Review Article - Hindawi Publishing...

Hindawi Publishing CorporationSarcomaVolume 2012, Article ID 704872, 10 pagesdoi:10.1155/2012/704872

Review Article

A Meta-Analysis of Osteosarcoma Outcomes inthe Modern Medical Era

Daniel C. Allison, Scott C. Carney, Elke R. Ahlmann, Andrew Hendifar, Sant Chawla,Alex Fedenko, Constance Angeles, and Lawrence R. Menendez

Division of Orthopedic Oncology, Department of Orthopedic Surgery, Keck School of Medicine, Los Angeles County Medical Center,University of Southern California, 1520 San Pablo Street, Suite 2000, Los Angeles, CA 90033, USA

Correspondence should be addressed to Daniel C. Allison, [email protected]

Received 18 October 2011; Accepted 20 December 2011

Academic Editor: Jose Casanova

Copyright © 2012 Daniel C. Allison et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Four decades ago, specialized chemotherapy regimens turned osteosarcoma, once considered a uniformly fatal disease, into adisease in which a majority of patients survive. Though significant survival gains were made from the 1960s to the 1980s, furtheroutcome improvements appear to have plateaued. This study aims to comprehensively review all significant, published dataregarding osteosarcoma and outcome in the modern medical era in order to gauge treatment progress. Our results indicate thatpublished survival improved dramatically from 1960s to 1980s and then leveled, or in some measures decreased. Recurrence ratesdecreased in the 1970s and then leveled. In contrast, published limb salvage rates have increased significantly every recent decadeuntil the present. Though significant gains have been made in the past, no improvement in published osteosarcoma survivalhas been seen since 1980, highlighting the importance of a new strategy in the systemic management of this still very lethalcondition.

1. Introduction

Osteosarcoma was once considered such a fatal conditionthat early studies measured outcome in terms of “months tometastasis” rather than actual survival. Shortly after the turnof the last century, Coventry measured osteosarcoma survivalat 5% [1]. In the 1950s, neither surgery, nor radiation, norrudimentary chemotherapy regimens significantly impactedsurvival, with the largest study of the decade citing a 22% 5-year survival [1]. With the advent of higher dose, multiagentchemotherapy regimens, 5-year survival steadily increased toas high as 81.6% in the 1970s [2].

However, casual inspection of published data indicatesthat since the 1970s, survival and perhaps other outcomemeasures have yet to further improve. As surgical techniquesand implants have evolved, chemotherapeutic agents usedtoday seem to be wholly similar to those used thirty yearsago.

A meta-analysis of the world’s data regarding osteosar-coma and outcomes would help us accurately gauge our

current state of treatment and not just speculate onimprovements or stasis based on isolated recent studies andanecdotal evidence. Several studies have attempted similarmeta-analyses; however, their scales were much smaller (thelargest of which contained 142 series) and their scopes werenarrower (focusing only on specific therapies) than ourintended breadth [3–5]. The purpose of our study is to thor-oughly inspect the expansive literature regarding prognosisof osteosarcoma since the inception of journal publication,in order to analyze the treatment trends across the globe inregards to time. Thus, we aim to determine treatmentprogress, as well as the current state of affairs, so that we mayin turn accurately gauge our progress and appropriately di-rect our efforts.

2. Materials and Methods

A comprehensive and complete MEDLINE search was per-formed, using only the search terms “osteosarcoma” and“survival.” Articles not written or translated into English,

2 Sarcoma

animal or in vitro studies, and articles not accessible throughthe University of Southern California Norris Medical Librarywere excluded. All articles describing outcome data were in-cluded, including clinical trials, case series, databases, letters,and reviews. General case series with less than 20 totalpatients were excluded. All studies including nonclassic orlower grade osteosarcoma variants as well as secondary oste-osarcoma or recurrent osteosarcoma were excluded, as werehead and neck cases. Pelvic and axial tumors were included.Studies that measured survival in terms of odd years (e.g.,7-year survival) and, for studies published after 1980, thoseseries which measured outcomes in less than 5-year termswere also excluded. Metastatic series were included, however,they were left apart from the general studies and analyzedseparately.

Both overall survival (OS) and disease-free survival(DFS) of 5 years or more were recorded from each study,focusing on 5- and 10-year survival numbers when possible.Local recurrence and limb salvage rates were also measured,if data was given. Each study was then assigned to specifictime intervals (decades), which were determined by thedescribed study period of each series. If a series spanned twodecades, it was placed in the decade in which a majority ofthe study time occurred, rounding to the more recent decadeif the division was equal. If a series spanned more than twodecades, it was placed in a separate table for direct review(Table 1), and not included in the decade-to-decade analysis.If the article did not mention the time period, the study wasplaced into the decade preceding that of publication. If astudy was divided according to decade or time period, eacharm was placed into its separate decade category accordingly.

