Second Solid Malignancies among Children, Adolescents and Young Adults Diagnosed with Malignant Bone Tumors after 1976: Follow-up of a Children’s Oncology Group Cohort

Abstract

Background

The growing number of individuals surviving childhood cancer has increased the awareness of adverse long-term sequelae. One of the most worrisome complications following cancer therapy is the development of second malignant neoplasms (SMN).

Methods

We describe the incidence of solid organ SMN in survivors of pediatric malignant bone tumors treated on legacy CCG/POG protocols from 1976 to 2005. This retrospective cohort study included 2842 patients, 1686 treated for osteosarcoma (OS) and 1156 treated for Ewings Sarcoma (ES).

Results

The cohort included 56% males and 44% females, with a median age at primary diagnosis of 13 years. The median length of follow-up was 6.1 years (range: 0 to 20.9 years). In this analysis, 64% of patients were alive. Seventeen patients with solid organ SMN were identified. The standardized incidence ratio was 2.9 (95% CI, 1.4–5.4) for patients treated for OS and 5.0 (95% CI, 2.6–9.4) for patients treated for ES. The median time from diagnosis to development of solid SMN was 7 years (range: 1 to 13 years). The 10-year cumulative incidence of solid organ SMN for the entire cohort was 1.4% (95%CI 0.6–2%).

Conclusions

The magnitude of risk of solid SMNs was modest after treatment for malignant bone tumors. However, radiation-related solid SMNs will increase with longer follow-up. As nearly one-third of patients succumb to their disease, recurrence remains the most significant problem. Development of improved therapies with fewer long-term consequences is paramount. Follow-up should focus on monitoring for both recurrence of primary malignancies and development of SMN.

The two most common malignant bone tumors in children and adolescents are osteosarcoma and Ewing sarcoma family of tumors (ESFT). As reported by SEER from 1975–95¹, the annual incidence rate of malignant bone tumors is 8.7 per million children younger than 20 years of age with approximately 400 children diagnosed with osteosarcoma and 200 children diagnosed with ESFT each year in the United States. The 5-year survival is improving for children with malignant bone tumors and, with aggressive, multimodal therapy, nearly 70% are expected to be long-term survivors. One of the most worrisome complications following cancer therapy is second malignant neoplasms (SMNs). The overall cumulative incidence of SMN in survivors of childhood cancer is reported as 3.2% at 20 years, but varies from 1.6% to 7.6% depending on the primary diagnosis.²

As osteosarcoma is generally considered radioresistant, chemotherapy and surgery are the primary therapeutic modalities for this disease. The backbone of osteosarcoma chemotherapy includes cisplatinum, doxorubicin and high dose methotrexate. The addition of other agents, such as carboplatinum, ifosfamide and etoposide, have been investigated ^3–5. While osteosarcoma is usually sporadic, a rare patient may have an underlying cancer predisposition syndrome, namely Li-Fraumeni syndrome, possibly resulting in an increased risk of SMNs because of genetic susceptibility. There is limited information regarding the risk of SMNs after the treatment of osteosarcoma^6,7

Therapy for ESFT involves multiagent chemotherapy and local control with either surgery and/or radiation. During the 1980s and 1990s the backbone of therapy included vincristine, doxorubicin, and cyclophosphamide. Therapeutic trials have demonstrated significant survival advantage by addition of ifosfamide and etoposide for patients with localized disease.^8,9 In contrast to osteosarcoma, Li-Fraumeni is not typically associated with ESFT.

Several studies have examined the risk of SMN after treatment for ESFTs. However, small sample size¹⁰, varying therapies¹¹, short follow-up¹² and single institution studies¹³ limit the generalizability of these results. While most of the previous reports have focused on secondary leukemia or myelodysplasia occurring after bone tumors, only a few have focused on solid tumors developing in this patient population. ¹⁴

This study aims to determine the incidence of solid second malignancies, and identify potential risk factors in children and adolescents with malignant bone tumors entered on legacy Children’s Cancer Group/Pediatric Oncology Group (CCG/POG) protocols since 1976.

Methods

CCG/POG conducted clinical trials in cooperation with member institutions throughout the United States, Canada, Australia and selected countries from Europe. The member institutions were required to register all newly diagnosed cancer patients with the operations office, after which eligible patients were entered into active therapeutic protocols. The operations office was responsible for determining patient eligibility, randomized assignments to the appropriate therapeutic arms (if necessary), and follow-up of patients for all potential outcomes. Member institutions were required to submit semi-annual follow-up reports on all patients enrolled in therapeutic protocols. Those reports included information on survival status, disease status, and development of second malignancies for all patients.

