Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma Stefano Ferrari and Emanuela Palmerini
Purpose of review The most recent developments regarding chemotherapy treatment of osteogenic sarcoma are reviewed, with special emphasis on prospective clinical trials and evaluations of late effects of chemotherapy. Recent findings In recent years, clinical research has essentially focused on possible refinements of the classic four-drug (methotrexate, cisplatin, doxorubicin and ifosfamide) therapy rather than investigating new drugs. It has been demonstrated that dose-intensification does not improve prognosis. Many investigators have evaluated late chemotherapy-related side effects, particularly in terms of cardiac, renal and auditive toxicity, risk of infertility and of second tumors. Recent findings recommend further studies to define the role of the immunostimulating agent muramyl tripeptide-phosphatidilethanolamine in osteosarcoma. Preclinical and phase II studies suggest an activity of mammalian target of rapamycin (mTOR) inhibitors in osteosarcoma, which also deserves further clinical studies. Summary At present, patients with nonmetastatic osteosarcoma of the extremity aged less than 40 years have an expected 5-year survival rate of 70% with a chemotherapy regimen based on methotrexate, cisplatin, doxorubicin and ifosfamide. Further improvement cannot be achieved by dose intensification of treatment and new strategies are required. Prolonged follow-up is mandatory due to the risk of late effects, second tumors and late relapse from osteosarcoma. Keywords chemotherapy, neoadjuvant chemotherapy, osteosarcoma
Introduction The present review will focus on the most recent developments regarding chemotherapy treatment of osteogenic sarcoma with special emphasis on data reported from prospective clinical trials and prospective evaluations of late effects of chemotherapy.
Background Osteosarcoma is a malignant bone tumor characterized by spindle cells producing osteoid. More frequently observed in males, it can be diagnosed at any age, but usually develops in the second decade of life. In children and adolescents, it is the most common primary malignant bone tumor [1]. In the younger age group, osteosarcoma is usually a primary tumor of bone, whereas in the elderly it can arise in previously irradiated areas or be secondary to Paget’s disease [1]. Treatment of osteosarcoma requires a combined approach of surgery of the primary tumor and systemic chemotherapy. The use of chemotherapy has significantly changed prognosis of patients with osteogenic sarcoma. In the past, when patients received surgery only, survival rate was under 20% [1]. In a retrospective analysis recently published [2], including patients treated at the Mayo Clinic, the percentage of long-term survivors of osteosarcoma treated in the prechemotherapy era was 17.8%. Interestingly, the authors report that not only localized patients survived without chemotherapy, but also some patients with lung metastases at presentation who achieved complete surgical remission. Standard strategy of chemotherapy for osteosarcoma is based on primary chemotherapy and delayed surgery followed by adjuvant chemotherapy.
Curr Opin Oncol 19:341–346. ß 2007 Lippincott Williams & Wilkins. Chemotherapy Department, Istituto Ortopedico Rizzoli, Bologna, Italy Correspondence to Stefano Ferrari, MD, Chemotherapy Department, Istituto Ortopedici Rizzoli, Via Pupilli 1, 40136 Bologna, Italy Tel: +39 051 6366411; fax: +39 051 6366277; e-mail:
[email protected] Current Opinion in Oncology 2007, 19:341–346 Abbreviations COSS EFS mTOR MTP-PE OS SMN
Cooperative Osteosarcoma Study Group event-free survival mammalian target of rapamycin muramyl tripeptide-phosphatidilethanolamine overall survival second malignant neoplasm
ß 2007 Lippincott Williams & Wilkins 1040-8746
Primary chemotherapy-induced tumor necrosis The use of chemotherapy before surgery (neoadjuvant) was introduced in the 1970s and was widely adopted as it offers the opportunity of evaluating chemotherapyinduced tumor necrosis by histological examination of the resected surgical specimen [3]. The degree of tumor necrosis used as a marker of chemosensitivity has proven an important factor predictive of survival. Additionally, in a recent paper exploring several prognostic factors of survival in nonmetastatic osteosarcoma, chemotherapyinduced tumor necrosis still retains prognostic significance [4]. Modern technology seems to be helpful in 341
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predicting histologic response. Microarray technology has been recently investigated to predict chemotherapy response and a multigene predictive model was developed to classify good and poor responders to preoperative chemotherapy [5]. A set of 45 genes that could discriminate good and poor responders to primary chemotherapy was identified. Most of these genes were overexpressed in poor responder specimens. Many of the predictor genes have properties that are related to bone development, cancer biology and drug resistance. The multigene classifier developed appears to be a very promising instrument for stratifying patients to different preoperative chemotherapy regimens or identifying patients who can benefit from preoperative chemotherapy. A further study on a larger sample of patients is strongly recommended to validate the predictor gene set.
