Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

17. Bone Sarcomas

Robert S. Benjamin

There are four major sarcomas of bone, each differing somewhat in clinical behavior, chemotherapy responsiveness, and prognosis. All present as painful bony lesions, and all metastasize preferentially to lung and then to other bones. The prognosis of untreated sarcomas of the bone is inversely proportional to their chemotherapy responsiveness. The sarcomas are considered in order of greatest to least chemotherapeutic responsiveness: Ewing sarcoma, osteosarcoma, malignant fibrous histiocytoma of bone, and chondrosarcoma.

Response to treatment is evaluated according to the usual criteria used for solid tumors and identical to that reported in Chapter 16 for soft-tissue sarcomas. It is often difficult to assess the response of primary bone tumors to chemotherapy prior to surgery, and the response on positron emission tomography-computed tomography correlates best with pathologic tumor destruction. Magnetic resonance imaging can be very misleading. Complete resection and examination of the total specimen often are required to determine response to therapy in a primary or even a metastatic lesion and to confirm complete remission.

I. STAGING

Bone tumors are staged according to American Joint Committee on Cancer (AJCC) criteria as well as the criteria of the Musculoskeletal Tumor Society.

A. The AJCC staging system

The stage is determined by tumor grade, tumor size, and presence and sites of metastases. There are four tumor grades:

bull Grade 1: Well differentiated—low grade

bull Grade 2: Moderately differentiated—low grade

bull Grade 3: Poorly differentiated—high grade

bull Grade 4: Undifferentiated—high grade.

Ewing sarcoma is classified as G4.

Tumor size is divided at less than or equal to 8 cm. Tumor size determines A and B, substages of stages I and II, and stage III:

bull Tl = ≤8 cm

bull T2 = >8 cm

bull T3 = Discontinuous tumors in the primary bone site.

Metastatic status is subdivided by presence and location of metastases:

bull M0 = No distant metastases

bull Ml = Distant metastases

bull Mla = Lung

bull Mlb = Other distant sites, including lymph nodes.

The AJCC stage groupingis as follows:

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B. The Musculoskeletal Tumor Society staging system

The Musculoskeletal Tumor Society stages sarcomas according to grade and compartmental localization. The Roman numeral reflects the tumor grade:

bull Stage I: Low grade

bull Stage II: High grade

bull Stage III: Any-grade tumor with distant metastasis.

The companion letter reflects tumor compartmentalization.

bull Stage A: Confined to bone

bull Stage B: Extending into adjacent soft tissue.

C. Evaluation of staging

Thus, a stage IA tumor is a low-grade tumor confined to bone, and a stage IB tumor is a low-grade tumor extending into soft tissue, and so forth. Patients are evaluated and followed according to the plan in Table l7.l.

II. EWING SARCOMA

A. General considerations and aims of therapy

1. Tumor characteristics. Ewing sarcoma is a highly malignant, small, round-cell tumor of bone. Together with other members of the Ewing Family of Tumors (EFT), most notably primitive neuroectodermal tumor, Ewing sarcoma is characterized by a specific t(ll;22) chromosome translocation that results most commonly in the EWS-FLI-l gene rearrangement. It is now believed that all members of the EFT should be considered as the same tumor. It occurs most commonly in the second decade of life, and 90% of patients are younger than 30 years. There is a slight male predominance. The most common locations are the pelvis or the diaphysis of long tubular bones of the extremities. Often, systemic symptoms of fever and leukocytosis suggest infection. Radiographically, the predominant feature is osteolysis, although sclerosis does occur. Frequently, the periosteal reaction has the so-called onion skin pattern with layering of subpe-riosteal new bone, frequently with spicules radiating out from the cortex. Prognosis, until the era of modern chemotherapy, was extremely poor, with a 5-year survival rate lower than l0% and almost half of patients dying within l year of diagnosis. Because Ewing sarcoma is a high-grade tumor and, by definition, is almost always accompanied by a soft-tissue mass, it usually is staged as AJCC stage IIB or IV depending on the demonstration of metastatic disease in lung (IVA), bone (IVB), or both. Bone metastases confer a markedly worse prognosis.

