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Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review

Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin,... Background: Data suggests that males experience less toxicity and poorer survival than females treated for Ewing’s sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety. Methods: A retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on 9 9 days 8, 12 and 15 for cycles 1–6. DE of 10%/cycle was applied if ANC > 1.5×10 /L and platelet > 100×10 /L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method. Results: 23 patients were identified (mean age: 27; range 17–54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1 = 0.003; C3 = 0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15–25 (n = 13) compared with older individuals (P-value = 0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value = 0.37). Conclusions: DE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE. Keywords: Ewing’s sarcoma, Dose escalation, Toxicity, Neutropenia, Chemotherapy * Correspondence: Jeremy.Lewin@petermac.org Sarcoma Service, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006, Australia Full list of author information is available at the end of the article © 2013 Lewin et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 2 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Background dose density from a 21 day cycle to a 14 day cycle with Ewing sarcoma family tumors (ESFT) are malignant tumors growth factor support [23] may be associated with im- of bone and soft tissue. Patients presenting with localized proved survival without increased toxicity [24]. These ap- disease are usually treated with multimodality approach, proaches have relied on dose intensification across all given high relapse rates (80-90%) without chemotherapy patients treated on these protocols, rather than intra- [1,2]. Modern treatment plans include neo-adjuvant and patient dose modification to achieve a pharmacodynamic adjuvant multi-agent chemotherapy, to target the high risk effect. Current studies of anthracycline pharmacokinetics of subclinical metastatic disease at the time of diagnosis. In and pharmacodynamics (ACTRN12609000956202) will studies predominantly involving pediatric populations, this aid in justifying and developing strategies for “individualiz- approach leads to 5 year survival rates around 70% [3-5]. ing” chemotherapy, enabling the use of readily available Even in patients presenting with metastatic disease, long- surrogate markers such as the degree of myelosuppres- term survival may be seen in 20% of patients [2]. The trad- sion, or measures of the antiproliferative activity of drugs, itional chemotherapy used in both localized and metastatic to guide dose-adjustments [25,26]. disease is Vincristine, Doxorubicin, Cyclophosphamide al- In the absence of more accurate algorithms for chemo- ternating with Ifosfamide and Etoposide (VDC/IE) [2,6], therapy dosing, one practical solution for personalized, with suggestions that the dose of doxorubicin may be re- intra-patient dosing is “toxicity-adjusted” dosing [20]. In lated to outcome [7]. 2009, we implemented a policy at the Peter MacCallum Despite a steady improvement in cancer care generally, Cancer Centre to individualized dose escalation of chemo- there has been a discouraging lack of improvement in therapy in Ewing sarcoma patients, using nadir bloods survival rates in adolescent and young adults (AYA) [8]. counts as the primary measure of a dose-related pharma- For patients diagnosed with ESFT between the ages 15– codynamic effect. We now report on our dose escalation 30, survival is approximately half that of children with (DE) policy over a 3 year period to assess overall deliver- males having increased mortality compared to females in ability, safety and treatment related toxicity. the AYA subgroup [9-11]. There has been much specu- lation as to the reasons for these observations. The sug- Methods gestion that relative underdosing of AYA compared to The primary objective was to assess the proportion of patients children may play a part is supported by data showing that received DE and the proportion of DE decisions that that adults with pediatric-type sarcomas experience less were appropriate according to the protocol. The secondary treatment-related toxicity compared with their younger objective was to assess rates of serious complications for the counterparts [10,12-14]. A meta-analysis in osteosar- entire group, investigate gender and age related differences in coma showed that children had higher rates of neutro- neutrophil and platelet nadirs, assess subsequent neutrophil penia compared with adolescent or adult patients, and and platelet nadirs for those who underwent dose escalation, that dose-related toxicities including thrombocytopenia and calculate relapse free survival (RFS) and overall survival and mucositis were strongly associated with improved (OS). In order to assess RFS and OS, a comparison was per- overall survival [9]. In addition to age, gender-related formed with a prior cohort of ESFT with localized disease differences also exist in osteosarcoma, with males ex- treated with the same regimen of VDC/IE, but prior to the periencing less myelosuppression and inferior survival initiation of our dose escalation policy. This study was ap- [7,9]. A retrospective study of 14,824 patients showed proved by the Institutional Review Board of Peter MacCallum that male AYA patients with osteosarcoma, Ewing sar- Cancer Centre for retrospective data collection. coma and Hodgkin lymphoma experienced less toxicity, Chemotherapy was delivered for ESFT every 3 weeks lower response rates and excess mortality relative to with vincristine (2 mg), doxorubicin (75 mg/m ), cyclo- children and female counterparts [12]. Similar findings phosphamide (1200 mg/m ) D1 alternating with ifosfa- 2 2 correlating lack of chemotherapy-induced toxicity and mide (1800 mg/m ) and etoposide (100 mg/m ) D1-5 [2]. inferior outcome [15-17], have also been reported in Blood counts were taken on Day 8, 12 and 15 for the first testis, breast and ovarian cancers [18]. 