Our Collaborators
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).
References
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).
References
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).
References
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).
Reference
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.