Harmonization of the Upfront Osteosarcoma Treatment Paradigm for Adolescents and Young Adults

Abstract

Limited guidance exists on streamlining cancer therapy for adolescent and young adult (AYA) patients 15–39 years of age, as much of the current data are extrapolated from pediatric or adult counterparts and can differ significantly between the two care models. Harmonization of standard treatment approaches has the potential to improve outcomes and establish a foundation for the development of future clinical trials. We present our experience harmonizing treatment and supportive care regimens for AYA patients with osteosarcoma receiving treatment with methotrexate, doxorubicin, and cisplatin (MAP) therapy on the pediatric and adult sarcoma services at the Memorial Sloan Kettering Cancer Center.

Introduction

Adolescents and young adults (AYAs), defined by the National Cancer Institute (NCI) as individuals between the ages of 15–39 years, comprise a distinct and vulnerable subpopulation of patients with cancers.¹ With diverse needs and issues, AYA cancer-specific and overall outcomes have often lagged behind those of younger and older patients.² This stems from several issues, including poor clinical trial access and participation, and unclear guidance about best antitumor and supportive care practices, delaying the creation of optimal treatment paradigms and improved understanding of specific cancer pathophysiology.³ In several prototypical AYA cancers, best exemplified by acute lymphoblastic leukemia, disparate outcomes have been observed for AYA patients treated in the context of a pediatric or adult cooperative group trials.⁴ Subsequent studies have demonstrated that when limited to patients sharing similar biology, more intensive dosing and schedule of chemotherapy utilizing pediatric-based regimens alone can deliver comparable outcomes, regardless of whether treated by adult or pediatric oncology services.⁵

Osteosarcoma (OS) is the most common primary malignancy of bone and another prototypical AYA cancer, with bimodal incidence peaks in the second and seventh decades. OS outcomes have been stagnant for more than four decades and remain universally unsatisfactory, particularly in patients with de novo metastatic or relapsed, refractory disease.⁶ Furthermore, the treatment of OS requires a multidisciplinary approach with medical, surgical, and sometimes radiation oncology services allowing several opportunities for a divergence in practice. While the consensus at Memorial Sloan Kettering Cancer Center (MSK) for upfront therapy of OS was the MAP regimen [high-dose methotrexate (HD-MTX), doxorubicin, and cisplatin] in the neoadjuvant and adjuvant setting, differences in treatment existed across the dosing and administration of cytotoxic agents, the utilization of various supportive care measures, and the criteria for inpatient hospital admission. This article outlines efforts to achieve consensus on standard practice (hereafter referred to as harmonization) and implement a unified institutional treatment approach to the upfront treatment of AYA patients 15–39 years of age with OS, termed “AYA-MAP.”

Methods

The MSK AYA Sarcoma Treatment Paradigm Working Group was established in August 2020 to harmonize adult and pediatric treatment plans for AYA patients with sarcoma. The core group comprised 7 sarcoma physicians (4 adult and 3 pediatric), 1 AYA advanced practice provider, and 1 clinical pharmacy specialist met virtually, on a biweekly basis, to review literature and current chemotherapy practice, focusing on therapeutic intent, potential toxicities, late effects, and supportive care, until achieving consensus. Once therapeutic recommendations were agreed upon, larger meetings with hospital administration, clinical nursing and pharmacy staff, and informatics occurred to organize implementation.

Harmonization efforts began with OS, given pre-existing agreement that “MAP” constituted standard-of-care first-line therapy for patients under the age of 40. Initially, areas of discrepancy between pediatric- and adult-based “MAP” were identified. These included methotrexate dosing, cisplatin dosing, renal function monitoring, mannitol use, intravenous hydration composition and administration, dexrazoxane frequency and timing, antiemetic guidance, prophylaxis against Pneumocystis jirovecii pneumonia, and inpatient vs. outpatient administration of HD-MTX. Between August 2020 and December 2022, the working group performed a literature review through PubMed ® to establish the rationale and evidence behind current practices. If no such literature existed, additional external expert opinion was sought from a minimum of 2 experts either extensively involved in the early clinical trials for OS, or those involved in establishing institutional or national chemotherapy administration guidelines. Consensus, defined as unanimous agreement of the core group, was achieved on each discrepant practice and a best-practice guideline for first-line therapy was created (AYA-MAP). AYA-MAP was circulated among all practicing adult and pediatric sarcoma specialists and providers for comment and discussed in team meetings; individual concerns were addressed by the core clinical working group. Once final harmonization was achieved, AYA-specific electronic order sets were created and disseminated across the institution together with the AYA-MAP guidelines and education provided for implementation.

