pediatric surgical oncology: update on wilms' tumor, neuroblastoma and rhabdomyosarcoma

PEDIATRIC SURGICAL ONCOLOGY: UPDATE ON WILMS' TUMOR,

NEUROBLASTOMA AND RHABDOMYOSARCOMA

ANTHONY SHAW, M.D. PATRIOIA N. KONRAD, M.D.

0147-0272/84/04-001-044-$7.95 �9 1984, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS

W I L M S ~ T U M O R (NEPHROBLASTOMA) . . . . . . . . . . . . . . . 5

NEUROBLASTOMA . . . . . . . . . . . . . . . . . . . . . . . . 1 8

RHABDOMYOSARCOMA . . . . . . . . . . . . . . . . . . . . . . 3 0

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . 4 1

A C K N O W L E D G M E N T . . . . . . . . . . . . . . . . . . . . . . . 4 1

is Director of Pediatric Surgery at the City of Hope National Medical Center, Duarte, California, and Clinical Professor of Sur- gery at the University of California, Los Angeles. After graduating from Harvard College and the New York University Col- lege of Medicine, Dr. Shaw completed his training in general and pediatric surgery at Columbia Presbyterian Medical Center and Babies Hospital in New York City. Dr. Shaw has authored over 200 publications on a wide variety of subjects for lay and professional readerships and has a major commitment to pediatric surgical oncology.

is a Hematologist/Oncologist on staff at the City of Hope National Medical Center in Duart e, California, and is an Associate Professor of Pediatrics at Los Angeles County--University of Southern Califor- rtia Medical Center in Los Angeles, Cali- fornia. Dr. Konrad graduated from the University of California at Los Angeles and completed her fellowship, residency, and internship at that institution.

CANCER is a rare disease in childhood. Only 6,000 new cases are diagnosed in the United States annually. Nevertheless, cancer is second only to accidental t r auma as the most f requent cause of morta l i ty in the first 15 years of life.

Although the etiologies of almost all forms of childhood cancer are unknown, both survival and cure rates have improved in recent years. For some cancers the improvement has been dramatic. Systematic laboratory investigation of tumor biology has contributed to the improved results, but even more significant has been the contribution of information obtained from meticulously designed prospective studies of a l ternat ive techniques of t rea tment in relat ively small pat ient populations.

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Although the l i terature is strewn with tantalizing clues to the etiology of many childhood cancers, it is unusual to identify any genetic, infectious, or environmental factor which causes a par- t icular tumor in infants or children. This is in contrast to the epidemiology of cancer in adults. Other differences are apparent with respect to tumor biology, response to t reatment , and age- related complications of t reatment.

The vast majority of adult cancers are carcinomas, while hemo- poietic neoplasms, sarcomas, and embryonal tumors, in that order, constitute most tumors of infants and children under 14 years of age. Common sites of origin of pediatric cancers include adrenal gland, bone marrow, lymph nodes, CNS, kidney, soft tissues, and eye; in contrast, the common sites of primaries in adults are the breast, lung, colon, skin, uterus, and prostate. In the pediatric population the relative incidence of cancers varies with age, race, and geography, useful considerations in the differential diagnosis of pediatric tumors.

The fact that many childhood cancers appear in the first year or two of life and histologically resemble embryonic tissues suggests strongly that many of these tumors, such as embryonal rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and Wilms' tumor, originate prenatal ly from disordered embryogenesis. If environmental factors play a role in tumor genesis, these are likely to be different in kind and duration of activity than those which have a role in causing cancer in adults.

Cancers in children in general grow faster than tumors in adults, reflecting a relatively greater growth fraction, that portion of tumor cells actively replicating at any one time. The dif- ference seen in response to t reatment between pediatric and adult cancers is directly related to the different growth rates.

The acute side effects of chemotherapy and radiation therapy in children, as in adults, are dose related. Long-term side effects in children as distinct from adults are also age related and reflect the vulnerabil i ty of immature tissues as well as the longer life span of children apparently cured of cancer, during which complications of therapy may appear. Long-term age-related complications include skeletal deformities and growth distur- bances, endocrine abnormalities, intellectual deficits, and treatment-related second malignancies.

As recently as 25 years ago, survival of infants and children with most mal ignant tumors depended on tumor resectability alone. Survival was brief, cure rates were low. For some cancers, such as Wilms' tumor, retinoblastoma, and embryonal rhabdomyosarcoma, the addition of radiotherapy and chemotherapy to resection caused survival and cure rates to soar and gave rise to the hope that nonsurgical t rea tment modalities would reduce the need for disabling and muti lat ing surgical procedures such as limb amputat ion or exenteration of orbit or pelvis.

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The experience with three of the most common pediatric solid malignancies il lustrates well the tr iumphs and frustrations of the multimodal t rea tment of pediatric cancer and is described in the following sections of this monograph.

Wilms' tumor represents a t r iumph of mult imodali ty treatment, with overall cure rates in excess of 80%.

The t rea tment of neuroblastoma has been quite frustrating. In spite of a na tura l tendency toward cellular maturat ion and spontaneous regression and a high initial t rea tment response rate, most neuroblastomas are unresectable or have widely me- tastasized when diagnosed. The addition of chemotherapy and radiation to tumor resection has had little, if any, effect on overall cure rates, which are more closely related to the age of the patient than to the methods of treatment.

The t reatment of rhabdomyosarcoma, a tumor of protean mor- phology, is a mixture of t r iumph and frustration. Although mul- t imodality t rea tment has dramatically improved cure rates, great differences in survival are related not only to the techniques of t rea tment but also to the site of pr imary tumor and to its histologic subtype.

Although all aspects of multimodali ty management of these tumors will be discussed, the emphasis will be on the current role of surgery in the diagnosis and t rea tment of these three malignancies of childhood.

WlLMS' TUMOR (NEPHROBLASTOMA)

Wilms' tumor represents one of the great success stories in the t rea tment of cancer. The cure rate, which was less than 10% in 1920. is now greater than 80%, regardless of stage at presenta- tion. ~ Much of this success was achieved through a national cooperative effort.

The first National Wilms' Tumor Study (NWTS I) was designed to determine how to maximize cure with the modalities and information available at the time, while minimizing complications of t reatment. Subsequent protocols (NWTS II and III) have been formulated on the basis of the information obtained from the prior study, so tha t these goals are approached in a logical, sequential, and well-controlled fashion.

DIAGNOSIS AND PREOPERATIVE EVALUATION

Wilms' tumor usually presents as an asymptomatic upper abdominal mass bulging into the flank (Fig 1). It is smooth, firm, fixed in position, and, contrary to conventional wisdom, often extends across the midline of the abdomen. Renal anomalies and malformations such as hydronephrosis and renal cysts and tumors including hepatoma, neuroblastoma, and teratoma may

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Fig 1.--Infant girl with stage 1 Wilms' tumor of left kidney. Note bulge of left flank and crossing of midline of abdomen.

have a similar physical appearance. Abdominal pain, hematuria, fever, hypertension, and anemia are commonly present. Wilms' tumors may be associated with other congenital anomalies such as nonfamilial aniridia, hemihypertrophy (Fig 2), Beckwith-Wiedemann syndrome, or renal malformations such as horseshoe kidney. The association with aniridia is particularly interesting in that a chromosomal abnormality, l l p13 deletion, has been identified in the anir idia-Wilms' tumor syndrome, a

Unlike the approach to management of most other solid tumors, definitive initial t rea tment of Wilm's tumor (nephrectomy) is usually under taken without histologic confirmation of malig- nancy. In a child with an upper abdominal flank mass and findings indicative of Wilms' tumor by current diagnostic techniques, including intravenous pyelography (IVP) (Fig 3), ultrasound, and computerized tomography (CT), the diagnosis is a virtual certainty. Although elevated levels of serum erythro- poietin activity and serum renin have been described in children with Wilms' tumor, a t tempts to find a diagnostic chemical marker for Wilms' tumor analogous to catecholamines in neuroblastoma have been unsuccessful. Normal levels of ur inary cate-

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Fig 2.--Left upper extremity hemihypertrophy in 4-year-old boy who underwent left nephrectomy for Wilm's tumor at age 8 months. Note transverse abdominal scar.

cholamines and their metabolites will usually exclude a diagnosis of neuroblastoma in a child with an abdominal mass.

At laparotomy, Wilms' tumor has a characteristic appearance: a firm, smooth, bluish mass replacing the kidney, its surface laced with dilated collateral veins (Fig 4). Biopsy, needle or incisional, either preoperative or intraoperative, is usually avoided because the friable, cellular nature of the tumor, confined by a taut ly stretched renal capsule, makes seeding, if not gross rupture, likely. An exception is made in bilateral tumors, the histology of which is usually favorable, where biopsy, especially at secondary and tert iary operations, is required as a guide to curative treatment. In one reported study, 17 of 19 children with bilateral Wilms' tumors who underwent biopsy survived, 3 good evidence that fears of reduced survival due to seeding of tumor by biopsy may be unfounded for tumors of favorable histology. However, patients with resectable unilateral lesions

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Fig 3.--Intravenous pyelogram of 14-month-old boy with left abdominal flank mass and hematuria. Note distorted left renal collecting system. At nephrectomy for stage II Wilms' tumor, the left renal vein was completely occluded by tumor.

pay a price for biopsy: in the NWTS protocol, tumor spillage moves a patient whose tumor might have been completely resectable into a less favorable stage where additional chemotherapy and radiotherapy, with their associated morbidity, may be required to achieve the same cure rate tha t might have been achieved by resection and minimal chemotherapy alone in the unbiopsied, resectable tumor.