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2. Primary treatment. Because of the poor prognosis and because of the mutilative surgery involved in resection of the primary lesion, radiotherapy has been the primary modality for local tumor control. As techniques for limb salvage surgery have become more widely practiced, attempts to use surgery rather than radiation therapy are again increasing. There are indications that the use of surgery not only increases the rate of local control but also may improve overall prognosis. While this may, in fact, be the case, conclusions need to be tempered by the fact that patients with the worst prognosis are not offered surgical resection.

B. Chemotherapy

The most effective primary chemotherapy regimens include vincristine, doxorubicin, and ifosfamide (high-dose VAI) or cyclophosphamide (VAdriaC), with or without the addition of dacarba-zine (CyVADIC). In most cases where ifosfamide is not used in the primary treatment, ifosfamide and etoposide are added in rotating fashion or after completion of the doxorubicin-based regimen.

1. The high-dose VAI regimen is as follows:

bull Vincristine 2 mg total dose on day l.

bull Doxorubicin (Adriamycin) by continuous 72-hour infusion at 75 mg/m2 intravenously (IV) (25 mg/m2/day for 3 days), and

bull Ifosfamide 2.5 g/m2 IV over 2 to 3 hours daily for 4 days.

bull Mesna 500 mg/m2 is mixed with the first ifosfamide dose, and l500 mg/m2 is given as a continuous infusion over 24 hours for 4 days in 2 L of alkaline fluid.

bull Filgrastim (granulocyte colony-stimulating factor) 5 μg/kg subcutaneously is given on days 5 to l5 or until granulocyte recovery to l500/μL. Alternatively, pegfilgrastim at a dose of 6 mg is given on day 5.

bull Repeat cycle every 3 weeks.

2. CyVADIC regimen. Another good chemotherapeutic regimen for Ewing sarcoma, particularly in adult patients, is the continuous-infusion CyVADIC regimen, which is mentioned in Chapter l6 ( Section II.C).

bull Cyclophosphamide 600 mg/m2 IV on day l.

bull Vincristine l.4 mg/m2 (2 mg maximum) IV weekly for 6 weeks, then on day l of each cycle.

bull Doxorubicin (Adriamycin) 60 mg/m2 IV by 96-hour continuous infusion through a central venous catheter (l5 mg/m2/day for 4 days).

bull Dacarbazine l000 mg/m2 IV by 96-hour continuous infusion (250 mg/m2/day for 4 days) mixed in the same bag or pump as the doxorubicin. Doses should be divided into four consecutive 24-hour infusions.

bull Repeat cycle every 3 to 4 weeks.

3. Dose modifications. Courses are repeated with a 25% increase or decrease in the doses of cyclophosphamide and doxoru-bicin, depending on morbidity. Courses are repeated in 3 to 4 weeks as soon as recovery to l500 granulocytes/μL and l00,000 platelets/μL occurs. Complications are as described in Chapter l6 (see Section II.E), with the addition of peripheral neuropathy from vincristine. When the cumulative dose of doxorubicin has reached 800 mg/m2, therapy is discontinued.

4. Alternative regimens. Alternative regimens omit dacarbazine; vary doses of cyclophosphamide up to 4200 mg/m2; give dactinomycin with, or in place of, doxorubicin; and in some patients, add other drugs. The most common pediatric regimen at present alternates two regimens every 2 to 3 weeks: ifosfamide plus etoposide; and vincristine and doxorubicin plus cyclophosphamide, with dactinomycin substituted for doxorubicin after a cumulative (bolus) dose of 375 mg/m2 (VAdCA). In a recent intergroup study, this regimen was superior to VAdCA alone. The schedule of drug administration is as follows.

a. Initial combination is as follows:

bull Ifosfamide l800 mg/m2 IV daily × 5 (with mesna), and

bull Etoposide l00 mg/m2 IV daily × 5.

b. Three weeks later, start is as follows:

bull Vincristine l.5 mg/m2 IV on day l, and

bull Doxorubicin 75 mg/m2 IV on day l, and

bull Cyclophosphamide l200 mg/m2 IV on day l.

c. Two to three weeks later, return to the first regimen, and repeat. At a cumulative doxorubicin dose of 375 mg/m2, substitute dactinomycin l.25 mg/m2. Chemotherapy continues for a total of l year for the 3-week regimen, but, especially for pediatric patients, the more intensive but shorter 2-week regimen is preferred.

d. Another version of the alternating regimen starts with an intensive VAdriaC regimen with the doxorubicin and vincristine given by 72-hour continuous infusion and the cyclophosphamide dose increased to 4200 mg/m2 divided into two equal doses on days l and 2.

