated with actinomycin-D and vincristine and reexplored 3 mo later. The right kidney was extensively involved by "'persistent tumor" and was removed. Following chemotherapy and renal dialysis, a successful kidney transplant was performed. The patient eventually suc-

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cumbed from sepsis due to immunosuppression. At autopsy, no active tumor was noted. A 3-yrold boy with hypospadias and undescended testis had nonsynchronous bilateral Wilms' tumor. At initial operation, a left-sided Wilms' tumor was completely excised. The right kidney became involved 18 mo later. Partial nephrectomy was done, leaving some gross residual disease. Following three drug chemotherapy with actinomycin-D, vincristine, and adriamycin, a second-look procedure was performed because of a questionable defect in the lower segment of the remaining kidney. At reoperation, only inflammatory and fibrous tissues were found with no evidence of tumor. Radiation was not given to the remaining renal segment and the patient is alive and free of disease 18 mo later. Therapy has been discontinued. EWlNGS" SARCOMA

Three children, aged 6, 7, and 8 yr, with Ewing's sarcoma of rib and extensive chest wall involvement underwent initial diagnostic biopsy. Following irradiation of the chest wall and chemotherapy (vincristine, Cytoxan, actinornycin-D, and adriamycin), tumor size decreased considerably. All three patients underwent second-look resection of the primary tumor and contiguous chest wall disease. The 6yr-old girl had an en bloc chest wall resection including the 3rd, 4th, and 5th ribs and right upper lobe of lung. The 7-yr-old boy had en bloc resection of the left 2nd through 6th ribs with contiguous left upper lobectomy. An 8-yr-old girl had excision of the left 4th through 8th ribs with preservation of the underlying pulmonary tissue. The latter patient developed a single metastatic focus in the right femur 8 mo later that was treated successfully by radiation and drug therapy. The remaining two patients are on chemotherapy and are free of disease 1 yr and 9 too, respectively, postresection. MALIGNANT TERATOMA

Following resection of a sacrococcygeal teratoma at a community hospital (in the neonatal period), malignant recurrence was noted in a 13-too-old girl. At laparotomy, a single liver metastasis was observed and excised. The primary tumor, however, which extended into the pelvis, was unresectable. Following pelvic irradiation and four drug chemotherapy

(actinomycin-D, vincristine, Cytoxan, and r ethotrexate), a laparotomy and presacral reexploration was done. There was no evidence of any intraabdominal involvement. Excision of tissues at the old biopsy site showed fibrous and inflammatory residue with no evidence of disease. Following 13 mo of chemotherapy, she is alive and well with no evidence of disease and has been offtherapy for 6 rno. A 4-yr-old girl was noted to have a sacrococcygeal mass and symptoms of bladder and rectal compression. Chest x-ray showed lung metastases. A biopsy of the sacral lesion showed malignant teratoma (endodermal sinus tumor). Following irradiation (4000 R) of the primary site and four drug chemotherapy, the primary tumor was reduced to one-third of its previous size. At second-look, complete excision was possible. Tumor histology showed maturation to benign teratoma. No evidence of malignant tumor was noted. Bilateral thoracotomies and multiple wedge excisions of lung metastases were performed with subsequent need for bilateral upper lobectomy. Six months later, the patient developed pneumocystis pneumonia on chemotherapy and died. At necropsy, there was no evidence of tumor. A 6-yr-old girl had resection of a "benign" ovarian teratoma at another institution. Three months later, tumor recurrence was observed. A second-look procedure resulted in an unsuccessful attempt to remove the tumor, which filled the entire lower half of the abdomen, extending between the pelvic wall on either side. She had a rapidly progressive downhill course despite intensive chemotherapy and pelvic irradiation and succumbed shortly thereafter. SUMMARY OF RESULTS

