Journal of Orthopaedic Surgery 2014;22(3):415-9
Late recurrence of osteosarcoma: a report of two cases Kentaro Igarashi, Norio Yamamoto, Toshiharu Shirai, Hideji Nishida, Katsuhiro Hayashi, Yoshikazu Tanzawa, Hiroaki Kimura, Akihiko Takeuchi, Shinji Miwa, Hiroyuki Inatani, Shingo Shimozaki, Takashi Kato, Hiroyuki Tsuchiya Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
ABSTRACT We report 2 cases of late recurrence of osteosarcoma after 6 and 7 years. One patient had pulmonary metastasis, and the other had soft tissue recurrence. Both patients underwent complete resection and chemotherapy. The first patient achieved complete remission and remained disease-free 47 months later and had no limitation in his daily life. The second patient had a re-recurrence and underwent further resection and chemotherapy. He remained diseasefree 35 months later and could walk using a T-handled walking cane. Key words: neoplasm metastasis; neoplasm recurrence, local; osteosarcoma
improvement in chemotherapy, >50% of patients with non-metastatic osteosarcoma of the extremities achieve long-term survival.1–6 Local recurrence usually occurs within the first 3 years,7–11 although late recurrence (after 5 years) has also been reported.12,13 Caffeine is a xanthine that enhances the action of substances that damage cellular DNA, and may inhibit post-replication repair of sublethally damaged DNA.14 Caffeine has a synergistic effect with anticancer drugs and enhances the action of various anticancer drugs that inhibit DNA synthesis.15 With caffeine-potentiated chemotherapy, the 5-year survival rate in patients with non-metastatic osteosarcoma has improved to 90%.16 We report 2 cases of late recurrence of osteosarcoma treated with caffeine-potentiated chemotherapy. CASE REPORTS
INTRODUCTION Long-term survival of patients with osteosarcoma is 10% to 20% after surgical resection alone. With
Patient 1 In June 2004, a 17-year-old man presented with pain in his right knee. Radiographs and magnetic
Address correspondence and reprint requests to: Dr Hiroyuki Tsuchiya, Department of Orthopedic Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan. Email: [email protected]
Journal of Orthopaedic Surgery
416 K Igarashi et al.
resonance imaging (MRI) revealed a bone tumour involving the periosteum of the right proximal tibia (Fig. 1). A biopsy revealed osteoid formation and atypical spindle cells. Metastasis was not found on full-body computed tomography (CT). The patient underwent 5 cycles of neoadjuvant caffeinepotentiated chemotherapy (cisplatin, adriamycin, and caffeine) prior to limb-salvaging surgery. Preoperative radiological evaluation indicated good response. He then underwent marginal excision and bone reconstruction using an external fixator. Histological examination revealed complete resection, as no viable tumour cells were noted in the margins, indicating grade IV/IV chemotherapeutic effect. Postoperatively, the patient underwent 3 cycles of chemotherapy (high-dose methotrexate). Six years later, chest radiographs revealed a left pulmonary lesion, which was confirmed by CT as metastasis. Nonetheless, he had no symptoms of pain or cough. He underwent left thoracotomy with wedge resection of the metastasis. Histological
Patient 2 In September 2003, a 10-year-old boy presented with pain in the right hip. Radiographs and MRI revealed a bone lesion in the right proximal femur (Fig. 2). A biopsy revealed osteoid formation and atypical spindle cells. Metastasis was not found on full-body CT. He underwent 5 cycles of neoadjuvant caffeinepotentiated chemotherapy (cisplatin, adriamycin, and caffeine) prior to limb-salvaging surgery. Preoperative radiological evaluation indicated a partial response, and he underwent wide excision and composite reconstruction using an autograft. Histological
(b)
(a)
(c)
examination showed complete resection. He then underwent 3 courses of caffeine-potentiated chemotherapy (ifosfamide, etoposide, and caffeine). He was followed up every 3 months for one year and every 6 months thereafter. He remained disease-free 47 months later and had no limitations in his daily life.
(d)
(e)
Figure 1 Patient 1: (a) osteosarcoma involving the periosteum of the right proximal tibia with extraskeletal mass formation, (b) metastatic osteosarcoma in the left lung, (c) osteoid formation and atypical spindle cells are noted (H&E, x400), (d) margin of the resected tumour showing no viable tumour cells (H&E, x400), and (e) resected metastatic tumour showing osteoid formation and spindle cells with atypia (H&E, x400).
