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Advances in the Surgical Treatment of Neuroblastoma
C H A P T E R
10 Advances in the Surgical Treatment of Neuroblastoma Nicole J. Croteau1, James A. Saltsman1, Michael P. La Quaglia1,2 1
Pediatric Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; 2Department of Surgery, Weill Cornell Medical College, New York, NY, United States
INTRODUCTION
surgical intervention in the management of neuroblastoma and recent advances in the field.
The initial diagnosis of neuroblastoma requires close collaboration among the surgical oncologist, pediatric oncologist, and pathologist, especially in the assessment of MYCN amplification, histopathology, and DNA index (ploidy) [1]. The surgeon has a vital role in neuroblastoma management. Specifically, the surgeon must acquire an adequate tumor sample for both histopathology and molecular biological studies, while being meticulous during surgical resection of the primary tumor in order to preserve the normal organs [1]. To ensure precise categorization of stage and risk status, the surgeon must evaluate both the ipsilateral and contralateral lymph nodes and accurately describe the extent of the primary tumor resection [1]. Additionally, the surgeon has a crucial role in performing supportive procedures, such as acquiring vascular access, and in the management of surgical and treatment-related complications like typhlitis, bowel obstructions, and others [1]. This chapter will describe the role of
Neuroblastoma https://doi.org/10.1016/B978-0-12-812005-7.00010-2
History A role for surgery in neuroblastoma was first reported in the 1950s. Among these first publications were the papers by Robert E. Gross in 1953 and C. Everett Koop in 1955. Gross noted that extensive and radical surgery has a definite place under certain circumstances and can lead to permanent cure for neuroblastoma [2]. Koop explained the positive effect of tumor debulking on outcome in his book, Neuroblastoma in Childhood: Survival After Major Surgical Insult to the Tumor [3]. In the 1960s, groups in Japan and Europe also described their experiences with resection of neuroblastoma [4e7]. Adjuvant chemotherapy was introduced in 1965 [8]. In 1968, C. Everett Koop made an early attempt to define risk status when he analyzed the impact of surgical interventions based on resectable, nonresectable, or metastatic tumors [9].
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In the 1970s, there were major advances in pediatric imaging, surgery, anesthesia, blood banking, and critical care [10e13], and the pediatric oncology cooperative groups were established. With this progress, multi-institutional data became available, and surgical reports have continued to increase. In the 1980s, retrospective studies from the Children’s Cancer Study Group discussing the role of surgery in localized and disseminated neuroblastoma were published [14,15]. In 1988, a prospective study was published by investigators from the Pediatric Oncology Group, which showed that certain localized neuroblastomas could be effectively treated with surgery alone, even with the involvement of regional nodes [16]. The authors noted that overall survival was excellent even in patients who relapsed, but without a uniform staging system, comparisons between cooperative group experiences could not be drawn. Later that same year, the International Neuroblastoma Staging System (INSS) was established and was revised in 1993 [17,18]. During the 1980s and early 1990s, the efficacy of primary tumor resection in patients with advanced-stage disease became controversial. In the 2000s, the International Neuroblastoma Risk Group (INRG) classification system was developed to allow for presurgical risk assessment. In this system, nonmetastatic tumors are assessed for surgical risk factors that predict unresectability using radiographic imaging, known as Image Defined Risk Factors (IDRFs) [19,20]. Since the turn of the century, the Children’s Oncology Group (COG) and the Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN) have conducted several prospective studies with the goal of evaluating chemotherapy protocols. As these studies did not use surgical outcomes as primary endpoints, the prospective studies have since been retrospectively reviewed to evaluate surgical outcomes [21]. The controversy surrounding the efficacy of primary tumor resection in patients with
advanced-stage disease continued into the 2010s. In 2014, multiple studies were published showing that high-risk, stage 4 neuroblastoma patients have increased event-free survival after undergoing primary tumor resection [21]. Surgery has an even more important role in low-risk and intermediate-risk diseases.
Staging and Risk Status The INSS, revised in 1993, was adopted by the COG and cooperative groups in Europe and Japan [18]. This system emphasizes the extent of the primary tumor, presence and location of positive lymph nodes, and metastasis as criteria for categorizing the patients into stages 1, 2A/ 2B, 3, and 4/4S. This staging system, along with tumor biology, is the basis of COG risk stratification, which divides patients into lowrisk, intermediate-risk, and high-risk groups in order to guide treatment. With the advent of the INRG classification system in the early 2000s, the comparison of published surgical outcomes has become difficult because investigators must choose one system on which to base their study [19]. In the INRG classification system, tumors are assessed for surgical risk factors that predict unresectability using IDRFs and are separated into L1 (no IDRFs), L2 (at least one IDRF), M (metastatic), or MS (the equivalent of 4S in the INSS). Based on this stage, along with histology and tumor biology, patients are grouped into very low, low, intermediate, and high-risk groups. Regardless of which system is chosen, the stage and risk status of the patient has a great impact on the surgical intervention. It is worthwhile to review the individual groupings, as they guide the surgical decision-making. Very Low and Low Risk The very-low-risk group exists only in the INRG risk group classification system and includes stage L1 without MYCN amplification and stage MS without MYCN amplification or 11q aberration. The low-risk group includes
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INSS stage 1, stage 2A/2B without MYCN amplification and greater than 50% tumor resection, and stage 4S without MYCN amplification. This group also includes INRG stage L1, stage L2 without MYCN amplification or 11q aberration, and stage M or MS without MYCN amplification or 11q aberration if the patient’s age is less than 18 months. The goal for the low-risk group is complete primary tumor resection, accurate staging by biopsy of nonadherent nodes, and adequate tissue sampling for molecular biologic studies. Patients with low-risk disease have an overall survival of >90% with almost all patients receiving surgery alone [22e24]. For this reason, the standard treatment for patients with low-risk disease is surgery alone.
In 2009, a single institution study of 54 patients with intermediate-risk and high-risk stage 3 MYCN-nonamplified disease found that these patients can be safely treated with minimal chemotherapy [27]. In the study, 14 patients were treated with surgery alone, while 39 patients had neoadjuvant chemotherapy that was discontinued after surgical resection. While a higher event-free survival (EFS) (97.1 3% vs. 84.6 10%, P ¼ .02) was seen in patients who received neoadjuvant chemotherapy, there was no difference in 10-year overall survival (OS) between the two groups. Patients with locoregional intermediate- and high-risk disease were able to achieve a 10-year EFS of >97% while minimizing chemotherapy.
