Sequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects

doi:10.1016/S1470-2045(10)70062-0

The Lancet Oncology

Volume 11, Issue 7, July 2010, Pages 670-678

https://doi.org/10.1016/S1470-2045(10)70062-0 Get rights and content

Summary

Since the introduction of multi-agent chemotherapy for osteosarcoma over 30 years ago, overall survival has exceeded 50%. A clear understanding of the acute complications and late effects of osteosarcoma therapy is required to care effectively for patients with osteosarcoma undergoing active treatment, and for the increasing number of osteosarcoma survivors. There has now been sufficient cumulative experience treating patients with osteosarcoma with active anti-osteosarcoma chemotherapy agents, high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide to recognise and understand rare toxicities associated with these agents, and to identify the late effects of osteosarcoma therapy. Late effects and rare toxicities of osteosarcoma include cardiac toxicity, acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms. Reducing the complications of osteosarcoma therapy is an important goal that will require the identification of clear prognostic indicators, the development of biologically-based therapies, and improved antidotes for the active anti-osteosarcoma cytotoxic drugs.

Introduction

Before the 1970s osteosarcoma was treated with surgery alone, and about 80% of patients ultimately died of the disease. The use of multi-agent chemotherapy in the 1970s led to significant increases in event-free and overall survival.¹ Present day 5-year event-free and overall survival for localised osteosarcoma are 60–65% and 75–80%, respectively.2, 3 Consequently, a clear understanding of acute complications and late effects of therapy is essential for oncologists caring for the increasing number of survivors of osteosarcoma therapy.

There is considerable agreement among experts about the standard components of multi-agent cytotoxic chemotherapy for osteosarcomas,⁴ as indicated by an ongoing international collaboration on a phase 3 trial in osteosarcoma: EURAMOS1. Since the 1980s virtually all osteosarcoma treatment and research protocols have included high-dose methotrexate (HDMTX), doxorubicin, and cisplatin, a regimen often referred to as MAP. The standard group of the EURAMOS1 trial (figure 1A) is representative of MAP regimens. Ifosfamide and etoposide are other agents with proven anti-osteosarcoma activity.⁵ Ifosfamide and etoposide have been variably incorporated into osteosarcoma research and treatment protocols since the mid-1980s. The experimental group of the EURAMOS1 trial (figure 1B) is representative of the manner in which ifosfamide and etoposide have been incorporated into the MAP regimen.

Acute toxicities of MAP and MAP plus ifosfamide and etoposide such as alopecia, myelosuppression, mucositis, and nausea and vomiting are common complications of most cytotoxic chemotherapy regimens. The incidence and management of these common acute toxicities are well known by most oncologists, and therefore common acute toxicities will not be discussed in this review. By contrast, the recognition and understanding of rare toxicities associated with these agents have required cumulative experience acquired through their use in a large number of patients. Thus, the incidence, management, and prevention of rare toxicities of osteosarcoma therapy are less well known. Because few patients with osteosarcoma were cured before the mid-1970s, data regarding the late effects of therapy have only recently become available. Late effects and rare toxicities of osteosarcoma therapy to be addressed in this review include cardiac toxicity (figure 2), acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms.

Section snippets

Cardiac toxicity

Cardiac toxicity during or following osteosarcoma therapy is exclusively due to doxorubicin, which is given at relatively high doses. Most MAP regimens call for treatment with a cumulative doxorubicin dose of 375–480 mg/m².2, 3, 6, 7, 8 Doxorubicin administration guidelines are variable, with some protocols recommending continuous infusion and others recommending short infusions. The doxorubicin per-course dose in osteosarcoma protocols varies slightly within the range of 60 to 90 mg/m², with

Methotrexate-induced neurotoxicity

HDMTX in MAP chemotherapy regimens is typically given at a dose of 12 g/m², with hydration and alkalinisation to promote methotrexate excretion and leucovorin rescue to protect normal cells from the effects of folate depletion. Acute, transient neurological dysfunction following HDMTX is reported to occur in 0·4–5% of children with osteosarcoma.7, 8, 25, 26 Neurological findings consist of behavioural changes ranging from inappropriate laughter to lethargy, coma, aphasia, and focal sensorimotor

Methotrexate-induced nephrotoxicity

Methotrexate and its metabolites can precipitate in renal tubules, particularly at alkaline pH, causing acute renal insufficiency and failure. Because methotrexate is eliminated primarily by the kidneys, renal insufficiency following methotrexate administration prolongs exposure to methotrexate, which in turn increases the risk of other methotrexate-associated toxicities, particularly myelosuppression, mucocitis, hepatitis, and dermatitis. Early studies of HDMTX done in the 1970s showed that