Our cohort consisted of 2842 patients with newly diagnosed osteosarcoma or ESFT who were younger than 33 years at diagnosis and were enrolled in one of the 11 therapeutic protocols for untreated osteosarcoma or ESFT conducted between 1976 and 2002. The distribution of patients by the therapeutic trials is summarized in Table 1. Informed consent was obtained from patients, parents, or guardians at the time of enrollment. Clinical results of many of the trials, with the therapeutic plans, have been published (references indicated in Table 1).

Table 1.

Treatment protocols, timing and distribution of patients included in this cohort study.

Protocol Numberref	Diagnosis	Date opened	Date closed	Number (%t)	Agents utilized*
CCG74125	OS	September 1976	October 1981	257(9%)	D,M,V
CCG78226	OS	August 1983	October 1986	232 (8%)	P,D,M,A,V,B,C
CCG792127	OS	October 1993	November 1997	777 (27%)	P,D,M,I
POG865128	OS	March 1987	March 1993	100 (4%)	P,D,M,A,B
POG925929	OS	January 1992	November 1994	37 (1%)	P,D,M,I,Ca
POG94504	OS	May 1995	September 1997	41 (1%)	P,D,M,I,E
POG975430	OS	September 1999	February 2002	242 (9%)	P,D,M,I,E
CCG78819	ESFT	December 1988	November 1992	324 (11%)	D,I,E,V,A,C
CCG794231	ESFT	May 1995	September 1998	465 (16%)	D,I,E,V,C
POG88509	ESFT	December 1988	December 1994	257 (9%)	D,I,E,V,A,C
POG945732	ESFT	August 1999	March 2000	110 (4%)	D,I,E,V,C

OS = osteosarcoma ESFT = Ewing Sarcoma Family of Tumors P=cisplatin, D=doxorubicin, M=methotrexate, I=ifosfamide, E=etoposide, V=vincristine, B=bleomycin, A=actinomycin D, C=cyclophosphamide, Ca=Carboplatin

^*not all patients received each agent on the protocol as some protocols were varying pilot studies and some were randomized clinical trials

For each protocol, a therapeutic summary was prepared that included the dose of radiation therapy (and assigned fields) and chemotherapeutic exposures. Assigned cumulative doses were calculated for cisplatinum, doxorubicin, etoposide, cyclophosphamide, and ifosfamide. The use of chemotherapy and radiation therapy was categorized as dichotomized variables (Yes/No) and was included in the analysis using intent to treat method. The total cumulative doses ranged from 0 to 480 mg/m² of body surface area for cisplatinum; from 90 to 600 mg/m² for doxorubicin; from 0 to 5000 mg/m² for etoposide; from 0 to 21.6 g/m² for cyclophosphamide; and from 0 to 140 g/m² for ifosfamide. Assigned radiation doses depended on tumor type, protocol and site of disease.

For patients with second neoplasms, date of diagnosis, histological characteristics, and tumor site were recorded. Pathology reports were requested from treating institutions and reviewed to verify diagnoses.

The time at risk for second neoplasms was computed from the date of diagnosis of osteosarcoma/ESFT to the date of diagnosis of second neoplasm, date of death, or date of last contact, whichever came first. The end of follow-up for the study was April 1, 2005. Overall and event-free survival was calculated using actuarial methods. Cumulative incidence of second solid malignancy (overall and by histological subtypes) over time was calculated and compared across characteristics of interest by the method proposed by Gray.¹⁵ To estimate the risk of second solid neoplasms, the number of person-years of observation was complied for subgroups of the cohort, defined by age and sex. Rates of incidence of cancer (obtained from the registry of Surveillance, Epidemiology, and End Results Program of the National Institute of Health)¹⁶ were used to calculate the expected number of cases of cancer. Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cases. The 95% confidence interval for the SIR was calculated assuming the number of cases follows a Poisson distribution.¹⁷

