Tag Archive for: chemotherapy

How important are surgical margins in Osteosarcoma?

 Volume 2 | Issue 1 | Jan-Apr 2016 | Page 22-26 |Thomas P Cloake, Lee M Jeys.

Authors: Thomas P Cloake[1], Lee M Jeys[2].

[1]The Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK.
[2]School of Health and Life Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.

Address of Correspondence
Professor Lee M. Jeys
Professor of Health and Life Sciences
Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
E-mail: lee.jeys@nhs.net


Surgical resection combined with chemotherapy is the mainstay of treatment of osteosarcoma. Traditionally, surgical margins were based upon tumour grade and classified into marginal, wide or radical resection. The definition of these margins, however, remains subjective and recent research has questioned the need for wide or radical margins. Advances in surgical technique and the use of neo-adjuvant chemotherapy have led to an improvement in outcome. By reducing tumour burden, chemotherapy has provided surgeons with the option of limb salvage surgery rather than radical resection. Surgical margins and response to chemotherapy are now considered the two most important predictors of outcome in osteosarcoma. This review focuses on surgical margins with respect to limb salvage surgery and discusses the importance of response to chemotherapy.
Keywords: osteogenic sarcoma, osteosarcoma, surgical margins, chemotherapy, limb salvage surgery.

Osteosarcoma is a high grade, primary tumour of bone in which the tumour cells produce osteoid [1]. It is the most common primary bone tumour, with an annual incidence rate of 5.0 per million [2]. Osteosarcoma is predominantly a disease of the young with a peak incidence in the second decade and displays a male predominance which is most pronounced at a younger age [3]. The treatment of osteosarcoma is challenging. The use of neo-adjuvant chemotherapy regimes combined with surgical resection has led to an improvement in outcome. Nevertheless, despite recent advances in surgical technique and chemotherapy agents, the survival rate has plateaued over the last 30 years [4]. There has been much research into prognostic factors that may help predict outcome in osteosarcoma, a number of these have been identified (see Table 1). Authors have suggested the most important, independent risk factors are the response to adjuvant chemotherapy and resection margins [5-7]. This review considers the impact of resection margins with a focus on limb salvage surgery and discusses the significance of response to chemotherapy.

Table 1

Resection margins
There has been much debate around the margin of clearance required for surgical treatment of osteosarcoma.  Enneking et al. were the first group to formally stage osteosarcoma into three distinct grades according to biologic aggressiveness, tumour site and distant metastases [8].  The authors suggested this system be used in surgical planning and inform the use of marginal, wide or radical resection margins. Nonetheless the definition of marginal or wide resection remains subjective and may vary between surgeons or units and has never been objectively defined (Fig 1).  Kawaguchi et al. developed this concept by giving distinct numerical values for desired resection margin according to the grade to tumour suggesting a 2cm margin was required for low-grade tumours and a 3cm margin was needed for high-grade neoplasms such as osteosarcoma [9].More contemporary studies have failed to reach a consensus on a numerical value for an adequate resection margin. Li et al. reported there was no difference in local recurrence when wide (>5mm) margins and close (<5mm) margins were used [10]. Bispo et al. failed to detect a difference in local recurrence using a margin of 2mm [11]. Betrand et al. found surgical margin to be the only independent risk factor for local recurrence and suggested a margin of 1mm may be adequate [12].  These papers suggest resection does not require a strict numerical margin, however efforts should be made to ensure no margins are intralesional. However, international consensus is in equipoise regarding margins, and this has made interpreting research articles very difficult. Even within units, tumour clear margins and ‘wide’ margins have become interchangeable when in reality they may be completely different and may lead to inappropriate treatment for patients. In the oncological world, the concept of patient specific treatment or ‘personalised medicine’ is gaining popularity and what is correct for one patient, may not be suitable for another patient, even with the same tumour type.

Figure 1

Limb salvage surgery

Prior to the advent of effective chemotherapy, the surgical treatment for osteosarcoma involved early radical amputation or disarticulation of the affected limb. Whilst ensuring complete removal of the tumour, performing this radical surgery on young patients caused loss of function and permanent disability, without improving patient survival. Limb salvage surgery (LSS) aims to resect the tumour, whilst maintaining function of the preserved limb, all with minimal risk to the patient (Fig 2).