6 cycles of chemotherapy and dose escalation (DE) was These data suggest that age and gender-related differ- implemented if the neutrophil and platelet count did not 9 9 ences in drug handling may account for some of the sur- fall below 1.5×10 /L or 100×10 /L, respectively, in the ab- vival and toxicity differences in the AYA population. If so, sence of non-hematologic toxicities of concern. Although dose intensification may improve outcomes in chemosen- these hematological cut-offs have not been validated in sitive cancers. Accurate dosing of chemotherapy is difficult prospective trials, these values have been suggested in the using traditional algorithms based on body surface area literature in recommendations for “toxicity adjusted dos- [19], with evidence for systematic underdosing [20,21]. ing” [15,18]. Dose escalation involved increasing the BSA While one study of dose escalation of alkylating agents did calculated dose of all chemotherapy agents, except vincris- not improve outcomes in Ewing sarcoma [22], increasing tine, by 10% for all equivalent subsequent cycles. Given Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 3 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Table 1 Baseline demographics the alternating regimen, nadir counts for cycle 1 and 2 led to DE decision for cycle 3 and 4, whereas nadir counts for Baseline demographics cycle 3 and 4 led to a DE decision in cycle 5 and 6. De- Number 23 escalation occurred on the basis of both hematological Female 10 (43%) and non-hematological toxicities at the discretion of the Male 13 (57%) treating physician. Median age (range) 23 (17 – 54) Median age female 21 (17 – 54) Inclusion All patients with ESFT (including peripheral primitive Median age male 26 (18 – 40) neuroectodermal tumor, Askin’s tumors, Ewing’s sarcoma, Diagnosis desmoplastic small round cell tumor) who underwent EWINGS 17 (74%) cytotoxic chemotherapy at Peter MacCallum with VDC/IE PNET 5 (22%) between March 2009 and August 2012 were included. DSRCT 1 (4%) Disease site Statistical analysis Analysis of primary endpoints and secondary endpoints Metastatic 6 (26%) was performed on an intention to treat basis. To address Localized the primary objective, the proportion of patients who re- Extremity 9 (39%) ceived DE was calculated for each of cycles 3 – 6 separ- Pelvic 2 (9%) ately as well as for any VDC cycle (3 and/or 5) and any Axial trunk 2 (9%) IE cycle (4 and/or 6). To evaluate adherence, the propor- Chest wall 3 (13%) tion of treatment decisions that were appropriate ac- cording to the DE protocol was calculated. Other 1 (4%) To address the secondary objectives, the proportion of BSA patients reporting grade 3/4 febrile neutropenia in each Female 1.79 (SD ± 0.22) of the VDC and IE cycles was calculated. Comparisons Male 1.94 (SD ± 0.15) between males and females in terms of neutrophil and platelet nadirs in cycles 1 – 4 were investigated using in- dependent 2-sample t-tests assuming unequal variances. females during VDC (7/13 vs 3/10), but not during IE Within cycle changes in neutrophil and platelet counts (7/13 vs 5/10). as well as between cycle changes in neutrophil and Protocol adherence was recorded at 90%. Nine events of platelet nadirs were assessed using repeated measures non-adherence to the protocol were recorded (7 events ANOVA. Overall survival was measured as the time of inappropriate escalation (7.7%) and 2 events of missed from first chemotherapy until death and relapse-free sur- escalation (2.2%); details of inappropriate escalation are vival was measured from time of first chemotherapy shown in Additional file 1: Table S1). No serious adverse until date of relapse. Patients were censored at the last outcomes occurred as a result of the inappropriate escal- date they were known to be alive and relapse-free re- ation. The rate of Grade 3/4 febrile neutropenia (FN) dur- spectively. OS and RFS curves were estimated using the ing VDC was 26.1% (6/23 patients) with median length of Kaplan-Meier product-limit method. OS and RFS com- Table 2 Number of patients who received dose escalation parison to the prior historical cohort was assessed using during VDC/IE the logrank test. A P-value of <0.05 was considered sta- Escalated Dose unchanged Dose reduced Number tistically significant. Statistical analysis was performed using Excel, GraphPad Prism 6 and R version 2.15.2 VDC software. C1 23 C3 10 10 3 23 Results C5 3 19 1 23 Between 2009 and 2012, 23 patients were treated on the Any cycle 10 10 3 23 DE protocol with a median follow up of 2.3 (0.7 – 3.4) IE years. Baseline demographics are shown in Table 1. In total, 91 events for consideration of dose escalation oc- C2 23 curred (1 decisions was excluded because of progressive C4 10 11 2 23 disease). This is presented in Table 2. There were 3 pa- C6 3 19 0 22 tients during VDC that were escalated twice. Although Any cycle 12 9 2 23 not statistically significant, more males had DE than Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 4 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 stay (LOS) of 4 days (range 1–20) with no ICU admis- receiving a higher relative dose intensity of VDC and IE sions. The rate of Grade 3/4 FN for IE was 17.4% (4/23 pa- compared to females (VDC: 107% vs 98%, P-value = 0.12; tients) with a median LOS of 4 days (3–7) and 1 ICU IE: 105% vs 102%, P-value = 0.49). admission. The ICU stay occurred in a patient who was To compare overall cancer-related outcomes between appropriately not dose-escalated. There were no deaths the traditional BSA associated chemotherapy dosing and related to chemotherapy and only 1 patient received a the toxicity-adapted dose escalation protocol, we com- platelet transfusion (during IE). There were no additional pared the RFS and OS between treated patients with documented grade 3/4 toxicities documented in those localized disease before (1995–2004) and during (2009– who underwent dose escalation. 