5. Responses. Most patients with metastatic disease obtain complete remission; however, almost all patients, especially those with bone metastases, experience relapse and ultimately die of disease. When chemotherapy is used in the therapy of primary disease with surgery or radiation therapy, prognosis depends on the size and location of the primary tumor. Patients with large flat-bone lesions have a lower than 30% cure rate compared with a 60% to 70% cure rate for those patients with long-bone lesions, which are generally smaller. An alarming complication of the chemotherapy and radiation therapy combination is a high frequency of second malignancies in cured patients, with 4 of l0 patients in one series developing secondary sarcomas within the radiated fields. This complication is another reason for considering surgical intervention rather than radiation because chemotherapy is required for cure whether or not the primary lesion can be controlled with radiation.

6. Secondary chemotherapy. Occasional responses have been seen with etoposide (VP-l6), topoisomerase I inhibitors, other al-kylating agents (especially ifosfamide), the nitrosoureas, and cisplatin. A combination of etoposide and ifosfamide is now frequently used in patients for whom those drugs were not used in initial therapy. High-dose ifosfamide (l4 g/m2 divided over 3 to 7 days, either as a 2-hour infusion with each dose or as a continuous infusion) with mesna or high-dose doxoru-bicin (90 mg/m2) plus dacarbazine (900 mg/m2) as a 96-hour continuous infusion is occasionally effective in producing brief remissions in patients for whom these agents were not used or were used at substantially lower doses during initial therapy. For patients receiving the five most active drugs in primary treatment, second-line therapy consists of a topoisomerase I inhibitor plus an alkylating agent. The most commonly studied regimen is cyclophosphamide plus topotecan, but increasingly in the United States the combination of vincristine, irinotecan, and temozolomide is gaining favor. Secondary responses are extremely poor, and the survival of a relapsed patient with Ewing sarcoma is measured in weeks unless the relapse occurs after a disease-free interval of more than 2 years.

7. High-dose chemotherapy. The standard chemotherapy used for Ewing sarcoma is accompanied by severe but transient myelosuppression. The availability of hematopoietic growth factors to reduce infectious complications provides an added measure of safety but is not routinely required. The author's policy has been to use growth factors for regimens known to cause febrile neutropenia in at least 30% of patients or in patients who have had febrileneutropenic episodes during a previous course of chemotherapy rather than to reduce the doses of the myelosuppressive drugs.

Bone marrow transplantation or peripheral stem cell rescue programs are still being investigated in patients presenting with poor prognostic features (large pelvic primary tumors, metastatic disease, poor response to induction chemotherapy) but have not yet been demonstrated to improve prognosis. Such regimens have been tried with negative results in patients relapsing after standard chemotherapy and have been demonstrated to have no significant benefit. Clearly, this approach should not be used in patients with relapse.

III. OSTEOSARCOMA

A. General considerations

Osteosarcoma is a tumor with a poor prognosis in the absence of effective chemotherapy. It is the most common primary bone sarcoma. Frequently, it affects patients l0 to 25 years old and tends to be located around the knee in about two-thirds of patients, with two-thirds of those tumors involving the distal aspect of the femur. As with other sarcomas of bone, pulmonary metastases are most common, followed by bone metastases. Because conventional osteosarcoma is a high-grade tumor by definition and is accompanied by a soft-tissue mass in 90% or more of patients, it is usually staged as IIB or IIIB, depending on the demonstration of metastatic disease in lung or bone.

B. Role of chemotherapy

Chemotherapy is usually employed in the neoadjuvant or adjuvant situation, and its value preoperatively has been conclusively demonstrated. Patients who show a complete response to preoperative chemotherapy with tumor destruction of at least 90% have significantly improved survival. Response rates in evaluable tumors range from 30% to 80%. Cure of primary disease with adjuvant chemotherapy is 50% to 80%.

C. Effective agents

The four major standard single agents in the treatment of osteosarcoma are cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate.

D. Recommended regimen

A variety of regimens may be recommended based on preliminary or more extensive evaluation.