Evaluation of the entire group of patients with second-look operations for either previously inoperable (stage III or IV) or recurrent neoplasms is illustrated in Fig. 2. In 81% (26/32)of cases at the second operation, the tumor could be completely or almost completely excised and/or new information was obtained leading to changes in staging and/or treatment. Diseasefree survival in this group of patients with less favorable tumors (e.g., stages III, IV, and recurrences) was achieved by second-look operations in 18 of 32 patients (56%) (Fig. 3). Three patients died as a result of sepsis from opportunistic infection related to immunosup-

PEDIATRIC SOLID TUMORS

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Fig. 2. Bar graph shows that tumor was resectable (white bar) in 26 of 32 cases (81%). Stippled areas demonstrate unresectahle cases. Second-look operations frequently yielded information that affected treatment.

pression and were disease-free at autopsy. Death in seven patients was related to tumor while four additional patients are alive with evidence of disease.

DISCUSSION Very little data is available concerning the efficacy of second-look operative therapy in childhood solid tumors. While there has been some precedent established for use of delayed primary and secondary operations following preoperative chemotherapy and/or irradiation therapy, 2-4 other reports document little success following second-look procedures. ~ This report, however, suggests that second-look operations are indeed beneficial in a significant number of patients with a variety of pediatric solid tumors. 14 13 12

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Fig. 3. Bar graph illustrates disease-free survival (white bar) was achieved in 18 of 32 cases (5R%). Death was related to progressive disease in seven patients, three died as a result of sepsis due to immunosuppression and had no evidence of disease at autopsy, and four children are alive with persistent evidence of t u m o r ; these 14 patients are represented by the stippled areas.

Although the need for a transperitoneal approach has been repeatedly suggested in cases of Wilms' tumor, flank operations are still being performed. It is obvious from the four cases included in this report that the flank approach is inadequate to properly stage the extent of disease or resect a large tumor, increases the risk of intraoperative tumor spill, and does not permit appropriate examination of the contralateral kidney for ruling out bilateral tumors. Two of three children who were considered group I patients proved to have unrecognized lymph node involvement at second-look transperitoneal operations changing both the stage of disease and the therapy. Another patient who was considered unresectable had a complete excision of the tumor that extended into the ureter and vena cava. These observations suggest that a second-look transperitoneal operation should be performed in patients initially managed by flank operation prior to institution of therapy. " S e c o n d - l o o k " p r o c e d u r e s were useful in instances of bilateral Wilms' tumor following partial resection or initial biopsy and chemotherapy, an observation that has also been noted by others. 2,6 Unfortunately, reoperative therapy has been unsuccessful in our hands in instances of Wilms' tumor with extensive liver metastases. Second-look procedures are particularly useful in cases of localized neuroblastoma (stage III) when resection is done prior to occurrence of metastases, and may be associated with c u r e / S e c o n d - l o o k procedures also appear useful in instances of metastatic neuroblastoma that show good response to treatment, but seem unfavorable in nonresponders. Previous reports indicate that even in th e absence of clinically apparent disease, residual tumor is usually encountered at reoperation in the retroperitoneum of patients with metastatic neuroblastoma. 3'4 While not curative in these cases, chemotherapy does result in histologic maturation from neuroblastoma to ganglioneuroblastoma, a decrease in tumor size, and often allows excision of previously unresectable neuroblastoma. A review of the rare survivors with metastatic neuroblastoma (stage IV) demonstrates that most of these individuals have had their tumor removed. 4 It is of interest that a delayed primary operation is as efficacious as a secondlook procedure in stage IV cases. 3,4