Clinical trials Most chemotherapy regimens adopted for osteogenic sarcoma are based on methotrexate, cisplatin, doxorubicin and ifosfamide. Results achieved with study protocols using different chemotherapy regimens are summarized in Table 1 [6–11]. In an attempt to improve prognosis of nonmetastatic osteogenic sarcoma by intensifying chemotherapy treatment, the Italian and Scandinavian Sarcoma Groups conducted a study based on methotrexate, cisplatin and doxorubicin with the addition of high-dose ifosfamide (15 g/m2 over a 5-day continuous infusion) starting from the preoperative phase [12]. In spite of this intensive treatment which caused three toxic deaths, results in terms of event-free and overall survival (5-year event-free survival (EFS) 63%, 5-year overall survival (OS) 75%) were not higher than those achieved with similar fourdrug chemotherapy regimens with ifosfamide used at standard doses. A different chemotherapy approach has been reported by the Brazilian Osteosarcoma Treatment Group [13]. In two subsequent studies, they investigated chemotherapy regimens with methotrexate, cisplatin, ifosfamide and doxorubicin with the addition of carboplatin and
epirubicin in different combinations. Overall results reported in localized patients (5-year EFS 45.5%, 5-year OS 60.5%) are worse than those achieved with the classic four-drug regimens and do not suggest the use of carboplatin and epirubicin in the first-line treatment of nonmetastatic osteosarcoma of the extremity, at least, in the combination used in the Brazilian study. A notable study from The Children’s Cancer Group and Pediatric Oncology Group has been recently reported in which classic cytotoxic chemotherapy was combined to a biologic treatment. This randomized study evaluated whether the addition of ifosfamide and/or muramyl tripeptide-phosphatidilethanolamine (MTPPE) to methotrexate, cisplatin and doxorubicin could improve prognosis [14]. MTP-PE is a component of the cell wall of the bacillus Calmette-Guerin conjugated to phosphatidil ethanolamine and incapsulated in liposomes with immunostimulating activity. Overall, the probability of 5-year EFS was 63% in localized patients. Those treated with the three-drug combination had 64% 5-year EFS compared with 56% obtained in patients treated with all four drugs. In patients treated with the three-drug combination, the addition of MTP-PE did not influence results (5-year EFS 63%), whereas patients treated with methotrexate, cisplatin, doxorubicin and ifosfamide seem to benefit from the addition of MTP-PE (5-year EFS 72%). While this study shows that the addition of ifosfamide to methotrexate, cisplatin and doxorubicin does not improve prognosis, it seems to suggest that, when ifosfamide is used in combination with MTP-PE, better results can be achieved, possibly due to an interaction between ifosfamide and MTP-PE. Methodological problems due to the unexpected positive interaction between ifosfamide and MTP-PE make results difficult to interpret and in spite of the promising results, the use of MTP-PE in osteosarcoma requires further investigation.
Dose-intensity in osteosarcoma The role of chemotherapy dose intensity in osteosarcoma is another issue widely debated in the literature. The Cooperative Osteosarcoma Study Group (COSS) investigated the role of dose intensity in a large retrospective
Table 1 Results with study protocols using different chemotherapy regimens Study group/institution EOI [6] EOI [7] CCG [8] SSG [9] Rizzoli [10] COSS [11]
Patients
Period
119 167 268 97 164 171
1983–1986 1986–1991 1983–1986 1982–1989 1983–1986 1986–1988
Treatment
Outcome
MTX-CDP-ADM CDP-ADM MTX-CDP-ADM-BCD MTX-CDP-ADM-BCD MTX-CDP-ADM-IFO MTX-CDP-ADM-IFO
5-year DFS 41% 5-year PFS 44% 8-year EFS 53% 5-year RFS 54% 5-year EFS 63% 10-year EFS 66%
EOI, European Osteosarcoma Intergroup; CCG, Children’s Cancer Group; SSG, Scandinavian Sarcoma Group; COSS, Cooperative Osteosarcoma Study Group; MTX, high-dose methotrexate; CDP, cisplatin; ADM, doxorubicin; BCD, bleomycin; cyclophosphamide; dactinomycin; IFO, ifosfamide; DFS, disease-free survival; PFS, progression-free survival; RFS, relapse-free survival; EFS, event-free survival.