Results

The key characteristics of the cohort are summarized in Table 2. The median age at diagnosis was 13 years (range, 0 to 33) for malignant bone tumors. The median follow up time from the date of enrollment to date of last contact was 6.1 years (range: 0 to 20.9 years) among the 1812 patients alive at last contact. The date of last contact was within three years for 46% of patients who were alive before April 1, 2005. The overall survival of this cohort was 60% at 10 years (Figure 1A) and there is a significant difference in overall survival based on logrank test; however, the ultimate cure rate is not significantly different by primary diagnosis (Figure 1B). Seventeen patients developed a solid second malignant neoplasm, at a median of 7 years (range 1 to 13) from primary diagnosis. The histological subtypes included breast cancer (n=3), malignant fibrous histiocytoma (n=3), osteosarcoma (n=2), chondrosarcoma, leimyosarcoma, undifferentiated sarcoma, undifferentiated carcinoma, lung adenocarcinoma, renal cell carcinoma, ovarian cancer, papillary carcinoma and anaplastic astrocytoma (n=1 each) –Table 3.

Table 2.

Characteristics of the patient population with second neoplasms

	Total Cohort	Patients with Solid Second Neoplasms
		All solid SMNs	Breast	Secondary Sarcomas
No. of Patients	2842	17	3	9
Type of Disease
Osteosarcoma	1686 (59 %)	8	3	3
Ewings Sarcoma	1156 (41 %)	9	0	6
Gender
Male	1579 (56 %)	5 (29 %)	0 (0 %)	4 (44 %)
Female	1263 (44 %)	12 (71 %)	3 (100 %)	5 (56 %)
Age at Diagnosis of Primary sarcoma (yr.)
Median (Range)	13 (0, 33)	14 (2, 17)	15 (14, 17)	8 (2, 16)
Years from study enrollment to second Neoplasm (yr.)
Median (range)	—	7 (1, 13)	7 (5, 13)	6 (2, 12)
Age at Diagnosis of Second Neoplasm (yr.)
Median (range)	—	19 (8, 31)	23 (19, 31)	16 (8, 26)
Therapeutic Exposure (yes)
Cisplatinum	1429 (50 %)	6(35 %)	1 (33 %)	3 (33 %)
Doxorubicin	2842 (100 %)	17(100 %)	3 (100 %)	9 (100 %)
Etoposide	1120 (39 %)	8 (47 %)	0 (0 %)	5 (56 %)
Cyclophosphamide	1488 (52 %)	15(88 %)	1 (33 %)	9 (100 %)
Ifosfamide	1625 (57 %)	8 (47 %)	0 (0 %)	5 (56 %)
Radiation
No	1329 (47 %)	5 (29 %)	1 (33 %)	3 (33 %)
Yes	1513 (53 %)	12(71 %)	2 (67 %)	6 (67 %)
Status
Died	1030 (36 %)	7 (41 %)	1 (33 %)	4 (44 %)
Alive	1812 (64 %)	10 (59 %)	2 (67 %)	5 (56 %)

Figure 1.

Figure 1A Overall survival of all bone tumor patients.

Figure 1B Overall survival of bone tumor patients by primary diagnosis (Ewing sarcoma vs Osteosarcoma)

Table 3.

Key clinical information on patients with solid SMN

Patient	Initial Diagnosis		Time to SMN diagnosis (yrs)	Treatment			Solid SMN
	Cancer type (COG study number)	Age- primary diagnosis (yrs)		Cyclophosphamide (yes/no)	Etoposide (yes/no)	Radiation (yes/no)	Cancer type
1	Osteosarcoma (741)	14	5	No	No	Yes	Infiltrating ductal carcinoma of L Breast
2	Osteosarcoma (741)	17	14	No	No	Yes	Inflitrating colloid mucinous carcinoma L Breast
3	Osteosarcoma(782)	16	1	Yes	No	No	Adenocarcinoma of lung L chest
4	Osteosarcoma(782)	14	12	Yes	No	No	Leiomyosarcoma - originating in radiated R orbital field
5	Osteosarcoma(782)	16	2	Yes	No	No	Malignant fibrous histiocytoma of bone(orbit/sinus)
6	Osteosarcoma(782)	15	8	Yes	No	No	Breast cancer
7	Osteosarcoma(782)	8	7	Yes	No	No	Malignant undifferentiated tumor of R chest wall
8	Ewing Sarcoma(7881)	13	10	Yes	Yes	Yes	Ovarian tumor(Stage I)
9	Ewing Sarcoma(7881)	7	9	Yes	Yes	Yes	Malignant fibrous histiocytoma of bone(orbit)
10	Ewing Sarcoma(7881)	7	5	Yes	Yes	Yes	Chondrosarcoma vs chondroblastic osteosarcoma
11	Ewing Sarcoma(7881)	15	8	Yes	Yes	Yes	Osteosarcoma
12	Osteosarcoma(8651)	14	10	Yes	No	Yes	Anaplastic astrocytoma
13	Ewing Sarcoma(8850)	5	10	Yes	No	Yes	Osteosarcoma
14	Ewing Sarcoma(8850)	2	6	Yes	Yes	Yes	Malignant fibrous histiocytoma of bone(femur)
15	Ewing Sarcoma(7942)	13	6	Yes	Yes	Yes	Poorly differentiated sarcoma with myogenic features
16	Ewing Sarcoma(7942)	7	8	Yes	Yes	Yes	Papillary carcinoma of the thyroid
17	Ewing Sarcoma(7942)	15	7	Yes	Yes	Yes	Renal cell carcinoma