2013) the introduction of the DE policy. The baseline Neutrophil nadirs by gender for cycle 1 – 4 are shown characteristics of this historical comparator group were in Table 3. Males were statistically significantly less similar to our cohort (An additional file shows this in neutropenic after C1 and C3 of VDC compared to females more detail [see Additional file 2: Table S2]) and patients (P-value C1 = 0.003; C3 = 0.005). VDC was associated with with DSRCT and metastatic disease were excluded from greater neutropenia on day 8 (ANC: D8: 0.98 ± 0.97 × this analysis. The 2 year RFS in the dose escalation co- 10 /L, P-value <0.001) whereas IE had greater neutropenia hort was 88%, compared to 63% in the historical com- on day 12 (ANC: D12: 3.74 ± 3.04 × 10 /L, P-value <0.001). parator cohort (HR = 0.33, 95% CI: (0.07-1.56); P-value = Although not statistically significant, there was also a 0.14) and 2 year overall survival was 88% vs 75% in the trend for less thrombocytopenia during VDC in males historical comparator cohort (HR = 0.48, 95% CI: (0.09- (data not shown, P-value = 0.11). After cycle 1 of VDC, in- 2.46) P-value = 0.37 (Figures 1 and 2). When making dividuals aged 15–25 (n = 13) had lower neutrophil nadirs comparisons in our cohort group only, there was no compared with older individuals (mean difference = 0.62 × statistically significant difference in RFS (P-value = 0.29) 10 /L, P-value = 0.15) although this was not statistically and OS (P-value = 0.31) when separated by those who significant. Differences in cytopenia in IE dosing according have had DE (for either VDC or IE) compared to those to gender were only seen in cycle 4 (mean difference = who did not in patients with localized disease. 2.31 × 10 /L, P-value = 0.05) (Table 3). Although the numbers were too small to achieve stat- Discussion istical significance, dose escalation, whether appropriate The key finding in this study is that individualized dose es- or not, was associated with a reduction in neutrophil calation of chemotherapy in ESFT is feasible in a single count in subsequent cycles. For those who received dose sarcoma unit. Less neutropenia was observed in males, escalation in cycle 1 of VDC, the mean nadir ANC de- and perhaps in older patients, during the anthracycline 9 9 creased from 1.59 ± 1.22 × 10 /L to 1.29 ± 1.07 × 10 /L in cycles, suggesting that BSA-based dosing alone may not cycle 3, and 1.04 ± 0.9 × 10 /L in cycle 5 (P-value = 0.29). be adequate in males. The protocol compliance rate was For IE cycles, those who received dose escalation after 90%. Given the experimental nature of a toxicity-adjusted cycle 2 showed a decrease from 4.82 ± 1.88 × 10 /L to protocol, we continually reviewed the safety and compli- 2.10 ± 1.8 × 10 /L in cycle 4. Using current dosing algo- ance after implementation of the protocol. Importantly, rithms, dose escalation resulted in a trend to males no short or long term adverse outcomes were seen in this Table 3 Gender related difference in nadir blood counts after C1 and C3 Gender Mean 95% CI P-value difference Male Female N Mean SD N Mean SD Neutrophil nadir VDC Cycle 1 13 1.56 1.35 9 0.16 0.19 1.40 (0.57, 2.21) 0.003 Cycle 3 12 1.59 1.08 9 0.42 0.56 1.17 (0.40, 1.93) 0.005 IE Cycle 2 13 3.77 2.70 10 4.40 4.59 −0.63 (−4.14, 2.88) 0.71 Cycle 4 12 3.17 3.54 9 0.86 1.18 2.31 (−0.04, 4.66) 0.05 Dose intensity (%) VDC 13 107 9 10 98 16 9 (−3, 22) 0.12 IE 13 105 7 10 102 11 3 (−5, 11) 0.49 P–values correspond to comparisons between genders. Dose intensity of VDC and IE is compared to baseline. Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 5 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Figure 1 Relapsed-free survival for localized ESFT compared between those who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004) showing a HR = 0.33 (95% CI: (0.07 – 1.53) P-value 0.14). Figure 2 Overall survival for localized ESFT compared between those who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004) showing a HR = 0.48 (95% CI: (0.09 – 2.46) P-value 0.37). Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 6 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 study as a result of intrapatient dose escalation. The RFS different pharmacologic profiles in the AYA population. and OS comparison to the prior ESFT cohort suggests that Nearly all the benefit of methotrexate’s use in osteosarcoma dose escalation is not associated with worse overall out- has been demonstrated in patients under the age of 40 [42] comes for patients with localized primary ESFT. Clearly, and doxorubicin, a key component of regimens used to safe dose escalation requires a formal program with strictly treat ESFT, osteosarcoma and hodgkins disease, demon- defined criteria for escalation, close monitoring of nadir strates significant pharmacokinetic variation according to blood counts, and patient selection limited to those with- gender and body habitus [43,44]. It is possible that the in- out other dose-related toxicities or co-morbid illnesses. ferior outcomes of EFST in older males may be attributed Given this study showed gender and age related differences to relative doxorubicin under-dosing of these individuals. in cytopenia, it is arguable that dose escalation should be Given the inherent inaccuracies in current dosing al- especially considered in older males during the anthracy- gorithms, and the importance of chemotherapy to cure cline component of treatment (Cycle 3 or 5 based on C1 for chemo-sensitive cancers, intra-patient dose modifica- nadir). Additionally, variation was seen in