Combination chemotherapy for osteogenic sarcoma Ferrari and Palmerini 343
study [15]. The analysis included 917 consecutive COSS patients aged under 40 years and it represents the largest study on dose intensity in osteosarcoma. Interestingly, no relation between dose intensity and prognosis was found, neither at univariate analysis of the four agents included in the analysis (methotrexate, cisplatin, doxorubicin and ifosfamide) nor after multivariate analysis. Furthermore, a negative interaction between methotrexate dose intensity and prognosis was observed at univariate analysis, suggesting a sort of detrimental effect of a high-dose intensity of methotrexate on prognosis. It must be kept in mind that these data were not confirmed at multivariate analysis. This large study adds important elements to the discussion on the role of dose intensity in osteosarcoma, and together with the study of the European Osteosarcoma Intergroup [16] it clearly indicates that approaches other than increasing dose intensity are required to improve prognosis. These conclusions are supported by the results of the recent Italian-Scandinavian study, which reported no relation between received dose intensity and outcome [12].
Metastatic osteosarcoma While no doubt can be raised on the importance of chemotherapy in the first-line treatment of osteosarcoma, the use of chemotherapy after relapse is still under discussion. Complete surgical remission of all the sites of recurrence is pivotal for survival after relapse, but the role of chemotherapy has been recently emphasized in patients with a relapse-free interval shorter than 24 months [17]. In particular, the use of high-dose ifosfamide was recommended to prevent or delay a second recurrence [17]. In a paper on the same topic, reporting a monoinstitutional experience, only complete surgical removal of metastatic disease was reported as important for long-term survival [18].
metastatic patients, as with localized patients [11], the use of carboplatin instead of cisplatin not only fails to improve outcome, but could even be detrimental. In spite of aggressive surgery and intensive chemotherapy, the prognosis of patients with synchronous multifocal osteosarcoma is particularly poor [20] and new therapeutic approaches are needed in this subset of patients. A better prognosis was reported for patients with regional bone metastases (skip metastases) treated with the same chemotherapy protocols used for localized patients [21]. Interestingly, a relation between histologic response in primary and metastatic bone lesions and prognosis is reported in this subgroup of metastatic patients. The ifosfamide-doxorubicin-etoposide combination was tested as part of the search for new and more aggressive chemotherapy approaches in a subset of high-risk patients with metastatic or axial-skeleton osteosarcoma [22]. The response rate reported was high (43%), but substantial toxicity was observed. Moreover, the high response rate did not translate into good prognosis and all but one of the patients included in the study had subsequent disease relapse or progression.
Chemotherapy late effects
The problem of chemotherapy treatment at the time of relapse has been widely discussed and contradictory results have been reported. At present, besides the need of aggressive surgical removal of all sites of metastases, no evidence on the best timing and on the best second-line chemotherapy treatment is available. The rarity of this tumor and the variety of relapse patterns, however, make it almost impossible to perform a randomized study to investigate the role of chemotherapy after recurrence.
The chemotherapy treatment of osteosarcoma is associated with substantial acute toxic effects. Differences inreporting toxicity data complicate the comparison of protocols. In a cisplatin/doxorubicin based protocol [7], the incidence of grade 3–4 leucopenia and thrombocitopenia were 75% and 46% respectively. No toxic deaths or cardiac failure were reported, whereas the rate of renal impairment was 2%. In a protocol based on high-dose methotrexate, cisplatin, doxorubicin and ifosfamide [10], the reported incidence of grade 4 leucopenia and thrombocitopenia were 12.4% and 1.4% respectively. Cardiac failure was documented in 4% of the patients and the incidence of renal impairment was 0.6%. With the addition of high-dose ifosfamide to high-dose methotrexate, cisplatin and doxorubicin [12], the incidence of grade 4 leucopenia and thrombocitopenia were 52% and 31% respectively. Three toxic deaths and one cardiac failure were reported, and the incidence of renal impairment was 10%.