Preoperative assessment should at tempt to answer the following questions:

1. Is the contralateral kidney normal? Because nephrectomy is the t reatment of choice for Wilms' tumor, normal contralateral function must be assured. In addition to the possibility of synchronous bilateral Wilms' tumor (seen in approximately 5% of cases), there may be absence of, or congenital anomalies of, the contralateral kidney as well, compromising function or resectability. IVP will usually give sufficient information when com-

B

Fig 4.--Wilms' tumor of left kidney. Note the smooth and encapsulated appearance of the tumor and the prominent venous pattern on its surface. Although it appears from the picture that the tumor arises from the surface of the kidney, almost all renal parenchyma has been replaced by tumor.

bined with an adequate history, physical examination, sonogra- phy, and laboratory studies of urine and blood. Additional studies such as renal scans, arteriography, and CT may be indicated in particular cases but are not part of the routine workup. A negative workup for bilateral disease does not relieve the surgeon of the responsibility of carefully inspecting the contralateral kidney in the operating room, where tiny nodules of Wilms' tumor which had eluded radiographic detection may be found.

2. Are there metastases? Wilms' tumors usually grow rapidly and may have achieved a large size at the time they are first detected. Even so, at the t ime of diagnosis most are still localized. Only 80 of 530 (15%) of patients enrolled in NWTS I between Oct. 1, 1969 and Dec. 31, 1973 had metastases at diagnosis. 4 The lungs are the most common site of distant metastases, with spread to liver, bone, and brain far less frequent. Unfortu- nately, because sampling of lymph nodes has never been a routine part of the surgical management of Wilms' tumors, statis- tically useful information about lymph node metastasis as related to survival is unavailable.

3. Is the tumor likely to be resectable? Wilms' tumor tends to remain confined within the renal capsule, compressing and dis- placing rather than invading adjacent viscera. Even when the tumor has penetrated its capsule it is only rarely unresectable. Even if tumor enfolds the great vessels it is often possible to find a plane of dissection between tumor capsule and vessel adventi- tia. Wilms' tumor commonly spreads by direct extension into the renal vein and centrally via the vena cava to the right atrium.

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Because of the modifications in surgical technique required by the presence of tumor distal to the invaded renal vein, it is important for the surgeon to know preoperatively the extent of vascular involvement. This information was once obtained by inferior vena cavography and/or right heart angiography. Such invasive studies have been largely replaced by ultrasonography.

STAGING

NWTS I (1969-1974) and NWTS II (1974-1978) identified histologic and clinical factors influencing prognosis and provided the rationale for the surgical-pathologic staging system now in use in NWTS III (Table 1). Many of the poor results of t rea tment were found to be in a subgroup of patients with anaplastic or sarcomatous tumors, which constituted approximately 12% of the series studied in NWTS I. ~ The identification of this group with "unfavorable histology" explained many of the inconsisten- cies in t rea tment response of tumors seeming to have similar clinical characteristics. At the other end of the spectrum, the benign nature of mesoblastic nephroma, a renal hamar toma re- sembling Wilms' tumor and first distinguished from Wilms' tumor by Bolande et al., ~ was confirmed by the NWTS. 7 Pat ients with mesoblastic nephromas are therefore excluded from the NWTS Wilms' tumor t rea tment protocols. Variables which in the past seemed prognostically important, such as tumor size and patient age, have lost their significance with the develop- ment of more effective therapy. Other factors once considered important, such as capsule invasion, renal vein or inferior vena caval vascular extension, local extrarenal spread, local operative spillage, and generalized abdominal spillage, have turned out to be relatively weak adverse prognostic factors, provided all gross tumor is resected and multiple agent chemotherapy is used. 3 The major prognostic factors appear to be histologic type, completeness of resection of the pr imary tumor, metastases, and bilateral involvement. The clinicopathologic staging system which served as the basis for the clinical trials of NWTS I and II has recently been modified to reflect the understanding of prognostic variables gained from those studies. The new staging system, which replaces the grouping system used in NWTS I and II (see Table 1), reflects the belief tha t localized tumor spill is not as serious as was previously thought (moved from group III to stage II) and that lymph node metastases carry a worse prognosis than was previously thought (moved from group II to stage III). It is hoped that in the NWTS III these changes in stratification will result in a more appropriate assignment of therapy. Pat ients currently enrolled in NWTS III are characterized by both stage and histology (e.g., stage III, favorable histology, or stage III, unfavorable histology).

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TABLE 1 . - -WILMS' TUMOR CLINICOPATHOLOGIC STAGING SYSTEMS

GROUP (NWTS I-II) 15 STAGE (NWTS III) 17

I Tumor limited to the kidney and corn- I Tumor limited to the kidney and completely resected. The surface of the renal pletely excised. The surface of the renal capsule is intact. The tumor was not rup- capsule is intact. The tumor was not ruptured before or during removal. There is tured before or during removal. There is no no residual tumor apparent beyond the residual tumor apparent beyond the mar- margins of resection, gins of excision.

II Tumor extends beyond the kidney, but is II Tumor extends beyond the kidney, but is completely resected. There is local exten- completely excised. There is regional ex- sion of the tumor, i.e., penetration beyond tension of the tumor, i.e., penetration the pseudocapsule into the perirenal soft through the outer surface of the renal cap- tissue or periaortic lymph node involve- sule into the perirenal soft tissues. Vessels ment. The renal vessel outside the kidney outside the kidney substance are infil- substance is infiltrated or contains tumor trated or contain tumor thrombus. The tu- thrombus. There is no residual tumor ap- mor may have been biopsied or there has parent beyond the margins of resection, been local spillage of tumor confined to the

III Residual nonhematogenous tumor confined to the abdomen. Any of the following m a y occur: A. The tumor has ruptured before or dur-

ing surgery, or a biopsy has been performed.

B. Implants are found on peritoneal surfaces.

C. Lymph nodes are involved beyond the abdominal periaortic chains.

D. The tumor is not completely resectable because of local infiltration into vital structures.

IV Hematogenous metastases: Deposits beyond those seen in group III, e.g., lung, liver, bone, and brain.

V Bilateral renal involvement either initially or subsequently.

flank. There is no residual tumor apparent at or beyond the margins of excision.

III Residual nonhematogenous tumor confined to the abdomen. Any of the following may Occur: A. Lymph nodes on biopsy are found to be

involved in the hi l ts , the periaortic chains or beyond.

B. There has been diffuse peritoneal contamination by the tumor such as by spillage of tumor beyond the flank before or during surgery, or by tumor growth that has penetrated through the peritoneal surface.

C. Implants are found on the peritoneal surfaces.

D. The tumor extends beyond the surgical margins either microscopically or grossly.

E. The tumor is not completely resectable because of local infiltration into vital structures.

IV Hematogenous metastases. Deposits beyond those seen in stage III, e.g., lung, liver, bone, and brain.

V Bilateral renal involvement at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of extent of disease prior to biopsy.

It is clear that the surgeon's role is crucial not only in the effectiveness of resective treatment but in gathering the staging data on which subsequent treatment is based.

T R E A T M E N T

Although the use of radiotherapy and chemotherapy is responsible for the excellent overall cure rate, with rare exception, nephrectomy is central to the cure of Wilms' tumor.

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Excision of a Wilms' tumor often entails minimal blood loss, but huge tumors, especially with inferior vena cava involvement, may present a formidible challenge with potential for hemorrhagic catastrophe. Therefore, preparations for surgery must include a wide bore central venous catheter for monitoring and rapid replacement of blood volume if necessary, a radial artery line for monitoring and blood gas sampling, and a bladder catheter for intraoperative and postoperative monitoring of urine output.

Wilms' tumors tend to be friable and easily ruptured. The abdominal incision must give wide exposure, facilitating the approach to the renal vessels and the search for other tumor sites with minimal handling of the tumor mass. This is best done through a transverse bilateral subcostal incision from the tip of the 12th rib on the tumor side to the anterior axillary line on the contralateral side. Ease and safety of excision of the largest tumors may be greatly enhanced by thoracic extension. The abdominal cavity should be meticulously searched for possible metastases in lymph nodes and/or liver. Suspicious nodes should be biopsied and the site marked with metal clips. The contralateral kidney is lifted from its bed and carefully inspected and palpated. The surgeon's goal is to remove all involved tissue. This may require extensive lymph node dissection or en bloc excision of adjacent structures invaded by tumor, such as stomach, intes- tine, or liver. The renal vein must be carefully palpated to en- sure ligation distal to tumor thrombus. If tumor thrombus extends up the inferior vena cava, venotomy and removal of thrombus may be feasible. Tumor thrombi extending into the right a t r ium have been successfully removed with the aid of car- diopulmonary bypass.

Ligation of the renal vessels early in the operation has traditionally been considered desirable in order to reduce risk of tumor embolism to the lungs. However, the NWTS data indicate that the timing of ligation of the vein does not influence prognosis, s Ligation of the renal artery should precede ligation of the renal vein; occlusion of venous outflow prior to inflow occlusion results in dramatic swelling and increased fragility of the tumor with turgid congestion and often rupture of the perinephric tumor veins. Early occlusion of the artery, if technically feasible, shrinks and reduces the friability of the mass, making subsequent dissection much easier.

When the tumor is very large it usually is impossible to approach the renal vessels until lateral, inferior, and superior at- tachments are divided, allowing lateral dislocation of the mass and access to the renal hilum, a maneuver greatly facilitated by thoracic extension of the incision.