Figure 2 Figure 3


The emergence of efficacious chemotherapy regimes, which acted to reduce tumour burden and reduce metastatic spread, and enhanced imaging techniques such as CT and MRI have led to the increased use of LSS [13-15]. By definition, the use of LSS requires preservation of limb neurovascular structures and narrower surgical margins when compared to amputation. Preservation of tissue during tumour resection has led to the inevitable decrease in resection margins, which potentially risks causing an increase in local recurrence (Fig 3). There are conflicting reports on the rate of local recurrence in LSS with some studies reporting an increase [15-17] and others a decrease [18], when compared to amputation. Considering local recurrence is associated with poor outcome, much work has been done to examine the impact of LSS on survival. Simon et al. were one of the first groups to investigate outcomes following LSS in a multi-centre retrospective review of 227 patients. They reported LSS had a comparable survival rate with amputation at 5 years follow up [19] and provided the impetus for increased uptake of LSS amongst surgeons. A large study by Bacci et al. retrospectively compared the outcome in patients who underwent LSS to amputation. The authors report that whilst LSS was associated with reduced resection margins, local recurrence and 5-year disease free survival were comparable to amputation [20]. These results are confirmed by a number of other groups, with each describing a survival rate equal to or better than that of amputation [15,17,18,21-27].It is important to consider, however, these studies are limited by their retrospective nature. Without robust methods of randomisation, treatment decisions have been based on individual patient and tumour characteristics, local practice and patient choice, leaving them open to the influence of selection bias. Postoperative quality of life is an important outcome measure in osteosarcoma. As patients with osteosarcoma are young and can expect a prolonged period of survival following treatment, the demands put upon a salvaged limb or prosthesis can be great. It is essential, therefore to ensure there is minimal risk of technical failure, the limb provides adequate function for the individual patient and has an acceptable cosmesis for both the patient and their care givers. Measurement of quality of life in children is difficult and there have been relatively few studies assessing this outcome measure. Using objective quality of life scores, LSS and amputation groups report reduced quality of life compared to population norms [29,30]. A meta-analysis comparing quality of life in patients who underwent LSS and amputation found there was no significant difference between the 2 groups. Taking into consideration all the above evidence LSS remains a safe and effective management option and when used in combination with adjuvant chemotherapy offers a good survival outcome.


The introduction of chemotherapy regimes alongside surgical resection has led to a dramatic improvement in survival. The use of chemotherapy in the treatment of osteosarcoma began in the 1970s with the use of doxorubicin and high dose methotrexate regimens [31]. Administration of chemotherapy agents before surgical resection as neo-adjuvant therapy enhanced survival from10 – 20% to 70% [32].Current modern chemotherapy regimes are based on combination therapy using methotrexate, adriamycin/doxirubicin and cisplatin. Poor response to chemotherapy has been identified as an important independent risk factor for poor prognosis. Histological evaluation of surgical resection specimens permits the classification of response to chemotherapy as good (>90% tumour necrosis) and poor (<90% tumour necrosis). Patients who display poor response are consistently reported to have worse outcome [33,34]. A number of strategies have been employed to improve results in poor responders. Evidence suggests modification of chemotherapy regime may improve results. Several groups have showed intensification of pre-operative chemotherapy enhances tumour response [35-37] and may improve survival [38-40]. This benefit however, is limited and intensification of chemotherapy beyond a certain level does not improve outcome [36,41-43]. The use of high dose, intensive treatment to induce a good response early in the disease process has also been shown not to convey overall survival benefit [38,42-44]. Further work is therefore required to optimize tumour response and improve outcome in patients with poor chemotherapy response. A recent, large, multi-national study EURAMOS-1 investigated the effect of adding the additional agents, ifosfamide and etoposide, to salvage poor response to chemotherapy, as well as evaluating the addition of pegylated interferon for good responding tumours [45]. The published initial results suggest that the addition of interferon for good responding tumours appears beneficial, however, it was poorly tolerated and frequently refused by patients. Current practice involves assessing tumour response using resection specimens following surgery, after the completion of neo-adjuvant chemotherapy, to advise further treatment[45]. Considering tumour response to chemotherapy is such a significant prognostic factor, measuring response early in the disease process may inform further management choices. Non-invasive imaging techniques such as CT [46], MRI [47-49] and F-FDG PET [50,51] have all be used to investigate response to neo-adjuvant chemotherapy. A combination of F-FDG PET and CT (F-FDG PET-CT) scanning is widely used for the detection of many cancers. Meta-analysis of the current evidence for its use in osteosarcoma has shown F-FDG PET-CT to be a valuable modality to assess chemotherapy-induced necrosis [52]. Newer techniques for evaluating response to chemotherapy prior to surgery, such as functional MRI (fMRI) are also promising and may inform surgeon’s decisions in planning surgical margins.
Patients with poor response to chemotherapy present a complex management challenge. There have been few studies presenting evidence to guide the surgical management of these patients. Bacci et al. suggested that amputation should be considered in the setting of poor response to chemotherapy due to its significant correlation with local recurrence rates [20]. Recent work in Birmingham investigated the influence of resection margins on survival in patients with poor response to chemotherapy [28]. The authors showed there was no survival benefit gained from amputation when compared to LSS with close margins, irrespective of the risk of developing local recurrence [28]. These data demonstrate resection with preservation of the limb to be a safe surgical option even in patients with poor chemonecrosis.