Intermediate Risk
The high-risk group includes INSS stage 2A/ 2B with MYCN amplification, stage 3 with MYCN amplification or without MYCN amplification but age >18 months with unfavorable histology, stage 4 with MYCN amplification, or without MYCN amplification between ages 12 and 18 months with unfavorable histology, or age >18 months regardless of tumor biology, and stage 4S with MYCN amplification. This group also includes INRG stages L1 and L2 with MYCN amplification, stage M with MYCN amplification or age >18 months, and stage MS with MYCN amplification or 11q aberration. The goal of surgery in patients with high-risk disease is an initial diagnostic biopsy to obtain an adequate amount of tissue for biologic studies. Treatment following diagnosis begins with neoadjuvant chemotherapy followed by complete resection of the primary tumor. The extent of primary tumor resection has been a controversial issue for some time. Several studies have recently been published supporting the complete resection in patients with high-risk disease. In 2011, Rich et al. reported a study of 207 highrisk patients with circumferential encasement of
The intermediate-risk group includes INSS stage 2A/2B without MYCN amplification and <50% tumor resection, stage 3 without MYCN amplification and age <18 months with any histology or age >18 months with favorable histology, and stage 4 or 4S without MYCN amplification and age <18 months. This group also includes INRG stage L2 without MYCN amplification, but with 11q aberration or poorly differentiated histology, and stage M without MYCN amplification, but with diploid tumor and age <18 months. The surgical goals for patients with intermediate-risk disease are to establish the diagnosis, to resect as much of the primary tumor as safely possible, to accurately evaluate the stage of the disease through the sampling of nonadherent lymph nodes, and to obtain an adequate amount of tissue for diagnostic studies. Patients in this group with unresectable tumors are treated with chemotherapy per COG guidelines. In patients with locoregional disease with intermediate-risk characteristics, surgery alone has been shown to be an effective treatment when the tumor can be completely resected [25,26].
High Risk
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renal vessels, celiac axis, and/or superior mesenteric artery in which 94% of patients treated with chemotherapy underwent a gross-total resection [28]. In this study, 10% of patients had grade 3e4 complications with a nephrectomy rate of 4.3%, suggesting that these high-risk patients with IDRFs could undergo a gross total resection without increasing morbidity [28]. In 2014, the prospective COG A3973 study supported attempts at complete resection in patients with high-risk disease [29]. In the study, 220 high-risk patients were grouped according to the extent of tumor resection. Tumor resection of 90% or more was achieved in 70% of patients; these patients had improved 5-year local recurrence-free survival (LRFS) and EFS when compared with the 30% of patients who had a tumor resection of <90% (LRFS: 91 6% vs. 77 9%, P ¼ .0014; EFS: 46 4% vs. 38 7%, P ¼ .043). There was no difference in OS between the two groups (57 4% vs. 49 7%, P ¼ .27). In addition to surgical resection, all of the patients included in the study were treated with induction chemotherapy and adjuvant radiotherapy. A 2014 report from SIOPEN evaluated the influence of surgical resection on the survival of patients with high-risk neuroblastoma [30]. The study included 1324 operation data sets from high-risk patients including INSS stages 2, 3, 4, 4S with MYCN amplification and INSS stage 4 with age >12 months. The extent of surgical resection was classified as: macroscopic complete (CE), macroscopic incomplete (IE), or not attempted (OE). A CE resection was achieved in 76%, while 23% underwent an IE resection, and 2% were OE. The 5-year EFS and OS for patients who underwent CE were 38% and 44%, respectively, versus 27% and 36%, respectively, for patients who underwent IE and OE combined (EFS: P ¼ .006; OS: P ¼ .013). For stage 4 patients, the 5-year EFS and OS after CE were 33% and 40%, respectively, compared with 24% and 33%, respectively, after IE and
OE combined (EFS: P ¼ .006; OS: P ¼ .049). These data show that patients with high-risk neuroblastoma who are treated with intensive multimodality therapy, including a macroscopic complete surgical resection, have a survival advantage over those patients who have an incomplete resection. In 2017, Fischer et al. reported that patients age 18 months or older with localized neuroblastoma, especially those with INRG high-risk disease with MYCN amplification, have a better local control rate and longer survival after undergoing complete resection when compared with those who underwent incomplete resection [31]. The study was a retrospective analysis of 179 patients from the German neuroblastoma trial NB97 who had localized neuroblastoma of INSS stages 1e3 and were >18 months of age. Tumor resection was defined as complete resection (95%e100%), gross total resection (90% e95%), incomplete resection (50%e90%), and biopsy (<50%). Imaging reports were reviewed for IDRFs and patients were grouped according to the INRG staging system. The primary tumor was completely resected in 68.7% of patients, gross total resection was achieved in 16.8%, 14% had an incomplete resection, and 0.5% were only biopsied. The patients who underwent complete resection had higher local progression-free survival (LPFS), EFS, and OS compared to the lesser resection groups. The 5-year EFS, LPFS, and OS for patients with complete resection were 82.0 3.4%, 87.1 3.1%, and 90.8 2.7%, respectively, compared with 59.8 9%, 62.7 9%, and 75.4 8.1%, respectively, for patients with gross total resection, and 58 10.2%, 66.2 10.5%, and 70.5 9.4%, respectively, for patients with incomplete resection (EFS: P ¼ .001; LPFS: P ¼ .001; OS: P ¼ .020). When analyzing 151 patients classified as INRG high-risk, this improved survival after complete resection was still evident, with a better EFS (P ¼ .001), LPFS (P ¼ .001), and OS
INTRODUCTION
(P ¼ .001). These data support the attempts to complete resection in patients with high-risk disease. Another recent study examined a cohort of 220 patients from the COG A3973 study to evaluate the impact of the extent of primary tumor resection on local progression and survival and to assess the concordance between clinical and central imaging review-based assessments of the extent of resection [32]. Patients were divided into two resection categories: <90% and 90%. A subset of 84 patients underwent blinded central imaging review of computed tomography scans to assess the concordance between clinical and imaging assessments. The extent of resection was 90% in 70% of patients and <90% in 30% of patients as assessed by the surgeon. The 5-year EFS was higher with 90% resection (45.9 4.3%) than with <90% resection (37.9 7.2%; P ¼ .04). A lower cumulative incidence of local progression (CILP) was associated with 90% resection (8.5 2.3%) compared with <90% resection (19.8 5.0%; P ¼ .01). The concordance between the surgeons’ extent of resection assessment and the imaging assessment was low, with only 63% agreement. Despite this discordance, a >90% resection as assessed by the surgeon was associated with a significantly better EFS and lower CILP, which supports attempts at complete resection in patients with high-risk neuroblastoma.