Rarely, a tumor is so big and/or a patient so debilitated that preoperative reduction of tumor size may be desirable to make

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the resection simpler and safer. Shrinkage of tumors has been described with each of the following: a course of vincristine, 9 irradiation, l~ and, most recently, tumor embolization. 11' 12 The survival rate has not been demonstrably improved by such preoperative maneuvers.

The disadvantages of preoperative t rea tment include the following:

1. Tumor destruction in response to even small doses may make accurate histologic and even gross staging impossible and therefore may result in both inappropriate t rea tment and loss of protocol patients for evaluation.

2. Some masses may be t reated which on exploration prove not to be Wilms' tumor.

3. Stage I tumors in infants will be inappropriately treated if they receive preoperative radiotherapy.

One study advocates preoperative radiotherapy on the basis of finding that intraoperative rupture is markedly reduced and that the accuracy of preoperative diagnosis is close enough to 100% to justify the procedure. 1~ Although the study did not show reduced survival following tumor rupture, it did show increased metastases and also pointed out that rupture moves the patient into a different stage requiring more aggressive therapy with increased morbidity.

Treatment of Bilateral Wilms' Tumor and Metastatic Disease Of the 606 patients registered in NWTS I, 5.4% had synchro-

nous bilateral disease, and 3.3% developed contralateral (metachronous) disease following nephrectomy. Two-year survival for 30 patients with synchronous disease was 87%. In only seven of the 30 was all tumor excised, with 100% survival. Nineteen with residual tumor survived. 3 In view of the excellent survival of patients with bilateral Wilms' tumor, a conservative t rea tment approach seems justified. Current recommendations include as many as three staged surgical procedures to monitor the effects of therapy and to remove tumor while preserving as much normal renal parenchyma as possible. The value of this approach is being assessed in a prospective study.

While bilateral synchronous Wilms' tumor appears to have a relatively favorable outcome, metachronous disease carries a much worse prognosis. 13 Because the second tumor occurs in the sole remaining kidney preserving normal renal tissue is difficult. Probably more significant, however, is tha t the second tumor occurs during or after chemotherapy for the pr imary tumor. Thus it is likely to be more resistant to chemotherapy than the usual Wilms' tumor.

The surgeon's role in the t rea tment of metastat ic disease is both diagnostic and therapeutic. That lymph node sampling has prognostic value is strongly suggested by NWTS I data but has not been examined critically by prospective studies. Current

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studies designed by the NWTS Surgical Subcommittee are under way to determine the significance of lymph node metastasis. At present there is no evidence that periaortic lymph node dissection is of value in Wilms' tumor even in the patients with unfavorable histology.

There are many long-term survivors who are disease free following single or multiple resections of metastat ic Wilms' tumor, including patients with deposits in lung (Fig 5), liver, and brain. The 2-year relapse-free survival in NWTS II for patients with metastases was approximately 50%. 14 Most if not all of these patients had radiotherapy and chemotherapy as well, making the contribution of resection to cure impossible to evaluate. The damage to lung or liver caused by irradiation of metastatic disease may result in death or chronic illness: for tha t reason, current efforts to eradicate metastases emphasize chemotherapy as

Fig 5.--Left upper lobe Wilms' tumor metastasis in 2-year-old boy, six months post nephrectomy while on chemotherapy. The child was disease free 10 years after excision of lung metastasis and bilateral pulmonary irradiation (1,200 rod). A, round solitary density in upper left lung field (arrow). B, solitary metastasis at thoracotomy.

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a first line and surgery as a second line of attack. A protocol developed as a substudy of the NWTS will evaluate the treatment of pulmonary metastases with chemotherapy and subsequent removal of residual deposits.

Surgical resection of metastases remaining after aggressive chemotherapy is not being studied for organs other than lung, but seems logical. Whether resection is likely to save patients with unfavorable histologic tumor types unresponsive to chemotherapy is dubious but may be worth trying in cases where it appears that total tumor resection is possible.

Nonoperative Treatment Radiotherapy, actinomycin-D, vincristine, Adriamycin, and

cyclophosphamide are all effective agents in the t rea tment of Wilms' tumor. As a result of comparing competing t rea tment arms NWTS I (1969-1974) clearly demonstrated that two-drug therapy (vincristine plus actinomycin-D) produced far bet ter results in groups II and III than either drug singly, and that radiation of the tumor bed did not improve survival in children under 2 years of age in group I who received chemotherapy. All t rea tment arms for groups I I - IV received radiotherapy.

NWTS II demonstrated that radiation was unnecesssary for a child of any age with group I disease receiving double agent chemotherapy and also showed that in this group, 6 months of chemotherapy was as effective as 15 months (96% 3-year relapse- free survival). Adding Adriamycin to vincristine and actinomycin-D (plus radiation) resulted in a 3-year relapse-free survival of 79% for groups II-IV, compared to 65% for those on the two- drug regimen.

Radiotherapy has been used in doses up to 4,000 rad in older children and in lower but maximally tolerated doses in infants and younger children. Doses of 2,000 rad appear to be as effective as higher levels for patients with tumors of favorable histology. 16

CURRENT RECOMMENDATIONS AND THE FUTURE

Results of treating patients with group I, II, and III tumors with favorable histology are so good that current efforts are being directed toward determining the minimum number of therapeutic agents and minimum duration of t rea tment required to maximize cure rates while minimizing t rea tment morbidity. Conversely, the poor results in group IV disease (50% 2- year relapse-free survival 14) and in tumors with unfavorable histology (39% relapse-free survival vs. 89% for favorable histology4, 5)justify a more aggressive therapeutic approach for patients in these poor prognostic categories. These dual objectives will be the goal of NWTS III using the new staging system shown in Table 1.17

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As a participant in NWTS III, the City of Hope Children's Cancer Service treats newly diagnosed patients with Wilms' tumor as follows:

Stage I. Nephrectomy, no radiotherapy. Children are ran- domly assigned to a 10-week or 6-month course of vincristine- actinomycin-D.

Stage II. Nephrectomy. Radiotherapy: random assignment to no radiotherapy or 2,000 rad. Chemotherapy: random assignment to actinomycin-D-vincristine-adriamycin for 15 months or intensive actinomycin-D-vincristine for 15 months.

Stage III. Nephrectomy. Radiotherapy: random assignment to 1,000 or 2,000 rad. Chemotherapy: same as for stage II.

Stage IV (favorable histology). Nephrectomy. Radiotherapy: 2,000 rad. Chemotherapy: random assignment to triple-drug regimen, as for stages II-III, or triple-drug regimen plus cyclophosphamide.

Unfavorable histology (any stage). Nephrectomy. Radiation: age-adjusted up to 4,000 rad. Chemotherapy: random assignment to triple-drug regimen or triple-drug regimen plus cyclophosphamide.

Thus the protocols for stages I, II, and III include one arm of reduced intensity of treatment and one arm of therapy found most effective for that stage by the NWTS I and II. Thus, for stage I, an attempt will be made to reduce the length of double- drug treatment; in stage II attempts will be made to eliminate radiotherapy and to determine whether intensifying treatment with relatively nontoxic drugs can compensate for eliminating a toxic drug (Adriamycin), and in stage III to reduce radiotherapy from current levels. In the poor prognostic categories, treatment giving the best results currently will be compared with treatment arms adding a fourth drug, cyclophosphamide, and for the tumors of unfavorable histology, the dose of radiation will be increased in the hope that the trade-off for increased treatment morbidity will be a marked improvement in survival.

The NWTS has established through its Surgical Subcommit- tee three special study aims; (1) to determine the most effective treatment of bilateral disease, (2) to improve the results of treating pulmonary relapse following initial treatment, and (3) to determine the prognostic significance of intra-abdominal lymph node metastases.

The object of the bilateral Wilms' study is to preserve as much functioning renal parenchyma as possible while providing adequate treatment to the tumor. The protocol calls for initial biopsy only with reexploration and conservative resective procedures following a course of chemotherapy with tumor response monitored by ultrasound, CT, and/or subtraction angiography. Nephrectomy is to be avoided at first and even second look operations and performed only if necessary following maximal re-

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sponse to safe doses of chemotherapy and radiotherapy. The facts that synchronous bilateral Wilms' tumors usually have favorable histology, and that the survival is already good with a variety of therapies, favor such a conservative approach. A more aggressive t rea tment plan is followed for bi lateral tumors of unfavorable histology.

Irradiation has been the pr imary means of t reat ing pulmonary recurrence of disease following nephrectomy and chemotherapy for Wilms' tumor, with a particularly poor prognosis associated with tumors of unfavorable histologic type and with early relapse following initial therapy. Although long-term relapse-free survival rates have followed radiotherapy-chemotherapy t rea tment of pulmonary metastases (Fig 6), studies have shown adverse effects on pulmonary function, is Some uncontrolled early reports suggest excision of lung metastases may improve survival. 19 The new protocol at tempts to improve survival rates and reduce pulmonary morbidity by using a "cascade retrieval system" in which pulmonary metastases failing to respond to a program of drug management (modified for initial therapy which depended on stage and histology) are excised and radiation therapy is withheld. Recurrent pulmonary nodules are excised with multiple thoracotomies if necessary.