Predicting outcome
The current classification systems used to grade osteosarcoma, pioneered by Enneking, incorporate tumour characteristics including the presence of metastases to guide surgical management and predict prognosis [8]. However, despite the widely accepted importance of response to chemotherapy in prognosis, the current classification fails to reflect this.  In a recent presentation at International Society of Limb Salvage (ISOLS 2015), Jeys et al introduced The Birmingham Classification, which uses numerically defined tumour margins and response to chemotherapy to predict both local recurrence and survival. In this series, chemotherapy response was reported to show a significant effect on the rate of local recurrence and overall survival. It was also reported that a margin of 2mm was a statistically significant cut off value for predicting local recurrence.  Furthermore, combining resection margins (greater or lesser then 2mm) with response to chemotherapy (good, >90% or poor, <90%) was more effective in predicting local recurrence and survival than other staging systems.  This classification, however, requires further validation on a multi-centre basis.


Osteosarcoma continues to present a number to treatment challenges. Although surgical resection margins are an important predictor of outcome, limb salvage surgery with close margins has been shown to be a safe and effective surgical option.  Response to chemotherapy is an important independent predictor of survival.  A distinct group of poor responders exist, who despite modification to chemotherapy regimes and complete surgical excision of the tumour continue to have a poor outcome.  Current classification systems have so far failed to reflect important prognostic indicators, the Birmingham Classification represents a new, robust system for classifying osteosarcoma and predicting outcome.


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How to Cite this article: Cloake T, Jeys L.How important are surgical margins in Osteosarcoma? . Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):22-26.

Dr. Thomas P Cloake

Dr. Thomas P Cloake

Prof Lee M Jeys

Prof Lee M Jeys

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Chemotherapy in Osteosarcoma: Current Strategies

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 27-32 | Sandeep Jain, Gauri Kapoor.

Authers: Sandeep Jain[1], Gauri Kapoor[1]

[1]Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi.

Address of Correspondence
Dr. Gauri Kapoor MD, PhD
Director Department of Pediatric Hematology and Oncology,
Rajiv Gandhi Cancer Institute & Research Centre, Delhi.
Email: kapoor.gauri@gmail.com