Surgical Technique The initial surgical procedure in all patients, except those with small, localized, easily resectable tumors, should be an incisional biopsy, which will facilitate the diagnostic procedures required to establish risk group status. The surgeon must obtain at least 1 cubic centimeter of viable tumor tissue in good condition for adequate biopsy analysis. Often, the tumor is enclosed by a pseudocapsule that can be exploited for hemostasis. The capsule is opened
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using a technique similar to a trephine hole and multiple biopsies are taken with a pituitary rongeur or similar instrument. Hemostatic agents can then be used to pack the capsule. Central line placement and staging bone marrow aspirations and biopsies can be conveniently performed at the same time as an incisional biopsy. When indicated, definitive surgical resection is undertaken as a second procedure. Achieving clear microscopic margins (R0 resection) is rarely possible in the surgical treatment of neuroblastoma; thus, the goal of surgical resection is gross total resection of the tumor. Dissection proceeds along the pseudocapsule of the mass. Sectioning of the tumor may be required to improve visualization or avoid injury to underlying vital structures. Cervical Lesions Most primary cervical lesions occur in infants younger than 1 year and have favorable biologic features. These patients occasionally present with Horner syndrome or anisocoria. Prior to surgery, it is important to assess the extent of a cervical lesion and determine whether the tumor invades the thoracic inlet. The general approach is through a transverse neck incision followed by dissection of the carotid sheath contents. Large lesions may require a division of the sternocleidomastoid muscle, for adequate exposure. In the case of grossly positive lymph nodes, a formal lymphadenectomy with a modified neck dissection technique should be performed. Parents should be advised that resection of cervical lesions often results in postoperative Horner syndrome, which is oculosympathetic paresis and characterized by ipsilateral palpebral ptosis, pupillary miosis, and facial anhidrosis. Cervicothoracic Lesions Primary cervical lesions may extend into the chest through the thoracic inlet. Adequate exposure is integral to achieving gross total resection
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of these tumors and is usually achieved using a trap-door thoracotomy, in which the neck is exposed to the sternal notch by an incision superior and parallel to the ipsilateral clavicle. The sternum is divided to the level of the fifth interspace, and then laterally to the anterior axillary line. A Finochetto retractor placed between the cut edges of the sternum allows for excellent exposure (Fig. 10.1). This approach can be modified for lesions with a larger cervical component by extending the neck incision superior along the anterior border of the sternocleidomastoid. Lesions that extend into both hemithoraces can be reliably exposed using a clamshell thoracotomy at the fifth interspace (Fig. 10.2). Nerve stimulation is often employed to monitor the vagus nerve and the brachial plexus. Mediastinal Lesions The posterior mediastinum is the second most common primary site for neuroblastomas. These lesions can generally be approached through a muscle-sparing posterolateral thoracotomy (Fig. 10.3). Infiltration through the spinal foramina may require foraminotomy. As with cervical lesions, injury to the stellate ganglion
and the resulting Horner syndrome is a potential complication of resection of superior mediastinal tumors. Upper Abdominal and Retroperitoneal Lesions A majority of neuroblastomas originate from the adrenal gland or sympathetic ganglia and are found in the upper abdomen. There is frequent involvement of regional lymph nodes in the ipsilateral para-aortic or pericaval chains, as well as interaortocaval lymph nodes. The primary tumor and involved lymph nodes often create a confluent mass that encases but does not invade the great vessels of the abdomen. For these tumors, a thoracoabdominal approach is ideal (Fig. 10.4). A right-sided incision is used when the vena cava or right renal hilar vessels are infiltrated, while a left-sided incision is best for tumors involving the aorta, celiac axis, superior mesenteric artery, or left renal hilum. The thoracoabdominal incision allows for excellent exposure and control of the encased blood vessels. Great care must be taken during this dissection, as a vascular injury is possible when the aorta and visceral vessels are cleared.
FIGURE 10.1 The trap-door incision (A) should be performed with the ipsilateral arm abducted 90 degrees at the shoulder. Full exposure of the cervicothoracic structures (B) facilitates gross total resection of primary cervical lesions that extend into the chest through the thoracic inlet and that may involve vascular invasion.
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FIGURE 10.2 The clamshell incision is performed with arms abducted 90 degrees at the shoulder. In this example, the patient has a large left-sided pleural tumor involving the pulmonary hilum with metastatic disease in the right hemithorax. (C) Closure of the sternum is achieved using a Steinmann pin and wires.
Pelvic Lesions Similar to cervical lesions, primary pelvic tumors usually present with favorable biology and without distant metastases. However, these tumors can be challenging to resect due to the encasement of the iliac vessels and infiltration of the lumbosacral plexus. A midline incision extending from the umbilicus to the pubic symphysis provides good exposure of the pelvis and allows adequate control of the distal aorta and vena cava. Internal iliac vessels, if involved, may be ligated and resected without significant morbidity. Injury to the pelvic nerve roots and the resulting foot drop is a common complication of pelvic tumor resection and should be discussed with parents prior to surgery. Minimally Invasive Surgery While open resection continues to be the standard of care for neuroblastoma, there is a
growing amount of literature on the use of minimally invasive approaches. Initial descriptions of laparoscopic surgery for abdominal neuroblastoma were published in the mid-1990s [33]; however, there is still no consensus on eligibility criteria for minimally invasive surgery. Most authors agree that laparoscopy is most suitable for small tumors (5 cm) with limited lymph node involvement and without vascular encasement. Kelleher et al. published a small study of 18 patients who met these criteria and were treated laparoscopically for adrenal neuroblastoma [34]. Median tumor size in the cohort was less than 3 cm, and there was no difference in overall survival or recurrence compared to those patients treated with laparotomy. Patients treated with laparoscopic resection had a shorter postoperative length of stay compared to those who underwent open resection.
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FIGURE 10.3
10. ADVANCES IN THE SURGICAL TREATMENT OF NEUROBLASTOMA
Neuroblastoma lesions in the posterior mediastinum can be approached using a muscle-sparing posterolat-
eral thoracotomy.