the timing of tion based on markers of toxicity provides a practical neutropenia nadirs, which may have ramifications for the strategy for individually tailored dosing [25,26]. In this timing of pegylated filgrastim delivery. context, this limited study suggests gender- and poten- It is important to put these findings into context given tially age-related differences in hematological nadirs, and evidence for gender- and age-related difference in toxicity that intra-patient dose escalation appears safe and feas- and outcome in chemo-sensitive cancers such as ESFT ible. It is important to note that this retrospective study [12]. Although the peak incidence of ESFT is during the only comprises 23 patients, with relatively short follow AYA years, these patients have a worse survival compared up. In particular, the non-significant trend to improved to a pediatric population [27]. The reasons behind this RFS and OS in the dose escalation group will require lar- comprise a combination of biological differences [27,28], ger numbers of patients and longer follow up. Addition- delayed diagnosis, poorer treatment compliance [29,30], ally, we did not assess long-term morbidity, including psychosocial overlay and limited involvement in clinical the potential for cumulative anthracycline cardiotoxicity trials [31,32]. With regards to biological differences, in the in a young population. EURO-Ewing 99 protocol [10], increasing age and male gender was associated with less toxicity using VIDE Conclusion chemotherapy, a protocol similar to VDC/IE. Additionally, Individualized, toxicity-adapted dosing of chemotherapy, gender related differences have previously been described added to an initial calculation of dosing based on BSA- in hodgkins lymphoma [33], osteosarcoma [9,34,35] and alone, aims to correct the gender and age related disparity ewings sarcoma [12,36,37]. A meta-analysis in osteosar- in outcomes, without relying on new chemotherapeutic coma confirmed differences in outcome related to gender agents. Pharmacological data in this age group is lacking and age and showed improved outcomes in females, and [28] and adequate dose–response is critical for chemo- those with Grade 3/4 mucositis [9]. Interestingly, it also sensitive diseases such as ESFT, germ cell tumors and confirmed the results of our study showing increased mye- Hodgkin’s in maximizing outcome where a dose–response losuppression in the younger age group although given relationship exists. The key finding in this study is that in- our small numbers, this was not statistically significant. dividualized dose escalation of chemotherapy in ESFT is Collectively, this data suggests a better understanding of feasible in a single sarcoma unit without increased adverse cytotoxic pharmacology is needed in the AYA population outcomes. Additionally we have showed that less neutro- [28,38], and may be used to improve cancer outcomes. penia was observed in males, and perhaps in older pa- Adolescent and young adult patients undergo gender- tients, during the anthracycline cycles and should be specific pubertal changes in body composition, size and especially considered for DE. Given the rarity of ESFT pre- hormonal status, which may alter the pharmacokinetic/ sents significant statistical challenges in stratifying gender pharmacodynamic properties of chemotherapy [38]. Young and age differences, pharmacological endpoints should be women have significant increase in fat mass during ado- designed into future prospective chemotherapy trials. lescent years, with subsequent higher body fat than men [39]. Higher fat distribution has effects on drug clearance Additional files and volume of distribution [28,40] which may cause varia- tions in the dose of chemotherapy delivered. That being Additional file 1: Table S1. Description of patients who inappropriately said, a large pediatric study in ALL showed no differences received dose escalation. in toxicity, survival or PK data in the obese patient [41]. It Additional file 2: Table S2. Comparison of baseline demographics with is difficult to isolate drug-specific effects in complex, for patients with localized disease who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004). multi-drug chemotherapeutic regimens, and it is import- Patients in both cohorts were treated with alternating VDC/IE. ant to recognize that different drugs may demonstrate Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 7 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Abbreviations 14. 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Bethesda, MD: National Cancer Institute; 2006. No. 06–5767. 1,702 patients treated on neoadjuvant cooperative osteosarcoma study 12. Khamly KK, Thursfield VJ, Fay M, Desai J, Toner GC, Choong PF, Ngan SY, group protocols. J Clin Oncol 2002, 20:776–790. Powell GJ, Thomas DM: Gender-specific activity of chemotherapy 36. Bacci G, Longhi A, Ferrari S, Mercuri M, Versari M, Bertoni F: Prognostic correlates with outcomes in chemosensitive cancers of young factors in non-metastatic Ewing’s sarcoma tumor of bone: an analysis of adulthood. Int J Cancer 2009, 125:426–431. 579 patients treated at a single institution with adjuvant or neoadjuvant 13. Gupta AA, Anderson JR, Pappo AS, Spunt SL, Dasgupta R, Indelicato DJ, chemotherapy between 1972 and 1998. Acta Oncol 2006, 45:469–475. Hawkins DS: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the 37. 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J Clin Oncol 1988, 6:1321–1327. doi:10.1186/2045-3329-3-15 Cite this article as: Lewin et al.: Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review. Clinical Sarcoma Research 2013 3:15. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review

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Copyright © 2013 by Lewin et al.; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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10.1186/2045-3329-3-15