1. Doxorubicin and cisplatin

bull Doxorubicin 90 mg/m2 IV by 96-hour continuous infusion through a central venous catheter, and

bull Cisplatin l20 mg/m2 intra-arterially (for primary tumor) or IV on day 6.

bull Repeat every 4 weeks.

Three to four courses of therapy should be administered preoperatively. Postoperative therapy depends on the response of the primary tumor. Patients with tumor necrosis of 90% or more should continue on the same regimen for three to six postoperative courses or until a cumulative doxorubicin dose of 800 mg/m2 is reached. If cisplatin must be discontinued earlier, decrease the doxorubicin dose to 75 mg/m2 IV by 72-hour continuous infusion and substitute ifosfamide 2500 mg/m2 IV over 3 hours daily for 4 days (the dose-intensive doxorubicin and ifosfamide regimen for soft-tissue sarcoma; see Chapter l6Section II.C.1).

2. Alternative regimen. After primary chemotherapy, if there is less than 90% tumor necrosis at surgery, switch to the alternative regimen as follows.

a. High-dose methotrexate l2g/m2 IV every 2 weeks for 8 weeks with leucovorin rescue (see Section III.E.2).

b. Three weeks later, administer ifosfamide 2 g/m2 IV over 2 hours for 5 consecutive days, with mesna l200 mg/m2 IV in three divided doses each day (i.e., 400 mg/m2 IV every 4 hours × 3) or by continuous infusion after a loading dose of 400 mg/m2 mixed with the first ifosfamide dose plus doxorubicin 75 mg/m2 IV by 72-hour continuous infusion. Three weeks later, repeat the course.

c. Three to four weeks later, repeat the entire cycle of four courses of methotrexate and two courses of ifosfamide-doxorubicin. End with four more courses of high-dose methotrexate.

3. There are many alternative approaches to chemotherapy, such as adding high-dose methotrexate and/or ifosfamide to the induction regimen and continuing with the same three to four drugs postoperatively. The combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) is rarely, if ever, used anymore.

E. Special precautions in administration

1. Cisplatin. Prehydration is necessary, with overnight infusion of IV fluids at l50 mL/h or l L of fluid over 2 hours (for adults), followed by at least 6 L of fluid containing potassium chloride (at least 20 mEq/L) and magnesium sulfate (at least 4 mEq/L) for the first l or 2 days or after cisplatin administration. The addition of mannitol (66 mL of a l5% solution) before cisplatin, followed by 266 mL of a l5% solution mixed with normal saline in a total volume of l L to run simultaneously with the cisplatin over 2 to 3 hours, is preferred by many investigators. Particular care in electrolyte balance, including frequent determinations of magnesium levels, is necessary. In the presence of severe hy-pomagnesemia, magnesium sulfate up to l to 2 mEq/kg may be infused over 4 hours.

2. High-dose methotrexate. The pretreatment-calculated creatinine clearance rate should be at least 70 mL/min.

a. Methotrexate administration and alkalization of urine. Before administration of high-dose methotrexate, 0.5 mEq/kg of sodium bicarbonate is infused IV over l5 to 30 minutes in an attempt to create an alkaline urine. Allopurinol 300 mg/day for 3 days is given starting l day before the methotrexate infusion. Methotrexate is dissolved in no more than l000 mL of 5% dextrose in water, with a final concentration of about 2 g/l00 mL. The total dose ranges from 8 g/m2 for patients over 40 years old to l2 g/m2 for children and young adults. The dose should be increased on subsequent courses if an immediate postinfusion methotrexate level is less than l0−3 M. Sodium bicarbonate 50 mEq is added per liter of methotrexate solution, which is infused over 4 hours. After completion of the methotrexate infusion, l0 mL/kg of an IV infusion of 5% dextrose in water with 50 mEq/L of bicarbonate is given over 2 hours if the patient is unable to drink or if the 24-hour methotrexate levels of the previous high-dose methotrexate treatment have been higher than l.5 × l0−5 M. The IV infusion is then discontinued, and the patient is encouraged to drink sufficient fluid to produce about l600 mL/m2 of alkaline urine for the first 24 hours and l900 mL/m2 daily for the next 3 days. Sodium bicarbonate l4 to 28 mEq by mouth every 6 hours is administered to ensure alkaline urine. The pH of the urine is measured, and if it is less than 7, an extra dose of bicarbonate is administered.

b. Leucovorin rescue. Twenty-four hours after the start of the methotrexate infusion, leucovorin l5 to 25 mg is administered by mouth every 6 hours for at least l0 doses or intramuscularly if the oral medication is not tolerated.

c. Serum methotrexate levels. These levels should be followed and should fall at approximately l log/day. When methotrexate concentration falls below l0−7 M, leucovorin may be safely discontinued. IV hydration is required whenever oral intake is inadequate to produce sufficient urine output as previously defined, for abnormal serum methotrexate concentration, for persistent vomiting, or for early toxicity.

