Recurrences following primary osteosarcoma in adolescents and adults previously treated with chemotherapy

doi:10.1016/S0959-8049(03)00435-0

European Journal of Cancer

Volume 39, Issue 14, September 2003, Pages 2050-2057

https://doi.org/10.1016/S0959-8049(03)00435-0 Get rights and content

Abstract

In this retrospective analysis, we report on the detailed management of 33 recurrent osteosarcoma patients from a population of 81 adolescents and adults previously treated (between November 1979 and November 1998) at the La Timone Adults Hospital, for an extremity-localised osteosarcoma. The site of the first recurrence was limited to the lung in 24 patients (73%), was local in 4 patients (12%), at multiple sites in 4 patients (12%), and limited to the bone for 1 patient (3%). The median interval between the diagnosis of the primary osteosarcoma and the first recurrence was 16 months (range 4–108 months). For all patients, the treatment combined aggressive chemotherapy and surgical resection of the recurrences whenever possible. 19 patients (58%) achieved a second complete remission. The median follow-up time from the first recurrence was 18 months (range 4–150 months). For all patients, the median overall survival from first recurrence was 17 months (95% confidence interval (CI), 11–22 months) and the projected 3- and 5-year survival rates were 31.6 and 23.7%, respectively. Patients with a second complete remission had a better 5-year survival than patients without (44.6% versus 0%, P=0.001). The achievement of a second complete remission has an independent significant prognostic value for an improved survival. Aggressive surgery with the removal of recurrence sites combined with multi-agent chemotherapy can either cure patients with recurrent osteosarcoma or significantly prolong their survival.

Introduction

With the advent of aggressive chemotherapy, the long-term survival of patients with high-grade osteosarcoma has improved considerably 1, 2, 3, 4, 5. However, despite the success of combined surgical and chemotherapeutic modalities, 30–40% of patients develop lung metastases or local recurrences. Studies on the management of patients who relapse are very limited in number 6, 7, 8 and mainly concern patients with pulmonary metastases 9, 10, 11, 12, 13, 14, 15, 16. An aggressive pulmonary metastasectomy is at present an accepted treatment strategy, with good results in patients with metastases confined to the lung 9, 10, 11, 12, 13, 14, 15, 16, whereas the value of second-line chemotherapy treatment 7, 9, 10, 14, 15 and the best treatment strategy for those patients with recurrences other than in the lung 8, 7 are not well defined. Nevertheless, since the introduction of effective chemotherapy for osteosarcoma 17, 18, 19, a more aggressive multidisciplinary approach to treat patients with metastatic disease has evolved, and the use of second-line chemotherapy treatment with resection of the recurrence is quite common 6, 7, 9, 10, 11, 12, 14, 15.

We report on a retrospective analysis of 33 adolescent and adult patients who developed metastases or local recurrences from extremity-localised high-grade osteosarcomas. We examine the pattern of recurrence, various treatment methods and results, with particular emphasis on the prognostic impact of previous treatment type, salvage surgery (‘metastasectomy’) and second-line chemotherapy.

Section snippets

Patients

From November 1979 to November 1998, 81 patients with histologically-proven high-grade osteosarcoma of the extremities were treated at the Oncology Unit of la Timone Adults University Hospital. All were initially free of metastatic disease. There were 51 males and 30 females.

At initial presentation, the absence of metastases at diagnosis was routinely ascertained by bone scans for all patients, conventional lung tomography prior to 1983, and by computed tomography (CT) scans of the chest

Patterns of recurrence

Patients' characteristics and sites of recurrence are presented in Table 1. 33 patients, 26 males and 7 females, were entered into this study. 7 patients (37%) relapsed after being given period 1 chemotherapy, 8 (50%) relapsed after period 2 (SO83) chemotherapy, and 18 (39%) after completing the T-10-derived protocol; this was not significantly different (P>0.05). The median age at the time of diagnosis of the primary tumours was 20 years (range 12–55 years). The median intervals from the

Discussion

Before the use of adjuvant chemotherapy, lung metastases appeared in more than 90% of patients 5–8 months after surgical treatment for primary osteosarcoma 15, 19, 25. With intensive chemotherapy, the long-term disease-free survival rate for localised high-grade osteosarcoma improved from less than 20% to the 55–75% range 3, 5, 26, 27, 28, 29. However, 30–40% of patients still relapse, most often with pulmonary metastases, but after a longer median disease-free interval of 10–17 months 15, 25,