Similarly, Ezekian and colleagues published their analysis of data from the National Cancer Database (NCDB) in which 98 of 579 patients undergoing surgery for neuroblastoma were treated with minimally invasive surgery [35]. Interestingly, this cohort included a sizable proportion of patients who underwent laparoscopic resection, despite having tumors greater than 6 cm in diameter (n ¼ 29, 32%). Additionally,
31% of patients in the minimally invasive cohort had metastatic disease at the time of surgery. This study found that patients treated with minimally invasive approaches achieved similar negative margin rates and equivalent 3-year overall survival compared to propensitymatched patients treated with laparotomy. Patients undergoing laparoscopy had a shorter length of hospitalization; however, they also
INTRODUCTION
FIGURE 10.4 For a majority of neuroblastomas, a thoracoabdominal approach facilitates exposure of the primary tumor, involved lymph nodes, and any encased major vessels of the abdomen.
had lower rates of lymph node sampling. The use of a national database for this study raises important questions about the validity of these findings at an individual patient level. In addition to laparoscopy, a number of authors have described thoracoscopic approaches to resection of isolated thoracic neuroblastoma. Potential advantages of thoracoscopy include decreased postoperative pain as well as decreased incidence of long-term chest wall deformities associated with thoracotomy. In a retrospective review of 36 cases of thoracic neuroblastoma, Malek et al. described thoracoscopic resection in 11 patients [36]. Although data on tumor size were not reported, patients were similar with respect to demographics and tumor characteristics. There were no observed differences in overall and disease-free survival or resection margin status between the patients
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who underwent open surgery and those who had thoracoscopic surgery; however, the length of follow-up was not specified. The thoracoscopy group had lower operative blood loss, shorter chest tube duration, and a decreased length of hospital stay. Despite the increase in the amount of literature on minimally invasive surgery for neuroblastoma, there is still no consensus on the safety and effectiveness of these approaches. To date, all studies on minimally invasive procedures for neuroblastoma have been small retrospective reviews or studies of large databases with limited data resolution at the patient level. A 2015 Cochrane review found no studies that met the criteria for inclusion in a metaanalysis, and the authors specifically noted the poor quality of data on the use of minimally invasive surgery for pediatric tumors [37]. The authors advocate for collaborative studies including randomized trials before the widespread adoption of minimally invasive surgery for pediatric tumors including neuroblastoma.
Surgical Complications and Mortality Neuroblastomas that involve and/or encase major vascular and neural structures in either their site of origin or surrounding nodes have a higher risk of surgical complications (Table 10.1). High-risk tumors tend to have these characteristics more often than lower-risk tumors. The most serious surgical complications include massive hemorrhage, major vascular injury, and respiratory failure requiring ventilatory support. The site of the tumor determines the possible surgical complications. Cervical and upper mediastinal resections can be associated with a permanent postoperative Horner syndrome. Paralysis can result from excision of epidural tumors or tumors heavily involving the spinal foramina [38]. Excision of retroperitoneal neuroblastomas can result in nephrectomy or renal infarction [39]. After removal of pelvic tumors, there is an
184 TABLE 10.1
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Surgical Complications
Organ System
Potential Complications
Vascular
• Arterial or venous laceration primary repair • Arterial laceration - graft • Lymphatic ascites • Renovascular hypertension
Genitourinary
• Nephrectomy • Renal infarction (arterial or venous occlusion or thrombosis) • Ureteral transection or fibrosis • Neurogenic bladder • Bladder perforation • Urinary tract infection
Gastrointestinal
• • • •
Nervous
Intussusception Chronic diarrhea Gastric atony Motility disorders
• • • •
Spinal cord injury with paralysis Horner syndrome Recurrent nerve injury Brachial or lumbosacral plexus injury • Sensory loss
increased frequency of complications such as foot drop [40]. Despite the extent of these massive resections, operative mortality is rare. Complications after primary tumor resection in patients with high-risk tumors are reduced after initial treatment with neoadjuvant chemotherapy [41] that reduces tumor volume [42,43].
Conclusion The role of surgery in the management of neuroblastoma continues to evolve as progress is made to reduce the toxicity of treatment while improving overall survival. Surgical intervention is required for both disease diagnosis and patient risk stratification and is becoming more important as the survival impact of a complete resection is elucidated. Cooperative groups worldwide have made great strides in the last 2 decades. A reduction in therapeutic intensity
is now possible, and complete resection is curative for low-risk and some intermediaterisk tumors. In the last few years, studies have shown that attempts at complete resection in high-risk neuroblastoma increases EFS, while overall survival remains the same. With the increased use of multimodality therapy and multidisciplinary collaboration among pediatric surgeons, pediatric oncologists, radiologists, radiation oncologists, and pathologists, progress in the treatment of high-risk neuroblastoma will continue.
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neuroblastoma and Wilms tumor. Pediatr Blood Canc 2018;65(1). Malek MM, Mollen KP, Kane TD, Shah SR, Irwin C. Thoracic neuroblastoma: a retrospective review of our institutional experience with comparison of the thoracoscopic and open approaches to resection. J Pediatr Surg 2010;45(8):1622e6. van Dalen EC, de Lijster MS, Leijssen LG, Michiels EM, Kremer LC, Caron HN, et al. Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children. Cochrane Database Syst Rev 2015;1:CD008403. Shimada Y, Sato K, Abe E, Suzuki T, Ishihara Y. Congenital dumbbell neuroblastoma. Spine 1995; 20(11):1295e300. Shamberger RC, Smith EI, Joshi VV, Rao PV, Hayes FA, Bowman LC, et al. The risk of nephrectomy during
[40]
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[42] [43]
local control in abdominal neuroblastoma. J Pediatr Surg 1998;33(2):161e4. Cruccetti A, Kiely EM, Spitz L, Drake DP, Pritchard J, Pierro A. Pelvic neuroblastoma: low mortality and high morbidity. J Pediatr Surg 2000;35(5):724e8. Shamberger RC, Allarde-Segundo A, Kozakewich HP, Grier HE. Surgical management of stage III and IV neuroblastoma: resection before or after chemotherapy? J Pediatr Surg 1991;26(9):1113e7. discussion 7e8. La Quaglia MP. Surgical management of neuroblastoma. Semin Pediatr Surg 2001;10:132e9. Medary I, Aronson D, Cheung NK, Ghavimi F, Gerald W, La Quaglia MP. Kinetics of primary tumor regression with chemotherapy: implications for the timing of surgery. Ann Surg Oncol 1996;3(6): 521e5.