3. Ifosfamide. Patients must be kept well hydrated with an alkaline pH to prevent central nervous system (CNS) toxicity and minimize nephrotoxicity. Sodium bicarbonate or sodium acetate should be added to IV fluids at an initial concentration of l00 to l50 mEq/L and fluid administration adjusted to produce a urine output of at least 2 L/day and maintain the serum bicarbonate concentration at 25 mEq/L or higher. Other electrolytes should be adjusted as needed on a daily basis. Serum albumin should be kept within normal limits.

F. Complications

Complications of chemotherapy depend on the drugs. For doxorubicin, the major complication is infection owing to neutropenia. Other complications include stomatitis, nausea and vomiting, and delayed cardiac toxicity, as discussed in the management of soft-tissue sarcomas (see Chapter l6Section II.E). Ifosfamide produces myelosuppression, nausea and vomiting, and alopecia, similar to doxorubicin. Hemorrhagic cystitis, once the dose-limiting toxicity, is rarely seen because the use of mesna has become routine. The most serious toxicities of ifosfamide are nephrotoxicity and CNS toxicity. Nephrotoxicity in the form of Fanconi syndrome is a frequent problem, the morbidity of which can be minimized by the routine use of alkaline infusions and correction of electrolyte levels with intravenous or oral replacement therapy. Only rarely does the nephrotoxicity progress to renal failure, often precipitated by dehydration or administration of minimally nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs). Patients treated with ifosfamide should be instructed to avoid NSAIDs, even years after chemotherapy. Correction of acid–base balance and hypoalbuminemia can essentially prevent the CNS toxicity (see Chapter l6, Section II.E). Dactinomycin causes similar side effects to those of doxorubicin, but not cardiac toxicity. Methotrexate predominantly causes stomatitis, but it may cause myelosuppression and renal, hepatic, and CNS abnormalities. Cisplatin and dacarbazine cause severe nausea and vomiting. In addition, cisplatin nephrotoxicity is primarily a tubular defect, with hypomagnesemia as the most prominent manifestation, but hypocalcemia, hypokalemia, and hyponatremia also occur. Delayed cumulative nephrotoxicity can cause impaired glomerular function as well. Ototoxicity may occur but is less common. Delayed neurotoxicity also occurs. Both cisplatin and methotrexate can, by causing renal toxicity, exacerbate their other side effects.

G. Recurrence and treatment of refractory disease

Patients with osteosarcoma who are refractory to a combination of doxorubicin and cisplatin may respond to high-dose methotrexate; patients refractory to high-dose methotrexate may respond to doxorubicin plus cisplatin; and patients refractory to both may respond to ifosfamide or, rarely, to BCD. However, treatment of refractory disease is usually disappointing, and participation in studies of new agents is indicated for patients whose disease cannot be resected. Surgical resection of pulmonary metastases remains the only viable secondary therapy for most patients. For this reason, careful follow-up for detection of metastases while they are still at the stage of resectability is indicated.

H. High-dose chemotherapy

The standard chemotherapy used for osteosarcoma is accompanied by severe but transient myelosuppression. The availability of hematopoietic growth factors to reduce infectious complications provides an added measure of safety but is not routinely required. Our policy has been to use growth factors only for regimens known to cause febrile neutropenia in at least 30% of patients or in patients who have had febrile–neutropenic episodes during a previous course of chemotherapy rather than to reduce the doses of the myelosuppressive drugs.

Bone marrow transplantation or peripheral stem cell rescue programs have not been demonstrated to improve prognosis.