The results obtained in patients with synchronous metastases, in spite of an aggressive surgical and chemotherapeutical approach, are worse than those obtained in patients without evident metastases at diagnosis. In a monoinstitutional study, carboplatin substituted cisplatin in a chemotherapy regimen that included methotrexate, ifosfamide and doxorubicin [19]. Very poor results were reported in the regimen with carboplatin compared with those obtained with cisplatin. This suggests that in
The late effects of chemotherapy represent a topic of particular interest. The good results achieved, at least in nonmetastatic extremity tumors, with a high rate of longterm survivors combined with intensive chemotherapy treatment delivered to children and adolescents have made the scientific community sensitive to these problems. Any organ or system of the body can be affected by late effects of chemotherapy. The incidence of infertility in males reported in a recent study based on the use
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of high-dose ifosfamide plus methotrexate, cisplatin and doxorubicin is 100% [12]. Cardiac toxicity due to doxorubicin can be a severe adverse event in treatment of osteosarcoma, sometimes lethal. In a recent study, the incidence of doxorubicin-induced cardiomyopathy was 7.5% in a population of pediatric sarcomas after a mean follow-up of 34 months [23]. In this regard we must highlight the study performed on a pediatric population with osteosarcoma to evaluate the cardioprotective role of dexrazoxane [24]. Better results were reported in the group treated with dexrazoxane, and the study also recommends the use of the cardioprotectant in the pediatric population treated with doxorubicin. In a report from the Late Effects Surveillance System, the problem of cisplatin-induced ototoxicity is well documented in patients enrolled in COSS studies [25]. A hearing loss of more than 20 dB in the frequency range of 4–8 kHz was described in 51% of patients, with higher incidence in patients under 12 years of age. Incidence and magnitude of ototoxicity were related to the cumulative dose of cisplatin. Regarding the problem of ototoxicity, pediatric populations treated with prolonged cisplatin infusion, as for osteosarcoma patients, showed a higher incidence of ototoxicity compared with that observed in children who received cisplatin in a short infusion [26]. These data may suggest further studies to evaluate the best means of administrating cisplatin in children. Another aspect of specific interest regarding the late effects of chemotherapy is that of second malignant neoplasm (SMN) in patients with osteosarcoma. The Mayo Clinic paper [2] reports a high incidence of SMN exceeding, even if not significantly, that of a normal population. In this study, only patients treated in the prechemotherapy era were considered and only solid tumors described. In another recently published study [27], the incidence of SMN was investigated in a population of osteosarcoma patients treated with chemotherapy. Not only was a significantly higher incidence of SMN compared with a healthy population reported, but almost 40% of SMNs were hematologic malignancies, not described in the populations treated without chemotherapy [2]. Besides the possible genetic predisposition of some osteosarcoma patients, it is certainly evident that the relation between chemotherapy treatment and hematologic malignancies increases the risk of second tumors in patients with osteosarcoma. This fact, combined with the recently reported possibility of a very late recurrence from osteosarcoma [28,29] clearly shows the need of prolonged follow-up in these patients.