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Rates of long-term survival for children with pulmonary metastatic osteosarcoma are low, and complete surgical resection of all visible pulmonary metastases is necessary for long term survival. Surgical approaches for metastasectomy include thoracotomy and thoracoscopy, with the approach chosen influenced by training and institutional bias. Thoracotomy with manual palpation of lung surfaces can identify nodules not seen on preoperative imaging, but no clear survival benefit has been demonstrated compared to complete thoracoscopic resection of all visible nodules.
All member of the American Pediatric Surgical Association were surveyed, and 204 members responded.
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Findings of this survey of North American pediatric surgeons confirm both the need for, and interest in, a prospective trial to define optimal surgical management of children with osteosarcoma with limited pulmonary metastasis.
V.
Atypical manifestation of lung metastasis 17 years after initial diagnosis of low-grade central osteosarcoma
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The patient was discharged within one week after surgery, and has since been well for one year, without any signs of recurrence. Despite the use of combined modality therapy, 30–40% of osteosarcoma patients develop metastasis [11], the lung being the most commonly affected site [4,12–14]. Almost one-third of patients with osteosarcoma suffer recurrence of the disease [15], mostly within 2–3 years after completion of treatment, and relapse after 5 disease-free years is uncommon [4].
A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review
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Cooperative studies support complete metastasectomy in osteosarcoma (OS). Pre-operative CT is used to identify and quantify metastases and can facilitate minimally invasive techniques. Here we assess the accuracy of pre-operative CT compared to findings at thoracotomy and its change over time.
We reviewed OS thoracotomies performed at our institution from 1996 to 2015. The number of metastases identified on pre-operative chest CT was compared to the number of metastases seen on pathology (both metastases with viable cells and non-viable, osteoid-only metastases).
Eighty-eight patients underwent 161 thoracotomies with a median of 14 days (range, 1–85) between CT and surgery, a median of 2 CT-identified lesions (range, 0–15), and a median of 4 resected lesions (range, 1–25). In 56 (34.8%) cases, more metastases were found surgically than were seen on CT, and among these, 34 (21.1%) had a greater number of viable metastases. There was poor overall correlation between CT and pathology findings (Kendall Tau-b = 0.506), regardless of CT slice thickness, decade of thoracotomy, or total number of CT-identified lesions.
CT accuracy in pre-operatively quantifying OS pulmonary metastases has not improved in recent decades. Consequently, we recommend an open technique with direct lung palpation for complete identification and resection of OS pulmonary metastases.
Level IV, retrospective study with no comparison group.
Survival after recurrent osteosarcoma: Data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials
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This includes, whenever possible, complete resection of a local recurrence and/or surgical treatment of all distant recurrences in the case of resectable disease. All other published series of patients with recurrent osteosarcomas confirm the importance of complete surgical resection of a recurrence.1,6–10 The role of chemotherapy for resectable recurrences is much more controversial, since randomised prospective studies in this setting are lacking.
Recurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance.
Between 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75 mg/m² and cisplatin 100 mg/m². The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods.
Median recurrence-free survival was 31 months; 8 recurrences were reported more than 5 years after the diagnosis. In 564 patients with a recurrence (median 13 months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2 years after randomization had a worse prognosis than those recurring after 2 years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, “other” 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group “other”) had significantly worse overall survival (local 39%, lung 19%, “other” 9% at 5 years).
These data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.
High grade osteosarcoma of the extremities metastatic to the lung: Long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005
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Outcome was significantly correlated with relapse interval. These data are in accordance with those reported by Duffaud et al. [21] in 24 cases, by van Geel and coworkers [10] and in 137 patients studied by Harting et al. [22]. Moreover, also Kandioler et al. [13] found that among 255 patients with lung metastases from soft tissue sarcoma treated by thoracotomy, outcome was more favorable when patients had a longer interval between surgery of the primary tumor and the time to lung relapse.
Approximately one-third of patients with localized osteosarcoma at presentation relapse as well as about three-fourths of the patients with metastases at diagnosis, about 90% of relapses are lung metastases. The role of lung metastasectomy remains to be determined.
and methods: Three hundred and twenty three patients, 88 with resectable lung metastases at diagnosis and 235 with localized disease at presentation who relapsed with lung metastases were treated.
A total of 498 lung surgeries and 607 thoracotomies were performed. The 5 year overall survival was 37%. Final outcome was significantly related to presence or absence of metastasis, time of first relapse and presence of local recurrences. According to stage of the disease, the rate of a 5 year event-free survival (EFS) was 36% for patients with localized disease who later relapsed and 9% for patients with resectable lung metastases at presentation (p < 0.0001). However, there were no differences in EFS between patients who underwent two or three thoracotomies and patients who had four or five thoracotomies (7.5 vs 18.7%, p = 0.29).
In patients with recurrent resectable pulmonary metastases from high grade osteosarcoma treated with adjuvant or neoadjuvant chemotherapy, thoracotomy should always be considered regardless the number of previous lung relapses and the number of secondary pulmonary lesions.
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Recurrences following primary osteosarcoma in adolescents and adults previously treated with chemotherapy

Abstract

Introduction

Section snippets

Patients

Patterns of recurrence

Discussion

J. Pediatr. Surg.

Ann. Oncol.

Eur. J. Cancer

J. Pediatr. Surg.

Preoperative chemotherapy fot osteogenic sarcomaselection of postperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy

Cancer

Chemotherapy for nonmetastatic osteogenic sarcomathe Memorial Sloan Kettering experience

J. Clin. Oncol.

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single agent high-dose methotrexatea Scandinavian Sarcoma Group Study

J. Clin. Oncol.

Neoadjuvant chemotherapy of osteosarcomaresults of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological response

J. Clin. Oncol.

Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapya report from the Children's Cancer Group

J. Clin. Oncol.

Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy

J. Clin. Oncol.

Systemic relapse of patients with osteogenic sarcomaprognostic factors for long term survival

Cancer

Patterns of recurrence after resection of osteosarcoma of the extremity

Arch. Surg.

P. Excision of pulmonary metastases of osteogenic sarcoma of the limbs

Eur. J. Cardiothorac. Surg.

Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases

J. Clin. Oncol.

Chemotherapy and thoracotomy for metastatic osteogenic sarcoma

Cancer

Prognostic significance of complete surgical resection of pulmonary meatastases in patients with osteogenic sarcomaanalysis of 32 patients

J. Clin. Oncol.

Resection of pulmonary metastases in osteosarcomas

Cancer

Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma

Arch. Surg.

Thoracotomy for Pulmonary Metastatic Osteosarcoma. An analysis of prognostic indicators of survival

Cancer

High dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma

Cancer

The rationale for multiple drug chemotherapy in the treatment of osteogenic sarcoma

Cancer

Recent advances in chemotherapy of metastatic osteogenic sarcoma

Cancer