10 Advances in the Surgical Treatment of Neuroblastoma Nicole J. Croteau1, James A. Saltsman1, Michael P. La Quaglia1,2 1
Pediatric Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; 2Department of Surgery, Weill Cornell Medical College, New York, NY, United States
INTRODUCTION
surgical intervention in the management of neuroblastoma and recent advances in the field.
The initial diagnosis of neuroblastoma requires close collaboration among the surgical oncologist, pediatric oncologist, and pathologist, especially in the assessment of MYCN amplification, histopathology, and DNA index (ploidy) [1]. The surgeon has a vital role in neuroblastoma management. Specifically, the surgeon must acquire an adequate tumor sample for both histopathology and molecular biological studies, while being meticulous during surgical resection of the primary tumor in order to preserve the normal organs [1]. To ensure precise categorization of stage and risk status, the surgeon must evaluate both the ipsilateral and contralateral lymph nodes and accurately describe the extent of the primary tumor resection [1]. Additionally, the surgeon has a crucial role in performing supportive procedures, such as acquiring vascular access, and in the management of surgical and treatment-related complications like typhlitis, bowel obstructions, and others [1]. This chapter will describe the role of
Neuroblastoma https://doi.org/10.1016/B978-0-12-812005-7.00010-2
History A role for surgery in neuroblastoma was first reported in the 1950s. Among these first publications were the papers by Robert E. Gross in 1953 and C. Everett Koop in 1955. Gross noted that extensive and radical surgery has a definite place under certain circumstances and can lead to permanent cure for neuroblastoma [2]. Koop explained the positive effect of tumor debulking on outcome in his book, Neuroblastoma in Childhood: Survival After Major Surgical Insult to the Tumor [3]. In the 1960s, groups in Japan and Europe also described their experiences with resection of neuroblastoma [4e7]. Adjuvant chemotherapy was introduced in 1965 [8]. In 1968, C. Everett Koop made an early attempt to define risk status when he analyzed the impact of surgical interventions based on resectable, nonresectable, or metastatic tumors [9].
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In the 1970s, there were major advances in pediatric imaging, surgery, anesthesia, blood banking, and critical care [10e13], and the pediatric oncology cooperative groups were established. With this progress, multi-institutional data became available, and surgical reports have continued to increase. In the 1980s, retrospective studies from the Children’s Cancer Study Group discussing the role of surgery in localized and disseminated neuroblastoma were published [14,15]. In 1988, a prospective study was published by investigators from the Pediatric Oncology Group, which showed that certain localized neuroblastomas could be effectively treated with surgery alone, even with the involvement of regional nodes [16]. The authors noted that overall survival was excellent even in patients who relapsed, but without a uniform staging system, comparisons between cooperative group experiences could not be drawn. Later that same year, the International Neuroblastoma Staging System (INSS) was established and was revised in 1993 [17,18]. During the 1980s and early 1990s, the efficacy of primary tumor resection in patients with advanced-stage disease became controversial. In the 2000s, the International Neuroblastoma Risk Group (INRG) classification system was developed to allow for presurgical risk assessment. In this system, nonmetastatic tumors are assessed for surgical risk factors that predict unresectability using radiographic imaging, known as Image Defined Risk Factors (IDRFs) [19,20]. Since the turn of the century, the Children’s Oncology Group (COG) and the Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN) have conducted several prospective studies with the goal of evaluating chemotherapy protocols. As these studies did not use surgical outcomes as primary endpoints, the prospective studies have since been retrospectively reviewed to evaluate surgical outcomes [21]. The controversy surrounding the efficacy of primary tumor resection in patients with
advanced-stage disease continued into the 2010s. In 2014, multiple studies were published showing that high-risk, stage 4 neuroblastoma patients have increased event-free survival after undergoing primary tumor resection [21]. Surgery has an even more important role in low-risk and intermediate-risk diseases.
Staging and Risk Status The INSS, revised in 1993, was adopted by the COG and cooperative groups in Europe and Japan [18]. This system emphasizes the extent of the primary tumor, presence and location of positive lymph nodes, and metastasis as criteria for categorizing the patients into stages 1, 2A/ 2B, 3, and 4/4S. This staging system, along with tumor biology, is the basis of COG risk stratification, which divides patients into lowrisk, intermediate-risk, and high-risk groups in order to guide treatment. With the advent of the INRG classification system in the early 2000s, the comparison of published surgical outcomes has become difficult because investigators must choose one system on which to base their study [19]. In the INRG classification system, tumors are assessed for surgical risk factors that predict unresectability using IDRFs and are separated into L1 (no IDRFs), L2 (at least one IDRF), M (metastatic), or MS (the equivalent of 4S in the INSS). Based on this stage, along with histology and tumor biology, patients are grouped into very low, low, intermediate, and high-risk groups. Regardless of which system is chosen, the stage and risk status of the patient has a great impact on the surgical intervention. It is worthwhile to review the individual groupings, as they guide the surgical decision-making. Very Low and Low Risk The very-low-risk group exists only in the INRG risk group classification system and includes stage L1 without MYCN amplification and stage MS without MYCN amplification or 11q aberration. The low-risk group includes
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INSS stage 1, stage 2A/2B without MYCN amplification and greater than 50% tumor resection, and stage 4S without MYCN amplification. This group also includes INRG stage L1, stage L2 without MYCN amplification or 11q aberration, and stage M or MS without MYCN amplification or 11q aberration if the patient’s age is less than 18 months. The goal for the low-risk group is complete primary tumor resection, accurate staging by biopsy of nonadherent nodes, and adequate tissue sampling for molecular biologic studies. Patients with low-risk disease have an overall survival of >90% with almost all patients receiving surgery alone [22e24]. For this reason, the standard treatment for patients with low-risk disease is surgery alone.
In 2009, a single institution study of 54 patients with intermediate-risk and high-risk stage 3 MYCN-nonamplified disease found that these patients can be safely treated with minimal chemotherapy [27]. In the study, 14 patients were treated with surgery alone, while 39 patients had neoadjuvant chemotherapy that was discontinued after surgical resection. While a higher event-free survival (EFS) (97.1 3% vs. 84.6 10%, P ¼ .02) was seen in patients who received neoadjuvant chemotherapy, there was no difference in 10-year overall survival (OS) between the two groups. Patients with locoregional intermediate- and high-risk disease were able to achieve a 10-year EFS of >97% while minimizing chemotherapy.