Of 3,948 initial series found in the search for “osteosar-coma” and “survival,” 3,684 did not meet the study inclusioncriteria, leaving a total of 264 series in the study. Datafrom these series were then combined in weighted fashion(according to the number of patients in each study) in orderto obtain mean values for each respective outcome measure.Nonmetastatic cases were evaluated in terms of survival (OS(5, 10 year) and DFS (3, 5, and 10 year)) recurrence, and limbsalvage rates, and analyzed according to decade. Articles thatrecorded specific subtypes (metastatic cases, pelvis, and limbsalvage) were also analyzed separately according to decadewith regard to 5-year OS. The data from metastatic serieswere not included in the general survival, limb salvage, andrecurrence data. Along each outcome measure, these meanswere then compared according to the t-test for proportions,set to a 95% confidence interval.

3. Results

3.1. General Survival. Among the series of nonmetastatic,high-grade osteosarcoma patients, the most commonly mea-sured statistic, 5-year OS was measured in 47,227 patientsthroughout the series. Figure 1 shows the 5-year OS trendfrom the beginning of the twentieth century to present day.Survival remained stable at approximately 20% from the1910s to the 1960s, with a sudden surge to approximately60% into the 1980s where it stabilized again. The increasein 5-year OS from the 1960s to the 1970s (P < 0.0001) and

from the 1970s to the 1980s (P < 0.0001) was statisticallysignificant; however, when comparing the 1980s to the 2000s,no further statistically significant increase in published 5-year OS was recorded (P = 0.66). Ten-year OS increased by37.6% from the 1960s to the 1970s (P < 0.0001), but thenshowed no difference when comparing the 2000s to the 1990s(P = 0.28) (Figure 2).

Disease-free survival was first recorded in the 1950sstudies, starting with 3-year DFS measures. Three-year DFSincreased significantly from the 1950s to the 1960s (P = 0.05)and from the 1960s to the 1970s (P < 0.0001), but then failedto improve after the 1970s (Figure 3). The published 5-yearDFS increased by 8.6% from the 1970s to the 1980s (P <0.0001) and 2.6% from the 1980s to the 1990s (P = 0.0007),but then significantly decreased by 11.2% from 1990 to 2000(P < 0.0001) (Figure 4). Similarly 10-year DFS remained sta-ble in the 1970s, 1980s, and 1990s at roughly 60%, onlyto statistically decrease to 44% in the 2000s (P < 0.0001)(Figure 5).

3.2. Local Control and Limb Salvage. Recurrence measureswere initially published in the 1970s, and have fluctuatedfrom decade to decade since (Figure 6). No significantimprovement has been seen in published recurrence ratesfrom the 1980s to the 2000s (P = 0.36).

Limb salvage rates have improved significantly from dec-ade to decade ever since the 1970s, improving by 16.2% fromthe 1970s to 1980s (P = 0.01), by 37% from the 1980s to the1990s (P < 0.0001), and by 7.3% from the 1990s to the 2000’s(P < 0.0001) (Figure 7).

3.3. Survival in Specific Osteosarcoma Populations. Starting inthe 1970’s, cases of metastatic osteosarcoma were analyzed inseparate series. Five-year survival rates in metastatic seriesimproved from the 1970’s to the 1980’s by 5.7%, thoughthis change was not statistically significant. Interestingly, 5-year survival rates in this population have decreased everydecade ever since, with no statistical change in survival whencomparing the 2000’s to the 1970’s (P = 0.21) (Figure 8).

When looking specifically at series of pelvic osteosarcomapatients, survival rates have also declined every decade sincetheir first recording in the 1980’s; however these drops werenot statistically significant (Figure 9).

In specifically documented limb salvage series, 5-year OSrates improved significantly from the 1990’s to the 2000’s by11.1% (P = 0.04) and from 1970’s to the 2000’s by 23.1%(P < 0.0001) (Figure 10).

4. Discussion

Advances in chemotherapy regimens in the seventies lead toextraordinary increases in survival of osteosarcoma patientswhich, combined with improved surgical technology andtechnique, also lead to significant improvements in limbsalvage. Physicians anecdotally refer to the lack of survivalprogress in the latter end of the last century, yet few studiesprobe into the extensive world literature. The few that at-tempt to address this issue narrow their reviews to control-lable numbers: as few as 8 in one review [5]. Anninga et al.