Results

Methotrexate dosing

In MAP therapy, the recommended dose of HD-MTX is 12 grams/m² based on prior trials. Pediatric practice at MSK was to cap the maximum methotrexate dose at 20 grams, regardless of body surface area; the adult practice had no dose cap, permitting doses >20 grams of methotrexate. No data could be identified documenting a biological or pharmacologic rationale for dose capping, but expert opinion gleaned from historical experience with toxicity, and international precedent led to the decision to cap the maximum individual methotrexate dose at 20 grams.⁷ Although historically adult patients >40 years of age did not receive methotrexate due to concern for tolerability, AYA patients should receive HD-MTX unless documented history of or concerns for significant toxicity exist.⁸

Cisplatin dosing

Historically within the Department of Pediatrics, cisplatin was dosed at 120 mg/m² intravenous (IV) once daily over 4 hours during weeks 1 and 6 of induction, and weeks 1 and 6 of consolidation chemotherapy after surgical resection.^9,10 Alternative dosing includes 120 mg/m² as a 72-hour continuous IV infusion (EURAMOS-1) or 60 mg/m² IV daily for two days (Children’s Oncology Group trials).⁷ Cumulative doses of cisplatin were equivalent between the different trials. Literature review revealed no comparative efficacy data; however, potential differences in the frequency of adverse effects, specifically ototoxicity, were noted. Ototoxicity with cisplatin has been shown to be dose dependent, with higher single, as well as cumulative doses >400 mg/m² resulting in hearing loss.^11–13 In a prior study by Lewis et al., 7 of 9 patients (78%) receiving single-day dosing developed hearing loss as compared with 8/27 (30%) who received split-day dosing (p = 0.019).¹⁴ As such, consensus recommendations are to administer cisplatin 60 mg/m² IV daily for two days to minimize potential dose-dependent ototoxic adverse effects associated with cisplatin. The data in current literature regarding the safe use of delayed sodium thiosulfate to mitigate cisplatin-associated hearing loss in patients with OS was considered too sparse to warrant its routine use.¹⁵

Renal function monitoring

The last large cooperative group trial for newly diagnosed OS patients (AOST0331/EURAMOS-1) recommended glomerular filtration rate (GFR) to be measured before each dose of cisplatin given the risk for cisplatin-induced nephrotoxicity, using radionuclide measurement or estimated based on the patient’s serum creatinine using the Schwartz formula (ages 1–18) or the Cockcroft–Gault formula (>18 years). A major limitation of using creatinine-based equations to measure renal function is reliance on muscle mass.¹⁶ A 24-hour urine collection to measure creatinine clearance and estimate GFR has similar limitations and can be both time consuming and prone to collection errors, leading to spurious results. The pediatric practice at MSK had transitioned to using a serum-based method incorporating measurements of cystatin-c, blood urea nitrogen, creatinine, and height. This method has been shown to provide the most precise and accurate estimate of GFR in both adult and pediatric patient populations.^16,17 Additionally, with a turnaround time of 2 hours at our institution, this method can be drawn on day 1 of a patient’s cisplatin cycle without significant delays in treatment. Therefore, the working group recommended cystatin-c for the routine monitoring of renal function in AYA patients receiving MAP therapy, with a radionuclide measurement of GFR if the estimate by this method were < 60 mL/minute/1.73 m².

Mannitol use

At MSK, mannitol has historically been administered to aid in diuresis and potentially minimize nephrotoxicity associated with cisplatin. There is conflicting data on the benefit of mannitol to reduce the incidence of nephrotoxicity when administered with cisplatin.¹⁸ When saline-alone hydration was compared with saline + furosemide and saline + mannitol in women receiving cisplatin 75 mg/m² for treatment of gynecological malignancies, saline alone or saline + furosemide was more effective at preventing nephrotoxicity compared with saline + mannitol, although the sample size was small.¹⁹ A systematic review performed by Crona and colleagues also concluded that hydration is the most effective way to prevent nephrotoxicity associated with cisplatin, however, concomitant mannitol use could be considered in patients receiving cisplatin doses ≥100 mg/m² or in those with baseline hypertension.²⁰ The pediatric literature similarly concluded that both pre- and posthydration alone for cisplatin doses <100 mg/m² should be considered.^21,22 Based on the mixed benefit of mannitol diuresis highlighted by the literature, especially for doses <100 mg/m², the decision was made to exclude routine mannitol diuresis in AYA patients receiving cisplatin 60 mg/m² IV daily for two days.^20–22 However, at provider discretion, mannitol could be administered if it was thought that the patient would benefit from forced diuresis.