Vol. 22 No. 3, December 2014
Late recurrence of osteosarcoma 417
(a)
(b)
(c)
(d)
(e)
Figure 2 Patient 2: (a) osteosarcoma involving the periosteum of the right proximal femur with extraskeletal mass formation, (b) recurrence of osteosarcoma of the right thigh, (c) osteoid formation and atypical spindle cells are noted in the osteosarcoma (H&E, x400), (d) margin of the resected osteosarcoma showing no viable tumour cells (H&E, x400), and (e) resected recurrent tumour showing spindle cells with atypia (H&E, x400).
Table Studies of late recurrence of osteosarcoma Study Bielack et al.,11 2002 Meyers et al.,9 1992 Strauss et al.,12 2004 Ferrari et al.,17 2006 Tsuchiya et al.,16 2000
No. of patients
Median followup (years)
No. (%) of patients with recurrence after 5 years
1702 279 484 648 113
3.8 7.75 11.1 10 5.5
23 (1.4) 8 (2.9) 8 (1.7) 13 (2.0) 2 (1.8)
examination revealed >90% necrosis of the tumour. He then underwent 3 cycles of chemotherapy (highdose methotrexate). Seven years later, he noticed a 15-cm swelling in his right thigh, with no pain or tenderness. MRI and positron emission tomography–computed tomography (PET-CT) revealed an intramuscular tumour, which was confirmed by biopsy to be a recurrence of the soft tissue osteosarcoma. He
Latest recurrence % of patients with (years) lung metastasis 14.3 9 14 19.3 7
50 77 50
immediately underwent wide-margin tumour resection and limb salvage surgery. Histological examination revealed complete resection of the tumour. He then underwent 3 courses of caffeinepotentiated chemotherapy (ifosfamide, etoposide, and caffeine). Eight months later, MRI revealed a local re-recurrence. He then underwent tumour resection and mega-prosthesis reconstruction, followed by 3 courses of adjuvant chemotherapy (gemcitabine and
Journal of Orthopaedic Surgery
418 K Igarashi et al.
docetaxel). Nine months later, he developed lung metastasis and underwent thoracotomy with wedge resection of the metastasis. Histological examination showed complete resection. He then underwent immunotherapy, combining tumour cryogenic treatment with dendritic cells. He was followed up every 3 months for one year and every 6 months thereafter. He remained disease-free 35 months later and could walk using a T-handled walking cane. DISCUSSION In a study of 1703 patients with osteosarcoma followed up for a median of 3.8 years, 23 (1.4%) patients had recurrence after 5 years.6,11 The late recurrence rate was 2.9% (8 of 279 patients) at the Memorial Sloan-Kettering Cancer Center in New York,9 and 2% (13 of 648 patients) at the Rizzoli Orthopedic Institute in Bologna, Italy.17 (Table). At our hospital, 1.8% of patients had a recurrence after >5 years; caffeine-potentiated chemotherapy achieved a 5-year survival of >90% in patients with non-metastatic osteosarcoma.16 Improvement in chemotherapy may alter the natural course of the disease and delay recurrences.8 The European Society for Medical Oncology suggested a 10-year follow-up for osteosarcoma patients.18 Nonetheless, recurrences have been reported after >10 years of disease-free interval. More than 75% of recurrences metastasise to the lung.5–7,9 Routine follow-up should include chest radiography in addition to radiography at primary disease sites. MRI is not suitable for detection of local recurrences owing to artefacts of the metal prosthesis for limb salvage. Bone scanning can
detect local recurrence and metastasis, but uptake with aseptic loosening may cause confusion. PETCT with full-body scanning is the investigative tool of choice, with the exception of the central nervous system. The prognosis for patients with late recurrence is good. Patients with a disease-free interval of >2 years have a better post-recurrence survival rate than those with shorter disease-free intervals.4 The median survival rate after recurrence was 17 (range, 2–68) months at the Meyerstein Institute of Oncology in London,12 and 60 (range, 5–119) months at the Rizzoli Orthopaedic Institute, with 65% of patients achieving complete remission.17 After recurrence, the effectiveness of cisplatin, adriamycin, ifosfamide, and etoposide is limited owing to drug resistance. Hence, development of new drugs is needed. Since 1998, gemcitabine has been used for treatment of sarcoma.19 Gemcitabine is a difluorinated analogue of deoxycytidine and acts as an S-phase–specific drug that interferes with DNA chain elongation and disruption of cell growth.20 The response rates of single-agent gemcitabine in patients with soft tissue and bone sarcomas in 5 phase 2 trials were 3%, 3%, 5.5%, 11%, and 18%, with a median of 5.5%.21–25 We have used cryoimmunotherapy for treatment of bone and soft tissue sarcomas since 2008.26 Combining tumour cryotreatment with dendritic cell therapy promotes tumour-specific immune responses and enhances systemic immune responses.27 DISCLOSURE No conflicts of interest were declared by the authors.
