The authors investigated the incidence and relative risk of secondary malignant neoplasms in long-term survivors of osteosarcoma.
The authors investigated the incidence and relative risk of secondary malignant neoplasms in long-term survivors of osteosarcoma.
A comprehensive list of 509 patients with primary osteosarcoma treated at our institution between February 1973 and March 2000 was identified. All study patients received chemotherapy and/or surgery on one of six different protocols (T4, 5, 7, 10, 12, and CCG-7921/POG-9351). Chemotherapy was scheduled for up to 40 weeks with some variations in the actual treatment period and consisted of various combinations of the following agents: high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin, and ifosfamide.
Secondary malignant neoplasms (SMN) occurred in 14 of 509 patients. Only one had pulmonary metastasis at diagnosis and subsequent multiple recurrences that required thoracotomies and further modification of the chemotherapy regimen. The median age at diagnosis for osteosarcoma was 16.6 years (range, 3.1–74.4 years). The median follow-up was 5.2 years (range, 0.1–25.0 years). The time interval from diagnosis of the primary osteosarcoma to the development of SMN was 1.3–13.1 years (median, 5.5; 95% confidence interval [CI], 3.6–9.6). The most common SMN occurred in the central nervous system (n = 4): anaplastic glioma, meningioma, high-grade glioma, and maxillary astrocytoma. There were two cases of acute myeloid leukemia and one case each of myelodysplastic syndrome, non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, breast carcinoma, and mucoepidermoid carcinoma. The overall 5 and 10-year cumulative incidences of SMNs were 1.4% ± 1.1% and 3.1% ± 1.8%. The standardized incidence ratio was 4.6 (95% CI, 2.53–7.78, P = 0.00001) for the cohort and 3.64 (95% CI, 1.82–6.52, P = 0.0007) when patients with a history of retinoblastoma or Rothmund-Thomson syndrome were excluded.
The overall incidence of secondary malignancies in long-term survivors of osteosarcoma was significantly higher than the expected incidence of cancer in the general population. However, the standardized incidence ratios were much lower than those reported for Hodgkin disease and retinoblastoma. Although additional follow-up is warranted, the successes of current treatment regimens consisting of intensive, high-dose chemotherapy in combination with topoisomerase II inhibitors outweigh the risks. Cancer 2002;95:1728–34. © 2002 American Cancer Society.
The improved survival of children with cancer has resulted in one of the most ominous and significant long-term problems associated with therapy, the development of second malignant neoplasms (SMNs). A significant amount of information regarding second malignancies following treatment of Hodgkin disease,1–3 retinoblastoma,4–6 and acute lymphoblastic leukemia (ALL)7 is available because a good cure rate has been achieved for many years, resulting in many long-term survivors.
However, there is limited information on SMNs that occur in long-term survivors of osteosarcomas (OS).8–11 This is due to a survival rate of about 20% before the introduction in the 1970s of systemic combination chemotherapy for patients with OS. Pratt et al.9 reported an overall 10-year cumulative incidence of second malignancies of 2% ± 1% for patients with localized OS versus 8% ± 5% for those who presented with metastatic disease (P = 0.05, n = 334).
The current study was undertaken to review the incidence of SMN among long-term survivors of OS treated with chemotherapy and/or surgery with or without radiation at our institution.
A comprehensive list of all patients who presented to our institution with newly diagnosed, high-grade OS was generated. The medical records and histopathology of each patient were reviewed. Inclusion was restricted to patients first seen between February 1973 and March 2000. The former date was chosen arbitrarily as a date by which OS treatment strategy included aggressive multiagent chemotherapy, preferably before definitive surgery with wide en bloc resection of primary disease. The latter date was chosen to allow time for follow-up after completion of adjuvant chemotherapy.
During the period of this study, we saw 509 patients with primary OS. Eighty-six of these patients presented with metastatic disease at diagnosis. We obtained the date of last contact for each patient from the medical records and from the hospital's computerized clinical data collection system, the Disease Management System. For the patients who developed SMN, we assessed the following: the age at diagnosis of the primary and secondary disease, the interval between diagnoses, the site and extent of primary malignancy, initial levels of lactate dehydrogense and alkaline phosphatase, the chemotherapy regimen received, type of surgery, Huvos histologic response, the outcome, the histologic characteristics of the SMN, and the incidence of family history of cancer wherever possible. If the patient died, the date and the cause of death were also reported. Only patients who developed a second neoplasm other than OS were included in this analysis. Those who developed a local recurrence or a metachronous metastatic OS were excluded. Of the 327 survivors, the median length of follow-up (from the last follow-up date of June 25, 2001) was 8.3 years (range, 0–23.4 years). Twenty-seven percent of the survivors had follow-up within 1 year of June 25, 2001. Thirty-six percent of the survivors had follow-up within 2 years. Each patient's medical records were reviewed thoroughly for the family history of cancer obtained at first visit and follow-up visits. We did not make any further attempts to contact any of the patients during the time of this analysis due to the longer time interval between the time of diagnosis of primary disease to last follow-up. This was also done for the protection of patient privacy.
