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Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure

Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and... Background: Doxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposo- mal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma. Case presentation: In this report, we describe a patient with high-grade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Second-line treat- ment with PLD resulted in long-term disease remission during a 20-year follow-up period. Mucositis and hand-foot syndrome were controlled by adjustment of dose and treatment interval. Conclusions: This case illustrates the curative potential of PLD after failure of free doxorubicin and the absence of long term cardiotoxicity with PLD. As with all drugs, individual adjustment of dose and treatment interval is important. Keywords: Pegylated-liposomal doxorubicin, Doxorubicin, Sarcoma Background toxicity obviates the need for premedication [6, 9–14]. The median survival of patients with metastatic soft tis - PLD’s main toxicities are hand-foot syndrome, low risk of sue sarcomas (STS) is only 12–15  months [1]. Doxo- infusion reaction, and some fatigue [6, 9–11, 13, 14]. It rubicin is one of the most active drugs available for has been hypothesized that the symptoms of the infusion treatment of STS [2–6], although cardiotoxicity can be reaction, which are associated with transient neutrope- dose-limiting. Pegylated-liposomal doxorubicin (PLD) is nia, reflect neutrophil sludging in the microvasculature a formulation of doxorubicin in which the doxorubicin as observed with hemodialysis neutropenia [15]. We do is encapsulated in liposomes coated with methoxypoly not routinely pre-medicate patients receiving PLD. In (ethylene glycol). Unlike doxorubicin, PLD’s uptake by addition, PLD has been shown to localize to implanted the reticuloendothelial system is decreased, resulting in tumors in animals [16] and deliver more doxorubicin different pharmacologic properties, including a longer to the tumor than free doxorubicin in Kaposi sarcoma, half-life in blood and different toxicities [ 7–10]. PLD is prostate cancer, and breast cancer [9, 17, 18]. While PLD associated with less cardiotoxicity, nausea, alopecia, and has a better toxicity profile than free doxorubicin, there myelosuppression than free doxorubicin; this reduced is no consensus on the relative efficacy of PLD and free doxorubicin in STS because of the small number of trials directly comparing these two agents. In this report, we describe a patient with high-grade *Correspondence: skubi001@umn.edu Department of Medicine, University of Minnesota Medical School, Office metastatic STS with rapid recurrence after adjuvant Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455, USA treatment with free doxorubicin, cisplatin, ifosfamide, Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Savani et al. Clin Sarcoma Res (2019) 9:1 Page 2 of 7 and dacarbazine. The patient’s treatment was changed to immunoprofile were thought to represent an undifferen - PLD, and no recurrence was observed during a follow- tiated pleomorphic sarcoma (UPS). up period of more than 20 years. This case illustrates the Two months after resection of the intra-abdominal curative potential of PLD after treatment failure with free mass, the tumor recurred (Fig.  1). He underwent resec- doxorubicin and the absence of long-term cardiotoxicity tion of multiple masses in the falciform ligament, left with PLD. pelvic side wall, small bowel, mesentery, and retroperito- neum. Multiple lymph nodes were also resected. Patho- logical examination was again thought to be consistent Case presentation with leiomyosarcoma. A 37-year-old white man with a past medical history of After recovery from surgery the patient received three mitral valve prolapse and gastritis presented with abdom- courses of adjuvant chemotherapy with cisplatin, ifos- inal pain. A computed tomography (CT) scan revealed an famide, dacarbazine, and doxorubicin. This involved 2 2 18 cm × 17  cm × 11 cm colonic flexure mass. The patient 50  mg/m of cisplatin on day 1; doxorubicin 65  mg/m underwent a resection of the intraabdominal mass with on day 1; dacarbazine 300 mg/m on days 1, 2 and 3; and partial small bowel resection, resection of distal trans- ifosfamide 2.5 grams/m a day by continuous infusion for verse and descending colon with enteroenterostomy, as 3 days. This treatment was well tolerated, aside from neu - well as colocolostomy, appendectomy and gastrostomy tropenic fevers requiring hospitalization. (Fig. 1). Pathology was thought to be consistent with leio- Three months later, however, a CT scan revealed myosarcoma, grade 3/3. a 4-cm metastatic lesion in the left lobe of the liver. The gastric wall tumor showed a high-grade spindle The patient underwent a partial left hepatectomy and cell neoplasm with focal epithelioid features (Fig.  2B). cholecystectomy. Numerous atypical mitotic figures were noted. The back - Three months later, a CT revealed multiple 2–3  cm ground showed moderate amounts of  chronic inflam - lesions along the margin of the previous partial left hepa- matory infiltrate. The tumor was originally thought to tectomy. At the time, the patient noted night sweats and represent a gastrointestinal leiomyosarcoma. Subsequent low-grade fevers of 99–100  °F, but good appetite and no studies performed 20 years later (Fig. 2) included immu- significant weight loss. The tumor doubled in size during nohistochemical stains showing patchy reactivity for the next 5  weeks and imaging revealed multiple lesions vimentin, cytokeratin AE1/AE3 and cytokeratin 7, while throughout the remaining left lobe. He subsequently other markers tested, including gastrointestinal stro- underwent a complete left hepatectomy and excision of mal tumor and smooth muscle markers were negative. perigastric lymph nodes. Pathological examination was Notably, calretinin was also negative. This histology and thought to confirm metastatic grade 3 leiomyosarcoma Fig. 1 Timeline of treatment