REFERENCES 1. Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006;42:2124–35. 2. Stiller CA, Craft AW, Corazziari I, EUROCARE Working Group. Survival of children with bone sarcoma in Europe since 1978: results from the EUROCARE study. Eur J Cancer 2001;37:760–6. 3. Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:1600–6. 4. Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5:21–6. 5. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350:911–7. 6. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Körholz D, et al. Long-term results of the co-operative German-AustrianSwiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9:893–9. 7. Ferrari S, Bacci G, Picci P, Mercuri M, Briccoli A, Pinto D, et al. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol 1997;8:765–71.
Vol. 22 No. 3, December 2014
Late recurrence of osteosarcoma 419
8. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/ osteosarcoma-2 protocol: an updated report. J Clin Oncol 2000;18:4016–27. 9. Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 1992;10:5–15. 10. Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145–50. 11. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, 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. J Clin Oncol 2002;20:776–90. 12. Strauss SJ, McTiernan A, Whelan JS. Late relapse of osteosarcoma: implications for follow-up and screening. Pediatr Blood Cancer 2004;43:692–7. 13. Kempf-Bielack B, Bielack SS, Jurgens H, Branscheid D, Berdel WE, Exner GU, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23:559–68. 14. Lau CC, Pardee AB. Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci U S A 1982;79:2942–6. 15. Tomita K, Tsuchiya H. Enhancement of cytocidal and antitumor effect of cisplatin by caffeine in human osteosarcoma. Clin Ther 1989;11:43–52. 16. Tsuchiya H, Yamamoto N, Asada N, Terasaki T, Kanazawa Y, Takanaka T, et al. Caffeine-potentiated radiochemotherapy and function-saving surgery for high-grade soft tissue sarcoma. Anticancer Res 2000;20:2137–43. 17. Ferrari S, Briccoli A, Mercuri M, Bertoni F, Cesari M, Longhi A, et al. Late relapse in osteosarcoma. J Pediatr Hematol Oncol 2006;28:418–22. 18. Saeter G, Kloke O, Jelic S; ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of osteosarcoma. Ann Oncol 2005;16(Suppl 1):i71–2. 19. Merimsky O, Meller I, Kollender Y, Inbar M. Palliative effect of gemcitabine in osteosarcoma resistant to standard chemotherapy. Eur J Cancer 1998;34:1296–7. 20. Huang P, Chubb S, Hertzel LW, Grindey GB, Plunkett W. Action of 2’,2’-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991;51:6110–7. 21. Okuno S, Edmonson J, Mahoney M, Buckner JC, Frytak S, Galanis E. Phase II trial of gemcitabine in advanced sarcomas. Cancer 2002;94:3225–9. 22. Svancarova L, Blay JY, Judson IR, van Hoesel QG, van Oosterom AT, le Cesne A, et al. Gemcitabine in advanced adult softtissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38:556–9. 23. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, et al. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol 2000;45:177–81. 24. Späth-Schwalbe E, Genvresse I, Koschuth A, Dietzmann A, Grunewald R, Possinger K. Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs 2000;11:325–9. 25. Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001;19:3483–9. 26. Nishida H, Tsuchiya H, Tomita K. Re-implantation of tumour tissue treated by cryotreatment with liquid nitrogen induces anti-tumour activity against murine osteosarcoma. J Bone Joint Surg Br 2008;90:1249–55. 27. Nishida H, Yamamoto N, Tanzawa Y, Tsuchiya H. Cryoimmunology for malignant bone and soft-tissue tumors. Int J Clin Oncol 2011;16:109–17.