During the study interval, six chemotherapy protocols were used: T4, T5, T7, T10, T12, and Children's Oncology Group (CCG)-7921/Pediatric Oncology Group (POG)-9351 (Table 1).12–15 The protocols consisted of multiagent chemotherapy and/or surgery totaling 40 weeks with some variations in the actual treatment period. Patients treated according to the T4 protocol received adjuvant chemotherapy following surgical resection of their primary tumor. The T5 protocol included preoperative chemotherapy and en bloc resection with reconstruction, followed by adjuvant chemotherapy. The T7 protocol comprised a more aggressive preoperative chemotherapy compared with T5, followed by en bloc resection and adjuvant chemotherapy. Patients treated with the T10 protocol, Regimen A, received high-dose methotrexate (HD-MTX), doxorubicin, and cisplatin. Regimen B consisted of these agents without the cisplatin. The T12 regimen was modeled after the T10 protocol, with more intensive preoperative chemotherapy. Patients were then stratified according to Huvos histologic grade and received HD-MTX, bleomycin, cyclophosphamide, dactinomycin (BCD), and doxorubicin with or without cisplatin following surgery. CCG-7921/POG-9351 Regimen A comprised HD-MTX, doxorubicin, and cisplatin. Regimen B included these agents plus ifosfamide. Patients who presented with detectable metastatic pulmonary disease underwent thoracotomy immediately after definitive surgery of the primary tumor. Thereafter, subsequent recurrences were treated with either surgery and/or additional individualized chemotherapy.
|Protocol Chemotherapy||T4 (1973–1976)||T5 (1973–1979)||T7 (1973–1979)||T10 (1978–1983)||T12 (1984–1993)||CCG/POG (1992–1997)|
|Cumulative||42||48||176||64–96 (Reg. A)||176||144|
|96–144 (Reg. B)|
|Cumulative||—||—||—||720 (Reg. A)||—||480|
|No. of patients with SMN||1||0||3||2||7||1|
The length of time at risk for the secondary neoplasm was calculated from the date of diagnosis of primary OS until the date of diagnosis of the second malignancy, or until death, or last follow-up. The cumulative incidence rate of second malignancies was calculated based on the competing risks method of Kalbfleisch and Prentice16 with comparison based on the method of Gray.17 The overall survival rate was calculated based on the product-limit method.17 The standardized incidence ratio was used to compare the observed number of occurrences of secondary malignancies in our cohort with the expected number of cancer cases using the comparison analysis based on the method of Rothman and Boice.18 The number of cancer cases expected to occur for the given lengths of follow-up was calculated based on age, gender, and calendar interval-specific rates published by the Surveillance, Epidemiology, and End Results (SEER) program of the National Institutes of Health.19 All statistical analyses were performed with SAS or S-PLUS software. A P value of less than 0.05 was considered to be statistically significant.
In 509 patients with primary OS treated at our institution during the study period, 295 (58%) were males and 214 (42%) were females. The median age at diagnosis of the primary OS was 16.6 years (range, 3.1–74.4 years). The distribution of the primary OS sites comprised 254 in the femur, 125 in the tibia/fibula, 62 in the humerus, 24 in the head and neck, 24 in the pelvis, 6 in the axial skeleton, and 14 in various other sites (ulna, 3; radius, 2; rib, 3; metatarsal, 2; calcaneus, 1; patella/index finger, 1; sternum, 1; scapula, 1). Of the 509 patients, 86 (17%) presented with detectable metastatic disease at diagnosis by chest X-ray and/or computed tomographic scan. During the follow-up period, 327 (64.2%) patients survived with a median follow-up of 8.7 years (range, 0.1–25.0 years). Of these patients, 232 (71%) were followed for 5 years or longer and 133 (41%) were followed for 10 years or longer. Of 327 survivors, 246 (75.2%) had no evidence of disease, 18 (5.5%) had evidence of disease, and 63 (19.3%) had unknown disease status. One hundred and eighty-two (35.8%) patients died. Among them, 158 (87%) died of disease, 7 (4%) died with no evidence of disease, and 17 (9%) had no specific cause of death recorded. The estimated 5 and 10-year actuarial survival rates were 66.2% ± 4.4% and 60.9% ± 4%, respectively.