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Although second-look procedures were not found to be beneficial in patients with retroperitoneal or mediastinal rhabdomyosarcoma, reoperative therapy was successful in those with paratesticular, labial, and abdominal wall tumors, and may also be useful in recurrent extremity lesions initially treated by wide local excision. Other reports have demonstrated that recurrent pelvic lesions initially treated by biopsy and primary chemotherapy may also be retrievable? It appears that multidrug chemotherapy has significantly altered the approach to the surgical management of many of these cases. All three children with Ewing's sarcoma involving the ribs had resectable lesions at second-look procedures. An increased incidence (20%-25%) of local recurrence following nonoperative therapy suggests that primary (when possible) or secondary resection of Ewing's sarcoma involving selected sites (e.g., ribs, fibula, clavicle, etc.) may be beneficial. En bloc chest wall resection (often including pulmonary lobectomy) followed by Marlex mesh prosthetic replacement of the chest wall has been well tolerated. Although malignant teratomas have had a poor prognosis in the past, recent experiences suggest that these tumors may be more responsive to combination chemotherapy and radiation than previously considered. 9 Chemotherapy used in patients in the present report included actinomycin-D, Cytoxan, vincristine, methotrexate, and adriamycin. Einhorn and Donahue ~~have recently demonstrated a dramatic antitumor effect using Velban, bleomycin, and cis-platinum in patients with malignant teratocarcinoma and endodermal sinus tumors.

Similar to the observations in children with neuroblastoma, chemotherapy in this study resulted in maturation of teratoma to a benign form in one case and tumor obliteration with fibrous tissue replacement in another, Furthermore, the findings of Woolner et al. ~ demonstrate a beneficial effect of reoperative therapy in instances of malignant ovarian tumors, which would tend to support our approach in these cases. Following combined chemotherapy, secondlook operations allowed for excision of previously unresectable tumors and/or yielded information concerning accurate staging of the extent of disease and subsequent therapy in 26 of 32 cases (81%). Disease-free survival was achieved in 56% (18/32) of these high-risk patients with initially unresectable or recurrent tumors. These extremely encouraging data suggest that modern techniques of combined sequential chemotherapy (and occasionally irradiation) have increased the use of second-look procedures. This report demonstrates that a significant variability in the initial surgical management of childhood tumors between the community hospital and a children's cancer center may be observed (e.g., what is a resectable or nonresectable lesion, and use of a flank versus transperitoneal operations for Wilms' tumor). These observations coupled with the often complicated aspects of multimodal cancer t r e a t m e n t (e.g., immunosuppression, hematologic, complications) suggest that these cases should be primarily referred to a children's cancer facility experienced in the management of such patients on a day-to-day basis.

REFERENCES

1. Grosfeld JL, Ballantine TVN, Baehner RL: Current management of childhood solid tumors. Surg Clin North Am 56:513-535, 1976 2. Kumar AM, Wrenn EL, Fleming ID, et al.: Preoperative therapy for unresectable malignant tumors in children. J Pediatr Surg 10:657-668, 1975 3. Grosfeld JL, Bernstein I, Sitarz A, el al.: The effect of primary tumor resection on survival in metastatic neuroblastoma. Proc Am Soc Clin Oncol 18:308, 1977 4. Grosfeld JL, Schatzlein M, Ballantine TVN, et al: Metastatic neuroblastoma: Factors influencing survival. J Pediatr Surg 13:59-65, 1978 5. Priebe CR, Clatworthy HW Jr: Neurohlastoma: an evaluation of 90 children. Arch Surg 95:538-545, 1967 6. Bishop HC, Tefft M. Evans AE, et al: Survival in bi-

lateral Wilm's tumor--Review of 30 National Wilm's Tumor Study cases. J Pediatr Surg 12:631 638, 1977 7. Koop CE, Schnaufer L: The management of abdominal neuroblastoma. Cancer 35:905-909, 1975 8. Hays DM" Persona/communications 9. Grosfeld JL, Ballantine TVN, Baehner RL: Benign and malignant teratomas in children: Analysis of 85 cases. Surgery 80:297-304. 1976 10. Einhorn LH, Donahue JP: Cisdiaminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer Ann Intern Med 86:293-298, 1977 11. Woolner N, Exelby P, Lewis J, et at: Malignant ovarian tumors in childhood. Cancer 37:1953-1964, 1976