Incorporation of chemotherapy to multi-modality management of high grade osteosarcoma has led to remarkable improvement in survival rates. Its use in the neoadjuvant setting is now accepted as standard of care and has the added advantage of providing important information on histologic response. Survival rates for non-metastatic disease are nearly 70%. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups. The current review focusses on evolution of chemotherapy, controversies in its use and current standard of care for osteosarcoma.
Keywords: Osteosarcoma, chemotherapy, neoadjuvant chemotherapy.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents accounting for 4% of all pediatric malignancies. Approximately 20% of children present with metastatic disease at diagnosis and it remains, unquestionably the most important factor affecting long term survival. Prior to 1970, the prognosis of patients with osteosarcoma was dismal, with a 10–20 % overall survival despite being treated with radical surgeries [1-3]. Outcome of patients with osteosarcoma has improved in the past three decades with the addition of effective systemic polychemotherapy and advances in surgical resection. These have led to improvements in overall survival of patients with localized disease to the tune of 70% [4-5]. Various well coordinated systemic trials by different co-operative groups in North America and Europe have identified high-dose methotrexate (HD-MTX), cisplatin, doxorubicin, ifosfamide and etoposide as active cytotoxic agents and combinations of these drugs make up the cornerstone of treatment. Chemotherapy not only takes care of micrometastatic disease at diagnosis but also facilitates limb salvage surgery. The choice of regimen and optimal schedule of chemotherapy is somewhat controversial. In this review we focus on evolution of chemotherapy, controversies in chemotherapy use and current standard of care.

Evolution of chemotherapy
Before the introduction of chemotherapy, the outcome of patients with osteosarcoma was only 15-20%, despite adequate local control. Most patients succumbed to metastatic lung disease. These findings led to the conclusion that patients with osteosarcoma have microscopic metastatic disease at the time of diagnosis and this prompted investigators to identify active agents to target it. Initial studies to demonstrate chemosensitivity of osteosarcoma were done in the early 1970s by Sutow et al [6]. He developed a regimen called “Conpadri”which included cyclophosphamide, Oncovin (vincristine), doxorubicin (adriamycin), and L-phenylalaninemustard. Later on with the inclusion of HD-MTX, the acronym was changed to “Compadri’ [6-7]. These regimes were the first rational attempt at confirming the role of adjuvant combination chemotherapy using drugs with non-overlapping toxicities in osteosarcoma. Compadri I–III yielded a 41% 18-month disease-free survival [8]. These results suggested that addition of chemotherapy improved survival in patients with osteosarcoma. However, in the absence of randomized trials, it was not clear, to what extent improvement in surgical techniques and radiological studies contributed to achieving these results. These observations were further supported by the first randomized trial from Mayo clinic wherein patients were randomized to receive adjuvant vincristine and HD-MTX versus surgery alone[9]. This trial did not show any difference between the two arms. All these concerns were put to rest by two subsequent randomized controlled trials from North America that clearly established the survival benefit of adjuvant chemotherapy. In both these trials patients receiving no adjuvant treatment had a 2 year event free survival of just 20% compared to 66% and 55% in patients who received adjuvant chemotherapy [10-11]. These trials also established adriamycin, cisplatin, HD-MTX and alkylating drugs like ifosfamide and etoposide as active agents in the treatment of osteosarcoma. The various trials showing benefit of chemotherapy in osteosarcoma are listed in Table 1[12-22].

Table 1

Role of neoadjuvant chemotherapy
The concept of neoadjuvant chemotherapy (NACT) was first introduced at Memorial Sloan-Kettering Cancer Center (MSKCC) in their T-10 protocol [23]. Preoperative chemotherapy was administered in an effort to increase the number of patients who could undergo limb salvage as the surgeons needed time to order the prosthetic devices. Administration of NACT also had the theoretical advantage of treating presumed microscopic metastatic disease. The outcome of the T-10 trial was similar to that of the Multi Institutional Osteosarcoma Study (MIOS), with a 65% survival rate at 5 years. Importantly, the results of this trial laid the foundation for the subsequent important association between histologic necrosis and prognosis. However, there were concerns regarding the impact of delayed surgery among patients with chemo-resistant disease as well as the probability of development of resistant clone in those with high volume disease. To answer this concern Pediatric Oncology Group conducted a randomized clinical trial (POG 8651) between 1986 and 1993, comparing NACT with adjuvant chemotherapy. This trial compared immediate surgery followed by postoperative adjuvant chemotherapy with 10 weeks of the NACT (same drugs) followed by surgery in 100 patients under the age of 30 years with non-metastatic,high grade osteosarcoma. Chemotherapy consisted of alternating courses of HD-MTX with leucovorin rescue, cisplatin, doxorubicin, and bleomycin, cyclophosphamide,dactinomycin (BCD). The five-year relapse-free survival rates were similar between the two groups, 65% versus 61% for adjuvant and neoadjuvant arms respectively. There was also no difference in the number of patients who underwent limb salvage procedures (55% and 50 % for immediate and delayed surgery, respectively) [24]. On the basis of these results, the use of preoperative chemotherapy has become standard of care, given its advantages, as it allows sufficient time for surgical planning, potentially facilitates tumor removal, and permits evaluation of response to therapy. Several investigators in single and multi-institutional studies in the United States and across Europe, support this general strategy [13,14,16,18].