Outpatient administration of HD-MTX and intravenous fluid harmonization for HD-MTX and cisplatin

Before harmonization, all OS patients treated by the adult service were admitted to the inpatient unit to receive HD-MTX, whereas patients treated by the pediatric service were initially treated as outpatient, and only admitted for recurrent delayed MTX excretion resulting in toxicity or for complex logistical or psychosocial challenges. Details of the MSK experience with outpatient administration of HD-MTX have been described by Zelcer and colleagues.²³ Briefly, HD-MTX is administered outpatient over 4 hours and is preceded by oral sodium bicarbonate starting 18 hours prior, to ensure urine pH ≥ 7. Intravenous hydration is administered daily in clinic at a starting rate of 3 L/m²/day, and adjusted as needed based on serum methotrexate levels, urine output, and creatinine. To maintain appropriate hydration overnight at home, patients are discharged from the outpatient infusion clinic with an ambulatory intravenous infusion. Oral leucovorin administration starts 24 hours after initiation of HD-MTX, and is adjusted based on serum methotrexate levels, which are drawn every 24 hours after the start of HD-MTX until the patient’s serum methotrexate level is <0.1 µmol/L. With extensive experience of administering outpatient HD-MTX on the pediatric oncology service, including AYA patients, and in the absence of evidence to suggest increased toxicity, it was decided to provide extensive education to the adult sarcoma service to be able to extend this practice to all AYA patients. Outpatient HD-MTX administration introduced the routine use of overnight IV hydration for AYA patients treated on the adult service. As a result, hydration for cisplatin was also harmonized, with plan to administer fluids with electrolytes post cisplatin over five hours, similar to current practices in pediatric service administration with the potential to continue hydration overnight for patients with significant nausea or emesis.

Dexrazoxane

Despite the potential benefits of dexrazoxane as a cardioprotectant against potentially cardiotoxic effects of doxorubicin, there were initial concerns that it may decrease therapeutic effects of anthracyclines or lead to secondary neoplasms, neither of which were definitively validated in prior trials.^24,25 Recent international guideline recommendations for children receiving anthracycline support the use of dexrazoxane when cumulative doses of doxorubicin are anticipated to exceed 250 mg/m².²⁶ Additionally, the use of dexrazoxane in patients with OS was shown by Schwartz and colleagues to not impact tumor response.²⁷ As a result, OS patients treated on the pediatric service receive dexrazoxane with the first dose of doxorubicin therapy. However, in part because of reimbursement issues, patients treated on the adult service did not routinely receive dexrazoxane until cumulative doses reached 300 mg/m² in accordance with the original U.S. Food and Drug Administration (FDA) approval for use in breast cancer therapy. The long-term efficacy of dexrazoxane has been evaluated, and patients who received dexrazoxane before doxorubicin are more likely to have a superior ejection fraction compared with those who did not receive the agent.²⁸ In light of this evidence, the working group recommended all AYA patients receiving MAP receive dexrazoxane with the start of doxorubicin to minimize anthracycline-related cardiotoxicity.

Antiemetics

A major challenge to antiemetic harmonization was the discrepancy between classification of emetic potential of HD-MTX (12 g/m²) between adult and pediatric guidelines. Current adult guideline recommendations classify HD-MTX as either low or moderate emetic potential.²⁹ However, current pediatric practice guidelines classify HD-MTX as highly emetogenic.³⁰ With the documented historical risk of chemotherapy-induced nausea and vomiting in pediatric patients receiving HD-MTX despite prophylaxis, HD-MTX for OS was reclassified as highly emetogenic across the institution, requiring prophylaxis with a neurokinin 1 receptor antagonist (NK1 RA), serotonin receptor antagonist (5-HT3 RA) and dexamethasone.

Additional variations in practice included the choice of intravenous NK1 RA and 5-HT3 RA. The adult practice administered IV aprepitant, whereas the pediatric practice historically administered IV fosaprepitant, given limited published data of IV aprepitant use in pediatric patients. Since IV aprepitant is associated with fewer allergic reactions and decreased cost, the safe use of IV aprepitant was extrapolated to all AYA patients due to similar weights, and subsequently to all pediatric patients ages 6 and above.³¹ The 5-HT3 RA for patients treated on the adult service was palonosetron whereas on the pediatric service, it was ondansetron. Due to variations in practice that would impact other services if choice of 5-HT3 RA was changed and minimal differences when used with an NK1 RA, it was decided to maintain the status quo.

Pneumocystis Jirovecii pneumonia (PJP) prophylaxis

As patients receiving MAP lack many of the high-risk factors for PJP development (e.g., hematopoietic stem cell transplantation, hematological malignancies, prolonged use of corticosteroids, use of purine analogs, or other T cell depleting agents, or prolonged CD4 T-lymphocyte counts <200/µL) and there are potential, although controversial, risk of drug–drug interactions when trimethoprim–sulfamethoxazole is administered with HD-MTX, neither the adult nor pediatric services routinely recommend PJP prophylaxis.^32–34 Based on current clinical experience and desire to avoid any potential drug–drug interactions, it was decided to continue to omit primary PJP prophylaxis in all patients receiving MAP therapy.