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24321600
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Abstract

Background: Data suggests that males experience less toxicity and poorer survival than females treated for Ewing’s sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety. Methods: A retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on 9 9 days 8, 12 and 15 for cycles 1–6. DE of 10%/cycle was applied if ANC > 1.5×10 /L and platelet > 100×10 /L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method. Results: 23 patients were identified (mean age: 27; range 17–54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1 = 0.003; C3 = 0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15–25 (n = 13) compared with older individuals (P-value = 0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value = 0.37). Conclusions: DE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE. Keywords: Ewing’s sarcoma, Dose escalation, Toxicity, Neutropenia, Chemotherapy * Correspondence: Jeremy.Lewin@petermac.org Sarcoma Service, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006, Australia Full list of author information is available at the end of the article © 2013 Lewin et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 2 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Background dose density from a 21 day cycle to a 14 day cycle with Ewing sarcoma family tumors (ESFT) are malignant tumors growth factor support [23] may be associated with im- of bone and soft tissue. Patients presenting with localized proved survival without increased toxicity [24]. These ap- disease are usually treated with multimodality approach, proaches have relied on dose intensification across all given high relapse rates (80-90%) without chemotherapy patients treated on these protocols, rather than intra- [1,2]. Modern treatment plans include neo-adjuvant and patient dose modification to achieve a pharmacodynamic adjuvant multi-agent chemotherapy, to target the high risk effect. Current studies of anthracycline pharmacokinetics of subclinical metastatic disease at the time of diagnosis. In and pharmacodynamics (ACTRN12609000956202) will studies predominantly involving pediatric populations, this aid in justifying and developing strategies for “individualiz- approach leads to 5 year survival rates around 70% [3-5]. ing” chemotherapy, enabling the use of readily available Even in patients presenting with metastatic disease, long- surrogate markers such as the degree of myelosuppres- term survival may be seen in 20% of patients [2]. The trad- sion, or measures of the antiproliferative activity of drugs, itional chemotherapy used in both localized and metastatic to guide dose-adjustments [25,26]. disease is Vincristine, Doxorubicin, Cyclophosphamide al- In the absence of more accurate algorithms for chemo- ternating with Ifosfamide and Etoposide (VDC/IE) [2,6], therapy dosing, one practical solution for personalized, with suggestions that the dose of doxorubicin may be re- intra-patient dosing is “toxicity-adjusted” dosing [20]. In lated to outcome [7]. 2009, we implemented a policy at the Peter MacCallum Despite a steady improvement in cancer care generally, Cancer Centre to individualized dose escalation of chemo- there has been a discouraging lack of improvement in therapy in Ewing sarcoma patients, using nadir bloods survival rates in adolescent and young adults (AYA) [8]. counts as the primary measure of a dose-related pharma- For patients diagnosed with ESFT between the ages 15– codynamic effect. We now report on our dose escalation 30, survival is approximately half that of children with (DE) policy over a 3 year period to assess overall deliver- males having increased mortality compared to females in ability, safety and treatment related toxicity. the AYA subgroup [9-11]. There has been much specu- lation as to the reasons for these observations. The sug- Methods gestion that relative underdosing of AYA compared to The primary objective was to assess the proportion of patients children may play a part is supported by data showing that received DE and the proportion of DE decisions that that adults with pediatric-type sarcomas experience less were appropriate according to the protocol. The secondary treatment-related toxicity compared with their younger objective was to assess rates of serious complications for the counterparts [10,12-14]. A meta-analysis in osteosar- entire group, investigate gender and age related differences in coma showed that children had higher rates of neutro- neutrophil and platelet nadirs, assess subsequent neutrophil penia compared with adolescent or adult patients, and and platelet nadirs for those who underwent dose escalation, that dose-related toxicities including thrombocytopenia and calculate relapse free survival (RFS) and overall survival and mucositis were strongly associated with improved (OS). In order to assess RFS and OS, a comparison was per- overall survival [9]. In addition to age, gender-related formed with a prior cohort of ESFT with localized disease differences also exist in osteosarcoma, with males ex- treated with the same regimen of VDC/IE, but prior to the periencing less myelosuppression and inferior survival initiation of our dose escalation policy. This study was ap- [7,9]. A retrospective study of 14,824 patients showed proved by the Institutional Review Board of Peter MacCallum that male AYA patients with osteosarcoma, Ewing sar- Cancer Centre for retrospective data collection. coma and Hodgkin lymphoma experienced less toxicity, Chemotherapy was delivered for ESFT every 3 weeks lower response rates and excess mortality relative to with vincristine (2 mg), doxorubicin (75 mg/m ), cyclo- children and female counterparts [12]. Similar findings phosphamide (1200 mg/m ) D1 alternating with ifosfa- 2 2 correlating lack of chemotherapy-induced toxicity and mide (1800 mg/m ) and etoposide (100 mg/m ) D1-5 [2]. inferior outcome [15-17], have also been reported in Blood counts were taken on Day 8, 12 and 15 for the first testis, breast and ovarian cancers [18]. 