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Decade

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d

Figure 1: Osteosarcoma 5-year overall survival.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

10-y

ear

over

all s

urv

ival

1960s(n = 452)

1970s(n = 763)

1980s 1990s(n = 2,952)

2000s(n = 635)

Decade

(n = 2,539)

Figure 2: Osteosarcoma 10-year overall survival.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

3-ye

ar d

isea

se-f

ree

1970s(n = 446)

Decade

1990s(n = 91)

2000s(n = 417)

1980s(n = 1061)

1950s(n = 33)

1960s(n = 233)

Figure 3: Osteosarcoma 3-year disease-free survival.

Sarcoma 7

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

5-ye

ar d

isea

se-f

ree

surv

ival

1970s(n = 3,846)

Decade

1990s(n = 9,987)

2000s(n = 513)

1980s(n = 7,216)

1950s(n = 145)

1960s(n = 20)

Figure 4: Osteosarcoma 5-year disease-free durvival.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1970s(n = 687)

Decade

1990s(n = 1384)

2000s(n = 165)

1980s(n = 1876)

10-y

ear

dise

ase-

free

su

rviv

al

Figure 5: Osteosarcoma 10-year disease-free survival.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1970s(n = 69)

Decade

1990s(n = 3,279)

2000s(n = 1,688)

1980s(n = 2,331)

Rec

urr

ence

Figure 6: Osteosarcoma recurrence rates.

8 Sarcoma

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1970s(n = 68)

Decade

1990s(n = 8,616)

2000s(n = 1510)

1980s(n = 694)

1960s(n = 142)

Lim

b sa

lvag

e

Figure 7: Osteosarcoma limb salvage rates.

Met

asta

tic

5-ye

ar o

vera

ll su

rviv

al

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1970s(n = 202)

Decade

1990s(n = 778)

2000s(n = 1,701)

1980s(n = 251)

Figure 8: Metastatic osteosarcoma 5-year overall survival.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Decade

1990s(n = 84)

2000s(n = 21)

1980s(n = 156)

Pel

vis

5-ye

ar o

vera

ll su

rviv

al

Figure 9: Pelvic osteosarcoma 5-year overall survival.

Sarcoma 9

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1970s(n = 145)

Decade

1990s(n = 179)

2000s(n = 190)

1980s(n = 1,022)

1960s(n = 132)

Lim

b sa

lvag

e 5-

year

ove

rall

surv

ival

Figure 10: Osteosarcoma 5-year overall survival among limb salvage cases.

recently published the previously most comprehensive re-view, but looked at specific treatment regimens and excludedother prognostic, observational, and review studies [3]. Weaimed to sort through the extensive osteosarcoma literatureto arrive at basic evidence-based interpretations regardingthe current status of osteosarcoma management, as it relatesto our past. Such information will help us determine themost appropriate steps to take as an osteosarcoma-treatingcommunity as we progress into the new century.

Despite its expansive scale, our study certainly has im-portant limitations. Our numbers are based on publishedstudies, which may not accurately represent outcomes in thecommunity as a whole. Many successive studies may containduplicate patients, skewing the data in this direction. Accord-ing to our exclusion criteria, we may have excluded impor-tant contributing data, especially with the removal of stud-ies with odd-year survival measures. Nevertheless, the USCNorris Medical Library is extensively complete, and the ex-clusion criteria narrow, decreasing the likelihood of missingsignificant data. Furthermore, our retrieved number ofstudies was so high that the addition of this data is veryunlikely to change any calculation. Furthermore, the analysisof the extensive amount of data could pose limitations. Thehomogenous blending of different survival curves from het-erogenous populations could skew outcome results. The in-corporation of numerous studies with large numbers ofpatients helps mitigate this risk for error. Not all of the pre-dominately survival studies gave data on recurrence or limbsalvage rates. These numbers were weighted averaged accord-ing to decade; however the exact number and subsequentpower of their information is less than that of survival; how-ever, even with these lower numbers, the numbers were stillhigh enough to note significant differences. Combining allosteosarcoma patient populations together may also skewresults, as certain patient populations may have different out-comes (i.e., axial versus appendicular cases). In order toaddress this limitation, we analyzed specific population seriesseparately in order to show their survival data (Figures 8, 9,and 10). Combining single center and multicenter studies

also poses a limitation, increasing the associated variablessuch as treatment regimens and outcome measures. Again,the very high numbers retrieved in our study (47,227 patientsin the 5 year overall survival data) help mitigate these lim-itations.

Our study confirms suspicions regarding the lack ofstatistical improvement in osteosarcoma survival over thelast thirty years. In fact, DFS at the 3-year, 5-year, and 10-yearmarks have shown recent decreases over the last two decades.After steep improvements up until the 1970’s, overall survivalat the 5 and 10-year marks has simply plateaued with lack ofstatistical improvements. Similarly, recurrence rates havefluctuated in the modern era, without significant improve-ment. This lack of improvement is also true in subsetpopulations like pelvic metastatic cases, with actual decreasesin survival in both of these populations over the last twodecades, though these decreases did not reach statisticalsignificance. Of note, limb salvage rates as well as survivalrates in limb salvage populations, have continued to climb,increasing significantly since the 1970’s on both accounts.This progress may indicate improvements in biopsy, respec-tive techniques, and limb salvage reconstructive methods.