Ototoxicity

Cisplatin causes hearing loss that is most pronounced at high frequencies, but progresses to include the lower frequencies in more severe cases. The risk of ototoxicity increases significantly with higher cumulative doses of cisplatin,⁶⁰ higher individual doses of cisplatin,61, 62, 63 younger age,⁶³ and co-administration of aminoglycosides. The reported rates of hearing loss following cisplatin therapy vary between studies, due to the use of different grading scales and different cumulative

Infertility

The effect of cisplatin on male fertility has been most often studied in men undergoing treatment for testicular cancer. In this setting, 36% of men with normal pre-treatment sperm production who received cisplatin-containing regimens developed oligospermia or azoospermia.⁶⁵ In these patients, the risk of gonadal dysfunction after cisplatin treatment was related to cumulative dose, with 19% of men who received 400 mg/m² cisplatin developing decreased sperm production compared with 47% of men

Second malignant neoplasms

Four reports have examined the incidence of second malignant neoplasms (SMNs) following osteosarcoma therapy.72, 73, 74, 75 The reported 10-year cumulative incidence of SMNs in osteosarcoma survivors ranges from 2–4·6%. This represents an increased risk of malignancy compared with the general population. The reported magnitudes of the increased risk are 4·6⁷⁴ and 10·4.⁷² The SMNs for which this population is at increased risk, in approximate order of decreasing frequency include leukaemia,

Implications for clinical practice

Preventing the rare therapy-associated toxicities discussed in this review involves careful adherence to well established administration guidelines particularly for HDMTX, cisplatin, and ifosfamide. Early recognition of treatment-related toxicities is essential, and can prevent the occurrence of further complications. Treatment-related toxicities requiring close monitoring during therapy include cardiac dysfunction, electrolyte imbalances, renal insufficiency, and delayed methotrexate

Future directions

Because osteosarcoma is rare, the number of patients available to participate in randomised trials is limited, and research questions to be explored by randomised trials need to be prioritised. Until higher overall survival is achieved, questions addressing therapeutic efficacy are likely to be prioritised over questions that address toxicity. Nevertheless, several important questions regarding chemotherapy administration practices and antidotes for active anti-osteosarcoma cytotoxic

Conclusion

Given the intensity of osteosarcoma therapy and the number of potential treatment-related complications, most patients with osteosarcoma will experience at least one of the treatment sequelae discussed here. Consequently, clinicians need to be familiar with the prevention, early recognition, and management of these rare toxicities and late effects. Reducing the complications of osteosarcoma medical therapy is an important goal for the sarcoma research community, and will require the

Search strategy and selection criteria

Phase 2 and 3 cooperative group trials of osteosarcoma therapy published in English after 1998 were identified by a pubmed search with the terms osteosarcoma and treatment. These studies were reviewed for reported adverse events and complications. A pubmed search using the terms “osteosarcoma”, “doxorubicin”, “cisplatin”, “methotrexate”, “ifosfamide”, “etoposide”, “complications”, “adverse effects”, “late effects”, “heart failure”, “nephrotoxicity”, “neurotoxicity”, “hearing loss”,

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ReviewSequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects

Summary

Introduction

Section snippets

Cardiac toxicity

Methotrexate-induced neurotoxicity

Methotrexate-induced nephrotoxicity

Ototoxicity

Infertility

Second malignant neoplasms

Implications for clinical practice

Future directions

Conclusion

Search strategy and selection criteria

Blood

Ann Oncol

Lancet

Eur J Cancer

Lancet

Cancer Treat Rev

J Ped

Eur J Cancer

Neurotoxicology

Endocrinol Met Clin North Am

Ann Oncol

The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity

N Engl J Med

Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate

J Clin Oncol

Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups

J Clin Oncol

Management of osteosarcoma

Curr Treat Options Oncol

Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial

J Clin Oncol

Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report

J Clin Oncol

Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup

J Natl Cancer Inst

Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651

J Clin Oncol

Anthracycline-induced cardiotoxicity

Annal Intern Med

Doxorubicin-induced cardiomyopathy

N Engl J Med

Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer

Cochrane Database Syst Rev

Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol

J Clin Oncol

Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience

J Clin Oncol

Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer

N Engl J Med

Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood

N Engl J Med

Risk factors for doxorubicin-induced congestive heart failure

Annal Intern Med

Cardiac toxicity 4 to 20 years after completing anthracycline therapy

JAMA

Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer

N Engl J Med

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin

J Clin Oncol

Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without evidence

J Clin Oncol

Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without compelling evidence

J Clin Oncol

Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease

J Clin Oncol

Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane

J Clin Oncol

Transient cerebral dysfunction secondary to high-dose methotrexate

J Clin Oncol

High dose systemic methotrexate-associated acute neurologic dysfunction

Med Ped Oncol

Transient neurologic disturbances induced by high-dose methotrexate treatment

Cancer

Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia

J Clin Oncol

Review
Sequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects