Olaratumab (Lartruvo)

Number: 0913

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of olaratumab is required of all Aetna participating providers and members in applicable plan designs.  For precertification of olaratumab, call (866) 752-7021, or fax (866) 267-3277.

Aetna considers initiating therapy with olaratumab (Lartruvo) in new members experimental and investigational.

The manufacturer of olaratumab (i.e., Lilly) has announced that the company has been working to facilitate the withdrawal of olaratumab (Lartruvo) from the market for the treatment of patients with advanced soft tissue sarcoma (STS). Lilly has opened a Lartruvo Patient Access Program (“PAP”) for those patients currently being treated with Lartruvo. Participation in the PAP will be the only way a patient may remain on therapy after Lartruvo has been withdrawn from the market. Enrollment in the PAP must be completed by July 31, 2019.

See also CPB 0903 - Trabectedin (Yondelis).

Dosing Recommendations

Lartruvo is administered at 15 mg/kg as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, Lartruvo is administered with doxorubicin. 

Source: Eli Lilly, 2016.

Background

Soft Tissue Sarcoma

Soft tissue sarcomas (STSs) are rare tumors that present with distant metastasis in up to 10 % of patients. Survival has improved significantly because of advancements in histologic classification and improved management approaches.  Older agents such as doxorubicin, ifosfamide, gemcitabine, and paclitaxel continue to demonstrate objective response rates (ORRs) from 18 % to 25 %.  Newer agents such as trabectedin, eribulin, aldoxorubicin, and olaratumab have demonstrated improvements in progression-free survival (PFS), overall survival (OS), or toxicity profiles (Sheng and Movva, 2016).

Martin-Broto and Hindi (2016) noted that sarcoma is a heterogeneous group of malignancies historically treated with classic cytotoxic chemotherapy. These investigators updated the recent advances in targeted therapies in STS, bone sarcoma and other connective diseases with local aggressiveness.  Platelet-derived growth factor receptor (PDGFR) inhibitors, anti-angiogenics, cell cycle inhibitors and immunomodulatory agents are the main targeted therapies in development in sarcoma.  PDGFRα inhibitor olaratumab is being evaluated in a phase III trial in combination with doxorubicin against doxorubicin in monotherapy and, in case of positive results, it could change the standard in the 1st-line setting.  Immunotherapy is still in the early phases of development, although some data in synovial sarcoma are promising.  Targeted agents are also in development in other mesenchymal neoplasms, such as the inhibitor of colony stimulating factor 1 receptor for pigmented villonodular synovitis.  The authors concluded that several targeted therapies are in development in sarcoma and could be added to the therapeutic armamentarium in the near future.  However, predictive factors still need to be identified to better select the target population of these new drugs.

On October 19, 2016, the Food and Drug Administration (FDA) granted accelerated approval to Lartruvo (olaratumab) with doxorubicin for the treatment of adults with certain types of STS based on preliminary clinical evidence indicated that it may offer a substantial improvement in effectiveness in the treatment of a serious or life-threatening disease or condition. Lartruvo was approved for use with doxorubicin for the treatment of patients with STS who cannot be cured with radiation or surgery and who have a type of STS (e.g., fat, muscles, tendons or other soft tissues) for which an anthracycline (chemotherapy) is an appropriate treatment.  The safety and effectiveness of Lartruvo (olaratumab) were studied in the clinical trial by Tap et al (2016).