Although the results of NWTS I and II suggested that patients with lymph node metastases may have a worse prognosis than those without, node biopsy was performed in such a haphazard and uncontrolled fashion that no conclusions are supportable. The new study requires participating surgeons to conduct a

Fig 6.- -A, diffuse bilateral pulmonary metastases in 1-year-old child at time of nephrectomy for Wilms' tumor. B, lungs clear after treatment with vincristine-actinomycin-D. The child subsequently died of recurrent disease.

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careful and complete sampling of abdominal nodes. Although de- cisions with respect to regional node dissection remain with the individual surgeon, data on node dissection will be gathered and examined.

The successes of NWTS I and II have created a great spirit of cooperation and optimism with respect to continuing under NWTS III to improve survival for children with Wilms' tumor, especially those with unfavorable histology and disseminated disease, while a t tempting to preserve the highest possible quality of life for all who survive.

NEUROBLASTOMA

When compared to the dramatic improvement in survival and cure rates achieved by multimodali ty t rea tment of Wilms' tumor, Hodgkin's disease, and embryonal rhabdomyosarcoma, the current results of t rea tment of neuroblastoma, the second most common solid tumor of childhood, are very disappointing. The natural tendency of pr imary and metastat ic disease to undergo degeneration or matura t ion into a benign neoplasm (ganglio- neuroma) and its initially favorable response to chemotherapy and radiotherapy (in most cases) led oncologists over 20 years ago to expect that the special biologic characteristics of neuroblastoma favored cure with the right combination of surgery, radiation, and drugs. This expectation has been unmet because of our failure to identify and make use of those factors causing spontaneous regression and cure of metastat ic neuroblastoma of infancy and the failure of radiation and chemotherapy to eradicate and prevent metastat ic disease. Except for that mysterious category of stage IV-S disease in infants under 1 year of age, it is still true, as it was 20 years ago, that cure is rare without total resection of disease.

DIAGNOSIS

Neuroblastoma arises in the adrenal gland and in sympathetic nervous t i s sue- -wherever cells of neural crest origin have mi- grated. Some 60%-75% of primaries appear in the abdomen, 16%-20% in the thorax, 5%-8% in the pelvis, and 2%-3% in the neck. 2~ Neuroblastoma disseminates early and widely. Me- tastases are present in 60%-90% of patients when first seen (Fig 7).

Because curability of neuroblastoma is directly related to stage of disease, diagnostic efforts are directed toward (1) clinical, chemical, and/or histologic identification of the tumor, (2) mapping metastat ic disease, and (3) assessing resectability of the pr imary tumor.

Biopsy of the pr imary lesion prior to undertaking definitive 18

Fig 7.--Three-month-old girl with diffuse hepatic metastases from a left adrenal neuroblastoma. She showed a complete response to chemotherapy but died of disseminated disease at age 8 months.

treatment is often unnecessary. Indeed, the site of the primary lesion may not be at all apparent, tissue diagnosis being established by biopsy of metastatic disease in marrow, bone, subcutaneous tissue, or liver. The combination of a small round cell neoplasm in any of these sites and elevated levels of urinary catecholamines or catecholamine metabolites establishes the diagnosis of neuroblastoma. Neuroblastoma shares with other tumors of neural crest origin (pheochromocytoma and ganglioneu- roma) the excessive synthesis of catecholamines, which are excreted and easily measured in the urine. Catecholamines (epi- nephrine, norepinephrine, and dopamine) and their metabolites therefore serve as useful markers for the differential diagnosis of neuroblastoma. Because neuroblastoma varies from patient to patient in the proportions of the various catecholamines produced in excessive quantity [some produce primarily norepinephrine, the principal metabolite of which is vanillylmandelic acid (VMA), while others produce primarily dopamine, whose principal metabolite is homovanillic acid (HVA)], a 24-hour urine sample tested for at least VMA and HVA and usually for VMA, HVA, and total catecholamines results in a degree of diagnostic accuracy of over 95%. 21' 22

While the presence of a mass is characteristically the presenting sign in Wilms' tumor, early signs of neuroblastoma are frequently related to systemic effects of increased catecholamine

19

and vasoactive intestinal peptide secretion, intraspinal extension of tumor, or distant metastases. Unlike the firm, smooth, abdominal flank mass typical of Wilms' tumor, abdominal neuroblastomas tend to be hard, nodular, fixed, and more centrally located. Pelvic neuroblastomas may cause bladder obstruction and constipation and can usual ly be palpated on digital examination of the rectum. Neck neuroblastomas are often associated with Horner's syndrome.

Delineation of metastat ic disease traditionally requires roentgenograms of chest, abdomen, and skeleton, bone and liver scans, and bone marrow aspiration. Bilateral renal function must be assured by IVP. Pat ients with signs of spinal cord compression such as extremity weakness or fecal or urinary incontinence should be studied by myelography and vertebral tomography to delineate extension of neuroblastoma into the spinal canal. Ultrasonography is invaluable for screening any abdominal tumor. Neuroblastoma usually appears as a "complex" mixture of cystic and solid components. The presence of calcification on the roentgenograms and ultrasound scans helps to differentiate neuroblastoma from tumors where calcification is rare, such as Wilms' tumor (Fig 8).

CT scan is particularly helpful in assessing tumor resectability (Fig 9). Encirclement or infiltration of vital structures can often be determined preoperatively, helping to avoid cata-

Fig 8.--Intravenous pyelogram of 2-year-old boy with left adrenal neuroblastoma. Note preservation of normal pelvicalyceal configuration and heavy calcification of tumor at upper pole of left kidney (arrows).

20

Fig 9.--CT scans of two patients with neuroblastoma. A, 6-year-old girl with left adrenal neuroblastoma (arrows). Note that tumor is well demarcated from surrounding structures (spleen, stomach, great vessels). The tumor was resected with ease. B, 3-year-old girl with neuroblastoma occupying most of mid-upper abdomen (arrows). Tumor was heavily calcified. Note absence of planes between tumor and adjacent viscera. Tumor was unresectable and had infiltrated liver, pancreas, and retroperitoneum. (From Shaw A.: Surgical treatment of neuroblastoma, in Pochedly C. (ed.): Neuroblastoma: Clinical and Biological Manifestations. New York, Elsevier Science Publishing Co., Inc., 1982. Reproduced by permission.)

strophic technical errors during the operation. CT scan also demonstrates metastases to lymph nodes, liver, and lungs, and is especially valuable in following response of tumor to chemotherapy and radiotherapy in the t iming of second look or delayed primary operations (Fig 10).

STAGING

The staging system introduced in 1971 by Evans and still used by the Children's Cancer Study Group (CCSG) is a clinical classification related to tumor size and resectability and presence of distant metastases (Table 2). 23 A new staging system was recently adopted by the Pediatric Onocology Group (POG) (see Ta- ble 2). It is a modification of the surgicopathologic system in use at St. Jude's Children's Research Hospital z4 and reflects the ad-

21

Fig IO.--CT scans of infant boy with large left adrenal neuroblastoma treated for 1 year with chemotherapy, at which time the tumor was easily resected (delayed pdmary operation). A, large tumor (arrows) partly overlying upper pole of left kidney. B, 1 year later, tumor was relatively much smaller (arrows) and more heavily calcified. It was completely resected.

verse effect on prognosis of lymph node metastases. The differences between stages in the POG classification are related to tumor resectability, lymph node involvement, and extranodal metastases.

The surgeon has a central role in both staging systems. How- ever, in the POG system, a patient may be staged A or B, depending on the skill of the surgical team. The use of a different staging system by each of the two major pediatric cancer study groups does not seem desirable, and it is hoped resolution of

22

TABLE 2.--NEUROBLASTOMA STAGING SYSTEMS

EVANS' SYSTEM POG

I Tumor confined to s tructure of origin.

II Tumor extending in continuity beyond the s t ructure of origin but not across midline. Includes tumors arising in midline structures. Regional nodes may be involved on same side as the tumor, or only one side of mid- l ine tumor may be involved.

III Tumors extending in continuity across the midline, including bi la tera l extension of a midline tumor. Re- gional nodes may be involved bilater- ally.

IV Metastat ic disease involving the skeleton, organs, soft tissue, d i s tan t nodes, etc.

IV-S Pat ients whose pr imary tumor would be stage I or II, who have metas ta t ic disease only to one or more of the following: liver, skin, bone marrow. Bone metas tases are not included in stage IV-S.

A Complete gross resection of pr imary tumor. Margins histologically negative or positive. Regional nodes not in t imate ly adherent to or incor- porated in pr imary free of tumor. Liver histologically free of tumor.

B Incomplete gross resection of primary tumor. Regional lymph nodes and l iver free.

C Complete or incomplete resection of primary. Regional nodes histologically positive. Liver free.

D Disseminated disease.

which system bet ter reflects the prognostic variables will lead to the adoption of a uniform classification in the not too distant future.

SURGICAL TREATMENT

Neuroblastomas are friable, highly vascular tumors which tend to surround and invade adjacent structures. Therefore, at- tempted excision requires careful planning and meticulous preparation of the patient. Operations need rarely be performed as emergencies. The exceptions are cases of massive hemorrhage from traumat ic rupture of the tumor and cases in which there is evidence of progressive spinal cord compression.