6 cycles of chemotherapy and dose escalation (DE) was These data suggest that age and gender-related differ- implemented if the neutrophil and platelet count did not 9 9 ences in drug handling may account for some of the sur- fall below 1.5×10 /L or 100×10 /L, respectively, in the ab- vival and toxicity differences in the AYA population. If so, sence of non-hematologic toxicities of concern. Although dose intensification may improve outcomes in chemosen- these hematological cut-offs have not been validated in sitive cancers. Accurate dosing of chemotherapy is difficult prospective trials, these values have been suggested in the using traditional algorithms based on body surface area literature in recommendations for “toxicity adjusted dos- [19], with evidence for systematic underdosing [20,21]. ing” [15,18]. Dose escalation involved increasing the BSA While one study of dose escalation of alkylating agents did calculated dose of all chemotherapy agents, except vincris- not improve outcomes in Ewing sarcoma [22], increasing tine, by 10% for all equivalent subsequent cycles. Given Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 3 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Table 1 Baseline demographics the alternating regimen, nadir counts for cycle 1 and 2 led to DE decision for cycle 3 and 4, whereas nadir counts for Baseline demographics cycle 3 and 4 led to a DE decision in cycle 5 and 6. De- Number 23 escalation occurred on the basis of both hematological Female 10 (43%) and non-hematological toxicities at the discretion of the Male 13 (57%) treating physician. Median age (range) 23 (17 – 54) Median age female 21 (17 – 54) Inclusion All patients with ESFT (including peripheral primitive Median age male 26 (18 – 40) neuroectodermal tumor, Askin’s tumors, Ewing’s sarcoma, Diagnosis desmoplastic small round cell tumor) who underwent EWINGS 17 (74%) cytotoxic chemotherapy at Peter MacCallum with VDC/IE PNET 5 (22%) between March 2009 and August 2012 were included. DSRCT 1 (4%) Disease site Statistical analysis Analysis of primary endpoints and secondary endpoints Metastatic 6 (26%) was performed on an intention to treat basis. To address Localized the primary objective, the proportion of patients who re- Extremity 9 (39%) ceived DE was calculated for each of cycles 3 – 6 separ- Pelvic 2 (9%) ately as well as for any VDC cycle (3 and/or 5) and any Axial trunk 2 (9%) IE cycle (4 and/or 6). To evaluate adherence, the propor- Chest wall 3 (13%) tion of treatment decisions that were appropriate ac- cording to the DE protocol was calculated. Other 1 (4%) To address the secondary objectives, the proportion of BSA patients reporting grade 3/4 febrile neutropenia in each Female 1.79 (SD ± 0.22) of the VDC and IE cycles was calculated. Comparisons Male 1.94 (SD ± 0.15) between males and females in terms of neutrophil and platelet nadirs in cycles 1 – 4 were investigated using in- dependent 2-sample t-tests assuming unequal variances. females during VDC (7/13 vs 3/10), but not during IE Within cycle changes in neutrophil and platelet counts (7/13 vs 5/10). as well as between cycle changes in neutrophil and Protocol adherence was recorded at 90%. Nine events of platelet nadirs were assessed using repeated measures non-adherence to the protocol were recorded (7 events ANOVA. Overall survival was measured as the time of inappropriate escalation (7.7%) and 2 events of missed from first chemotherapy until death and relapse-free sur- escalation (2.2%); details of inappropriate escalation are vival was measured from time of first chemotherapy shown in Additional file 1: Table S1). No serious adverse until date of relapse. Patients were censored at the last outcomes occurred as a result of the inappropriate escal- date they were known to be alive and relapse-free re- ation. The rate of Grade 3/4 febrile neutropenia (FN) dur- spectively. OS and RFS curves were estimated using the ing VDC was 26.1% (6/23 patients) with median length of Kaplan-Meier product-limit method. OS and RFS com- Table 2 Number of patients who received dose escalation parison to the prior historical cohort was assessed using during VDC/IE the logrank test. A P-value of <0.05 was considered sta- Escalated Dose unchanged Dose reduced Number tistically significant. Statistical analysis was performed using Excel, GraphPad Prism 6 and R version 2.15.2 VDC software. C1 23 C3 10 10 3 23 Results C5 3 19 1 23 Between 2009 and 2012, 23 patients were treated on the Any cycle 10 10 3 23 DE protocol with a median follow up of 2.3 (0.7 – 3.4) IE years. Baseline demographics are shown in Table 1. In total, 91 events for consideration of dose escalation oc- C2 23 curred (1 decisions was excluded because of progressive C4 10 11 2 23 disease). This is presented in Table 2. There were 3 pa- C6 3 19 0 22 tients during VDC that were escalated twice. Although Any cycle 12 9 2 23 not statistically significant, more males had DE than Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 4 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 stay (LOS) of 4 days (range 1–20) with no ICU admis- receiving a higher relative dose intensity of VDC and IE sions. The rate of Grade 3/4 FN for IE was 17.4% (4/23 pa- compared to females (VDC: 107% vs 98%, P-value = 0.12; tients) with a median LOS of 4 days (3–7) and 1 ICU IE: 105% vs 102%, P-value = 0.49). admission. The ICU stay occurred in a patient who was To compare overall cancer-related outcomes between appropriately not dose-escalated. There were no deaths the traditional BSA associated chemotherapy dosing and related to chemotherapy and only 1 patient received a the toxicity-adapted dose escalation protocol, we com- platelet transfusion (during IE). There were no additional pared the RFS and OS between treated patients with documented grade 3/4 toxicities documented in those localized disease before (1995–2004) and during (2009– who underwent dose escalation. 2013) the introduction of the DE policy. The baseline Neutrophil nadirs by gender for cycle 1 – 4 are shown characteristics of this historical comparator group were in Table 3. Males were statistically significantly less similar to our cohort (An additional file shows this in neutropenic after C1 and C3 of VDC compared to females more detail [see Additional file 2: Table S2]) and patients (P-value C1 = 0.003; C3 = 0.005). VDC was associated with with DSRCT and metastatic disease were excluded from greater neutropenia on day 8 (ANC: D8: 0.98 ± 0.97 × this analysis. The 2 year RFS in the dose escalation co- 10 /L, P-value <0.001) whereas IE had greater neutropenia hort was 88%, compared to 63% in the historical com- on day 12 (ANC: D12: 3.74 ± 3.04 × 10 /L, P-value <0.001). parator cohort (HR = 0.33, 95% CI: (0.07-1.56); P-value = Although not statistically significant, there was also a 0.14) and 2 year overall survival was 88% vs 75% in the trend for less thrombocytopenia during VDC in males historical comparator cohort (HR = 0.48, 95% CI: (0.09- (data not shown, P-value = 0.11). After cycle 1 of VDC, in- 2.46) P-value = 0.37 (Figures 1 and 2). When making dividuals aged 15–25 (n = 13) had lower neutrophil nadirs comparisons in our cohort group only, there was no compared with older individuals (mean difference = 0.62 × statistically significant difference in RFS (P-value = 0.29) 10 /L, P-value = 0.15) although this was not statistically and OS (P-value = 0.31) when separated by those who significant. Differences in cytopenia in IE dosing according have had DE (for either VDC or IE) compared to those to gender were only seen in cycle 4 (mean difference = who did not in patients with localized disease. 2.31 × 10 /L, P-value = 0.05) (Table 3). Although the numbers were too small to achieve stat- Discussion istical significance, dose escalation, whether appropriate The key finding in this study is that individualized dose es- or not, was associated with a reduction in neutrophil calation of chemotherapy in ESFT is feasible in a single count in subsequent cycles. For those who received dose sarcoma unit. Less neutropenia was observed in males, escalation in cycle 1 of VDC, the mean nadir ANC de- and perhaps in older patients, during the anthracycline 9 9 creased from 1.59 ± 1.22 × 10 /L to 1.29 ± 1.07 × 10 /L in cycles, suggesting that BSA-based dosing alone may not cycle 3, and 1.04 ± 0.9 × 10 /L in cycle 5 (P-value = 0.29). be adequate in males. The protocol compliance rate was For IE cycles, those who received dose escalation after 90%. Given the experimental nature of a toxicity-adjusted cycle 2 showed a decrease from 4.82 ± 1.88 × 10 /L to protocol, we continually reviewed the safety and compli- 2.10 ± 1.8 × 10 /L in cycle 4. Using current dosing algo- ance after implementation of the protocol. Importantly, rithms, dose escalation resulted in a trend to males no short or long term adverse outcomes were seen in this Table 3 Gender related difference in nadir blood counts after C1 and C3 Gender Mean 95% CI P-value difference Male Female N Mean SD N Mean SD Neutrophil nadir VDC Cycle 1 13 1.56 1.35 9 0.16 0.19 1.40 (0.57, 2.21) 0.003 Cycle 3 12 1.59 1.08 9 0.42 0.56 1.17 (0.40, 1.93) 0.005 IE Cycle 2 13 3.77 2.70 10 4.40 4.59 −0.63 (−4.14, 2.88) 0.71 Cycle 4 12 3.17 3.54 9 0.86 1.18 2.31 (−0.04, 4.66) 0.05 Dose intensity (%) VDC 13 107 9 10 98 16 9 (−3, 22) 0.12 IE 13 105 7 10 102 11 3 (−5, 11) 0.49 P–values correspond to comparisons between genders. Dose intensity of VDC and IE is compared to baseline. Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 5 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Figure 1 Relapsed-free survival for localized ESFT compared between those who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004) showing a HR = 0.33 (95% CI: (0.07 – 1.53) P-value 0.14). Figure 2 Overall survival for localized ESFT compared between those who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004) showing a HR = 0.48 (95% CI: (0.09 – 2.46) P-value 0.37). Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 6 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 study as a result of intrapatient dose escalation. The RFS different pharmacologic profiles in the AYA population. and OS comparison to the prior ESFT cohort suggests that Nearly all the benefit of methotrexate’s use in osteosarcoma dose escalation is not associated with worse overall out- has been demonstrated in patients under the age of 40 [42] comes for patients with localized primary ESFT. Clearly, and doxorubicin, a key component of regimens used to safe dose escalation requires a formal program with strictly treat ESFT, osteosarcoma and hodgkins disease, demon- defined criteria for escalation, close monitoring of nadir strates significant pharmacokinetic variation according to blood counts, and patient selection limited to those with- gender and body habitus [43,44]. It is possible that the in- out other dose-related toxicities or co-morbid illnesses. ferior outcomes of EFST in older males may be attributed Given this study showed gender and age related differences to relative doxorubicin under-dosing of these individuals. in cytopenia, it is arguable that dose escalation should be Given the inherent inaccuracies in current dosing al- especially considered in older males during the anthracy- gorithms, and the importance of chemotherapy to cure cline component of treatment (Cycle 3 or 5 based on C1 for chemo-sensitive cancers, intra-patient dose modifica- nadir). Additionally, variation was seen in