Fourteen (2.8%) of the 509 patients with primary OS developed SMNs within 3413.2 person-years. In the cohort, the 5 and 10-year estimated cumulative SMN incidence rates were 1.4% ± 1.1% and 3.1% ± 1.8%, respectively (Fig. 1). The 5 and 10-year SMN-free survival rates were 98.6% and 97.0%, respectively. Based on age, gender, and calendar interval-specific incidence rates published by SEER,19 the expected number of cancer incidence was 3.02. The standardized incidence ratio of SMN for the 14 patients was 4.6 (95% confidence interval [CI], 2.53–7.78, P = 0.00001). When the three patients with a history of retinoblastoma and Rothmund-Thomson syndrome were excluded, the standardized incidence ratio of SMN was 3.64 (95% CI, 1.82–6.52, P = 0.0007). The 5 and 10- year cumulative incidence rates were 1.2% ± 1.0% and 2.5% ± 1.6% respectively. Neither age at diagnosis of the primary (0–14 vs. 15–19 > 19 years, P = 0.31) nor gender (male vs. female, P = 0.97) was a significant factor in developing SMNs.
The 14 patients who developed SMN received the following chemotherapy regimens (Table 2): 7 received the T12 protocol; 2 received the T10 protocol; 3 received the T7 protocol; 1received the T4 protocol; and 1 received the CCG-7921/POG-9351 protocol. The median age at diagnosis for OS was 16.4 years (range, 6.8–43.5 years). The SMNs were diagnosed at a median age of 24.2 years (range, 16.5–44.4 years). The time interval from the diagnosis of the primary tumor to development of SMN ranged from 1.0 to 13.1 years (median, 5.2 years; 95% CI, 3.6–9.6). Patient 12 developed a third malignant neoplasm, follicular papillary carcinoma of the thyroid, 1.8 years after the diagnosis of SMN and 3.2 years after primary OS. This patient received HD-MTX and BCD before surgical resection but received no further postoperative chemotherapy or irradiation for the primary tumor. Of the 14 patients who developed SMN, 7 were alive (5 were alive with no evidence of disease) at the last follow-up, with a median follow-up time of 4.3 years (range, 0.6–18.2 years) after the diagnosis and treatment of the SMN.
|Patient no.||Site of primary OS||Chemotherapy||Huvos||Age at diagnosis of OS (yrs)|
|2||Patella, index finger||T12||—||15.4|
The most common SMN site was the central nervous system (n = 4): one anaplastic glioma, one meningioma, one high-grade glioma, and one maxillary astrocytoma. There were two cases of acute myeloid leukemia (AML), one myelodysplastic syndrome (MDS), and one case each of non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, cancer, and mucoepidermoid carcinoma. Patients 1 and 6 had received radiation therapy before the development of the SMN.
Only Patient 8 had pulmonary involvement at the time of diagnosis and underwent bilateral thoracotomies. He subsequently developed multiple recurrences of the OS in the lung and was treated with multiple thoracotomies, ifosfamide (cumulative dose, 72 g/m2), and etoposide (4.8 g/m2) before the development of the MDS.
Whenever possible, attempts were made to obtain complete or partial family histories. Of the 14 patients who developed SMN, Patient 2 had a history of Rothmund-Thomson syndrome20 and an extensive family history of cancer (Table 3). Patient 1 had a mother who died of OS in her 30s, Patient 9 had a history of retinoblastoma as a child, and Patient 12 has a son with retinoblastoma who was doing well, indicating the presence of a probable germline mutation. Five patients had no known family history of cancer whereas three patients had a positive family of various carcinomas (lymphoma, breast, or colon carcinoma). Family history was not available for two patients.
|Patient no.||Age at diagnosis||Interval from primary to SMN (yrs)||Type of SMN||Outcome||Family history|
|7||20.5||3.6||Mucoepiderm CA||A-NED||Fhx lymphoma|
|8||24.2||4.8||MDS (−7, 5)||DOD||Unknown|
|12||29.9||10.9||Leiomyosarcoma||AWD||Son with Rb|
|14||19.2||12.4||Leiomyomartous hamartoma||A-NED||Fhx colon CA|
The introduction of aggressive multiagent chemotherapy followed by adjuvant chemotherapy for the treatment of OS has improved dramatically the survival rates among these patients. As the number of pediatric cancer survivors increases, there is increasing concern about the development of SMNs.