Preparations for surgery include measures for monitoring and measures for support. The possibility of severe bleeding from even biopsy of neuroblastoma must always be anticipated. A wide bore catheter should be placed centrally through a subcla- vian or jugular vein both for rapid infusion of blood and fluid and for monitoring central venous pressure. Because most patients will be placed on a course of chemotherapy postopera-

23

tively, a Hickman or Broviac catheter placed through a cephalic vein cutdown at the deltopectoral groove or through a great sa- phenous cutdown at the groin serves both intraoperative and postoperative needs. A radial artery catheter allows continuous monitoring of arterial pressure and sampling of arterial blood for pH and blood gas determinations intraoperatively. A Foley catheter is essential for intraoperative and postoperative monitoring of urine output. Because abdominal neuroblastomas may invade the colon, making segmental colectomy in continuity with resection of the tumor desirable, a full mechanical and an- tibiotic colon preparation should precede surgery. A preoperative intravenous dose of cefamandole nafate should be given in anticipation of possible contamination under such circumstances and repeated intraoperatively and for the first 24 hours postoperatively should actual contamination take place.

Abdominal neuroblastomas arise from the adrenal glands, organ of Zuckerkandl, or from the sympathetic ganglia anywhere from pelvis to diaphragm. Surgical exposure of abdominal neuroblastomas is best achieved through a flank to flank upper abdominal t ransverse incision which permits accurate assessment of the extent of local disease, facilitates detection of regional metastases, and provides access to the numerous blood vessels supplying and draining the tumor. A support such as a sandbag or kidney bridge under the upper lumbar spine thrusts posterior abdominal organs forward, making them more accessible. A thoracic extension into the eighth intercostal space is often helpful in the exposure of large upper abdominal tumors and is essential in exposing tumors involving structures on both sides of the diaphragm.

Pelvic neuroblastomas often require a combined abdominal and perineal approach. A lower abdominal vertical midline incision provides good access for the abdominal portion of the pelvic dissection.

Thoracic neuroblastomas arise in the posterior mediast inum and often extend into the spinal canal through intervertebral foramina. Excellent exposure of the posterior mediast inum is provided by a posterolateral incision through an intercostal space. Exposure can be improved by extending the incision an- teriorly or by dividing one or more costal cartilages or by resect- ing a rib. Portions of rib and chest wall invaded by neuroblastoma should be removed en bloc. Superior mediastinal neuroblastomas may extend up into the neck (and, conversely, cervical neuroblastomas may extend into the mediastinum) and may require separate thoracic and cervical incisions or a combined incision with removal of the head of the clavicle to allow complete excision (Fig 10).

Although it is desirable to remove the tumor en bloc (Fig 11), the surgeon should not hesitate to excise the tumor piecemeal

24

Fig 11.--Neuroblastoma surrounding left renal vessels and infiltrating kidney in 6- month-old boy. Top, tumor in situ (arrows). It was not possible to tell if tumor arose in adrenal or sympathetic ganglion. Bottom, tumor completely resected en bloc with kidney. No further treatment was given. Child is free of disease at age 8 years.

when vital structures such as the celiac and superior mesenteric arteries are surrounded with tumor and when tumor invades the spinal canal.

Intraspinal extension of tumor is common and may be asymptomatic. Children presenting with paraspinal neuroblastoma

25

should have preoperative myelography and/or CT scan to determine whether intraspinal tumor is present. Signs of spinal cord compression, including extremity weakness and paralysis, pain, and incontinence of urine and stool, part icularly if they are of recent onset and progressing, constitute an emergency. Al- though laminectomy with excision of the intraspinal tumor with or without irradiation has been the traditional method used for rapid cord decompression, a recent s tudy provides strong evidence that chemotherapy may be more effective in relieving neurologic symptoms and result in less long-term morbidity than laminectomy and radiation. 25

Although it appears tha t cure rate is directly related to the completeness of resection, the surgeon operating on neuroblastoma must be aware of the capricious nature of this tumor. For children under the age of 1, tumor regression or matura t ion to a benign form is not unusual. When confronted with a situation where efforts to extirpate all gross tumor is likely to lead to death of the patient or life-threatening morbidity, the better part of valor for the surgeon is to remove as much tumor as is compatible with full recovery of the patient, to follow up with chemotherapy, and, when appropriate, to return for a second look.

Surgical deaths are usual ly due to massive hemorrhage from inadvertent injury of major vascular structures or unrecognized or irreversible damage to vessels supplying or draining vital organs. If the celiac or superior mesenteric arteries are damaged they may be successfully repaired by the use of microsurgical techniques.

Based on their laboratory experiments demonstrat ing retar- dation of growth of residual murine neuroblastoma and isolated skin implants following resections of three fourths of the tumor by electrocautery, an effect not seen when cold knife resection was used, Ziegler et al. postulate that electrocoagulation poten- tiates host anti tumor immune response and therefore recom- mend that electrocoagulation be used in place of sharp surgical excision. 26

The contribution of surgery to the cure rate of neuroblastoma eludes assessment for two major reasons: (1) the unpredictable but significant incidence of spontaneous tumor regression in the first year of life, and (2) the fact that most surgically treated neuroblastoma patients have also been treated with radiotherapy, chemotherapy, or both. Still, the evidence available suggests tha t there is a direct relationship between resectability and cure. Of 16 children whose tumors were completely excised at St. Jude 's Research Children's Hospital since 1975 and who received no other t reatment , 15 were free of disease in 1983. 27 Although neuroblastomas are sensitive to irradiation and che-

26

motherapy, recurrence of tumor in the absence of complete excision is still the rule. Whether chemotherapy and radiotherapy enhance cure rate over tha t of surgery alone is still unclear for incompletely resected and disseminated disease. In patients under 1 year of age, survival is remarkably good, even for babies whose tumors are incompletely resected.

Delayed Primary Operation and Second Looks Neuroblastomas are highly sensitive, if only transiently, to

the effects of chemotherapy and radiation therapy. A regimen of cyclophosphamide, imidazole carboxamide, and vincristine resulted in complete or good partial response in approximately 80% of patients with disseminated disease. 2s After mult iagent chemotherapy with or without radiotherapy has reduced to man- ageable proportions tumors deemed unresectable or only par- tially resectable on initial surgical exploration, a second operation, the so-called second look operation, may be under taken to resect residual tumor. Similarly, the first look operation may be delayed pending chemotherapy of a tumor apparently unresectable on the basis of clinical assessment and/or CT scan. Chemo- therapy cannot be relied on to eradicate residual gross disease, especially in patients over the age of 1 year. All eight of a series of stage IV, POG stage D, patients who had good tumor response to chemotherapy were found to have residual tumor at exploration, 29 and, similarly, 22 of 23 patients treated by the CCSG had residual tumor found at second look or delayed primary operation following chemotherapy, s~ In a recent CCSG report of 62 patients with stage IV disease in whom residual tumor was found at delayed primary operation or second look, total resection of the primary was achieved in 34. However, of those 34 only six survived free of disease. The authors were unable to demonstrate any significant contribution of complete resection of the primary tumor whether at delayed primary operation or second look to the imj~rovement of the dismal survival rates of patients in group IV. ~1 Although the tumor may be completely excised at a second look procedure, recurrence is the rule in stage IV disease. However, of 16 patients with localized but unresectable disease treated since 1974 by sequential cyclophosphamide and Adriamycin followed by resection at a second look operation, 14 were reported disease free in 1983. 27 Eleven never received radiation. Until the results of prospective studies be- come available, the therapeutic role of second look procedures remains unresolved.

In most treated neuroblastomas where regression has occurred, subsequent biopsy has shown transformation to a more benign cellular type, i.e., neuroblastoma to ganglioneuroblas- toma. There is, however, no evidence tha t such transformation of residual tumor improves the cure rate.

27

Surgery for Metastatic Disease Neuroblastoma tends to disseminate widely to liver, bone, and

subcutaneous tissues. Thus metastat ic neuroblastoma does not lend itself to metastasectomy, an approach which has improved survival in metastat ic Wilms' tumor and osteogenic sarcoma.

NONOPERATIVE TREATMENT

The unique behavior of neuroblastoma has made evaluation of response to t rea tment very difficult. Numerous modalities have seemed to be effective and later been shown to have been inad- vertently evaluated only in good prognosis groups. Conversely, dramatic responses are often seen in poor prognosis groups and patients with large tumor burdens. Complete responses may be obtained only to have the patient die with disseminated disease after an unusual ly long disease-free interval.

Localized, completely resected disease has an excellent prognosis which is not improved with the addition of either chemotherapy or radiotherapy. Prospective studies have thus far not documented any benefit from any modality added to surgery for localized but completely resected disease.

The majority of patients with neuroblastoma are not infants, have disseminated disease, and have a dismal prognosis. The unique behavior of the tumor and the possibility of prolonged but not permanent remissions make extended observation at least as important as controlled prospective study for these patients. Approaches being studied include aggressive mult iagent chemotherapy, second look or multiple operations, and very high-dose chemotherapy and radiation therapy followed by allo- geneic or autogeneic bone marrow transplantation.

Although surgical t rea tment of neuroblastoma can, by itself, cure a relatively small percentage of patients with neuroblastoma, few children with nonresectable tumors are cured, despite dramatic initial responses to chemotherapy and/or irradiation. It appears tha t stage A tumors can be cured by excision alone, regardless of age. The prognosis of stage B tumors is also excellent in the first year of life even though tumor is left behind. The extent to which chemotherapy, radiation, and second look surgery can improve the cure rate of the vast majority of neuroblastoma patients with residual disease remains to be determined.


Newly diagnosed patients at the City of Hope are staged according to the new POG classification as well as the Evans' classification. Treatment depends both on age and stage of disease, with more aggressive t rea tment given to patients over 1-2 years

28

of age. In the absence of distant metastases, a t tempts at tumor resection usually precede chemotherapy and radiation therapy. If the tumor is assessed as unresectable, either operatively or on the basis of prel iminary CT scan, mult idrug chemotherapy is used to shrink the tumor to allow complete resection at a second look or delayed pr imary operation. If resection is complete, no further t reatment is given, whatever the patient 's age.

