We found wide variation in the regimens used across all LOTs for the treatment of mSTS. In LOT1, only 53% of patients combined were treated with the 5 most common LOT1 regimens, and about 47% of patients received a regimen other than these regimens. The most commonly used regimen within the ‘other’ category accounted for < 6% of the STS population. Our findings may, in part, be explained by the numerous histological types (> 40) of STS, varying chemosensitivity of histological types, disease progression, and the lack of evidence on the optimal treatment and sequence of treatment of each histology. It is also possible that our results reflect variable clinician expertise with and adherence to recommended chemotherapy treatment guidelines [2]. Consistent with the findings of Wagner et al. [13], no consistent regimens were used beyond second-line treatment in the current study. Docetaxel + gemcitabine, followed by doxorubicin and pazopanib, were the top three regimens in LOT1, and docetaxel + gemcitabine was the first line regimen in 47% of patients who received pazopanib as LOT2 and 58% of patients who received doxorubicin as LOT2. Doxorubicin has generally been the mainstay of first line therapy for most mSTS, due to its lower toxicity and relative ease of administration [15, 16]. The recent GeDDiS trial compared first line treatment of doxorubicin to docetaxel + gemcitabine among patients with advanced or metastatic STS in the United Kingdom and Switzerland. Study investigators concluded that doxorubicin is appropriate as the standard first line treatment for most patients with advanced STS, as compared to docetaxel + gemcitabine, it is less difficult to administer, perceived by patients as less toxic, and less expensive, despite comparable survival outcomes [15]. The addition of olaratumab to first line therapy is likely to solidify the use of doxorubicin in the first line [17]. Prior studies of first-line treatment have found that the most common regimens were doxorubicin monotherapy (34%) or an anthracycline + ifosfamide (30%) [11], anthracycline-based (44%) or gemcitabine-based (28%) [13], doxorubicin (± ifosfamide) (46%) [12], or doxorubicin (± ifosfamide) (66%) [18]. Docetaxel + gemcitabine may be preferred for certain mSTS including leiomyosarcomas and undifferentiated pleomorphic sarcomas (UPS) [16]. Since histology was not captured in the claims data used for the current study, we have no knowledge of whether our study’s results were driven by histologic subtype, and it is unclear whether inconsistent findings between studies, even for preferred first-line regimens, is more related to histologic subtypes represented by the individual study populations or true differences in practice patterns. Doxorubicin alone was more popular than doxorubicin + ifosfamide while docetaxel + gemcitabine were more popular than gemcitabine alone. Published evidence suggests that the therapeutic effect of doxorubicin + ifosfamide is additive with no statistically significant overall survival benefit and is associated with more adverse effects compared to the synergistic relationship between gemcitabine and docetaxel [16, 19, 20].
In the current study, pazopanib, followed by docetaxel + gemcitabine, were the leading regimens in LOT2. Compared to other regimens used in mSTS, pazopanib may be preferred by patients due to its oral route of administration. Clinical trials of pazopanib have found lower rates of certain adverse events (anemia, neutropenia, nausea/vomiting, and elevated AST/ALT) than reported for clinical trials of trabectedin, though anorexia was more common with pazopanib [7, 21, 22]. However, the lack of head-to-head clinical trials comparing these agents and the use of different patient populations to evaluate event rates makes direct comparisons problematic. Trabectedin was not available in the US until late 2015, though it has been commonly used as a second-line treatment in Europe since 2007. Prior to pazopanib’s availability in the US, Wagner et al. (2000–2011) found that gemcitabine-based (28%) and anthracycline-based (24%) regimens were used most often in LOT2 [13]. The most common second-line treatment was docetaxel + gemcitabine (18%) in the SABINE study by Leahy et al. [11]. Also, Chen et al. found that docetaxel + gemcitabine (52%) was the most common regimen in LOT2 [12]. These results suggest widespread use of gemcitabine in LOT2 prior to pazopanib’s US availability, either alone or in combination with docetaxel, and less variation in LOT2 regimen preference across different study populations. In contrast, Bae and colleagues found that 53% used ifosfamide in LOT2 in an Australian advanced STS population, although pazopanib was sporadically used as subsequent LOTin Bae’s study population following its availability in Australia in March of 2014 [18].