Tap and colleagues (2016) evaluated the effectiveness of olaratumab plus doxorubicin in patients with advanced or metastatic STS. These researchers performed an open-label, phase Ib and randomized phase II clinical trial of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic STS at 16 clinical sites in the USA.  For both the phase Ib and phase II parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic STS not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and available tumor tissue to determine PDGFRα expression by immunohistochemistry.  In the phase II part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to 8 cycles.  Randomization was dynamic and used the minimization randomization technique.  The phase Ib primary end-point was safety and the phase II primary end-point was PFS using a 2-sided α level of 0.2 and statistical power of 0.8.  A total of 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase Ib study, and 133 patients were randomized (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase II clinical trial, 129 (97 %) of whom received at least 1 dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin).  Median PFS in phase II was 6.6 months (95 % confidence interval [CI]: 4.1 to 8.3) with olaratumab plus doxorubicin and 4.1 months (2.8 to 5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44 to 1.02, p = 0.0615).  Median OS was 26.5 months (20.9 to 31.7) with olaratumab plus doxorubicin and 14.7 months (9.2 to 17.1) with doxorubicin (stratified HR 0.46, 0.30 to 0.71, p = 0.0003).  The ORR was 18.2 % (9.8 to 29.6) with olaratumab plus doxorubicin and 11.9 % (5.3 to 22.2) with doxorubicin (p = 0.3421).  Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/ml (geometric coefficient of variation in percentage [CV %] 26.2) to 487 μg/ml (CV % 33.0) and from 123 μg/ml (CV % 31.2) to 156 μg/ml (CV % 38.0), respectively.  Adverse events (AEs) that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58 %] versus 23 [35 %]), mucositis (34 [53 %] versus 23 [35 %]), nausea (47 [73 %] versus 34 [52 %]), vomiting (29 [45 %] versus 12 [18 %]), and diarrhea (22 [34 %] versus 15 [23 %]).  Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: 8 [13 %] of 64 patients versus doxorubicin: 9 [14 %] of 65 patients).  The authors concluded that the findings of this study of olaratumab with doxorubicin in patients with advanced STS met its pre-defined primary end-point for PFS and achieved a highly significant improvement of 11.8 months in median OS, suggesting a potential shift in the treatment of STS.

The FDA originally granted olaratumab an accelerated approval in October 2016 on the basis of data from the smaller trial by Tap et al, but required further data from a larger study to confirm that it improved survival. The ANNOUNCE trial is a phase 3, randomized, double-blind study of olaratumab, in combination with doxorubicin, followed by olaratumab monotherapy compared with doxorubicin plus placebo, followed by placebo, in patients with advanced or metastatic soft tissue sarcoma (STS). The two primary endpoints were overall survival (OS) in the intent-to-treat (ITT) population and in the leiomyosarcoma sub-population. Patients with locally advanced, unresectable or metastatic STS not amenable to curative treatment were enrolled and were eligible with any prior number of treatment regimens, provided they had not previously received treatment with an anthracycline. Olaratumab was administered at a loading dose of 20 mg/kg on days 1 and 8 of cycle 1 and 15 mg/kg on days 1 and 8 of all subsequent cycles in combination with doxorubicin 75 mg/m2 administered on day 1 of each cycle. Placebo was administered in combination with doxorubicin for 8 cycles. Olaratumab was continued as monotherapy until disease progression. Key secondary endpoints include safety, progression-free survival, objective response rate, and patient-reported outcomes.

In January 2019, Eli Lilly and Company reported that the results of ANNOUNCE did not confirm the clinical benefit of olaratumab in combination with doxorubicin as compared to doxorubicin. Specifically, the study did not meet the primary endpoints of overall survival (OS) in the full study population or in the leiomyosarcoma (LMS) sub-population; there was no difference in survival between the study arms for either population. In patients treated with olaratumab and doxorubicin OS was 20.4 months, compared with 19.7 months for doxorubicin alone. In the leiomyosarcoma sub-population OS was 21.6 months on the olaratumab combination compared with 21.9 months for doxorubicin. Progression-free survival for patients taking olaratumab and doxorubicin was 5.4 months, compared with 6.8 months on doxorubicin. Olaratumab was well tolerated; there were no new safety signals identified and the safety profile was comparable between treatment arms.

Lilly plans to present the ANNOUNCE data at an upcoming medical conference and will publish the results in a medical journal. Meanwhile, patients who are already receiving olaratumab may, in consultation with their physician, continue their course of therapy if they are receiving clinical benefit. For patients who have not previously received olaratumab, the results of the Phase 3 trial do not support initiating treatment with olaratumab in patients with STS, outside of participation in a clinical trial.