The estimated cumulative incidence rate for solid second malignant neoplasm was 1.4% (S.E. 0.4%) at 10 years for the entire cohort (Figure 2A), and was 0.9% (S.E. 0.4%) for osteosarcoma and 1.8% (S.E. 0.65%) for ESFT (Figure 2B). Compared to a gender and age matched general population, patients with ESFT were at a 5-fold increased risk of developing a solid second malignancy (SIR=5.0, 95% CI 2.6 to 9.4), while patients with osteosarcoma were at a 2.9-fold increased risk (SIR=2.9, 95% CI 1.4 to 5.4).

Figure 2.

Figure 2A Cumulative incidence of SMN among all bone tumor patients

Figure 2B Cumulative incidence of SMN among bone tumor patients by primary diagnosis (Ewing sarcoma vs Osteosarcoma)

Certain therapeutic exposures were associated with increased risk of solid second malignant neoplasms. Exposure to etoposide and cyclophosphamide were associated with an increased the risk of solid second malignant neoplasms with a standardize incidence ratio of 4.8 (95% CI. 2.5 to 9.5) and 5.8 (95% CI 3.5 to 9.5), respectively. Exposure to radiation therapy also increased the risk of solid second malignancies with a standardized incidence ratio of 4.1 (95% CI 2.4 to 7). With a median follow up time of 9.3 years (range:3.0 to 18.7 years) for the 17 patients who developed solid SMN, the estimated five-year overall survival after development of a solid second malignant neoplasm was 38% (Figure 3).

Figure 3.

Overall survival of 17 patients with solid second malignant neoplasms since their solid second malignant neoplasms date.

Sensitivity Analysis

At the time of the analysis, contact was documented with 46% of those alive within the previous 3 years. To alleviate potential problems related to incomplete follow-up, sensitivity analyses were performed where all patients who had not had an event (death or SMN) were censored as of April 1, 2005, irrespective of their actual date of last contact. It was assumed that those lost to follow-up did not develop an SMN. With these extremely conservative assumptions, a lower boundary was placed on the reported estimates. The results of the sensitivity analysis are presented in Table 4.

Table 4.

Standardized Incidence Ratio – Sensitivity Analysis

		Estimate from Observed Data		Follow-up until April 1, 2005
		SIR	95% CI	SIR	95% CI
All SMNs		3.73	2.35–5.99	1.57	0.99–2.52
By Primary Diagnosis
Osteosarcoma		2.93	1.41–5.39	1.05	0.50–2.63
Ewing Sarcoma		4.96	2.64–9.42	2.79	1.49–5.30
By type of SMN
Breast Cancer		27.80	10.05–81.26	5.17	1.87–15.12
Sarcomas		17.66	9.41–33.53	8.46	4.51–16.06
By key therapeutic exposures
Cyclophosphamide	Yes	5.77	3.52–9.51	2.54	1.55–4.19
	No	1.03	0.32–3.71	0.41	0.13–1.47
Etoposide	Yes	4.83	2.49–9.53	2.74	1.41–5.40
	No	3.11	1.66–5.91	1.14	0.61–2.17
Radiation	Yes	4.08	2.35–7.13	1.88	1.09–3.29
	No	3.12	1.37–7.27	1.13	0.50–2.63

SIR denotes standardized incidence ratio

CI denotes confidence interval

SMN denotes second malignant neoplasms

Discussion

This retrospective cohort study showed that the cumulative incidence of solid SMNs in patients diagnosed with primary malignant bone tumors is relatively low with a cumulative incidence of 1.4% at 10 years. Comparable risks of second solid malignancies were observed in patients with ESFT and osteosarcoma. We found that radiation, cyclophosphamide and etoposide may be associated with an increased risk of solid SMNs. The outcome after development of a solid SMN is poor with a 5 year overall survival of less than 40%.