Histological response to chemotherapy
Most trials reveal that patients with greater than 90% necrosis following NACT have significantly better event free survival (EFS) compared to those with less than 90% necrosis. Several grading systems have been developed for assessing the effect of preoperative chemotherapy on the tumor. The two most commonly used classification systems are the Picci and Huvos classifications[Table 2]. The Institute of Rizzoli (IOR) reviewed data on localized extremity osteosarcoma in more than 1000 patients over the 19-year period from 1983 to 2002 [25]. Fifty-nine percent of all patients had good response to chemotherapy (Picci), and had a 5-year survival of 76%, compared to 56% for poor responders. The Cooperative Osteosarcoma Study group (COSS) database analyzed 1,700 patients between 1980 and 1998 that included all sites, ages, and presence or absence of metastases [26]. The data revealed that 55.6% of patients had good response to therapy. The 5-year survival rate for good and poor responders was 77.8% and 55.5% respectively. The European Osteosarcoma Intergroup (EOI) analyzed data of two consecutive studies between 1983 and 1986 and 1986 and 1991 [27]. A total of 570 patients were analyzed in the report. This analysis is notable for several differences compared to the COSS and IOR analyses. Only 28% of patients had a good histologic response, whereas 72% of patients had a poor histologic response. Their 5-year survival rate was 75% and 45% respectively. Interestingly, many of the patients included in the analysis did not receive HD-MTX as they were randomized to receive either doxorubicin and cisplatin or more intensive therapy including doxorubicin and HD-MTX. This data clearly established that histological response to chemotherapy is an important prognostic factor.

Table 2

Intensification of neoadjuvant and adjuvant chemotherapy
As it became clear that the degree of histological necrosis after pre-operative chemotherapy predicts survival, efforts were directed to intensify chemotherapy so as to achieve maximum therapeutic response. This strategy of preoperative chemotherapy intensification has been tested in COSS-86 and MSKCC T-12 study [14,28]. Although this strategy resulted in increased proportion of good responders achieving >90% necrosis, it did not translate into improved overall survival (OS) or EFS rates. Till date only INT-0133 study has shown benefit of NACT intensification [19]. The next group of trials focused to alter or intensify chemotherapy for patients with sub-optimal response to preoperative chemotherapy. In the early 1980s at Memorial Sloan-Kettering Cancer Center, poor responders had cisplatin substituted for HD-MTX in addition to continuing BCD (bleomycin, cyclophosphamide, and dactinomycin) and doxorubicin [13]. Survival of patients with intensified adjuvant treatment was similar to others. Several other reports have also failed to demonstrate benefit of intensification of therapy for poor responders[20,29]. Thus, till date it has not been possible to improve the outcome of poor responders by altering postoperative chemotherapy. An explanation for this may be that the NACT response is a surrogate measure of chemo-sensitivity of tumor and an inherently biologic unresponsive tumor is not modifiable by currently available therapies.