Intermediate Risk
The high-risk group includes INSS stage 2A/ 2B with MYCN amplification, stage 3 with MYCN amplification or without MYCN amplification but age >18 months with unfavorable histology, stage 4 with MYCN amplification, or without MYCN amplification between ages 12 and 18 months with unfavorable histology, or age >18 months regardless of tumor biology, and stage 4S with MYCN amplification. This group also includes INRG stages L1 and L2 with MYCN amplification, stage M with MYCN amplification or age >18 months, and stage MS with MYCN amplification or 11q aberration. The goal of surgery in patients with high-risk disease is an initial diagnostic biopsy to obtain an adequate amount of tissue for biologic studies. Treatment following diagnosis begins with neoadjuvant chemotherapy followed by complete resection of the primary tumor. The extent of primary tumor resection has been a controversial issue for some time. Several studies have recently been published supporting the complete resection in patients with high-risk disease. In 2011, Rich et al. reported a study of 207 highrisk patients with circumferential encasement of
The intermediate-risk group includes INSS stage 2A/2B without MYCN amplification and <50% tumor resection, stage 3 without MYCN amplification and age <18 months with any histology or age >18 months with favorable histology, and stage 4 or 4S without MYCN amplification and age <18 months. This group also includes INRG stage L2 without MYCN amplification, but with 11q aberration or poorly differentiated histology, and stage M without MYCN amplification, but with diploid tumor and age <18 months. The surgical goals for patients with intermediate-risk disease are to establish the diagnosis, to resect as much of the primary tumor as safely possible, to accurately evaluate the stage of the disease through the sampling of nonadherent lymph nodes, and to obtain an adequate amount of tissue for diagnostic studies. Patients in this group with unresectable tumors are treated with chemotherapy per COG guidelines. In patients with locoregional disease with intermediate-risk characteristics, surgery alone has been shown to be an effective treatment when the tumor can be completely resected [25,26].
High Risk
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renal vessels, celiac axis, and/or superior mesenteric artery in which 94% of patients treated with chemotherapy underwent a gross-total resection [28]. In this study, 10% of patients had grade 3e4 complications with a nephrectomy rate of 4.3%, suggesting that these high-risk patients with IDRFs could undergo a gross total resection without increasing morbidity [28]. In 2014, the prospective COG A3973 study supported attempts at complete resection in patients with high-risk disease [29]. In the study, 220 high-risk patients were grouped according to the extent of tumor resection. Tumor resection of 90% or more was achieved in 70% of patients; these patients had improved 5-year local recurrence-free survival (LRFS) and EFS when compared with the 30% of patients who had a tumor resection of <90% (LRFS: 91 6% vs. 77 9%, P ¼ .0014; EFS: 46 4% vs. 38 7%, P ¼ .043). There was no difference in OS between the two groups (57 4% vs. 49 7%, P ¼ .27). In addition to surgical resection, all of the patients included in the study were treated with induction chemotherapy and adjuvant radiotherapy. A 2014 report from SIOPEN evaluated the influence of surgical resection on the survival of patients with high-risk neuroblastoma [30]. The study included 1324 operation data sets from high-risk patients including INSS stages 2, 3, 4, 4S with MYCN amplification and INSS stage 4 with age >12 months. The extent of surgical resection was classified as: macroscopic complete (CE), macroscopic incomplete (IE), or not attempted (OE). A CE resection was achieved in 76%, while 23% underwent an IE resection, and 2% were OE. The 5-year EFS and OS for patients who underwent CE were 38% and 44%, respectively, versus 27% and 36%, respectively, for patients who underwent IE and OE combined (EFS: P ¼ .006; OS: P ¼ .013). For stage 4 patients, the 5-year EFS and OS after CE were 33% and 40%, respectively, compared with 24% and 33%, respectively, after IE and
OE combined (EFS: P ¼ .006; OS: P ¼ .049). These data show that patients with high-risk neuroblastoma who are treated with intensive multimodality therapy, including a macroscopic complete surgical resection, have a survival advantage over those patients who have an incomplete resection. In 2017, Fischer et al. reported that patients age 18 months or older with localized neuroblastoma, especially those with INRG high-risk disease with MYCN amplification, have a better local control rate and longer survival after undergoing complete resection when compared with those who underwent incomplete resection [31]. The study was a retrospective analysis of 179 patients from the German neuroblastoma trial NB97 who had localized neuroblastoma of INSS stages 1e3 and were >18 months of age. Tumor resection was defined as complete resection (95%e100%), gross total resection (90% e95%), incomplete resection (50%e90%), and biopsy (<50%). Imaging reports were reviewed for IDRFs and patients were grouped according to the INRG staging system. The primary tumor was completely resected in 68.7% of patients, gross total resection was achieved in 16.8%, 14% had an incomplete resection, and 0.5% were only biopsied. The patients who underwent complete resection had higher local progression-free survival (LPFS), EFS, and OS compared to the lesser resection groups. The 5-year EFS, LPFS, and OS for patients with complete resection were 82.0 3.4%, 87.1 3.1%, and 90.8 2.7%, respectively, compared with 59.8 9%, 62.7 9%, and 75.4 8.1%, respectively, for patients with gross total resection, and 58 10.2%, 66.2 10.5%, and 70.5 9.4%, respectively, for patients with incomplete resection (EFS: P ¼ .001; LPFS: P ¼ .001; OS: P ¼ .020). When analyzing 151 patients classified as INRG high-risk, this improved survival after complete resection was still evident, with a better EFS (P ¼ .001), LPFS (P ¼ .001), and OS
INTRODUCTION
(P ¼ .001). These data support the attempts to complete resection in patients with high-risk disease. Another recent study examined a cohort of 220 patients from the COG A3973 study to evaluate the impact of the extent of primary tumor resection on local progression and survival and to assess the concordance between clinical and central imaging review-based assessments of the extent of resection [32]. Patients were divided into two resection categories: <90% and 90%. A subset of 84 patients underwent blinded central imaging review of computed tomography scans to assess the concordance between clinical and imaging assessments. The extent of resection was 90% in 70% of patients and <90% in 30% of patients as assessed by the surgeon. The 5-year EFS was higher with 90% resection (45.9 4.3%) than with <90% resection (37.9 7.2%; P ¼ .04). A lower cumulative incidence of local progression (CILP) was associated with 90% resection (8.5 2.3%) compared with <90% resection (19.8 5.0%; P ¼ .01). The concordance between the surgeons’ extent of resection assessment and the imaging assessment was low, with only 63% agreement. Despite this discordance, a >90% resection as assessed by the surgeon was associated with a significantly better EFS and lower CILP, which supports attempts at complete resection in patients with high-risk neuroblastoma.
