Annals of Oncology Advance Access originally published online on October 24, 2007
Annals of Oncology 2007 18(12):2037-2040; doi:10.1093/annonc/mdm382
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© 2007 European Society for Medical Oncology
sarcomas |
Adjuvant and neo-adjuvant chemotherapy for Ewing's sarcoma family tumors and osteosarcoma of the extremity: further outcome for patients event-free survivors 5 years from the beginning of treatment
1 Section of Chemotherapy
2 Department of Orthopaedic Surgery
3 Section of General Surgery
4 Laboratory of Oncologic Research, Department of Musculoskeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy
* Correspondence to: Dr G. Bacci, Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136 Bologna, Italy. Tel: +39-051-6366829; Fax: +39-051-6366277; E-mail: gaetano.bacci{at}ior.it
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Abstract |
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Background: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarcoma (OS) treated with adjuvant and neo-adjuvant chemotherapy and event-free survivors 5 years from the beginning of treatment we evaluated outcome in the following years. Post 5-year follow-up for these patients was 9.7 years (5.5–29 years).
Patients and methods: Adverse events observed after 5-year follow-up were 73 (7.6%): 38 late relapses, nine leukemia, 14 second solid tumor, seven radioinduced sarcoma, three severe adriamycin-related cardiomyopathy, one suicide and one death by car crash.
Results: Of the patients who developed late events, 16 (22.5%) are alive and event free after 8 years from the last treatment (2–22 years).
Conclusion: We conclude that the high rate of late adverse events after 5 years in patients with OS and ESFT is noteworthy and indicates that these patients should be followed for >5 years.
Key words: adriamycin cardiopathy, Ewing's sarcoma, late events, osteosarcoma, radioinduced sarcoma, second malignancy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Many uncontrolled and controlled studies [1, 2] demonstrated that outcome of patients with nonmetastatic Ewing's sarcoma family tumor (ESFT) and nonmetastatic osteosarcoma (OS) of the extremity has dramatically improved by combining local treatment with adjuvant or neo-adjuvant chemotherapy. However, most studies report their results only in terms of probability of 5-year event-free survival (EFS), the traditional benchmark for cure in most cancers. There are very few studies that report further outcome of patients who were event free after 5 years. A longer follow-up for these patients could be very important for at least two reasons. First, that combined treatment, in addition to increased cure rate of patients with ESFT and OS, modifies the natural history of these diseases, deleing time of recurrence in patients who relapse [3–6]. Secondly, new treatments may be associated with conditions such as second malignant tumor [7, 8] or cardiac failure that may develop many years after the beginning of treatment [9].
In the current paper, we were interested in determining final outcome at a long-term follow-up of patients with ESFT and OS who were alive and event free after 5 years from the start of adjuvant or neo-adjuvant treatment. These patients were followed, respectively, for a mean of 16.3 years (5.5–34 years) and 15.4 years (5.5–34 years).
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient population
Records of 596 patients with ESFT of bone and of 1148 patients with OS treated at the authors' institution between April 1972 and June 2001 with different protocols of adjuvant or neo-adjuvant chemotherapy were reviewed retrospectively. In patients with ESFT, the tumor was located in different sites while for patients with OS the tumor was always in the extremities. Criteria of diagnosis and eligibility to enter these trials as well as the chemotherapy protocols used have been previously reported [10, 11]. In this paper, we will update follow-up of patients who were free of adverse events 5 years after the start of treatment. The mean follow-up, after the first 5 years from the beginning of treatment, for the 954 evaluated was 9.7 years (5.5–29 years). Annual contact with these patients was kept either through the outpatient clinic or by phone or mail. Only five patients treated in the reported period and here not included were lost to follow-up.
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results |
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As summarized in Table 1, for 73 out of 954 cases (7.6%) adverse events were observed after 5-year follow-up. The time of appearance of adverse events from the beginning of treatment was in both groups (ESFT and OS) super imposable: 8 years. Regarding chemotherapy, the rate of late events was significantly higher in patients treated with adjuvant chemotherapy than in those who had neo-adjuvant chemotherapy (6.4% versus 3.4%; P < 0.002). It must, however, be considered that the mean follow-up from the beginning of treatment was 28 years in the first group and only 13 years in the second.
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Ewing's sarcoma family tumor
Mean time of follow-up for these 326 patients who were event free at 5 years was 16.3 years (5.5–29 years). The outcome of these patients was: 287 (88.5%) remained continuously event free for another 5.5–29 years (mean 11.3 years) and 39 (11.9%) had an unfavorable event after 5 years. As reported in Table 1, unfavorable events consisted in 25 late relapses (7.7%), seven radioinduced OSs (2.2%), three leukemias, two second tumors (both lung cancer) and two severe adriamycin cardiopathies.
The first late relapse event was lung metastases in 13 patients, bone metastases in three, lung and bone metastases in two, central nervous system metastases in one and local recurrence in six. The six local recurrences were all followed by metastases located in bone [3] or lung [3]. In 165 patients, locally treated by radiotherapy alone or combined with surgery, radioinduced sarcomas were observed in 7 of 39 patients with >5-year EFS (17.9%) and locally treated with radiotherapy (5000–6000 rads) or surgery followed by radiotherapy [2] at reduced doses (3500–4500 rads). The rate of radioinduced sarcoma was higher in the first group (5 of 25, 20.0%) than in the second (2 of 14, 14.2%). This difference, however, is not statistically significant. In spite of different treatments, 21 of the patients who relapsed died from tumor and four are alive and disease free 2, 6, 8 and 9 years after relapse. Of these last four patients, three relapsed for lung and one for bone metastases. Seven patients developed a radioinduced sarcoma 6–20 years after radiotherapy (mean 9.2 years). Of these patients, five died from the second sarcoma and two are alive and disease free 3 and 22 years after treatment. Of the patients who developed leukemia [two acute lymphoblastic leukemia (ALL) and one acute myeloid leukemia (AML) or lung carcinoma [2], respectively, 5.5, 7 and 8 years and 20 and 23 years from the beginning of treatment], four died from the secondary disease and one is alive and disease free 6 years after the appearance of ALL. Of the two patients who had a late adriamycin myocardiopathy, one died from this side-effect, while the other is alive and well 4 years after a heart transplantation.
