Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 18 - Bone Sarcomas

Chapter 18

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's 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 17. Angiography is particularly helpful in defining the response of primary bone tumors to chemotherapy, and the angiographic response correlates well with pathologic tumor destruction. Complete resection and examination of the total specimen are often 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.

• Grade 1: well differentiated low grade

• Grade 2: moderately differentiated low grade

• Grade 3: poorly differentiated high grade

• Grade 4: undifferentiated differentiated high grade

Ewing's sarcoma is classified as G4 Tumor size is divided as less than or equal to 8 cm. Tumor size determines A and B substages of stages I and II, and stage III.

• T1 = less than or equal to 8 cm

• T2 = more than 8 cm

• T3 = Discontinuous tumors in the primary bone site

Metastatic status is subdivided by presence and location of metastases.

• M0 = No distant metastases

• M1 = Distant metastases

  • M1a = Lung

  • M1b = Other distant sites, including lymph nodes

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The AJCC stage grouping is as follows:

B. The Musculoskeletal Tumor Society (MSTS) staging system

The Musculoskeletal Tumor Society stages sarcomas according to grade and compartmental localization.

The Roman numeral reflects the tumor grade.

• Stage I: low grade

• Stage II: high grade

• Stage III: any-grade tumor with distant metastasis.

The companion letter reflects tumor compartmentalization.

• Stage A: confined to bone

• Stage B: extending into adjacent soft tissue

C.

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 up according to the plan in Table 18.1.

II. Ewing's sarcoma

A. General considerations and aims of therapy

• Tumor characteristics. Ewing's sarcoma is a highly malignant, small, round-cell tumor of bone. 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 subperiosteal 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 10% and almost half the number of patients dying within 1 year of diagnosis. Because Ewing's sarcoma is a high-grade tumor and, by definition, is almost always accompanied by a soft tissue mass, it is usually 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.

• 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

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  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 may also improve overall prognosis. While this may, in fact, be the case, the 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 dacarbazine (CyVADIC). In most cases where ifosfamide is not used in the primary treatment, ifosfamide and etoposide are added in an alternating fashion or after completion of the doxorubicin-based regimen.

• The high-dose VAI regimen is as follows:

  • Vincristine 2 mg total dose on day 1,

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

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

  • Mesna 500 mg/m² is mixed with the first ifosfamide dose, and 1,500 mg/m² is given as a continuous infusion over 24 hours for 4 days in 2 L of alkaline fluid.

  • Filgrastim (granulocyte colony-stimulating factor) 5 g/kg SC is given on days 5 to 15 or until granulocyte recovery to 1, 500/ L. Alternatively, Pegfilgrastim at a dose of 6 mg is given on day 5.

    Repeat cycle every 3 weeks.

• CyVADIC regimen. Another good chemotherapeutic regimen for Ewing's sarcoma, particularly in adult patients, is the continuous-infusion CyVADIC regimen, which is mentioned in Chapter 17 (see Section II.C).

  • Cyclophosphamide 600 mg/m² IV on day 1.

  • Vincristine, 1.4 mg/m² (2 mg maximum) IV weekly for 6 weeks, then on day 1 of each cycle.

  • Doxorubicin (Adriamycin) 60 mg/m² IV by 96-hour continuous infusion through a central venous catheter (15 mg/m²/day for 4 days).

  • Dacarbazine (DTIC) 1,000 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.

    Repeat cycle every 3 to 4 weeks.

  Dose modifications. Courses are repeated with a 25% increase or decrease in the doses of cyclophosphamide and doxorubicin, depending on morbidity. Courses are repeated in 3 to 4 weeks as soon as recovery to 1,500 granulocytes/ L and 100,000 platelets/ L occurs. Complications are as described in Chapter 17 (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.

• Alternative regimens. Alternative regimens omit dacarbazine; vary doses of cyclophosphamide up to 4,200 mg/m²; give dactinomycin with, or in place of, doxorubicin; and in some patients, add other drugs. The

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  most common pediatric regimen at present alternates two regimens every 3 weeks: ifosfamide plus etoposide; and vincristine, 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:

  • Initial combination

    • Ifosfamide 1,800 mg/m² IV daily 5 (with mesna), and

    • Etoposide 100 mg/m² IV daily 5.

  • Three weeks later, start

    • Vincristine 1.5 mg/m² IV on day 1, and

    • Doxorubicin 75 mg/m² IV on day 1, and

    • Cyclophosphamide 1,200 mg/m² IV on day 1.