Late recurrence of osteosarcoma: a report of two cases Kentaro Igarashi, Norio Yamamoto, Toshiharu Shirai, Hideji Nishida, Katsuhiro Hayashi, Yoshikazu Tanzawa, Hiroaki Kimura, Akihiko Takeuchi, Shinji Miwa, Hiroyuki Inatani, Shingo Shimozaki, Takashi Kato, Hiroyuki Tsuchiya Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
ABSTRACT We report 2 cases of late recurrence of osteosarcoma after 6 and 7 years. One patient had pulmonary metastasis, and the other had soft tissue recurrence. Both patients underwent complete resection and chemotherapy. The first patient achieved complete remission and remained disease-free 47 months later and had no limitation in his daily life. The second patient had a re-recurrence and underwent further resection and chemotherapy. He remained diseasefree 35 months later and could walk using a T-handled walking cane. Key words: neoplasm metastasis; neoplasm recurrence, local; osteosarcoma
improvement in chemotherapy, >50% of patients with non-metastatic osteosarcoma of the extremities achieve long-term survival.1–6 Local recurrence usually occurs within the first 3 years,7–11 although late recurrence (after 5 years) has also been reported.12,13 Caffeine is a xanthine that enhances the action of substances that damage cellular DNA, and may inhibit post-replication repair of sublethally damaged DNA.14 Caffeine has a synergistic effect with anticancer drugs and enhances the action of various anticancer drugs that inhibit DNA synthesis.15 With caffeine-potentiated chemotherapy, the 5-year survival rate in patients with non-metastatic osteosarcoma has improved to 90%.16 We report 2 cases of late recurrence of osteosarcoma treated with caffeine-potentiated chemotherapy. CASE REPORTS
INTRODUCTION Long-term survival of patients with osteosarcoma is 10% to 20% after surgical resection alone. With
Patient 1 In June 2004, a 17-year-old man presented with pain in his right knee. Radiographs and magnetic
Address correspondence and reprint requests to: Dr Hiroyuki Tsuchiya, Department of Orthopedic Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan. Email: [email protected]
Journal of Orthopaedic Surgery
416 K Igarashi et al.
resonance imaging (MRI) revealed a bone tumour involving the periosteum of the right proximal tibia (Fig. 1). A biopsy revealed osteoid formation and atypical spindle cells. Metastasis was not found on full-body computed tomography (CT). The patient underwent 5 cycles of neoadjuvant caffeinepotentiated chemotherapy (cisplatin, adriamycin, and caffeine) prior to limb-salvaging surgery. Preoperative radiological evaluation indicated good response. He then underwent marginal excision and bone reconstruction using an external fixator. Histological examination revealed complete resection, as no viable tumour cells were noted in the margins, indicating grade IV/IV chemotherapeutic effect. Postoperatively, the patient underwent 3 cycles of chemotherapy (high-dose methotrexate). Six years later, chest radiographs revealed a left pulmonary lesion, which was confirmed by CT as metastasis. Nonetheless, he had no symptoms of pain or cough. He underwent left thoracotomy with wedge resection of the metastasis. Histological
Patient 2 In September 2003, a 10-year-old boy presented with pain in the right hip. Radiographs and MRI revealed a bone lesion in the right proximal femur (Fig. 2). A biopsy revealed osteoid formation and atypical spindle cells. Metastasis was not found on full-body CT. He underwent 5 cycles of neoadjuvant caffeinepotentiated chemotherapy (cisplatin, adriamycin, and caffeine) prior to limb-salvaging surgery. Preoperative radiological evaluation indicated a partial response, and he underwent wide excision and composite reconstruction using an autograft. Histological
(b)
(a)
(c)
examination showed complete resection. He then underwent 3 courses of caffeine-potentiated chemotherapy (ifosfamide, etoposide, and caffeine). He was followed up every 3 months for one year and every 6 months thereafter. He remained disease-free 47 months later and had no limitations in his daily life.
(d)
(e)
Figure 1 Patient 1: (a) osteosarcoma involving the periosteum of the right proximal tibia with extraskeletal mass formation, (b) metastatic osteosarcoma in the left lung, (c) osteoid formation and atypical spindle cells are noted (H&E, x400), (d) margin of the resected tumour showing no viable tumour cells (H&E, x400), and (e) resected metastatic tumour showing osteoid formation and spindle cells with atypia (H&E, x400).