OS of the extremity
Mean follow-up for the 628 assessable patients with OS who were event free at 5 years from the beginning of treatment was 15.4 years (5–34 years). Outcome after a further 5 years was the following (Table 1): 594 (94.6%) remained continuously event free and 34 had second adverse events. Adverse events were 13 late relapses, six leukemias, 12 second solid tumors, one severe adriamycin myocardiopathy and two deaths (one suicide and one car crash). Mean time of appearance of adverse events was 9.2 years (5.5–19 years). For the 13 patients who had a late relapse, this was due to lung metastases [9], bone metastases [1], local recurrence plus lung metastases [2] and local recurrence plus bone metastases [1]. In spite of treatment, eight patients died from tumor 3.5–20 years from the time of appearance of the adverse event (mean 10.1 years), four are alive and event free 7–20 years (mean 11 years) from the last treatment and one is alive with uncontrolled disease. Mean time to appearance of leukemia or second tumors was, respectively, 6.6 years (6–7 years) and 11.8 years (5.5–21 years). Leukemias were four ALL and two AML while the second tumors were breast [5], lung [2] and colon carcinoma [2]. Second malignancies in the other three patients were glyoblastoma, Ewing's sarcoma and melanoma. Outcome of these patients after treatment of the adverse event was: five of the six patients who developed leukemia died while one is alive and well 10 years from diagnosis of leukemia, whereas of the 12 patients who had a second solid tumor eight died and four are alive disease free 4, 4, 6 and 6 years from the last treatment. The case of adriamycin cardiopathy was diagnosed in a patient during pregnancy 7 years after the start of chemotherapy; treated with drugs, the patient apparently recovered but died for heart failure 3 years later during a second pregnancy.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Over the past 30 years, outcome of patients with ESFT and OS at presentation has improved considerably. This progress has been possible due to the development of efficient chemotherapy combined with local treatment. The 5-year EFS that was <15%–20% [12, 13] has improved to >50%–60% [14–16] for both these tumors. However, these recent adjuvant and neo-adjuvant studies have reported in general their results in terms of probability up to 5 years on study populations in which follow-up was often <3 years [17, 18]. In this respect, it is important to outline, at least in ESFT, that studies that have updated their results are contrasting. Some authors [19, 20] report that, although late events may occur, the 5-year disease-free survival in general equates with cure, whereas other authors found that >10%–15% of patients can relapse after that time lapse [21–23]. For this reason, it is still uncertain whether these promising results reflect a real reliable final cure rate. In addition to late relapse, the use of aggressive chemotherapy protocols is associated with severe side-effects, in particular second neoplasms, that usually developed >5 years from the beginning of treatment. Literature indicates that for ESFT the peak incidence of most secondary malignancies with a detrimental outcome is reported to occur at 5 years for chemotherapy-related tumors and 10 years for second tumors associated to radiation [24]. Li et al. [25] reported that also survival rate of 5-year survivors of different types of childhood cancer treated before the era of megavoltage irradiation and combination chemotherapy was significantly poorer than that of the USA population. Therefore, the number of late relapses was also present in historic series. Moreover, adjuvant and neo-adjuvant chemotherapy, at least in bone sarcomas, have delayed time interval to the first relapse [3, 6, 23].
Our study demonstrates that in ESFT and OS, late dramatic events are possible also after an EFS of 5 years. These adverse late events were observed in 71 of 954 patients who were event free at 5 years (7.4%). Most frequent late events were relapses (3.9%), followed by leukemia or second solid tumors (2.4%). In ESFT, there was also a high rate of radioinduced sarcomas which always appear after 5 years. The higher rate of late events observed in patients treated with adjuvant in comparison with those treated with neo-adjuvant chemotherapy is probably a consequence of the significantly longer follow-up of the first group. It is important to stress, however, that outcome after the second event was not completely poor. Sixteen of 71 (22.5%) patients who had a second adverse event are long-term survivors; in detail, 8 of 38 (21.0%) for late relapses and 8 of 23 (34.7%) for those who developed a second malignancy or a leukemia. These results confirm what Hayes et al. [26] reported years ago for ESFT. In their series, no patients who relapsed locally or in distant sites before the third year from diagnosis were salvaged and the course of disease after recurrence was generally rapidly fatal. In contrast, 6 of 17 patients who relapsed after 3 years from diagnosis after second-line treatments resulted to be long-term survivors. This suggests that in late relapses, there is a better chance of achieving a lasting treatment response. Results of this study show that also patients with late adverse events have some chances to be cured.
We conclude that the relatively high rate of late events observed in our group of patients with ESFT and OS long-term survivors and the chance of successful second-line treatment indicates that long-term follow-up should be mandatory for these patients.
Received for publication March 27, 2007. Revision received June 14, 2007. Accepted for publication July 7, 2007.
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References |
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