Surgical Technique The initial surgical procedure in all patients, except those with small, localized, easily resectable tumors, should be an incisional biopsy, which will facilitate the diagnostic procedures required to establish risk group status. The surgeon must obtain at least 1 cubic centimeter of viable tumor tissue in good condition for adequate biopsy analysis. Often, the tumor is enclosed by a pseudocapsule that can be exploited for hemostasis. The capsule is opened
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using a technique similar to a trephine hole and multiple biopsies are taken with a pituitary rongeur or similar instrument. Hemostatic agents can then be used to pack the capsule. Central line placement and staging bone marrow aspirations and biopsies can be conveniently performed at the same time as an incisional biopsy. When indicated, definitive surgical resection is undertaken as a second procedure. Achieving clear microscopic margins (R0 resection) is rarely possible in the surgical treatment of neuroblastoma; thus, the goal of surgical resection is gross total resection of the tumor. Dissection proceeds along the pseudocapsule of the mass. Sectioning of the tumor may be required to improve visualization or avoid injury to underlying vital structures. Cervical Lesions Most primary cervical lesions occur in infants younger than 1 year and have favorable biologic features. These patients occasionally present with Horner syndrome or anisocoria. Prior to surgery, it is important to assess the extent of a cervical lesion and determine whether the tumor invades the thoracic inlet. The general approach is through a transverse neck incision followed by dissection of the carotid sheath contents. Large lesions may require a division of the sternocleidomastoid muscle, for adequate exposure. In the case of grossly positive lymph nodes, a formal lymphadenectomy with a modified neck dissection technique should be performed. Parents should be advised that resection of cervical lesions often results in postoperative Horner syndrome, which is oculosympathetic paresis and characterized by ipsilateral palpebral ptosis, pupillary miosis, and facial anhidrosis. Cervicothoracic Lesions Primary cervical lesions may extend into the chest through the thoracic inlet. Adequate exposure is integral to achieving gross total resection
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of these tumors and is usually achieved using a trap-door thoracotomy, in which the neck is exposed to the sternal notch by an incision superior and parallel to the ipsilateral clavicle. The sternum is divided to the level of the fifth interspace, and then laterally to the anterior axillary line. A Finochetto retractor placed between the cut edges of the sternum allows for excellent exposure (Fig. 10.1). This approach can be modified for lesions with a larger cervical component by extending the neck incision superior along the anterior border of the sternocleidomastoid. Lesions that extend into both hemithoraces can be reliably exposed using a clamshell thoracotomy at the fifth interspace (Fig. 10.2). Nerve stimulation is often employed to monitor the vagus nerve and the brachial plexus. Mediastinal Lesions The posterior mediastinum is the second most common primary site for neuroblastomas. These lesions can generally be approached through a muscle-sparing posterolateral thoracotomy (Fig. 10.3). Infiltration through the spinal foramina may require foraminotomy. As with cervical lesions, injury to the stellate ganglion
and the resulting Horner syndrome is a potential complication of resection of superior mediastinal tumors. Upper Abdominal and Retroperitoneal Lesions A majority of neuroblastomas originate from the adrenal gland or sympathetic ganglia and are found in the upper abdomen. There is frequent involvement of regional lymph nodes in the ipsilateral para-aortic or pericaval chains, as well as interaortocaval lymph nodes. The primary tumor and involved lymph nodes often create a confluent mass that encases but does not invade the great vessels of the abdomen. For these tumors, a thoracoabdominal approach is ideal (Fig. 10.4). A right-sided incision is used when the vena cava or right renal hilar vessels are infiltrated, while a left-sided incision is best for tumors involving the aorta, celiac axis, superior mesenteric artery, or left renal hilum. The thoracoabdominal incision allows for excellent exposure and control of the encased blood vessels. Great care must be taken during this dissection, as a vascular injury is possible when the aorta and visceral vessels are cleared.
FIGURE 10.1 The trap-door incision (A) should be performed with the ipsilateral arm abducted 90 degrees at the shoulder. Full exposure of the cervicothoracic structures (B) facilitates gross total resection of primary cervical lesions that extend into the chest through the thoracic inlet and that may involve vascular invasion.
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FIGURE 10.2 The clamshell incision is performed with arms abducted 90 degrees at the shoulder. In this example, the patient has a large left-sided pleural tumor involving the pulmonary hilum with metastatic disease in the right hemithorax. (C) Closure of the sternum is achieved using a Steinmann pin and wires.
Pelvic Lesions Similar to cervical lesions, primary pelvic tumors usually present with favorable biology and without distant metastases. However, these tumors can be challenging to resect due to the encasement of the iliac vessels and infiltration of the lumbosacral plexus. A midline incision extending from the umbilicus to the pubic symphysis provides good exposure of the pelvis and allows adequate control of the distal aorta and vena cava. Internal iliac vessels, if involved, may be ligated and resected without significant morbidity. Injury to the pelvic nerve roots and the resulting foot drop is a common complication of pelvic tumor resection and should be discussed with parents prior to surgery. Minimally Invasive Surgery While open resection continues to be the standard of care for neuroblastoma, there is a
growing amount of literature on the use of minimally invasive approaches. Initial descriptions of laparoscopic surgery for abdominal neuroblastoma were published in the mid-1990s [33]; however, there is still no consensus on eligibility criteria for minimally invasive surgery. Most authors agree that laparoscopy is most suitable for small tumors (5 cm) with limited lymph node involvement and without vascular encasement. Kelleher et al. published a small study of 18 patients who met these criteria and were treated laparoscopically for adrenal neuroblastoma [34]. Median tumor size in the cohort was less than 3 cm, and there was no difference in overall survival or recurrence compared to those patients treated with laparotomy. Patients treated with laparoscopic resection had a shorter postoperative length of stay compared to those who underwent open resection.
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FIGURE 10.3
10. ADVANCES IN THE SURGICAL TREATMENT OF NEUROBLASTOMA
Neuroblastoma lesions in the posterior mediastinum can be approached using a muscle-sparing posterolat-
eral thoracotomy.