New drugs The rarity of osteosarcoma makes this tumor an orphan disease, and the interest in developing new drugs seems
very low. Nitrogen-containing bisphosphonates are the most potent inhibitors of bone resorption used in clinical trials in patients with bone metastases. Preclinical data showed that bisphosphonates have cytotoxic activity against tumor cell lines and are capable of inhibiting angiogenesis, tumor cell adhesion and invasion of extracellular matrix. In particular, bisphosphonates induce apoptosis by caspase-3-like proteases activation and significantly reduce cell invasion in a dose-dependent manner, through zinc chelation of metalloproteinases enzymes. In-vitro studies demonstrated inhibitory activity of bisphosphonates on human osteosarcoma cell growth, suggesting a beneficial contribution treatment, including analgesic effects in patients with osteosarcoma. It is worth reporting some papers that confirm the possible role of zoledronic acid against osteosarcoma [30,31], even if we are only in the preclinical research phase. Clinical trials should investigate the role of zoledronic acid in addition to conventional chemotherapy. A new interest is growing around the use of interferon in an adjuvant setting in osteosarcoma patients [32]. The EURAMOS 1 trial [33] in the coming years will answer the question on the possibility of improving prognosis, thanks to an adjuvant biologic treatment with interferon. A possible, different strategy is suggested in a recent article [34] describing a case of disease progression during chemotherapy for osteosarcoma. Conventional chemotherapy was interrupted, and the patient treated with antiangiogenetic therapy with thalidomide and celecoxib. The patient showed objective radiological response and had clinical benefit from the treatment. The administration of methotrexate at low doses showed a new and promising pattern of activity in osteosarcoma. In fact, in a preclinical investigation using an animal model, low-dose methotrexate inhibited lung metastases in rat osteosarcoma [35]. Another interesting approach was presented at the last ASCO meeting with the use of mammalian target of rapamycin (mTOR) inhibitor in osteosarcoma. mTOR is a member of the phoshoinositide-kinase related kinase family and a central component of the phosphoinositide 3-kinase/Akt signaling pathway that mediates cell growth and proliferation. mTOR inhibitors are a new class of drugs derived from rapamycin. They are active against tumor cells by blocking mTOR activity leading to growth arrest of cells in the G1 phase of the cell cycle. Preclinical studies showed an activity of mTOR inhibitors against a wide range of tumoral cell lines including sarcoma cell lines. In a phase II trial in patients with advanced soft tissue or bone sarcomas, three partial responses were reported in osteosarcoma patients who received AP23573,
Combination chemotherapy for osteogenic sarcoma Ferrari and Palmerini 345
a novel mTOR inhibitor delivered intravenously [36]. These data make it worthwhile to test the use of mTOR inhibitors in a larger population of patients with osteosarcoma.
Conclusion At present, in patients with nonmetastatic osteosarcoma of the extremity aged under 40 years, a 5-year survival rate of 70% is expected with chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. With the use of conventional chemotherapy, a sort of plateau in the survival curve seems to have been reached and the results of recent papers show that dose intensification cannot improve prognosis of patients with nonmetastatic osteosarcoma. Scarcer results have been obtained in patients with metastatic osteosarcoma. Clinical research should focus on this subset of patients to identify new and more effective clinical treatments. A recent strategy based on chemotherapy with the addition of an immunostimulating agent (MTP-PE) has been evaluated in a large phase III trial with conflicting results. Further studies are required to define the role of MTP-PE in osteosarcoma. Preclinical and phase II studies have suggested an activity of mTOR inhibitors in osteosarcoma, and promising data have been reported with the use of zoledronic acid and interferon. The latter will be tested in a prospective randomized trial. The high survival rate achieved in nonmetastatic osteosarcoma has attracted the attention of many investigators researching the problem of late chemotherapy-related side effects. This aspect, together with the risk of very late relapse, clearly shows the need for prolonged followup in these patients.
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28 Hauben EI, Bielack S, Grimer R, et al. Clinico-histologic parameters of osteosarcoma patients with late relapse. Eur J Cancer 2006; 42:460– 466. 29 Ferrari S, Briccoli A, Mercuri M, et al. Late relapse in osteosarcoma. J Pediatr Hematol Oncol 2006; 28:418–422. 30 Kubista B, Trieb K, Sevelda F, et al. Anticancer effects of zoledronic acid against human osteosarcoma cells. J Orthop Res 2006; 24:1145– 1152. A preclinical study. The authors report that zoledronic acid can inhibit growth and migration of osteosarcoma cells. 31 Benassi MS, Chiechi A, Ponticelli F, et al. Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells. Cancer Lett 2006; Nov 17; epub ahead of print. A preclinical study. A positive interaction between zoledronic acid and cisplatin is reported. 32 Muller CR, Smeland S, Bauer HC, et al. Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol 2005; 44:475–480. 33 European and American Osteosarcoma Study Group. EURAMOS 1; 2006. Available online: www.ctu.mrc.ac.uk/euramos/euramos_i_trial.asp. 34 Tsai YC, Wu CT, Hong RL. Response of refractory osteosarcoma to thalidomide and celecoxib. Lancet Oncol 2005; 6:997–999. 35 Tomoda R, Seto M, Hioki Y, et al. Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma. Clin Exp Metastasis 2005; 22:559–564. 36 Chawla SP, Tolcher AW, Staddon AP, et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas [Abstract]. ASCO Annual Meeting Proceedings 2006: Abstract 9505.
