Children’sOncology Group (COG)
The North American Children’s Oncology Group (COG) was formed by the merger of the Children’s Cancer Group (CCG), National Wilm’s Tumor Study Group (NWTSG), Intergroup Rhabdomyosarcoma Study Group (IRSG), and the Pediatric Oncology Group (POG) in 2000. COG recently reported the results of INT 0133, a 2´2 factorial design trial examining the addition of ifosfamide and muramyl tripeptide (MTP), a biological agent, to a control regimen of methotrexate, doxorubicin, and cisplatin (MAP). Preliminary results of INT 0133 indicate that although neither treatment offers an event-free survival benefit when added to MAP individually, there is a synergistic effect when ifosfamide and MTP are administered together (Meyers et al, 2001).
Meyers PA, Schwartz CL, Bernstein M, et al. Addition of ifosfamide and muramyl tripeptide to cisplatin, doxorubicin and high-dose methotrexate improves event-free survival (EFS) in localized osteosarcoma (OS). Proceedings of the American Society of Clinical Oncology 2001, 20, 1463a.
Cooperative Osteosarcoma Study Group (COSS)
The Cooperative Osteosarcoma Study Group (COSS), consisting of centers in Germany, Austria, Hungary and Switzerland, has performed a series of studies since 1977 incorporating multi-agent chemotherapy and surgical resection. Neoadjuvant chemotherapy was first incorporated into trial COSS-80, which turned out to be the first multi-institutional study to confirm the close correlation between histological response to preoperative treatment and the development of metastatic disease (Winkler et al, 1984). The follow-up study, COSS-82, failed to demonstrate a salvage effect for aggressive postoperative chemotherapy in patients who – in an effort to spare them from the drugs most likely to cause late effects – had received a ‘mild’, low-toxicity pre-operative regimen devoid of doxorubicin and cisplatin (Winkler et al, 1988).
The best results from COSS were achieved with the use of methotrexate, cisplatin, doxorubicin and ifosfamide, with a 10-year survival of 71% (Fuchs et al, 1998). This trial also evaluated the use of intra-arterial cisplatin and found no benefit compared to intravenous administration (Winkler et al, 1990). More recently, COSS has reduced chemotherapy associated late effects by altering doxorubicin and cisplatin administration to continuous infusions. Neither resulted in a measurable reduction of efficacy (Bielack et al, 1999a). An attempt to abbreviate chemotherapy for presumed good prognostic patients in the current trial, COSS-96, had to be abandoned prematurely because of an unexpectedly high number of relapses.
Based on 1702 patients entered into COSS trials until 1998, it was concluded that incomplete surgery was the most important negative prognostic indicator, followed by poor response, primary metastases, and axial location (Bielack et al, 2002), as well as tumor size in those patients where it could be evaluated (Bieling et al, 1996; Bielack et al, 2002).
Bielack S, Kempf-Bielack B, Schwenzer D, et al. Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients. Klinische Padiatrie 1999a, 211, 260-270.
Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. Journal of Clinical Oncology 2002, 20, 776-790.
Bieling P, Rehan N, Winkler P, et al. Tumor size and prognosis in aggressively treated osteosarcoma. Journal of Clinical Oncology 1996, 14, 848-858.
Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Annals of Oncology 1998, 9, 893-899.
Winkler K, Beron G, Kotz R, et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. Journal of Clinical Oncology 1984, 2, 617-624.
Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. Journal of Clinical Oncology, 1988, 6, 329-337.
Winkler K, Bielack S, Delling G, et al. Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histological tumor response in osteosarcoma (study COSS-86). Cancer 1990, 66, 1703-1710.
European Osteosarcoma Intergroup (EOI)
For the last twenty years, UK and mainland European centers have participated in trials under the auspices of the European Osteosarcoma Intergroup (EOI) consisting of the National Cancer Research Institute (NCRI) Sarcoma Clinical Studies Group, the Soft Tissue and Bone Sarcoma Group of the European Organization for the Research and Treatment of Cancer (EORTC), the United Kingdom Children’s Cancer Study Group (UKCCSG) and the International Society of Paediatric Oncology (SIOP). The cornerstone of EOI trials has been a two-drug regimen consisting of six cycles of cisplatin and doxorubicin. Two randomized trials conducted by EOI during the 1980s and 1990s have demonstrated that this regimen is not inferior to more complex schedules incorporating methotrexate (Bramwell et al, 1992; Souhami et al, 1997). EOI have recently concluded the BO06 trial comparing the two-drug regimen with the same regimen intensified under G-CSF cover. Preliminary results have shown that intensifying treatment in this manner does not improve progression-free or overall survival (Lewis and Nooij, 2003).
Bramwell VHC, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: The first study of the European Osteosarcoma Intergroup. Journal of Clinical Oncology 1992, 10, 1579-1591.
Lewis IJ, Nooij M. Chemotherapy at standard or increased dose intensity in patients with operable osteosarcoma of the extremity; A randomised controlled trial conducted by the European Osteosarcoma Intergroup (ISRCTN 86294690). Proceedings of the American Society of Clinical Oncology 2003, 22, 3821a. Souhami RL, Craft AW, van der Eijken JW, et al. Randomized trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European Osteosarcoma Intergroup. Lancet 1997, 350, 911-917.
Scandinavian Sarcoma Group (SSG)
The Scandinavian Sarcoma Group (SSG) comprises the Scandinavian countries (Denmark, Finland, Iceland, Norway and Sweden) with a population of about 25 million people. Since 1979, SSG has performed three non-randomized neo-adjuvant chemotherapy trials for high-grade osteosarcoma localized to the extremities. The first, SSG II, was based on the Memorial Sloan Kettering’s T-10 protocol and included high-dose methotrexate and doxorubicin in the pre-operative chemotherapy regimen. 17% of the patients obtained a good histologic response and the difference in outcome between good and poor responders was 28% (Sæter et al 1991). The second osteosarcoma trial (SSG VIII) utilized a three-drug combination of methotrexate, doxorubicin and cisplatin. The 5-year projected overall survival was 74%, which represented an improvement of 9% compared to the SSG II study (Smeland et al, 2003a). With a relatively low dose of ifosfamide (4.5 g/m2) the combination of ifosfamide and etoposide failed to improve outcome for poor histologic responders and the data did not support the strategy used with discontinuation and exchange of all drugs used pre-operatively in the salvage regimen. The following trial, the first joint Italian/Scandinavian study (ISG/SSG I), was undertaken to explore the benefit of adding high-dose ifosfamide (15 g/m2) to the induction therapy. Preliminary analyses suggest that this attempt with maximum dose-intensity of conventional chemotherapy does not improve outcome compared to previous trials (Smeland et al, 2003b).
Saeter G, Alvegård TA, Elomaa I et al. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: A Scandinavian Sarcoma Group study. J Clin Oncol 1991, 9, 1766-1775.
Smeland S, Müller C, Alvegard TA, et al. Scandinavian sarcoma group osteosarcoma study SSG VIII: Prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histologic responders. European Journal of Cancer, 2003a, 39, 488-494.
Smeland S, Bacci G, Ferrari S, et al. Neoadjuvant chemotherapy with high-dose ifosfamide added to methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity. A joint study by the Italian (ISG) and Scandinavian (SSG) sarcoma groups. Proceedings of the American Society of Clinical Oncology 2003b, 22, 3282a.