Non-CNS solid tumors account for approximately 40% of malignancies in patients < 20 years of age. Risk-adapted therapy developed through clinical studies initially focused on clinical presentation features, such as patient age and extent of disease but now includes biologic and molecular features as well. A brief review of several of the more common tumor types follows.
Neuroblastoma
Studies by the Pediatric Oncology Group (POG) and the Children' Cancer Group (CCG) have identified biologic tumor features (especially DNA ploidy and MYCN amplification) that allow risk-directed therapy.[23] In general, patients with resectable localized disease enjoy a > 90% chance of cure with surgery alone. Most children < 1 year old with disseminated disease also have a high likelihood of cure with surgery and chemotherapy. In contrast, survival is suboptimal for patients older than 12 months with disseminated disease, although recent studies report a subset of 12- to 18-month-old children with favorable biologic features who have a much greater chance of survival with intensive therapy.[24] Some patients with local or locoregional disease and other unfavorable features, such as tumor MYCN amplification or, in the infant group, diploidy, also have a poor prognosis.
Studies by the Pediatric Oncology Group (POG) and the Children' Cancer Group (CCG) have identified biologic tumor features (especially DNA ploidy and MYCN amplification) that allow risk-directed therapy.[23] In general, patients with resectable localized disease enjoy a > 90% chance of cure with surgery alone. Most children < 1 year old with disseminated disease also have a high likelihood of cure with surgery and chemotherapy. In contrast, survival is suboptimal for patients older than 12 months with disseminated disease, although recent studies report a subset of 12- to 18-month-old children with favorable biologic features who have a much greater chance of survival with intensive therapy.[24] Some patients with local or locoregional disease and other unfavorable features, such as tumor MYCN amplification or, in the infant group, diploidy, also have a poor prognosis.
A landmark CCG study (recently confirmed by European investigators) found that progression-free survival in high-risk disease is slightly improved by intensive induction chemotherapy followed by high-dose consolidation chemotherapy and autologous stem cell rescue, irradiation, and maintenance therapy.[25,26] New approaches being investigated include immunotherapy, multiple autologous stem cell transplants, targeted radiotherapy with iodine-131-meta-iodobenzylguanidine (MIBG), newer chemotherapy agents, such as the camptothecins, and antiangiogenic agents.[27,28]
Wilms Tumor
The improved outcome of Wilms tumor, one of the greatest clinical trials group successes, reflects a balanced use of radiation therapy, chemotherapy, and surgery. Survival has improved from 30% in the 1930s to more than 85% today.[29,30] The National Wilms Tumor Study Group (NWTSG, now part of the Children' Oncology Group [COG]) clinical trials, beginning in 1969, demonstrated that vincristine, dactinomycin(Drug information on dactinomycin) (Cosmegen), and doxorubicin(Drug information on doxorubicin) are active against Wilms tumor and refined the use of these drugs to maximize EFS while minimizing toxicity. The role of radiation therapy has also been successively reassessed. Treatment of Wilms tumor in North America and in Europe differs in the timing of surgery. In the United States, resection with nephrectomy is done at the time of diagnosis if feasible, whereas in Europe, neoadjuvant chemotherapy is used. Both approaches yield excellent clinical outcomes.
Two major challenges remain in the treatment of Wilms tumor. One is the poorer outcome of patients with tumor anaplasia. In the NWTS-3 ,-4, and -5 studies, the addition of cyclophosphamide(Drug information on cyclophosphamide) improved the 5-year relapse-free survival of patients with stage II-IV disease and diffuse anaplasia from 27% to 55%. Unfortunately, recent trials have not led to a further increment in survival.[31]
The second major challenge is to minimize the late effects of therapy while maintaining a high cure rate. Each therapeutic modality carries some risk of long-term sequelae. Through refinement of surgical techniques and addition of preoperative chemotherapy, the rate of renal failure in patients with bilateral Wilms tumor has fallen from 16.4% to 3.8%.[32] Radiation therapy can cause or contribute to damage to the remaining kidney, lungs, heart, and female reproductive organs. The NWTS-1 through -3 studies demonstrated that radiation could be safely eliminated for stage I and II disease.[33] The late effects of chemotherapy are increasingly well understood. The cardiovascular effects of doxorubicin and the congestive heart failure and subclinical cardiac abnormalities caused by anthracyclines are well known. NWTS-3 demonstrated that doxorubicin is unnecessary for stage II disease and for stage III disease (if 20 Gy abdominal irradiation is given).