In a time of unprecedented technological growth andadvance, systemic cancer treatment clearly lags behind. Thislag is further accentuated by the tremendous surge in survivalof osteosarcoma until the 1980’s. Our study indicates thatthis stagnation is not limited to a single outcome measure,but across all outcomes ranging from survival to recurrence.

After noting the problem, our next charge is to find theunderlying cause. Given the expense of drug development,trialing, and now even marketing, the relatively low numbersassociated with osteosarcoma, especially in relation to vis-ceral malignancy, renders the orphan condition less popularamong pharmaceutical companies that have an obligation toshareholders. Furthermore, the lack of profit from cure ofdisease as opposed to prolongation of disease likely lessensthe industry’s quest for a cure. Unfortunately, in the currentsystem, economic incentives do not always align with patientwellness incentives. A similar problem was addressed with

10 Sarcoma

osteosarcoma in the early 1970’s with the touching storyof Terry Fox, which highlighted the lack of efforts put intoosteosarcoma research and drug development. The patient’sstory, which became a feature film, helped spawn an un-precedented interest and motivation in curing the diseaseworldwide. Perhaps efforts to show the public the plights ofthe often young patients struck with this disease will lead to asecond surge in interest. Another potential cause of this lackof progress could be complacency among those who treatsarcomas. While many oncologists have cited the lack ofprogress in the treatment of non-sarcoma cancers in the past,opponents would cite the survival jump of osteosarcoma as asign of cancer fighting progress. The idea that osteosarcomais a bastion of chemotherapeutic advance may have decreasedthe scientific sense of urgency in finding a cure.

Regardless of the underlying cause, which may be verydifficult to ever determine, a change in strategy must be em-ployed if we are to change our results. The paradigm shiftfrom the use of cytotoxic agents to molecularly targetedagents may be a source of positive change. The theory oftumor stem cells explaining tumor behavior is an exampleof potential fundamental changes in the way we understandthese tumors, which lead to fundamental changes in treat-ment. Using the gains in the treatment of other condi-tions that gain high level industry attention (e.g., RANK-Linhibitors for skeletally related events in metastatic diseaseand in osteoporosis) would be another potential area forimprovement. Increased media attention in the form of newsoutlets, publications, or even entertainment forums woulddirect attention and money to the cause. Empowering aca-demic centers to research, develop, and even market them-selves would bring competition into the chemotherapy mar-ketplace and focus on outcome measures and potentials forlong-term economic gain in the form of cure that short-sighted companies may not currently see. Increased regula-tion regarding the use of human subjects in research may bean issue, but the unfortunate, but real number of patientswith metastases may serve as a pool for such studies, and thuswould be the first to benefit.

5. Conclusions

Our study confirms suspicions about the stagnation ofprogress in systemic osteosarcoma management in recentdecades. Limb salvage rates have continued to improve sig-nificantly throughout the modern era to the present day;however, after tremendous improvement in the 1970’s, sur-vival measures have failed to demonstrate any further in-creased since the 1980’s. After 30 years of lack of progress, weshould reevaluate our treatment paradigms and think alongdifferent lines, especially in regard to the current players be-hind drug and medical technology development as well asour own attitudes toward disease treatment and outcomes wedeem appropriate.

Conflict of interserts

None of the authors have any financial conflicts of interest inregard to this study.

References

[1] M. B. Coventry and D. C. Dahlin, “Osteogenic sarcoma: acritical analysis of 430 cases,” The Journal of Bone and JointSurgery, vol. 39, no. 4, pp. 741–758, 1957.

[2] G. Rosen, “Preoperative (neoadjuvant) chemotherapy for oste-ogenic sarcoma: a ten year experience,” Orthopedics, vol. 8, no.5, pp. 659–664, 1985.

[3] J. K. Anninga, H. Gelderblom, M. Fiocco et al., “Chemother-apeutic adjuvant treatment for osteosarcoma: where do westand?” European Journal of Cancer, vol. 47, no. 16, pp. 2431–2445, 2011.

[4] S. K. Carter, “The dilemma of adjuvant chemotherapy forosteogenic sarcoma,” Cancer Clinical Trials, vol. 3, no. 1, pp. 29–36, 1980.

[5] A. M. Davis, R. S. Bell, and P. J. Goodwin, “Prognostic factorsin osteosarcoma: a critical review,” Journal of Clinical Oncology,vol. 12, no. 2, pp. 423–431, 1994.

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