IV. MALIGNANT FIBROUS HISTIOCYTOMA OF BONE

This entity, characterized by a purely lytic lesion in bone, has an exceptionally poor prognosis when treated with surgery alone, although the number of reported patients is small. It may be extremely difficult to distinguish from fibroblastic osteosarcoma and may be best considered as a fibroblastic osteosarcoma with minimal (i.e., no detectable) osteoid production. The tumor responds well to the CyADIC regimen for soft-tissue sarcomas, with more than half of patients obtaining at least partial remission. In addition, cisplatin at a dose of l20 mg/m2 every 4 weeks has caused remissions, even in patients who did not respond to primary therapy. A particularly attractive approach for patients with large, unresectable primary tumors is the administration of cisplatin by the intra-arterial route. Complete tumor destruction in one patient and a good partial remission in a second patient are the reported results among three patients so treated. Systemic doxorubicin may be added, as for osteosarcomas (see Section III.D.l). Alternatively, responses have been seen after high-dose methotrexate-based regimens for osteosarcomas (see Section III.D.2). After local tumor destruction, surgery may be employed to remove residual disease. Because of the poor prognosis, adjuvant chemotherapy with the continuous-infusion CyADIC regimen is recommended until an 800 mg/m2cumulative doxorubicin dose has been reached.

V. CHONDROSARCOMA

The chemotherapy for chondrosarcoma is totally inadequate, and no regimen can be recommended except for the rare patients with mesenchymal chondrosarcoma, a subtype that may respond to CyADIC chemotherapy or cisplatin, or with dedifferentiated chondrosarcoma, which should be treated the same way as osteo-sarcoma. Most patients have conventional chondrosarcoma and are candidates only for surgical management. Metastatic disease should be treated with phase II protocols in an attempt to determine some effective type of chemotherapy that may be recommended in the future.

Selected Readings

Bacci G, Briccoli A, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol. Eur J Cancer. 2001;37:2030–2039.

Bacci G, Ferrari S, Bertoni F, et al. Neoadjuvant chemotherapy for peripheral malignant neuroectodermal tumor of bone: recent experience at the Istituto Rizzoli. J Clin Oncol. 2000;18:885–892.

Bacci G, Ferrari S, Bertoni F, et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol.2000;18:4–11.

Bacci G, Ferrari S, Longhi A, et al. Neoadjuvant chemotherapy for high grade osteosarcoma of the extremities: long-term results for patients treated according to the Rizzoli IOR/OS-3b protocol. J Chemother.2001;13:93–99.

Benjamin RS, Murray JA, Carrasco CH, et al. Preoperative chemotherapy for osteo-sarcoma: a treatment approach facilitating limb salvage with major prognostic implications. In: Jones SE, Salmon SE, eds. Adjuvant therapy of cancer, vol IV. New York: Grune & Stratton; 1984:601–610.

Bone sarcoma. In: Greene FL, Page DL, Fleming ID, et al. (eds.) AJCC cancer staging manual (6th ed.). New York, NY: Springer-Verlag; 2002:187–192.

Chawla SP, Benjamin RS, Abdul-Karim FW, et al. Adjuvant chemotherapy of primary malignant fibrous histiocytoma of bone: prolongation of disease free and overall survival. In: Jones SE, Salmon SE, eds. Adjuvant therapy of cancer, vol IV. New York: Grune & Stratton; 1984:621–629.

Gehan EA, Sutow WW, Uribe-Botero G, et al. Osteosarcoma: the M. D. Anderson experience, 1950–1974. In: Terry WD, Windhorst D, eds. Immunotherapy of cancer: present status of trials in man. New York: Raven Press; 1978.

Grier H, Krailo M, Link M, et al. Improved outcome in non-metastatic Ewing's sarcoma (EWS) and PNET of bone with the addition of ifosfamide (D) and etoposide (E) to vincristine (W), Adriamycin (Ad), cyclophosphamide (C), and actinomycin (A): a Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) report. Proc Am Soc Clin Oncol. 1994;13:A1443.

Kushner BH, Meyers PA, Gerald WL, et al. Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma in children and young adults. J Clin Oncol. 1995;13:2796–2804.

Rosen G, Caparros B, Nirenberg A. The successful management of metastatic osteogenic sarcoma: a model for the treatment of primary osteogenic sarcoma. In: van Oosterom AT, Muggia FM, Cleton FJ, eds. Therapeutic progress in ovarian cancer, testicular cancer and the sarcomas. Hingham; New Zealand: Leiden University Press; 1980:244–265.