At this time, Lilly is suspending promotion of olaratumab and has announced that the company has been working to facilitate the withdrawal of olaratumab from the market for the treatment of patients with advanced soft tissue sarcoma (STS). Lilly has now opened a Lartruvo Patient Access Program (“PAP”) for those patients currently being treated with olaratumab . Participation in the PAP will be the ONLY way a patient may remain on therapy after olaratumab has been withdrawn from the market. Enrollment in the PAP must be completed by July 31, 2019.

Warnings and Precautions

  • Infusion-Related Reactions: Monitor for signs and symptoms during and following infusion.  Discontinue Lartruvo for grade 3 or 4 infusion-related reactions.
  • Embryo-Fetal Toxicity: Can cause fetal harm.  Advise females of potential risk to the fetus and to use effective contraception during treatment with Lartruvo and for 3 months after the last dose.

Adverse Reactions

  • The most common (greater than or equal to 20 %) adverse reactions of Lartruvo plus doxorubicin are nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache.
  • The most common (greater than or equal to 20 %) laboratory abnormalities are lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated activated partial thromboplastin time (aPTT), hypokalemia, and hypophosphatemia. 

The NCCN Drugs and Biologics Compendium (NCCN, 2019) removed doxorubicin and olaratumab as a combination regimen for soft tissue sarcoma subtypes with non-specific histologies.

Solid Tumors

In a phase I study, Chiorean and colleagues (2014) evaluated the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary anti-tumor activity of olaratumab in patients with advanced solid tumors. Patients were enrolled into 5 dose-escalating cohorts of 3 to 6 patients each.  Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1 to 3) or once every other week at 15 or 20 mg/kg (cohorts 4 to 5), with 4 weeks/cycle.  A total of 19 patients were treated in 5 cohorts.  There were no dose-limiting toxicities (DLTs); the MTD was not identified with the doses studied.  The most common olaratumab-related AE were fatigue and infusion reactions (10.5 % each).  With the exception of 1 patient (20 mg/kg) experiencing 2 grade 3 drug-related AEs after the DLT assessment period, all drug-related AEs were grade 1 or 2.  The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg bi-weekly were higher than 155 μg/ml, and the concentration found to be effective in pre-clinical xenograft models; 12 patients (63.2 %) had a best response of stable disease [SD; median duration of 3.9 months (95 % CI: 2.3 to 8.7)].  The authors concluded that olaratumab was well-tolerated and showed preliminary anti-tumor activity; RP2Ds were 16 mg/kg weekly and 20 mg/kg bi-weekly.  They stated that phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.

In a single-center, dose-escalation, phase I clinical trial, Doi and associates (2014) examined the effectiveness of olaratumab in Japanese patients with advanced/refractory solid malignancies; 3 to 6 patients were enrolled into each of 3 cohorts: Patients received intravenous olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3.  The primary objective was to establish the safety and pharmacokinetic profile of olaratumab.  A total of 16 patients were treated across 3 cohorts.  There were no DLTs, so the MTD was not reached.  The most common olaratumab-related treatment-emergent adverse events (TEAEs) were proteinuria (25.0 %) and elevated aspartate transaminase (12.5 %); 1 patient (cohort 2) had 2 olaratumab-related grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab-related TEAEs were grade ½; 7 patients (43.8 %) had a best response of stable disease.  The authors concluded that based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/ml target.  They stated that these 2 doses could represent an acceptable schedule for future trials in Japanese patients.  Olaratumab had an acceptable safety profile and was well-tolerated.

Uterine Sarcoma

National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2019) removed doxorubicin and olaratumab as a combination regimen for the treatment of uterine sarcoma.