Table 3

Role of intra-arterial chemotherapy
The intra-arterial route was introduced in an attempt to enhance the efficacy of drugs by increasing the local concentration of chemotherapy. Alkylating agents like ifosfamide and cyclophosphamide could not be used as they required phosphorylation in liver for activation. Doxorubicin was not a suitable agent as it is associated with skin and subcutaneous necrosis. MTX achieved high tumoricidal concentrations intra-arterially but similar concentrations could also be attained via the intravenous route. Intra-arterial cisplatin was therefore, selected and found to be highly effective. Response rates with the intra-arterial route were better when compared to the intravenous route[30]. It has been used extensively at the MD Anderson Cancer Center in the TIOS pediatric trials. It was highly effective in patients with pathological fractures and neurovascular involvement. Unfortunately, intra-arterial route is labor intensive and requires general anaesthesia or conscious sedation in a radiological suite. It also requires intensive monitoring of the distal arterial vascular status during and after the infusion. Moreover, similar results could be achieved with multiple courses of combination chemotherapy administered by the intravenous route over a more prolonged period. Therefore, intra-arterial route is generally not preferred.

High Dose Methotrexate
High dose methotrexate is one of the oldest drugs used in the treatment of osteosarcoma. It is generally administered over 4-6 hours and requires aggressive hydration, leucovorin rescue, serum level monitoring and adequate infrastructure to safeguard delivery and manage toxicity. Moreover, it adds substantially to the overall cost of treatment. In addition, there are no randomized studies to compare the efficacy of higher versus intermediate doses of HD-MTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone. Furthermore, investigators at St. Jude Children’s Research Hospital have demonstrated good outcomes with five-year EFS and OS of 66% and 75% respectively with non-methotrexate-containing chemotherapy regimen consisting of carboplatin, ifosfamide and doxorubicin [31]. All of this has led to considerable controversy regarding the optimum role of HD-MTX. Methotrexate is the only active agent that has been subjected to a comparative trial of efficacy with another active agent i.e. cisplatin. Compared to 5-20% survival of historical controls in pre-chemotherapy era, HD-MTX increased survival to 40% – 60% as a single agent. When combined with other active agents like cisplatin and doxorubicin the long term survival of 65% – 75% was reported [12-15]. Many studies have shown a favorable correlation between peak serum levels and outcome [19,32-33]. Therefore, optimum doses and administration schedule is crucial to derive optimum benefit from HD-MTX therapy. Chemotherapy regimes devoid of HD-MTX were considered, among the “major poor prognostic factors” in the treatment of osteosarcoma by Graf et al. [33]. Despite the absence of randomized trials evaluating osteosarcoma treatment with and without HD-MTX, it is generally acknowledged that methotrexate is a standard component of almost all contemporary osteosarcoma protocols in children and adolescents.

Current standard of care for patients with osteosarcoma
It is well established that chemotherapy is an integral component of osteosarcoma treatment and is essential in addition to local surgery in order to achieve a reasonable expectation of cure. Therefore, optimum treatment for osteosarcoma demands a multidisciplinary strategy. The treatment generally consists of three stages: initial cytoreduction with chemotherapy to eradicate micro metastatic disease and facilitate effective local control measures with wide negative margins; and consolidation therapy for eradication of occult residual disease to reduce the likelihood of tumor recurrence. Importantly, NACT not only helps to achieve optimal cytoreduction in facilitating limb salvage procedures but also provides a chance to assess the histologic response to chemotherapy. Most treatment protocols include cisplatin, doxorubicin and HD-MTX with or without ifosfamide plus etoposide(IE). In the recently concluded EURAMOS study, all patients received NACT: 2 blocks of MAP (methotrexate, doxorubicin and cisplatin) chemotherapy for 10 weeks followed by surgery (wide excision). Surgical excision of tumor with oncologically safe margins was the best means of local control. Post surgery, poor responders were randomized to receive MAP for 28 weeks with or without IE. All good responders continued on MAP for 28 weeks and then were randomized to no further therapy and maintenance therapy with pegylated interferon. This is the largest international trial in the history of osteosarcoma treatment and its results show that intensification of adjuvant chemotherapy by addition of IE in poor responders did not improve survival. Furthermore, in good responders addition of pegylated interferon maintenance was not useful [22]. Schema of this treatment is shown in [Figure 1] and most of the study groups endorse this strategy as current standard of care.