The strength of this study lies in the size of the cohort and, despite limitations, the quality of the data. The COG cohort of patients with malignant bone tumors includes more patients than those included in SEER and the Childhood Cancer Survivorship Study (CCSS) databases. Of the 752 children diagnosed with osteosarcoma and 479 initially diagnosed with Ewing sarcoma followed in the SEER database, there were 10 and 15 SMN reported with 15 and 44 excess cancers per 10,000 person-years, respectively.¹⁸ In the initial report from CCSS, 25 of the 1136 patients being followed with malignant bone cancer developed a SMN.¹⁹ Of these, it is notable that 6 were breast cancers. There was a 17.9 absolute excess risk for second cancers per 10,000 person-years of follow-up. The outcome was not separately reported for osteosarcoma and Ewing sarcoma. The data from the COG cohort expand on and corroborate the findings from these studies.

Earlier studies have reported a high incidence of SMNs in patients with ESFT, with the magnitude of risk approaching 30% at 10 to 20 years after treatment.^20,21 More recent studies suggest a lower incidence ranging from 1% at five years to 6.5 percent at 10 years.^11–13,22 While each of these studies is based on relative small sample sizes, most identify radiation as playing a role in the risk of developing a solid second malignant neoplasm. The current study reports a cumulative incidence of solid second malignant neoplasms in patients with ESFT in this cohort to be 1.8% at 10 years. It is anticipated that the incidence will rise with increasing follow-up, as has been reported for radiation-related second malignancies in other cohorts.

There are fewer reports on the incidence of SMNs in survivors of osteosarcoma. In our study, the overall 10-year cumulative incidence of solid second malignant neoplasms was 0.9%. Others have reported a 10-year cumulative incidence of 2 to 3% at 10 years, but the studies also included hematologic malignancies.^6,7 Although the relative risk of solid SMNs in long-term survivors of osteosarcoma was higher than the general population in the current study, the magnitude of risk was lower than that for Ewing sarcoma. This likely reflects increased utilization of radiation in patients surviving Ewing sarcoma, but may also relate to higher cumulative doses of alkylating agents and etoposide in patients with Ewing sarcoma (data not shown). Of note, all 3 of the solid SMN of the breast arose in survivors of osteosarcoma. These, and perhaps others, may be patients with Li-Fraumeni syndrome, which is characterized by the development of sarcomas and early-breast cancer and an exceptionally high risk of developing multiple primary cancers.²³

Thus, our study, with relatively large numbers confirms the reports of others ^11–13,22 that the magnitude of risk of solid SMNs is modest after treatment for a primary bone cancer. There are two major possible explanations for the low cumulative incidence of solid SMNs. First, and more optimistically, there may be fewer solid SMNs in the recent era related to improved therapeutic techniques. For example, it is possible that a patient may be able to achieve adequate local control with surgery alone after neoadjuvant therapy, thus omitting the need for radiation. Additionally radiation techniques have substantially improved reducing the normal tissue exposure. The second reason could stem from the fact that the cohort has been followed for a median of 6 years, and that, with increasing follow-up, radiation-related solid malignancies will emerge, since they typically occur after a latency of 10 to 15 years.

However, as with other large cohorts, there is patient attrition with extended follow-up. In order to compensate for the impact of loss to follow-up on the magnitude of risk, we have conducted sensitivity analyses, based on the assumption that patients lost to follow-up are alive and have not had an adverse event of interest. This extremely conservative assumption allows one to put a lower limit on the magnitude of risk, thus permitting an estimate of the true risk somewhere between the reported value and that derived by these sensitivity analyses. Another limitation relates to the small numbers of events that preclude any significant examination of the risks for SMNs or any meaningful subset analyses. Also, there is no family history data available preventing us from predicting if any patients were likely to have Li-Fraumeni or another cancer predisposition syndrome. Finally, we were not able to accurately assess whether the SMN arose within the radiation field.

Methods to assure ongoing, long-standing follow-up of children surviving cancer are necessary. The Children’s Oncology Group has instituted long-term follow-up guidelines that may help assure ongoing surveillance of late effects.²⁴ Additional resources are necessary and are currently being instituted by COG, to assure the long-term follow-up of cancer survivors.