Gastro-Intestinal Stromal Tumors

In a phase-II clinical trial, Wagner and colleagues (2017) evaluated tumor response to olaratumab in previously treated patients with metastatic gastro-intestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively).  Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred.  Outcome measures were 12-week tumor response, PFS, OS, and safety.  Of 30 patients enrolled, 21 patients received greater than or equal to 1 dose of olaratumab.  In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed; SD was observed in 3 patients (50.0 %) in cohort 1 and 2 patients (14.3 %) in cohort 2.  Progressive disease (PD) was observed in 3 patients (50.0 %) in cohort 1 and 12 patients (85.7 %) in cohort 2.  The 12-week clinical benefit rate (CR + PR + SD) (90 % CI) was 50.0 % (15.3 to 84.7 %) in cohort 1 and 14.3 % (2.6 to 38.5 %) in cohort 2; SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2).  Median PFS (90 % CI) was 32.1 (5.0 to 35.9) weeks in cohort 1 and 6.1 (5.7 to 6.3) weeks in cohort 2.  Median OS was not reached in cohort 1 and was 24.9 (14.4 to 49.1) weeks in cohort 2.  All patients in cohort 1 and 9 (64.3 %) in cohort 2 experienced an olaratumab-related AE, most commonly fatigue (38.1 %), nausea (19.0 %), and peripheral edema (14.3 %).  Two grade greater than or equal to 3 olaratumab-related AEs were reported (cohort 1, syncope; cohort 2, hypertension).  The authors concluded that olaratumab had an acceptable AE profile in patients with GIST.  While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype.  These investigators stated that in the present study’s cohort of 7 patients with PDGFRα-mutant tumors treated with olaratumab, median PFS exceeded 24 weeks.  While the small sample sizes (n = 6 and n= 14) and inter-study heterogeneity limited the ability to reach definitive conclusions, these results provided interest for further study of PDGFRα-mutant GIST in a larger study.

Other Experimental Indications

Mo and associates (2018) characterized the pharmacokinetics (PKs) of olaratumab in a cancer patient population.  Olaratumab was tested at 15 or 20 mg/kg in 4 phase-II clinical trials (in patients with non-small cell lung cancer (NSCLC), glioblastoma multiforme (GBS), STS, and GISTs) as a single-agent or in combination with chemotherapy.  PK sampling was performed to measure olaratumab serum levels; PK data were analyzed by non-linear mixed-effect modeling techniques using NONMEM.  The PKs of olaratumab were best described by a 2-compartment PK model with linear clearance (CL).  Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL.  A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab.  There was no difference in the PKs of olaratumab between patients who received olaratumab as a single-agent or in combination with chemotherapy.  The authors concluded that the PKs of olaratumab were best described by a model with linear disposition.  Patient body weight and tumor size were found to be significant co-variates; and the PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

In a phase-II clinical trial, Gerber and colleagues (2017) evaluated the safety and effectiveness of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC.  Patients received up to 6 21-day cycles of P 200 mg/m2 and C AUC 6 (day 1) ± olaratumab 15 mg/kg (days 1 and 8).  Primary end-point was PFS.  Olaratumab was continued in the olaratumab+P/C arm until disease progression.  A total of 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74 % had non-squamous NSCLC.  Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95 % CI: 0.86 to 1.93]; p = 0.21).  Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95 % CI: 0.68 to 1.57; p = 0.87).  Both arms had similar toxicity profiles.  All evaluable cases were PDGFR-negative by immunohistochemistry.  Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78 % were positive.  The authors concluded that the addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC.  Olaratumab studies in other patient populations, including soft tissue sarcoma, pancreatic cancer, and pediatric malignancies are underway.

There are also clinical trials that examine the use of olaratumab for the treatment of various diseases/disorders including angiosarcoma, epithelioid sarcoma, fibrosarcoma, gastro-intestinal stromal tumors, glioblastoma, liposarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, synovial sarcoma, and undifferentiated pleomorphic sarcoma.

Table: CPT Codes / HCPCS Codes / ICD-9 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB :

96413 - 96415 Chemotherapy administration, IV infusion technique

HCPCS codes covered if selection criteria are met:

J9285 Injection, olaratumab, 10 mg

Other HCPCS codes related to the CPB:

J9000 Injection, doxorubicin hydrochloride, 10 mg

ICD-10 codes covered if selection criteria are met:

C22.3 Angiosarcoma of liver
C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9 Malignant neoplasm of other connective and soft tissue [only covered for soft tissue sarcoma (STS)]
C54.0 - C55 Malignant neoplasm of corpus uteri