Chemotherapy can have numerous long-term effects, one of the most important of which is the leukemogenic effect. In the literature, several authors have documented secondary leukemias and myelodysplastic syndromes in patients who were treated with HD-MTX, doxorubicin, and cisplatin for OS.21–31 Recent reports have emphasized the concern of treatment-related myelodysplasia/myeloid leukemia (t-MDS/t-AML) for regimens that use high cumulative doses of alkylating agents in addition to combination therapy with topoisomerase II inhibitors (epipodophyllotoxins). Abnormalities of chromosome 5 and/or 7 and a peak incidence at 4–7 years from the start of the chemotherapy are typical of the t-MDS/t-AML that occurs after alkylating agent therapy.31–33 In contrast, a short latency period with abnormalities of chromosome 11q23 are typical following therapy with epipodophyllotoxins.34–39 Pui et al.30 reported their experience with 734 children with ALL who were treated with epipodophyllotoxins (etoposide and teniposide). The overall cumulative risk of AML at 6 years was 3.8% (95% CI, 2.3–6.1). Kushner et al.31 reported six patients with t-AML among 380 receiving very intensive alkylator therapy in combination with topoisomerase II inhibitors for neuroblastoma, a 36-month cumulative incidence of 7% (95% CI, 0–15). Bhatia et al.40 reported a cumulative incidence of t-MDS/t-AML of 3.3% ± 1.2% at 6 years in a cohort of 778 children with OS treated according to the CCG-7921/POG-9351 protocol, which consisted of HD-MTX, doxorubicin, and cisplatin with or without the addition of ifosfamide. Jeha et al.41 reported secondary acute nonlymphoblastic leukemia following treatment with a cis-diamminedichloroplatinum-II–based regimen in children with OS. In our experience with long-term OS survivors, the 5 and 10-year cumulative incidence of t-MDS/t-AML was 0.7% ± 0.8%. Two patients developed AML and one patient developed MDS. All three of these patients also received HD-MTX, doxorubicin, and cisplatin-containing regimens. Patient 9 suffered multiple recurrencesbefore the development of MDS with chromosome 5 and 7 deletions at 4.83 years after diagnosis of his primary OS. This patient received intensive chemotherapy with alkylating agents as well as an ifosfamide/etoposide-based regimen, indicating the relevancy of postrecurrence therapy to treat MDS. The cytogenetic analysis of the other two patients with AML was not available.
It has been well documented that radiation therapy can induce secondary malignancies at the site of exposure.2, 42, 43 In our analysis, Patients 1 and 6 received radiotherapy for local control of the primary OS in addition to systemic chemotherapy, before the development of SMN (fibrosarcoma and maxillary astrocytoma, respectively) that arose in the radiation field. Patient 13 received external beam radiation (3500 cGy) at age 1 year for his retinoblastoma. He then developed OS and subsequently high-grade glioma of the nasal ridge with lung and skull metastasis. This patient's family history is also significant for a son with retinoblastoma. This is in accordance with the findings of Hawkins et al.44 Tucker et al.45 also reported that patients with hereditary retinoblastoma who received radiation therapy are at increased risk of developing subsequent bone tumors.
It is well known that patients with OS with a family history consistent with a familial cancer syndrome (e.g. Li-Fraumeni syndrome) have an increased risk of developing second malignancies.46 In our analysis, none of the patients seemed to have had a strong, documented history of familial cancer syndromes. Two patients had an individual or family history of retinoblastoma, one patient had Rothmund-Thomson syndrome, and four other patients had a positive family history of other types of cancer. Some studies have shown a correlation between SMN risk and familial cancer aggregation.47 The risk of SMN in our cohort may be more frequent than expected if there were an absence of any family history of cancer. Although we did not make any further attempts to contact any of the patients at the time of this analysis, the medical records of each patient were reviewed thoroughly. However, this may still have underestimated the true presence of the interactions that exist among the patients' genetic characteristics, predisposition to certain cancers, and the therapy received.
In our study population, the overall 10-year cumulative incidence of SMNs after surviving OS was 3.1% ± 1.8%. The rate was 2.5% ± 1.6% when the three patients with history of retinoblastoma or Rothmund-Thomson syndrome were excluded. Similarly, Pratt et al.9 reported an overall 10-year cumulative incidence of second malignancies of 2% ± 1%. The standardized incidence ratio of secondary malignancies in long-term survivors of OS is much less than that reported for Hodgkin disease3 (9.7; 95% CI, 8.1–11.6) and retinoblastoma6 (relative risk, 30; 95% CI, 24–47). This may be related to several factors, such as an earlier age at diagnosis, the higher cumulative dose and dose per course of alkylating agents received, genetic predisposition to certain cancer syndromes, or higher event-free survivals with longer follow-up. Although the observed overall incidence of developing SMN in long-term survivors of OS increased significantly compared with the expected incidence of cancer in the general population at large, the frequency is still low. Based on our data, longer follow-up is warranted. However, for this particular disease, the successes of current treatment regimens for the primary tumor consisting of intensive, high-dose chemotherapy in combination with topoisomerase II inhibitors greatly outweigh the risks.