Vol. 22 No. 3, December 2014
Late recurrence of osteosarcoma 417
(a)
(b)
(c)
(d)
(e)
Figure 2 Patient 2: (a) osteosarcoma involving the periosteum of the right proximal femur with extraskeletal mass formation, (b) recurrence of osteosarcoma of the right thigh, (c) osteoid formation and atypical spindle cells are noted in the osteosarcoma (H&E, x400), (d) margin of the resected osteosarcoma showing no viable tumour cells (H&E, x400), and (e) resected recurrent tumour showing spindle cells with atypia (H&E, x400).
Table Studies of late recurrence of osteosarcoma Study Bielack et al.,11 2002 Meyers et al.,9 1992 Strauss et al.,12 2004 Ferrari et al.,17 2006 Tsuchiya et al.,16 2000
No. of patients
Median followup (years)
No. (%) of patients with recurrence after 5 years
1702 279 484 648 113
3.8 7.75 11.1 10 5.5
23 (1.4) 8 (2.9) 8 (1.7) 13 (2.0) 2 (1.8)
examination revealed >90% necrosis of the tumour. He then underwent 3 cycles of chemotherapy (highdose methotrexate). Seven years later, he noticed a 15-cm swelling in his right thigh, with no pain or tenderness. MRI and positron emission tomography–computed tomography (PET-CT) revealed an intramuscular tumour, which was confirmed by biopsy to be a recurrence of the soft tissue osteosarcoma. He
Latest recurrence % of patients with (years) lung metastasis 14.3 9 14 19.3 7
50 77 50
immediately underwent wide-margin tumour resection and limb salvage surgery. Histological examination revealed complete resection of the tumour. He then underwent 3 courses of caffeinepotentiated chemotherapy (ifosfamide, etoposide, and caffeine). Eight months later, MRI revealed a local re-recurrence. He then underwent tumour resection and mega-prosthesis reconstruction, followed by 3 courses of adjuvant chemotherapy (gemcitabine and
Journal of Orthopaedic Surgery
418 K Igarashi et al.
docetaxel). Nine months later, he developed lung metastasis and underwent thoracotomy with wedge resection of the metastasis. Histological examination showed complete resection. He then underwent immunotherapy, combining tumour cryogenic treatment with dendritic cells. He was followed up every 3 months for one year and every 6 months thereafter. He remained disease-free 35 months later and could walk using a T-handled walking cane. DISCUSSION In a study of 1703 patients with osteosarcoma followed up for a median of 3.8 years, 23 (1.4%) patients had recurrence after 5 years.6,11 The late recurrence rate was 2.9% (8 of 279 patients) at the Memorial Sloan-Kettering Cancer Center in New York,9 and 2% (13 of 648 patients) at the Rizzoli Orthopedic Institute in Bologna, Italy.17 (Table). At our hospital, 1.8% of patients had a recurrence after >5 years; caffeine-potentiated chemotherapy achieved a 5-year survival of >90% in patients with non-metastatic osteosarcoma.16 Improvement in chemotherapy may alter the natural course of the disease and delay recurrences.8 The European Society for Medical Oncology suggested a 10-year follow-up for osteosarcoma patients.18 Nonetheless, recurrences have been reported after >10 years of disease-free interval. More than 75% of recurrences metastasise to the lung.5–7,9 Routine follow-up should include chest radiography in addition to radiography at primary disease sites. MRI is not suitable for detection of local recurrences owing to artefacts of the metal prosthesis for limb salvage. Bone scanning can
detect local recurrence and metastasis, but uptake with aseptic loosening may cause confusion. PETCT with full-body scanning is the investigative tool of choice, with the exception of the central nervous system. The prognosis for patients with late recurrence is good. Patients with a disease-free interval of >2 years have a better post-recurrence survival rate than those with shorter disease-free intervals.4 The median survival rate after recurrence was 17 (range, 2–68) months at the Meyerstein Institute of Oncology in London,12 and 60 (range, 5–119) months at the Rizzoli Orthopaedic Institute, with 65% of patients achieving complete remission.17 After recurrence, the effectiveness of cisplatin, adriamycin, ifosfamide, and etoposide is limited owing to drug resistance. Hence, development of new drugs is needed. Since 1998, gemcitabine has been used for treatment of sarcoma.19 Gemcitabine is a difluorinated analogue of deoxycytidine and acts as an S-phase–specific drug that interferes with DNA chain elongation and disruption of cell growth.20 The response rates of single-agent gemcitabine in patients with soft tissue and bone sarcomas in 5 phase 2 trials were 3%, 3%, 5.5%, 11%, and 18%, with a median of 5.5%.21–25 We have used cryoimmunotherapy for treatment of bone and soft tissue sarcomas since 2008.26 Combining tumour cryotreatment with dendritic cell therapy promotes tumour-specific immune responses and enhances systemic immune responses.27 DISCLOSURE No conflicts of interest were declared by the authors.