Similarly, Ezekian and colleagues published their analysis of data from the National Cancer Database (NCDB) in which 98 of 579 patients undergoing surgery for neuroblastoma were treated with minimally invasive surgery [35]. Interestingly, this cohort included a sizable proportion of patients who underwent laparoscopic resection, despite having tumors greater than 6 cm in diameter (n ¼ 29, 32%). Additionally,
31% of patients in the minimally invasive cohort had metastatic disease at the time of surgery. This study found that patients treated with minimally invasive approaches achieved similar negative margin rates and equivalent 3-year overall survival compared to propensitymatched patients treated with laparotomy. Patients undergoing laparoscopy had a shorter length of hospitalization; however, they also
INTRODUCTION
FIGURE 10.4 For a majority of neuroblastomas, a thoracoabdominal approach facilitates exposure of the primary tumor, involved lymph nodes, and any encased major vessels of the abdomen.
had lower rates of lymph node sampling. The use of a national database for this study raises important questions about the validity of these findings at an individual patient level. In addition to laparoscopy, a number of authors have described thoracoscopic approaches to resection of isolated thoracic neuroblastoma. Potential advantages of thoracoscopy include decreased postoperative pain as well as decreased incidence of long-term chest wall deformities associated with thoracotomy. In a retrospective review of 36 cases of thoracic neuroblastoma, Malek et al. described thoracoscopic resection in 11 patients [36]. Although data on tumor size were not reported, patients were similar with respect to demographics and tumor characteristics. There were no observed differences in overall and disease-free survival or resection margin status between the patients
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who underwent open surgery and those who had thoracoscopic surgery; however, the length of follow-up was not specified. The thoracoscopy group had lower operative blood loss, shorter chest tube duration, and a decreased length of hospital stay. Despite the increase in the amount of literature on minimally invasive surgery for neuroblastoma, there is still no consensus on the safety and effectiveness of these approaches. To date, all studies on minimally invasive procedures for neuroblastoma have been small retrospective reviews or studies of large databases with limited data resolution at the patient level. A 2015 Cochrane review found no studies that met the criteria for inclusion in a metaanalysis, and the authors specifically noted the poor quality of data on the use of minimally invasive surgery for pediatric tumors [37]. The authors advocate for collaborative studies including randomized trials before the widespread adoption of minimally invasive surgery for pediatric tumors including neuroblastoma.
Surgical Complications and Mortality Neuroblastomas that involve and/or encase major vascular and neural structures in either their site of origin or surrounding nodes have a higher risk of surgical complications (Table 10.1). High-risk tumors tend to have these characteristics more often than lower-risk tumors. The most serious surgical complications include massive hemorrhage, major vascular injury, and respiratory failure requiring ventilatory support. The site of the tumor determines the possible surgical complications. Cervical and upper mediastinal resections can be associated with a permanent postoperative Horner syndrome. Paralysis can result from excision of epidural tumors or tumors heavily involving the spinal foramina [38]. Excision of retroperitoneal neuroblastomas can result in nephrectomy or renal infarction [39]. After removal of pelvic tumors, there is an
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Surgical Complications
Organ System
Potential Complications
Vascular
• Arterial or venous laceration primary repair • Arterial laceration - graft • Lymphatic ascites • Renovascular hypertension
Genitourinary
• Nephrectomy • Renal infarction (arterial or venous occlusion or thrombosis) • Ureteral transection or fibrosis • Neurogenic bladder • Bladder perforation • Urinary tract infection
Gastrointestinal
• • • •
Nervous
Intussusception Chronic diarrhea Gastric atony Motility disorders
• • • •
Spinal cord injury with paralysis Horner syndrome Recurrent nerve injury Brachial or lumbosacral plexus injury • Sensory loss
increased frequency of complications such as foot drop [40]. Despite the extent of these massive resections, operative mortality is rare. Complications after primary tumor resection in patients with high-risk tumors are reduced after initial treatment with neoadjuvant chemotherapy [41] that reduces tumor volume [42,43].
Conclusion The role of surgery in the management of neuroblastoma continues to evolve as progress is made to reduce the toxicity of treatment while improving overall survival. Surgical intervention is required for both disease diagnosis and patient risk stratification and is becoming more important as the survival impact of a complete resection is elucidated. Cooperative groups worldwide have made great strides in the last 2 decades. A reduction in therapeutic intensity
is now possible, and complete resection is curative for low-risk and some intermediaterisk tumors. In the last few years, studies have shown that attempts at complete resection in high-risk neuroblastoma increases EFS, while overall survival remains the same. With the increased use of multimodality therapy and multidisciplinary collaboration among pediatric surgeons, pediatric oncologists, radiologists, radiation oncologists, and pathologists, progress in the treatment of high-risk neuroblastoma will continue.
References [1] Kushner BH, Cohn SL, Matthay KK, Cheung NK, La Quaglia MP, Haas-Kogan DA, et al. Treatment of neuroblastoma. In: Cheung NV, Cohn SL, editors. Neuroblastoma pediatric oncology. Berlin, Heidelberg: Springer; 2005. [2] Gross R. Neuroblastoma sympatheticum, the surgery of infancy and childhood. Philadelphia: Saunders; 1953. [3] Koop CE, Kiesewetter WB, Horn RC. Neuroblastoma in childhood; survival after major surgical insult to the tumor. Surgery 1955;38(1):272e8. [4] Kasai M, Watanabe I. Surgery of malignant tumors in infants and children. Gan No Rinsho 1968;14: 719e24. [5] Menjyo M. Surgery of mediastinal tumors. Geka Chiryo Surgical Ther 1968;19(6):851e9. [6] Schega W. Surgery of adrenal medulla. Chirurg 1969; 40:304e8. [7] Zittel RX, Wuttke U. Urgent surgery of early childhood thoracic diseases. Thoraxchir Vaskulare Chir 1969; 17(4):325e33. [8] James DH, Hustu O, Wrenn EL. Combination chemotherapy in childhood neuroblastoma. J Am Med Assoc 1965;194:123e6. [9] Koop CE. The role of surgery in resectable, nonresectable, and metastatic neuroblastoma. J Am Med Assoc 1968;205(3):157e8. [10] Harrison J, Myers M, Rowen M, Vermund H. Results of combination chemotherapy, surgery, and radiotherapy in children with neuroblastoma. Cancer 1974;34(3): 485e90. [11] Hollmann G, Lampert F. Carcinochemotherapy in pediatric surgery (author’s transl). Langenbecks Archiv fur Chirurgie 1975;339:95e8. [12] Stephen CR. Anesthesia for adrenal surgery. Urol Clin 1977;4:319e26.
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