Figure 1

Non-methotrexate based chemotherapy for countries with limited resources
There is paucity of published data on osteosarcoma from India. Historically, the role of high dose methotrexate in the treatment of osteosarcoma has always been debatable. From the practical perspective, it requires rigorous pharmacokinetic monitoring and often the infrastructure required for monitoring is not available in many centers with limited resources. Therefore, most of the centers in India use cispaltin, doxorubicin and ifosfamide based chemotherapy. Pathak et al have reported relapse-free survival was 72% nonmetastatic osteogenic sarcoma of the extremities using cisplatin and doxorubicin as adjuvant therapy [35]. Recently, results from a single center study from India have revealed 2yr progression free survival of 70 % for patients with non-metastatic osteosarcoma [36]. In light of these results use of non methotrexate based therapy in resource constraint setting seems justified. In addition, it is desirable to focus on developing infrastructure to provide limb salvage procedures and direct resources to develop indigenous affordable prosthesis.

Treatment of relapsed osteosarcoma
Treatment of relapsed osteosarcoma has not been tested in randomized clinical trials, and thus, there is no single standard approach. Prognosis of patients with relapse depends on duration of off therapy and site of relapse. In a large database of 565 osteosarcoma patients who relapsed after being treated with one of three different NACT protocols within the European Osteosarcoma Intergroup, five year survival post relapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively[37]. There is no reasonable chance of cure without complete surgical resection of all sites of disease. Choice of chemotherapy depends on agents used in front line therapy. In most of contemporary studies, most of the patients receive cisplatin and doxorubicin in front line therapy. Therefore, ifosfamide, etoposide and HD-MTX are the most commonly used drugs in relapse setting. In general, patients should be treated with any of the four most active agents that were not included in front line therapy. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate significant advantage of standard salvage therapy approaches [38-39].

Newer therapies
There has been significant progress in the management of patients with osteosarcoma from 1970 to 1990. However, thereafter, progress has been stalled due to limited options available for patients with poor histologic response and those with metastatic and recurrent disease. It is clear that intensification of available chemotherapeutic agents has not translated into survival benefit for these group of patients and novel agents are required. Some of the agents being tested include mTOR inhibitor (ridaforolimus), inhibitors of insulin-like growth factor I receptor, tyrosine kinase inhibitor (sorafenib), microtubule inhibitor (oferibulin), human monoclonal antibody against RANKL (Denosumab) and anti-disialoganglioside antibody (theuseofan) [40-44]. Some of these agents have demonstrated promising results in preclinical data and may offer a potential role in adjuvant therapy in the future.

Acute toxicities and Late Effects
The most frequent acute toxicities due to chemotherapy are infections secondary to myelosuppression and mucositis. Renal dysfunction may lead to hypomagnesemia and other electrolyte abnormalities from tubular and glomerular damage induced by ifosfamide and cisplatin respectively. Ototoxicity from cisplatin and cardiac dysfunction related to anthracyclines are the other commonly observed side effects. Late effects in osteosarcoma may be attributed to local therapy i.e. surgery or to systemic chemotherapy. Those related to chemotherapy are usually agent specific. Doxorubicin is known to cause chronic cardiomyopathy which is dependent on the total cumulative dose. Longhi et al reported 2% incidence of symptomatic cardiomyoathy at a median follow up of 10 years [45]. In general, cumulative dose of doxorubicin is usually limited to less than 450 mg/m2. Anthracycline and alkylating agents may also result in second malignant neoplasm (SMN). The same authors report a 10-year and 20-year cumulative incidence of SMN of 4.9% and 6.1% respectively in osteosarcoma survivors. The alkylating agent, ifosfamide is associated with infertility, especially male infertility, so sperm cryopreservation should be offered to postpubertal boys if treatment plan includes alkylating agents. In addition, ifosfamide can cause a persistent renal tubular electrolyte loss and, less commonly, a decrease in glomerular function, in a dose-dependent fashion.


Inclusion of chemotherapy in the multimodality treatment of osteosarcoma has undoubtedly improved survival from a dismal 20% to the present 60%. NACT has enabled limb salvage rates to the tune of 90-95% in most advanced centers. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups.


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How to Cite this article:Jain S, Kapoor G. Chemotherapy in Osteosarcoma: Current Strategies. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):27-32 .


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