In selected cases with microscopic residual disease we tend to give radiotherapy, especially if the child is over 1 year of age, although there is no evidence to support this practice. Indeed, in the absence of any data showing that radiotherapy increases survival, and with the known contribution of radiotherapy to long-term morbidity, many centers are experimenting with mul- t idrug regimens tha t exclude radiotherapy from primary treatment of any stage of disease. 27

Pat ients with gross residual disease are in most cases treated postoperatively with mult iagent chemotherapy. Radiotherapy is used in selected cases of localized or unresectable disease which fails to respond well to chemotherapy. Residual tumor is followed by CT scan and subsequent at tempts at complete resection are made at second and even third look procedures following clinical and radiographic response to treatment. Results of treatment of disseminated neuroblastoma are so bad with current methods of multimodal t reatment that totally new approaches are required to salvage patients with stage D disease. Several institutions have treated such patients with high-dose chemotherapy and total body irradiation, repopulating their marrow subsequently with marrow from a sibling or with autologous marrow removed prior to the massive therapeutic assault. Pa- tients with tumor in the marrow have had their marrow "cleaned" of neoplastic cells prior to harvesting by various techniques based on monoclonal antibodies. At present the numbers of patients are too few and the follow-up period too short to allow appraisal, but the early results suggest that survival at least has been prolonged in some of these patients.

Pat ients with stage IV-S disease are individualized for treatment depending on site and rate of growth of metastases. The primary is often removed. Chemotherapy and/or radiotherapy may be used selectively in reduced dosages.

The surgeon's role in the t rea tment of neuroblastoma has ex- panded, especially in institutions using the new staging system which defines t rea tment categories by completeness of resection and operative assessment of tumor spread and lymph node metastasis. Results of deferred primary operations and second look procedures in disseminated disease will be improved when we have bet ter ancillary techniques for destroying micrometastases and thus preventing relapse.

The recent explosion of knowledge in the areas of cellular bi- 29

ology and genetics offers the possibility of finally understanding the natural mechanisms leading to regression of neuroblastoma in the first year of life and revives the optimism of 20 years ago that understanding of the natural mode of regression can be turned into an effective therapeutic instrument for cure of this lethal cancer.

RHABDOMYOSARCOMA

As a group, soft t issue sarcomas are the fourth most common of the solid tumors of childhood. Rhabdomyosarcoma is the most common soft tissue sarcoma in children under 15 years of age. 32 Rhabdomyosarcoma has a double peak incidence, one in the first few years of life, due to tumors of the head and neck and pelvis, and one in the teens, when paratest icular tumors appear. Ex- tremity and t runk primaries occur at all ages. Rhabdomyosar- comas arise from primitive mesenchymal cells in many areas of the body in which mature skeletal muscle is not necessarily found. The most frequently involved pr imary sites are head and neck area (28%), orbit (10%), genitourinary tract (21%), extremities (18%), t runk (7%), retroperi toneum (7%), perineum and anus (2%), and other sites (7%). 33

Histologic subclassification of rhabdomyosarcoma is not an area of general agreement. Although the rhabdomyoblast is common to all rhabdomyosarcomas, as many as six histologic subtypes have been identified. The most important variants are embryonal and alveolar, constituting 57% and 19% of rhabdomyosarcomas, respectively. 34 A polypoid subtype of the embryonal rhabdomyosarcoma, sarcoma botryoides, is found extending into body cavities (e.g., nasopharynx, vagina, bladder and bile ducts) and accounts for an additional 7% of rhabdomyosarcomas. In most sites, rhabdomyosarcomas are embryonal except for those of the t runk and extremities, where the alveolar form predominates.

Prognosis of rhabdomyosarcoma following t rea tment of lesions with favorable histology has improved dramatically in recent years as a result of intensive multimodal management. Accurate histologic classification and clinical-pathologic staging have been major factors in evaluating the results of prospective multimodal t rea tment trials, the most important of which are the Intergroup Rhabdomyosarcoma Studies (IRS I, II and III).

DIAGNOSIS

Clinical signs and symptoms of rhabdomyosarcoma vary with tumor site and size, and extent and sites of metastasis. Orbital tumors cause proptosis; nasopharyngeal tumors may cause air- way obstruction, dysphagia, nasal discharge, and sinusitis; mid-

3o

dle ear tumors may cause pain, ear discharge, and serous otitis media. Because tumors of the ear and nose are often the botryoid variant, polypoid masses may protrude from nasal passages or ear canals. There may be neurologic symptoms due to direct extension of head and neck tumors into the CNS, as occurred in 35% of children with parameningeal rhabdomyosarcoma (primary in nasopharynx, paranasal sinuses, or middle ear) in IRS I. 35 Diagnostic evaluation of head and neck rhabdomyosarcoma includes, in addition to biopsy, skull films, head CT, brain scan, and examination of cerebrospinal fluid. Nuclear magnetic reso- nance imaging (NMR) may have diagnostic advantages over current radiographic and radioisotopic techniques.

Pelvic rhabdomyosarcomas arising in the bladder or prostate may appear only as palpable hypogastric masses or may cause symptoms of constipation, ur inary frequency, or ur inary reten- tion. Rhabdomyosarcomas arising in the vagina or uterus may also cause ur inary or bowel symptoms and may also present with vaginal bleeding and hemorrhagic masses of botryoid tumor extruding from the introitus. Useful studies include IVP, ultrasound, CT scan, voiding cystourethrogram, lymphangio- gram, and endoscopy of bladder, vagina, and rectum.

Paratest icular rhabdomyosarcoma presents in preteen or teen- age boys as a sometimes painful mass in the scrotum along the spermatic cord.

Rhabdomyosarcomas of the t runk and extremities present as painless masses. Such masses in the extremity of an active youngster are likely to be dismissed as hematomas and, as a

Fig 12.--Right thoracocervical neuroblastoma in 16-month-old boy with right- sided Homer's syndrome. A, preoperative roentgenogram showing tumor in apex of right hemithorax. (From Shaw A.: Surgical treatment of neuroblastoma, in Pochedly C. (ed.): Neuroblastoma: Clinical and Biological Manifestations. New York, Elsevier Science Publishing Co., Inc., 1982. Reproduced by permission.) B, roentgenogram following excision of tumor through cervical incision with thoracic extension. Metal clips mark tumor bed.

31

result, diagnostic biopsy is often delayed for weeks and even months. This potentially lethal error undoubtedly contributes to the low salvage rate of extremity lesions.

Rhabdomyosarcoma has no diagnostic chemical markers; biopsy is the key to diagnosis. The rhabdomyoblast can usually be recognized by light microscopy, although additional confirma- tory studies such as electron microscopy, immunoperoxidase stain for myoglobin, and immunofluorescence studies for myosin may be required to confirm the myomatous nature of the tumor. Good communication between surgeon and pathologist is essential for correct processing of biopsy specimens, thus avoiding re- peat procedures which, in young children, often require general anesthesia. Unfortunately, many soft tissue sarcomas in children are unclassifiable by current techniques. Many of these undifferentiated tumors have been included in the IRS even though they lack evidence of myoblastic differentiation, because their biologic behavior and response to treatment are similar to the behavior and response of rhabdomyosarcoma. 3~

Fine needle aspiration biopsy, while often permitting identification of the rhabdomyoblast by a skilled and experienced cytol- ogist, is usually inadequate to permit a complete histologic classification because it fails to preserve the histologic architecture upon which the distinction between embryonal and alveolar subtypes must be made. Fine needle aspiration biopsy may be most helpful in identifying recurrent or metastatic disease, or as a screening procedure to be followed by incisional biopsy of primary lesions (Fig 13).

When extremity lesions are biopsied, the incision should be made in the longitudinal axis of the limb, an important technical point with respect to subsequent excisional operations which require en bloc resection of muscle and fascia.

The most common sites of metastasis are lungs, bone, bone marrow, liver, regional lymph nodes, and CNS. Beyond the routine studies of blood and marrow, the radiologic, radioisotope, and other special studies of the primary and possible sites of metastatic spread will be guided by the site of the primary tumor. CT has proved of particular value in delineating the limits of primary tumor and thus helps the surgeon in assessing resectability.

STAGING

The staging system most frequently used is that developed by the IRS which consists of four surgically defined categories determined by completeness of tumor resection (Table 3). 37 There was good correlation between clinical staging according to this system and prognosis in IRS I, i.e., prognosis was best in pa-

32

Fig 13.--Cytologic appearance of needle aspirate of recurrent perineal embryonal rhabdomyosarcoma in 3-year old girl. Tumor is composed of single and multinuclear giant rhabdomyoblasts. Tumor cells have ample cytoplasm and eccentrically placed nuclei (hematoxylin-eosin, 500 x). (Courtesy of Hyun Pak, M.D., Division of Cyto- genetics and Cytology, City of Hope Medical Center.)

t ients wi th group I tumors and wors t in pa t ien ts wi th group IV tumors . Unfor tuna te ly , most pa t i en t s wi th r h a b d o m y o s a r c o m a have unresec table or widespread disease when first seen. Thus, only 36% of the pa t ien ts regis tered in IRS I were in groups I and II, which in par t accounts for the poor resul ts achieved in the pas t by surgery alone. IRS I demons t r a t ed a corre la t ion be tween p r i m a r y t umor site and prognost ic s tage in t h a t most pa t ien ts wi th pr imar ies of the head and neck (excluding orbit), extremi-

TABLE 3.--INTERGROUP RHABDOMYOSARCOMA STUDY STAGING SYSTEM

Group I: Localized disease, completely resected (regional nodes not involved). A. Confined to muscle or organ of origin. B. Contiguous involvement, with infiltration outside the muscle or

organ of origin, as through fascial planes. Group II: A. Grossly resected disease with microscopic residual. No evidence of

regional node involvement. B. Regional disease, completely resected (regional nodes involved

and/or extension of tumor into an adjacent organ). No microscopic residual.

C. Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual.

Group III: Incomplete resection or biopsy with gross residual disease. Group IV: Distant metastatic disease present at onset.

33

ties, t runk, thorax, and retroperi toneum were in groups III and IV because of unresectabili ty of the pr imary or because of widespread metastasis. 3s

This surgical staging system is open to criticism because of several apparent shortcomings: (1) Stage may reflect the skill or experience of the surgeon rather than true resectability of disease. (2) A lesion may be resectable, but bet ter or equivalent results may be achieved by treat ing with irradiation and/or chemotherapy. Examples are orbital tumors, where biopsy alone followed by chemotherapy and irradiation achieves a 90% cure rate, and extremity lesions, where amputat ion with chemotherapy does not achieve bet ter results than en bloc excision with chemotherapy and irradiation, both approaches yielding a low cure rate. (3) The IRS staging system does not take into account the possible differences in prognosis related to tumor histology.

As in Wilms' tumor, histology appears to influence response to treatment, patients with embryonal rhabdomyosarcoma having a higher survival rate than those with the alveolar subtype. Tu- mors with the best prognosis--geni tourinary and orbital tu- m o r s - a r e almost always embryonal, while in relatively treatment-resistant extremity and t runk lesions the alveolar pat tern predominates. It is not clear, however, whether the factors influencing response to t rea tment are related more to site or to histologic type. Furthermore, the lack of consensus among pa- thologists regarding interpretation of rhabdomyosarcoma histopathology makes current conclusions about the relation of histology to prognosis and to t rea tment response controversial.

Staging of extremity lesions should include biopsy of inguinal or axillary lymph nodes. However, although positive regional nodes are involved in 10%-17% of extremity lesions, 39 there is no evidence to indicate that node dissection or radiation influ- ences prognosis.

TPEATMENT

Many published insti tutional series at test to the poor results of surgery alone or surgery with irradiation in achieving cure of rhabdomyosarcoma. Prior to chemotherapy, cure rates were in the 10%-20% range even with apparently localized disease. In spite of the haphazard, uncontrolled, and diverse t reatments ap- plied to rhabdomyosarcoma in the prechemotherapy era, the t rea tment results were so uniformly bad that the dramatic rise in remission, survival, and cure rates reported from several institutions in the late 1960s was clearly due to the introduction of three drugs highly effective singly, and more so in combina- t ion--vincrist ine, actinomycin-D, and cyclophosphamide (VAC).

Polydrug t rea tment was first introduced in a t rea tment program that included maximal surgical and radiation therapy, re-

34

sulting in unprecedented local control of disease in over 85% of cases and 2-year cure rates in excess of 80% in infants with pelvic disease and over 50% in those with extremity and head and neck lesions. The price, however, was high in terms of quality of life. Radical extirpative surgery left many children with multiple abdominal stomas and others with severe disfigurement, often compounded by stunted growth, impotence, sterility, and skeletal deformity related to radiation and chemotherapy. Clat- worthy's group was among the first to at tempt to reduce the extent of surgical procedures, relying on chemotherapy to eradicate residual disease. 4~

The IRS established the first randomized prospective study designed to identify the major prognostic factors in rhabdomyosarcoma and to develop for each primary site and stage of disease a mult imodali ty t rea tment plan that would achieve maximum cure rate with minimal long-term t rea tment morbidity. Al- though the problems inherent in a study of such an enormously complex tumor as rhabdomyosarcoma are much greater than those in a study of Wilms' tumor, the results of IRS I (1972- 1978) and IRS II (1978-1980) have provided, for the first time, a scientifically supported rationale for t reat ing rhabdomyosarcoma. The results of the t reatment studies in IRS I have been published over the past 2 years. Prel iminary results of IRS II are jus t beginning to be published. The following sections sum- marize the results of IRS I, present the questions to be answered over the next few years by IRS II, and introduce IRS III, just getting under way. Finally, current t rea tment recommendations supported by the IRS as well as by studies performed elsewhere are presented.

INTERGROUP RHABDOMYOSARCOMA STUDY FINDINGS

Head and Neck There were 202 patients registered in IRS I with head and

neck primaries, 103 of whom were free of distant metastases at diagnosis and were followed up for 3 years or to death. Orbital tumors were treated primarily by irradiation and chemotherapy, with a 3-year relapse-free survival of 91%. The relapse-free survival for those with parameningeal primaries was 46%, and for those with other head and neck sites, 75%. 35, 41 Prognosis of par- amenigeal primaries has always been poor because of CNS extension which has proved refractory to treatment. In a recently evaluated study, Gasparini et al. achieved a 91% complete remission rate and a 64% relapse-free survival (medium follow-up, 32 months) in 11 children with parameningeal primaries t reated by local radiotherapy, systemic chemotherapy, brain radiotherapy, and intrathecal methotrexate between 1978 and 1980. 42 Unfortunately, in that study, variation from the IRS study in

35

t rea tment of the pr imary site does not allow the conclusion that brain radiotherapy and intrathecal methotrexate are responsible for the superior results. Newman and Rice at UCLA, in a retrospective review, found that survival following introduction of chemotherapy was bet ter in those patients who had total removal of gross disease than in comparable patients who had biopsy only. They also found that in patients with head and neck primaries, the presence of cervical lymph node metastases car- ried a grave prognosis. 43

At present it appears that the role of surgery in head and neck tumors is biopsy in all cases and resection in those few situ- ations where the tumor is relatively superficial and can be completely resected without creating severe deformity. As with ex- t remity lesions, there is no evidence that lymph node dissecton improves prognosis. Unfortunately, severe deformity is also likely to result from effective doses of radiotherapy of the immature facial skeleton.

The IRS I has separated out the good prognosis orbital primaries as well as the poor prognosis parameningeal primaries. For the remaining patients, with adjunctive chemotherapy, the 5-year relapse-free survival is 78% for patients with primary tumor in the head, but only 54% for those with a pr imary in the neck. 44

Bladder and Prostate Tumors Prior to introduction of effective chemotherapy almost all chil-

dren with rhabdomyosarcoma of the bladder or prostate relapsed despite radical surgery and intensive radiotherapy. With the addition of chemotherapy, response rates of over 90% and 2-year disease-free rates of over 80% were reported in patients with localized disease.

Hays et al. recently reported the results of t rea tment of 64 children with pr imary bladder or prostate rhabdomyosarcoma enrolled in the first 5 years of IRS I and observed from 21/2 to 8 years. 45 Eleven patients with bladder primaries were treated initially with pelvic exenteration, followed by chemotherapy with or without radiation. Two relapsed. Seventeen patients underwent tumor excision without exenteration either before or after radiation and chemotherapy. Eight relapsed. Twenty-five patients had prostate primaries; of these, 14 were treated with primary exenteration, and none relapsed. Eleven had surgery after radiation and chemotherapy; two relapsed. The remaining 12 patients in the entire group were not surgically evaluable. Although the numbers are small, they suggest that the highest cure rates in rhabdomyosarcoma of bladder and prostate were obtained in patients who had exenterative surgery.

The results of mult imodali ty t rea tment were particularly good in rhabdomyosarcoma of the female urogenital tract. ~6 Of 27 such patients enrolled in IRS I, 23 had disease confined to the

36

pelvis. Nine of ten with vulvovaginal rhabdomyosarcoma and nine of 13 with bladder tumors were long-term survivors. Ex- enteration was performed in only two of the seven long-term survivors with vulvovaginal rhabdomyosarcoma and two of the nine survivors with bladder tumors. The seven survivors with bladder tumors who underwent partial cystectomy were all in clinical group I. The three patients with incomplete excisions died. In contrast, the seven survivors with vulvovaginal rhabdomyosarcoma who did not have exenteration all had limited resections in which gross or microscopic disease was left behind. Fewer than half the long-term survivors in either group had radiotherapy. 46

Several institutions have reported good survival with reduced t rea tment morbidity in small series of patients t reated initially with chemotherapy with and without radiotherapy, followed by conservative resection of residual tumor. Hays et al. recently summarized the results of several such series and found grounds for encouragement in that 75% of patients responded to initial chemotherapy with a dramatic reduction in tumor size, allowing in many a limited operation. 47 In a series of 13 patients with pelvic rhabdomyosarcoma described by Ortega, all were treated with VAC initially. Subsequent t reatment depended on tumor response to chemotherapy. Eight patients were alive and free of disease 24-96 months after diagnosis. There was only one sur- vivor (24 months) following chemotherapy alone. Radiotherapy at lower than conventional doses was used in seven of eight survivors. Only three patients required resective procedures, only one of which was an exenteration. 4s In another small series, Ka- plan et al. described ten children with pelvic disease, eight of whom are well, free of disease, after 1-8 years, and none of whom required pelvic exenteration. 49

Although results like these are encouraging, the numbers of cases are so small, especially when further subdivided by histology, site, and stage, and the therapy is so individualized, that they fail to provide clear guidelines for management of new cases. Moreover, the follow-up time is often too short, especially as rhabdomyosarcomas notoriously may recur as late as 7 years after treatment. IRS II has tested in a prospective, randomized trial the feasibility of limiting radiotherapy and surgery by initial t rea tment with chemotherapy for bladder-prostate tumors. The recently published results of this approach in 29 children with nondisseminated disease were somewhat disappointing: 62% either required exenteration or died, for an overall mortal- ity of 27% in a 2-21/2 year follow-up. Although 11 patients were alive and well with "salvaged" functional bladders (38%), it is likely that some of these will develop bladder dysfunction as a result of radiotherapy damage. The response to chemotherapy varied tremendously from patient to patient, s~ A major deft-

37

ciency of this study lay in the absence of initial laparotomy in 23 of 29 patients; thus, accurate assessment of the location and extent of primary tumor was only approximated in most cases, and nodal metastases as well as other intra-abdominal metastatic spread were probably underdiagnosed, perhaps accounting for some of the disappointing results of at tempts to reduce treatment morbidity by reducing treatment.