To our knowledge, the current study is the first published study of treatment patterns in mSTS since pazopanib became available in the US in 2012. A somewhat unexpected finding of our study was that ~ 7% of patients received pazopanib as initial therapy, as pazopanib is approved as second or later line of management for mSTS in the US. This may represent off-label use of pazopanib, possibly related to early clinical trial results suggesting a role for pazopanib in first-line treatment of soft tissue sarcomas, including solitary fibrous tumor (SFT) and clear cell sarcoma [23,24,25]. However, it may be that physicians may be more comfortable with this drug early on and consider it to be a more tolerable treatment than other first-line options, such as high dose doxorubicin. Additionally, it is possible that the use of pazopanib as first LOT in our study may be a misclassification of LOT2 as LOT1 regimens using administrative claims data to ascertain LOT. Additionally, another unexpected finding of our analysis was significant usage of carboplatin in our mSTS cohort, since this drug has very limited efficacy in sarcoma. These observations may reflect the somewhat fragmented oncology care for sarcoma within the American health system. While in Europe, most sarcoma patients are referred as standard practice to high-volume referral centers, many patients in the United States are treated in private, non-academic practices. Lack of experience with sarcomas may result in therapeutic choices that do not align with evidence-based best practices and therefore receiving care under the guidance of a high-volume referral center may be important for patients’ receipt of optimal recommendations for therapy.
Treatment with new drugs (different agents from LOT1) was the common strategy during disease progression/subsequent LOTs. Drug rechallenge, the repeat administration of the same regimen which may occur following drug holiday, disease progression or relapse, was low in general, but higher among docetaxel + gemcitabine-treated patients than pazopanib-treated patients, and in later LOTs than earlier LOTs. This may reflect fewer regimen options for subsequent therapy to choose from after selection of initial treatment regimen. Shorter duration of therapy for later LOTs relative to LOT1 as observed in our study could be multifactorial and be suggestive of worsening disease or resistant disease. Longer duration of therapy on pazopanib may suggest ease of use, relative effectiveness, and/or tolerability of pazopanib. Finally, results of sensitivity analyses in more rigorously defined mSTS patient subsets confirmed our overall results.
Limitations
Our study’s results should be interpreted in the context of several important study limitations. This study relied on identification codes on administrative claims data to determine STS, disease metastasis and the earliest date of pharmacy claims for identifying the initial patient population. The reporting of metastatic disease through the listing of its ICD code on claims by the treating physician may not be done consistently, and it was not possible for us to independently verify via pathological diagnosis; hence there is possibility for misclassification of patients with mSTS. Administrative claims data also do not contain clinical prognostic information (e.g. histologic subtype, clinical stage and extent of disease) of patients. The codification of sarcomas is particularly problematic, since most of the diagnostic subtypes utilize the same ICD-9-CM code. Conducting sub-analyses on patients with prevalent histologic subtypes would have provided better information applicable to patients with similar histologic subtype, but this was not possible using medical claims data. A regimen change may not always be due to disease progression but also other events like adverse events or drug toxicities, which may not be ascertainable using claims data. We used information from the public view of the SSA death files for cohort selection, and these files do not comprehensively capture all deaths. Finally, a medical-claims based algorithm was developed to classify LOT1-4, and may not accurately identify specific LOTs. The LOT algorithm reflects gaps in therapy but, due to the nature of claims data, the reason for these gaps is unknown, and therapy lapses due to tolerability issues, medication persistence and adherence, drug rechallenge, and other clinically relevant therapy gaps may have been classified as distinct LOTs; this may explain why a small number of patients were treated with the same regimens for two sequential LOTs. Furthermore, our LOT algorithm considered all anti-cancer agents administered within 45 days following the first infusion as the initial regimen received, and it is possible that a true subsequent LOT may start within 45 days and represent a distinct LOT but not correctly be classified as such.