the timing of tion based on markers of toxicity provides a practical neutropenia nadirs, which may have ramifications for the strategy for individually tailored dosing [25,26]. In this timing of pegylated filgrastim delivery. context, this limited study suggests gender- and poten- It is important to put these findings into context given tially age-related differences in hematological nadirs, and evidence for gender- and age-related difference in toxicity that intra-patient dose escalation appears safe and feas- and outcome in chemo-sensitive cancers such as ESFT ible. It is important to note that this retrospective study [12]. Although the peak incidence of ESFT is during the only comprises 23 patients, with relatively short follow AYA years, these patients have a worse survival compared up. In particular, the non-significant trend to improved to a pediatric population [27]. The reasons behind this RFS and OS in the dose escalation group will require lar- comprise a combination of biological differences [27,28], ger numbers of patients and longer follow up. Addition- delayed diagnosis, poorer treatment compliance [29,30], ally, we did not assess long-term morbidity, including psychosocial overlay and limited involvement in clinical the potential for cumulative anthracycline cardiotoxicity trials [31,32]. With regards to biological differences, in the in a young population. EURO-Ewing 99 protocol [10], increasing age and male gender was associated with less toxicity using VIDE Conclusion chemotherapy, a protocol similar to VDC/IE. Additionally, Individualized, toxicity-adapted dosing of chemotherapy, gender related differences have previously been described added to an initial calculation of dosing based on BSA- in hodgkins lymphoma [33], osteosarcoma [9,34,35] and alone, aims to correct the gender and age related disparity ewings sarcoma [12,36,37]. A meta-analysis in osteosar- in outcomes, without relying on new chemotherapeutic coma confirmed differences in outcome related to gender agents. Pharmacological data in this age group is lacking and age and showed improved outcomes in females, and [28] and adequate dose–response is critical for chemo- those with Grade 3/4 mucositis [9]. Interestingly, it also sensitive diseases such as ESFT, germ cell tumors and confirmed the results of our study showing increased mye- Hodgkin’s in maximizing outcome where a dose–response losuppression in the younger age group although given relationship exists. The key finding in this study is that in- our small numbers, this was not statistically significant. dividualized dose escalation of chemotherapy in ESFT is Collectively, this data suggests a better understanding of feasible in a single sarcoma unit without increased adverse cytotoxic pharmacology is needed in the AYA population outcomes. Additionally we have showed that less neutro- [28,38], and may be used to improve cancer outcomes. penia was observed in males, and perhaps in older pa- Adolescent and young adult patients undergo gender- tients, during the anthracycline cycles and should be specific pubertal changes in body composition, size and especially considered for DE. Given the rarity of ESFT pre- hormonal status, which may alter the pharmacokinetic/ sents significant statistical challenges in stratifying gender pharmacodynamic properties of chemotherapy [38]. Young and age differences, pharmacological endpoints should be women have significant increase in fat mass during ado- designed into future prospective chemotherapy trials. lescent years, with subsequent higher body fat than men [39]. Higher fat distribution has effects on drug clearance Additional files and volume of distribution [28,40] which may cause varia- tions in the dose of chemotherapy delivered. That being Additional file 1: Table S1. Description of patients who inappropriately said, a large pediatric study in ALL showed no differences received dose escalation. in toxicity, survival or PK data in the obese patient [41]. It Additional file 2: Table S2. Comparison of baseline demographics with is difficult to isolate drug-specific effects in complex, for patients with localized disease who underwent a DE policy (2009 – 2012) compared with a prior cohort who did not have a DE policy (1995 – 2004). multi-drug chemotherapeutic regimens, and it is import- Patients in both cohorts were treated with alternating VDC/IE. ant to recognize that different drugs may demonstrate Lewin et al. Clinical Sarcoma Research 2013, 3:15 Page 7 of 8 http://www.clinicalsarcomaresearch.com/content/3/1/15 Abbreviations 14. Ferrari S, Palmerini E, Staals E, Abate ME, Longhi A, Cesari M, Balladelli A, ANC: Absolute neutrophil count; AYA: Adolescent and young adult; DE: Dose Pratelli L, Bacci G: Sex- and age-related chemotherapy toxicity in patients escalation; ESFT: Ewing’s sarcoma family tumors; FN: Febrile neutropenia; with non-metastatic osteosarcoma. J Chemother 2009, 21:205–210. ICU: Intensive care unit; IE: Ifosfamide, etoposide; VDC: Vincristine, 15. Gao B, Klumpen HJ, Gurney H: Dose calculation of anticancer drugs. doxorubicin, cyclophosphamide; LOS: Length of stay; OS: Overall survival; Expert Opin Drug Metab Toxicol 2008, 4:1307–1319. RFS: Relapse free survival. 16. Canal P, Chatelut E, Guichard S: Practical treatment guide for dose individualisation in cancer chemotherapy. Drugs 1998, 56:1019–1038. 17. Cortes EP, Holland JF, Wang JJ, Sinks LF, Blom J, Senn H, Bank A, Glidewell Competing interests O: Amputation and adriamycin in primary osteosarcoma. 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J Clin Oncol 1988, 6:1321–1327. doi:10.1186/2045-3329-3-15 Cite this article as: Lewin et al.: Intra-patient dose escalation in Ewing’s sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review. Clinical Sarcoma Research 2013 3:15. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Dec 10, 2013

References