  • Three weeks later, return to the first regimen, and so forth. At a cumulative doxorubicin dose of 375 mg/m², substitute dactinomycin 1.25 mg/m². Chemotherapy continues for a total of 1 year.

  • 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 4,200 mg/m² divided into two equal doses on days 1 and 2.

• 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 less than 30% cure rate as 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 four of ten patients in one series developing secondary sarcomas within the irradiated 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.

• Secondary chemotherapy. Occasional responses have been seen with etoposide (VP-16), topoisomerase I inhibitors, other alkylating 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 (14 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 doxorubicin (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.

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  Nonetheless, secondary responses are extremely poor, and the survival of a relapsed patient with Ewing's sarcoma is measured in weeks.

• High-dose chemotherapy. The standard chemotherapy used for Ewing's 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. Our policy has been to use growth factors for regimens known to cause febrile neutropenia in greater than or equal to 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 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 10 to 25 years old and tends to be located around the knee in approximately 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, (MSTS), 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. In addition, the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) has been effective.

D. Recommended regimen

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

• Doxorubicin and cisplatin

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

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  • Cisplatin 120 mg/m² intra-arterially (for primary tumor) or IV on day 6.

    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 with ifosfamide 2,500 mg/m² IV over 3 hour daily for 4 days (the dose-intensive AI regimen for soft tissue sarcoma; see Chapter 17, Section II.C.1).

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

  • High-dosemethotrexate 12 g/m² IV every 2 weeks for 8 weeks with leucovorin rescue (see Section III.E.2).

  • Three weeks later, administer ifosfamide 2 g/m² IV over 2 hours for 5 consecutive days, with mesna 1,200 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.

  • Three to 4 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.

• There are many alternative approaches to chemotherapy, 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

• Cisplatin. Prehydration is necessary, with overnight infusion of IV fluids at 150 mL/hour or 1 L of fluid over 2 hours (for adults), followed by at least 6 L of fluid containing potassium chloride (KCl; at least 20 mEq/L) and magnesium sulfate (MgSO4; at least 4 mEq/L) for the first 1 or 2 days or after cisplatin administration. The addition of mannitol (66 mL of a 15% solution) before cisplatin, followed by 266 mL of a 15% solution mixed with normal saline in a total volume of 1 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 hypomagnesemia, magnesium sulfate up to 1 to 2 mEq/kg may be infused over 4 hours.

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

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  • Methotrexate administration and alkalization of urine. Before administration of high-dosemethotrexate, 0.5 mEq/kg of sodium bicarbonate is infused IV over 15 to 30 minutes in an attempt to create an alkaline urine. Allopurinol 300 mg/day for 3 days is given starting 1 day before the methotrexate infusion. Methotrexate is dissolved in no more than 1,000 mL of 5% dextrose in water, with a final concentration of approximately 2 g/100 mL. The total dose ranges from 8 g/m² for patients over 40 years to 12 g/m² for children and young adults. The dose should be increased on subsequent courses if an immediate postinfusion methotrexate level is less than 10-3 M. Sodium bicarbonate 50 mEq is added per liter of methotrexate solution, which is infused over 4 hours. After completion of the methotrexate infusion, 10 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-dosemethotrexate treatment have been higher than 1.5 10-5 M. The IV infusion is then discontinued, and the patient is encouraged to drink sufficient fluid to produce approximately 1,600 mL/m² of alkaline urine for the first 24 hours and 1,900 mL/m² daily for the next 3 days. Sodium bicarbonate 14 to 28 mEq PO 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.

  • Leucovorin rescue. Twenty-four hours after the start of the methotrexate infusion, leucovorin 15 to 25 mg is administered PO every 6 hours for at least ten doses or IM if the oral medication is not tolerated.

  • Serummethotrexate levels. These levels should be followed up and should fall by approximately 1 log/day. When methotrexate concentration falls below 10-7 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.

• 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 100 to 150 mEq/L and fluid administration adjusted to produce a urine output of at least 2 L/day and to 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 17, Section II.E). Ifosfamide produces

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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 equal to or more than 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

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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 osteosarcoma. 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.

Suggested 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. 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, 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, 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 osteosarcoma: 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, eds. AJCC cancer staging manual, 6th ed. New York, NY: Springer-Verlag, 2002:187 192.

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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, et al. 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: Leiden University Press, 1990:244 265.