Despite the risks, 634 young adult survivors of Wilms tumor reported a health-related quality of life that did not differ significantly from population norms.[34] The challenge remains to find new therapies that can maintain the high cure rate with less risk or to identify patients who require less intensive therapy. NWTS-5 used surgery alone for patients < 24 months old who had small stage I tumors with favorable histology. Unfortunately, 2-year relapse-free survival was reduced from 94.9% to 86.5% (although overall survival was 100%).[35] NWTS-5 also identified loss of heterozygosity at chromosome 1p and 16q as an adverse prognostic factor.[36] Future research will focus on further therapy reduction in the absence of unfavorable genetic findings and on other ways to decrease late effects, such as use of cardioprotective agents.
Rhabdomyosarcoma
The Intergroup Rhabdomyosarcoma Study Group (IRSG, now part of COG) has significantly increased cure rates for rhabdomyosarcoma over the past 30 years. Approximately 70% of patients in the United States are now cured.[37] As with Wilms tumor, the histologic features of rhabdomyosarcoma are important prognostic factors. The favorable embryonal histologic subtype (ERMS) has an approximately 80% cure rate, and the unfavorable alveolar subtype (ARMS), approximately 30%.[38]
Successive IRSG studies have refined multimodality therapy to maximize survival while decreasing early and late toxicity (Figure 4). IRS-I through IRS-III reduced or eliminated radiation therapy for a subset of patients with low-risk ERMS without compromising survival.[39] Surgery has been modified to preserve the bladder, reduce aggressive resection of vaginal rhabdomyosarcoma, and eliminate retroperitoneal lymph node dissection for boys < 10 years of age with paratesticular primary tumor and no evidence of retroperitoneal lymph node involvement.[40-42]
Advances in chemotherapy include the identification of a subset of low-risk patients who benefit from the addition of cyclophosphamide to vincristine and dactinomycin and the demonstration that addition of ifosfamide(Drug information on ifosfamide) and etoposide(Drug information on etoposide) does not improve outcome for intermediate-risk patients.[43] The Soft Tissue Sarcoma Committee of COG continues to revise risk stratification in order to better tailor therapy for each patient.
Approximately 20% of patients with rhabdomyosarcoma continue to have a poor prognosis (5-year relapse-free survival rate < 25%). In recent years, patients with ARMS and metastatic disease have been eligible for experimental therapy with new agents in the 6- to 8-week "upfront window" at the start of therapy. This approach has identified several active drugs and drug combinations, including ifosfamide/doxorubicin, melphalan (Alkeran), topotecan (Hycamtin)/cyclophosphamide, and irinotecan (Camptosar)/vincristine. Targeted therapy against the unique gene fusion products of ARMS, PAX3-FKHR and PAX7-FKHR, is being developed.[44]
Osteosarcoma
In the 1960s, localized osteosarcoma of an extremity was treated with amputation alone, and more than 80% of these patients died of distant metastatic disease.[45] In the mid-1980s, the benefit of adjuvant chemotherapy with cisplatin(Drug information on cisplatin), doxorubicin, and high-dose methotrexate(Drug information on methotrexate) was demonstrated, and these agents form the backbone of chemotherapy today.[46] Neoadjuvant chemotherapy followed by surgical resection and additional chemotherapy results in a 3-year EFS rate of 71% for patients with localized disease and a 5-year EFS rate of 46.7% for those with metastatic disease at diagnosis.[47] The goal of surgery—en bloc tumor removal with adequate margins—initially required amputation of the involved limb. However, limb salvage can be performed in most cases, with comparable local control (Figure 5).[48,49]
Unfortunately, endoprostheses require removal or revision as patients grow. Some devices can now be lengthened without surgery as the child grows, although the lifespan of the prosthesis is limited.[50] Remaining challenges include improving therapy for metastatic disease and decreasing the need for modification of prostheses.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