REFERENCES 1. Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006;42:2124–35. 2. Stiller CA, Craft AW, Corazziari I, EUROCARE Working Group. Survival of children with bone sarcoma in Europe since 1978: results from the EUROCARE study. Eur J Cancer 2001;37:760–6. 3. Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:1600–6. 4. Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5:21–6. 5. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350:911–7. 6. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Körholz D, et al. Long-term results of the co-operative German-AustrianSwiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9:893–9. 7. Ferrari S, Bacci G, Picci P, Mercuri M, Briccoli A, Pinto D, et al. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol 1997;8:765–71.
Vol. 22 No. 3, December 2014
Late recurrence of osteosarcoma 419
8. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/ osteosarcoma-2 protocol: an updated report. J Clin Oncol 2000;18:4016–27. 9. Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 1992;10:5–15. 10. Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145–50. 11. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, 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. J Clin Oncol 2002;20:776–90. 12. Strauss SJ, McTiernan A, Whelan JS. Late relapse of osteosarcoma: implications for follow-up and screening. Pediatr Blood Cancer 2004;43:692–7. 13. Kempf-Bielack B, Bielack SS, Jurgens H, Branscheid D, Berdel WE, Exner GU, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23:559–68. 14. Lau CC, Pardee AB. Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci U S A 1982;79:2942–6. 15. Tomita K, Tsuchiya H. Enhancement of cytocidal and antitumor effect of cisplatin by caffeine in human osteosarcoma. Clin Ther 1989;11:43–52. 16. Tsuchiya H, Yamamoto N, Asada N, Terasaki T, Kanazawa Y, Takanaka T, et al. Caffeine-potentiated radiochemotherapy and function-saving surgery for high-grade soft tissue sarcoma. Anticancer Res 2000;20:2137–43. 17. Ferrari S, Briccoli A, Mercuri M, Bertoni F, Cesari M, Longhi A, et al. Late relapse in osteosarcoma. J Pediatr Hematol Oncol 2006;28:418–22. 18. Saeter G, Kloke O, Jelic S; ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of osteosarcoma. Ann Oncol 2005;16(Suppl 1):i71–2. 19. Merimsky O, Meller I, Kollender Y, Inbar M. Palliative effect of gemcitabine in osteosarcoma resistant to standard chemotherapy. Eur J Cancer 1998;34:1296–7. 20. Huang P, Chubb S, Hertzel LW, Grindey GB, Plunkett W. Action of 2’,2’-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991;51:6110–7. 21. Okuno S, Edmonson J, Mahoney M, Buckner JC, Frytak S, Galanis E. Phase II trial of gemcitabine in advanced sarcomas. Cancer 2002;94:3225–9. 22. Svancarova L, Blay JY, Judson IR, van Hoesel QG, van Oosterom AT, le Cesne A, et al. Gemcitabine in advanced adult softtissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38:556–9. 23. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, et al. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol 2000;45:177–81. 24. Späth-Schwalbe E, Genvresse I, Koschuth A, Dietzmann A, Grunewald R, Possinger K. Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs 2000;11:325–9. 25. Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001;19:3483–9. 26. Nishida H, Tsuchiya H, Tomita K. Re-implantation of tumour tissue treated by cryotreatment with liquid nitrogen induces anti-tumour activity against murine osteosarcoma. J Bone Joint Surg Br 2008;90:1249–55. 27. Nishida H, Yamamoto N, Tanzawa Y, Tsuchiya H. Cryoimmunology for malignant bone and soft-tissue tumors. Int J Clin Oncol 2011;16:109–17.