Implementation of the AYA MAP guidelines

Implementation of the harmonized AYA MAP care paradigm required a coordinated effort of the pediatric and adult services to achieve evidence-based consensus beyond the core working group and support outpatient administration of HD-MTX. Decisions were made to enhance patient experience, minimize long-term toxicities and to support financial stewardship and were ultimately supported by the hospital administration. Once the clinical guidelines were finalized, a subsequent taskforce met to formulate practical application and roll out, including development of electronic order sets for chemotherapy, hydration, and supportive medications, as well as multidisciplinary workflows. Compliance with the AYA MAP order set was encouraged using an alert through the electronic health system if a provider ordered MAP therapy for patient ages 15–39 years outside of the AYA specific order set.

Given the high volume of patients receiving chemotherapy at MSK at various sites, the harmonization of ordering, verification, preparation, administration, supportive care, and monitoring had to be extensively orchestrated. Workflows and staff education were developed for prescribing physicians, advanced practice providers, clinical pharmacists, infusion nurses, medical oncology office practice nurses, clinical nurse specialists, and nurses and pharmacists who verify chemotherapy and supportive medication orders. Training was also needed for after-hours teams, on-call medical oncology fellows, and facilities and scheduling operations. Patient education resources describing the necessity and process for monitoring urine output and pH were refined and published in the MSK Patient and Caregiver Education Resource Library for access by patients and health care providers. The harmonization of AYA MAP diverged from other historical care models (e.g., younger patients treated with MAP by the pediatric service) for which adjustments in nomenclature, practice, and education were made to optimize safety and comprehension. The total harmonization and implementation of AYA MAP required approximately 2.5 years from inception to completion. Given this was the first AYA practice guideline to be implemented at MSK, the assumption is future initiatives will be less time intensive. Further details of harmonization can be found in Table 1.

Table 1.

Details of Prior Pediatric and Adult Practice at MSK and Harmonization Agreed upon for AYA Sarcoma Patients

	Department of medicine	MSK kids	AYA harmonization
HD-MTX Administration	Inpatient	Outpatient	Outpatient
HD-MTX Dose	No dose cap	Dose cap: 20 grams	Dose cap: 20 grams
Urine pH Monitoring	Inpatient	Chemo infusion & home	Chemo infusion & home
Mannitol	No	Yes	No
Dexrazoxane	Physician discretion	Initiation of anthracycline	Initiation of anthracycline
Venous Access	Usually Peripheral	Central	Central
Supportive care (i.e., hydration, antiemetics) harmonized

AYA, adolescent and young adult; HD‐MTX, high‐dose methotrexate; MSK, Memorial Sloan Kettering Cancer Center.

Conclusion

Through the process of MAP harmonization for AYA patients between the adult and pediatric practices at MSK, the differences surrounding the administration of upfront MAP chemotherapy were better understood and rectified based on literature review and expert consensus. In addition to our work at MSK, recent European clinical recommendations highlight the disparities in treatment for adolescents with OS, highlighting the need for further studies in this area.³⁵ Harmonization is expected to facilitate a data-driven treatment paradigm of patients by removing historical and anecdotal biases and identifying a single standard of care upon which future novel therapies can be layered. Such consensus has further promoted awareness of the unique needs of the AYA population and has spurred further efforts in other canonical AYA tumors. Future directions of this harmonization effort include evaluating patient outcomes and adverse effects, as well as provider satisfaction for AYA sarcoma patients treated with the AYA MAP regimen. Overall, this working group established a process for harmonizing roadmaps and treatment paradigms for AYA cancers at our institution that will be applied to other cancers, incorporating decisions regarding multimodal therapy, salvage regimens, and clinical trial prioritization.

Footnotes

Authors’ Contributions

N.P.D.: conceptualization (equal); writing—original draft (equal); and writing—review and editing (equal). V.A.: conceptualization (equal); writing—original draft (equal); and writing—review and editing (equal). E.L.S.: conceptualization (equal); writing—original draft (equal); and writing—review and editing (equal). M.D.K.: writing—review and editing (equal). E.K.S.: writing—review and editing (equal). K.T.: writing—review and editing (equal). M.A.D.: writing—review and editing (equal). N.T.S.: writing—review and editing (equal). W.D.T.: conceptualization (equal); and writing—review and editing (equal). J.G.B.: conceptualization (equal); writing—review and editing (equal).

Author Disclosure Statement

N.P.D. is a shareholder in Merck, with stock options < $5,000. K.T. is currently employed by Janssen Research and Development, L.L.C., and M.D.K. is currently employed by Regeneron, however work was done while employed at MSK. All other authors have no major conflicts of interests to disclose.

Funding Information

This work was supported by the NCI Cancer Center Support Grant P30 CA008748.

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