At present it does not appear that we can rely on chemotherapy to compensate for inadequate surgical resections of pelvic disease in the male or bladder disease in the female. Moreover, the rate of relapse appears to be unacceptably high in patients with incomplete resection of tumor who have not had adequate doses of radiotherapy.

Paratest icular tumors have an excellent overall prognosis despite 40% regional node involvement. Radical orchiectomy plus pelvic node dissection with chemotherapy and radiotherapy result in 2-year relapse-free survival of 89%. 51 More experience with CT or NMR may obviate the need for nodal exploration in those patients without radiographic evidence of nodal disease.

Extremity and Trunk The prognosis of rhabdomyosarcoma of the extremities and

t runk has been and continues to be poor. At least part of the reason for this is the relatively high (approximately 40%) incidence of unfavorable alveolar histology in these sites. Survival in early series of pat ients t reated by amputat ion or wide excision alone was almost nil. Addition of radiotherapy was effective in achieving local control when doses in the range of 6,000- 7,000 rad in 6 -7 weeks were given, 52 but caused severe growth disturbance and deformity in the growing bones of young children.

By 1970 survival rates in localized extremity lesions treated by mult imodali ty therapy, including chemotherapy, had risen close to 50%, and most institutions had abandoned amputat ion in favor of primary wide local excision or excision following shrinkage of tumor by chemotherapy and radiation therapy. The results of mult imodali ty t rea tment of all stages of disease in IRS I were disappointing. One third of patients with localized disease--groups I and II--relapsed. Most patients with advanced disease responded to therapy but subsequently relapsed and died. ~3

Histologic type seems significant in clinical group I extremity tumors in that relapse figures for patients not having amputa- tion were one of seven, five of eight, and 1 of six for embryonal, alveolar, and miscellaneous subtypes, respectively. The differ- ence disappeared in clinical group II, where relapse figures were five of 11, six of 12, and three of ten. 53 It is possible that in the effort to reduce t rea tment morbidity, the resective procedures and radiotherapy dosages used were less than adequate in po-

38

tentially curable lesions. Fur ther studies will be required to determine if more aggressive t rea tment will improve results in nondisseminated extremity lesions, especially those of unfavorable histologic type. Although approximately 17% of extremity lesions have positive regional nodes, no studies have been done to determine the possible effects of nodal dissection or radiation on survival.

The recently reported IRS I data on 30 children with soft tissue sarcomas of the t runk included 40% with alveolar rhabdomyosarcoma, 20% with embryonal rhabdomyosarcoma, 17% with undifferentiated sarcoma, and 23% with other subtypes of rhabdomyosarcoma (20% with extraosseous Ewing's sarcoma, 3% with pleomorphic sarcoma). Twenty-five of the total group had localized disease, and 15 (50%) of the group were alive and free of disease at a median of 5 + years. The authors concluded that paraspinal tumors had the best prognosis, chest wall tumors the worst, and that, as in other sites, major prognostic differences were related to extent of disease at diagnosis and histologic type, as well as body site. ~4

Relapse Recurrence of disease carries a poor prognosis regardless of

site of recurrence. Of 98 patients in IRS I who relapsed after an initial complete response to multimodal therapy, only 5% achieved long-term disease-free survival. 55 The patients most likely to relapse were those initially presenting with metastat ic disease and those whose pr imary tumors were in the perineum, gastrointestinal tract, retroperitoneum, or extremity. The incidence of relapse was lowest in patients without metastases with primary disease in the orbit, genitourinary tract, and nonparameningeal head and neck sites. The IRS I data show median survival t ime following relapse to be 20 weeks, regardless of clinical group and mode of salvage treatment. ~5


Newly diagnosed patients at the City of Hope are currently treated as follows.

In General The primary is resected, followed by VAC chemotherapy. In

selected cases in which total tumor excision would require radical head and neck operations, limb amputations, or pelvic exen- terations, pr imary chemotherapy is used with or wi thout radiotherapy and followed by resection of residual disease.

In incompletely excised tumors, with or without regional node involvement, we use radiotherapy and VAC and return in appropriate cases for a second look to at tempt complete resection of residual disease.

39

With disseminated disease we add Adriamycin to VAC (although Adriamycin has not yet been shown to improve results), with selective use of radiotherapy.

Tumors with alveolar histology are managed more aggres- sively by all t rea tment modalities.

By Site

ORBIW.--Exenteration rarely is indicated. Radiation alone results in over 90% cure rate. Because radiation may cause growth disturbance result ing in deformity, trials now center on using chemotherapy with lower doses of radiation.

NONPARAMENINGEAL HEAD AND NECK.--Primary excision if nonmutilating, followed by VAC. Otherwise, partial excision followed by chemotherapy and radiation.

PARAMENINGEAL.--As for other head and neck sites, with the addition of intrathecal chemotherapy and CNS radiation if tumor cells are detected in the cerebrospinal fluid.

PROSWAWE.--Anterior exenteration followed by VAC with or without radiotherapy.

BLADDER.--Partial cystectomy followed by VAC if the tumor is completely resectable; otherwise, anterior exenteration and VAC. With or without radiotherapy. For bladder and prostate tumors, we consider primary chemotherapy (with or without irradiation) followed by resection of residual tumor.

VULVOVAGINAL.--Resection limited to genitalia even if it must be incomplete. Anterior exenteration is not done. Surgery is followed by VAC (and radiotherapy if disease is left behind).

PARATESTICULAR.--Radical orchiectomy followed by VAC. Pelvic lymph node dissection and/or irradiation are determined by CT or lymphangiographic evaluation. Temporary transloca- tion of the contralateral testis to the thigh may protect the gonad against effects of radiation.

EXTREMITY, TRUNK, PERINEUM.--Wide excision, VAC, and radiotherapy, although not necessarily in that order. Amputat ion is not currently recommended for soft tissue sarcomas.

For now and the immediate future, for tumors of favorable stage, site, and histology, where cure rates are high, efforts are being made to reduce the disability and deformity caused by radical surgical resections and high-dose radiation by develop- ing more effective chemotherapeutic regimens. At this time it is too early to determine whether the overall morbidity of treatment will be reduced by such a shift in the proportions of modes of t rea tment and it is also too early to tell whether the at tempts

40

to reduce t rea tment morbidity will result in a reduced survival from the results achieved by maximum use of surgery, radiation, and chemotherapy in each case.

For rhabdomyosarcomas of unfavorable site and histology, where survival is predictably poor in spite of aggressive multi- modality t reatment, new drugs and innovative combinations of therapies pursued through cooperative studies such as tha t currently under taken by IRS III will be required to improve the statistics in the largest and most dismal end of the rhabdomyosarcoma spectrum.

CONCLUSIONS

To die of cancer at any age is terrible. The death of a child from cancer is an outrage. We can be encouraged by the improvement in survival in some forms of pediatric cancer, notably acute lymphocytic leukemia, Wilms' tumor, embryonal rhabdomyosarcoma, and germ cell tumors, result ing from advances in multimodali ty therapy, especially chemotherapy, over the past 15 years. But we have a long way to go. Refining of multimodal- ity t reatment, including the adding of new, more effective, and less toxic drugs, will undoubtedly increase survival and cure rates, while balancing benefits against side effects of t rea tment in carefully controlled studies should help reduce the morbidity and mortal i ty of therapy which is the price paid for current curative efforts. Because these tumors are uncommon and few institutions see numbers sufficient to perform definitive studies of different t rea tment approaches, the importance of enrolling patients in the kinds of multi-institutional cooperative studies ex- emplified by NWTS and IRS cannot be overemphasized.

Success in eradicating cancer in children is not likely to be attained, however, until the basic mechanisms that result in the disordered embryogenesis of pediatric tumors are understood and supply the key by which physicians can turn off the repli- cation of cancer cells by young growing bodies-- to finally be able to rid the body of cancer cells without radiating it, poison- ing it, or cutting precious portions of it away.

ACKNOWLEDGMENT

Research was supported in part by the John M. "Jack" Hayes Research Fund.

Portions of the text appeared in different form in Shaw A.: Surgical management of neuroblastoma, in Pochedly C. (ed.): Neuroblastoma: Clinical and Biological Manifestations. New York, Elsevier Science Publishing Co., Inc., 1982.

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pediatric surgical oncology: update on wilms' tumor, neuroblastoma and rhabdomyosarcoma

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