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C25.0 - C25.9 Malignant neoplasm of pancreas
C34.00 - C34.92 Malignant neoplasm of bronchus and lung [Non-small cell lung cancer].
C40.00 - C41.9 Malignant neoplasm of bone and articular cartilage
C49.A0 - C49.A9 Gastrointestinal stromal tumors [only covered for soft tissue sarcoma (STS)]
C56.1 - C56.9 Malignant neoplasm of ovary
C71.0 - C71.9 Malignant neoplasm of brain

The above policy is based on the following references:

  1. Chiorean EG, Sweeney C, Youssoufian H, et al. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;73(3):595-604.
  2. Doi T, Ma Y, Dontabhaktuni A, et al. Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(7):862-869.
  3. Sheng JY, Movva S. Systemic therapy for advanced soft tissue sarcoma. Surg Clin North Am. 2016;96(5):1141-1156.
  4. Martin-Broto J, Hindi N. Targeted treatments of sarcomas and connective tumors beside gastrointestinal stromal tumor. Curr Opin Oncol. 2016;28(4):338-344.
  5. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: An open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497.
  6. U.S. Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. Silver Spring, MD: FDA; October 19, 2016. 
  7. Eli Lilly and Company. Lartruvo (olaratumab) injection, for intravenous use. Prescribing Information. LAR-0001-USPI-20161019. Indianapolis, IN: Lilly; revised October 2016. 
  8. National Comprehensive Cancer Network (NCCN). Olaratumab. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN; 2019.
  9. Wagner AJ, Kindler H, Gelderblom H, et al. A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors. Ann Oncol. 2017;28(3):541-546.
  10. Gerber DE, Swanson P, Lopez-Chavez A, et al. Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC. Lung Cancer. 2017;111:108-115.
  11. National Institutes of Health. ClinicalTrials.gov. Olaratumab/United States. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=olaratumab&cntry1=NA%3AUS&state1=&Search=Search. Accessed October 4, 2017.
  12. Mo G, Baldwin JR, Luffer-Atlas D, et al. Population pharmacokinetic modeling of olaratumab, an anti-PDGFRα human monoclonal antibody, in patients with advanced and/or metastatic cancer. Clin Pharmacokinet. 2018;57(3):355-365.
  13. Singhi EK, Moore DC, Muslimani A. Metastatic soft tissue sarcomas: A review of treatment and new pharmacotherapies. P T. 2018;43(7):410-429.
  14. Zobniw CM, Trinh VA, Posey K, Somaiah N. Olaratumab in the management of advanced soft tissue sarcoma. J Oncol Pharm Pract. 2018 Jan 1 [Epub ahead of print].
  15. Zheng G, Richmond A, Liu C, et al. Clinicopathologic features and genetic alterations of a primary osteosarcoma of the uterine corpus. Int J Gynecol Pathol. 2018 Apr 6 [Epub ahead of print].
  16. Eli Lilly and Company (Lilly). Lilly Reports Results of Phase 3 Soft Tissue Sarcoma Study of LARTRUVO. Press Release. Princeton, NJ: BMS; July 6, 2017.
  17. U.S. Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. FDA News. Silver Spring, MD: FDA; January 24, 2019 update.
  18. Staines R. No new patients should take Lilly’s cancer drug Lartruvo, say regulators. Pharmaphorum, January 28, 2019. Available at: https://pharmaphorum.com/news/no-new-patients-should-take-lillys-cancer-drug-lartruvo-say-regulators/. Accessed October 6, 2019.
  19. Eli Lilly and Company. Lartruvo (olaratumab) injection, for intravenous use. Prescribing Information. LAR-0003-USPI-20180808. Indianapolis, IN: Lilly; revised August 2018. 
  20. National Comprehensive Cancer Network (NCCN). Soft Tissue Sarcoma. NCCN Clinical Practice Guidelines in Oncology, version 2.2019. Fort Washington, PA: NCCN; 2019.
  21. National Comprehensive Cancer Network (NCCN). Uterine Neoplasms. NCCN Clinical Practice Guidelines in Oncology, version 3.2019. Fort Washington, PA: NCCN; 2019.