Savani et al. Clin Sarcoma Res (2019) 9:1 Page 3 of 7 Fig. 2 A, C, and E (bladder wall tumor): A highly cellular epithelioid (top right) and spindle cell (bottom left) malignancy involving the outer wall of the urinary bladder (A) (H&E ×100). The cells demonstrate round to oval nuclei with variably prominent nucleoli, moderate eosinophilic cytoplasm and indistinct borders (C) (H&E ×400). Immunohistochemistry shows diffuse reactivity for cytokeratin AE1/AE3 and calretinin (inset) (E) (IHC ×100). B, D, and F (remote abdominal tumor): A moderately cellular malignancy with intermixed spindled and epithelioid cells involving the outer gastric wall (B) (H&E ×200). The cells demonstrate irregular nuclei with prominent multiple eosinophilic nucleoli, abundant eosinophilic cytoplasm and indistinct borders (D) (H&E ×400). Immunohistochemistry shows reactivity for cytokeratin AE1/AE3 and negative calretinin (inset) (F) (IHC ×100) of the liver. No extrahepatic involvement or lesions in the PLD, CT imaging revealed multiple metastases in the right lobe were noted by intraoperative ultrasound. remaining left lobe of the liver, the largest being 4 × 4 cm, Five weeks later, the patient noted right upper abdomi- and one spleen nodule. The left ventricular ejection frac - nal fullness and pain, left shoulder pain, and presented to tion (EF) was 58% by multi-gated acquisition (MUGA). our clinic. Pathology review of the earlier resections at The patient began treatment with PLD at 55  mg/m our institution and at another large sarcoma center in the monthly. After 2 cycles of PLD a CT scan showed regres- US agreed with the diagnosis of leiomyosarcoma. A CT sion of tumor nodules. Because of mucositis and hand- scan showed multiple metastases in the right lobe of the foot syndrome the dose was reduced 10% for cycles 2–4 liver and splenic metastases. Immediately before starting and 50% for cycle 5; thereafter, the dose was increased to Savani et al. Clin Sarcoma Res (2019) 9:1 Page 4 of 7 30.8  mg/m monthly starting with cycle 6 and the treat- poorly differentiated biphasic mesothelioma, the overall ment interval lengthened to every 6  weeks starting with clinical presentation, lack of serosal continuity and non- cycle 7. The left ventricular EF was 61% by MUGA before reactivity for ancillary mesothelial markers (WT1, D2-40 cycle 12. After 14 cycles the EF was 62% by MUGA and a and CK 5/6) precluded a definitive diagnosis of the same. CT scan showed a persistent lesion in the spleen. At this The morphology and immunohistochemical staining point, after 14 cycles of PLD, CT imaging revealed no vis- patterns of the remote gastric lesion were compared to ible disease in the liver and the spleen nodule that was that of the bladder neoplasm. Both were poorly differ - unchanged in size but had a lower density. Thus, while entiated neoplasms, but the high magnification cytology a complete response by RECIST criteria was evident in and calretinin reactivity were dissimilar; there was no the liver, the stable size of the spleen nodule indicated a clear evidence that the tumor on the bladder wall repre- partial response to PLD by RECIST. A splenectomy was sented a recurrence of the remote malignancy. His hospi- performed revealing some viable tumor cells in a necrotic tal course was complicated by Citrobacter urinary tract nodule. The patient received 3 more cycles of PLD for a infections and intraabdominal abscesses requiring three total PLD dose of 595 mg/m and a total dose of free dox- intraabdominal drains and intravenous antibiotics. EF orubicin of 196  mg/m . CT imaging revealed no tumor by ultrasound was normal at 55–60%. He subsequently and MUGA showed an EF of 70%. The patient was fol - underwent neoadjuvant gemcitabine and cisplatin fol- lowed with interval imaging with no recurrence. lowed by total cystectomy; the cystectomy specimen Twenty-two years later, the patient experienced sev- showed no evidence of residual tumor. He continues eral months of scrotal pain radiating to his urethra and to do well 4  months after surgery, with no evidence of localized to his right testicle. An ultrasound showed a tumor recurrence. 2.8  cm × 1.6  cm × 0.8  cm mass on the outer surface of the bladder. Fine needle aspiration of the mass showed Discussion and conclusions poorly differentiated carcinoma that was CK7+/CD20+ Doxorubicin remains one of the most active agents and histologically compatible with urothelial origin. A with therapeutic activity against advanced STS [2–6]. PET-CT revealed an intense hypermetabolic pelvic mass Numerous phase II and III trials have been conducted contiguous with the right side of the bladder. An explora- showing superior response rates using a combination of tory laparotomy, intraabdominal mass resection, and doxorubicin and other agents in the treatment of meta- partial cystectomy were performed. static STS, though demonstration of a clear survival Pathologic examination of the bladder wall tumor benefit has been elusive. A phase III trial conducted by showed a 5.5  cm high-grade malignancy with epithe- Judson et  al. found no statistically significant improve - lioid and sarcomatoid features (Fig.  2A). Margins were ment in overall survival with the addition of ifosfamide negative on the perivesical soft tissue mass, and 16 of to doxorubicin for palliative treatment of advanced STS 16 lymph nodes were negative for malignancy. Mitotic [19]. However, this study did show a higher response activity was high, and the background showed moderate rate (26% vs 14%) and longer median progression-free chronic inflammation. It appeared predominantly located survival (7.4 months vs 4.6 months) in the combination in the outer half of the bladder wall, involving the mus- cohort, raising the argument in favor of adding ifosfa- cularis propria and perivesical fat. No mucosal involve- mide to doxorubicin [2, 19]. Our case failed adjuvant ment or in  situ urothelial carcinoma was identified. The treatment with a combination of doxorubicin, cispl- tumor was diffusely and strongly positive for calretinin, atin, ifosfamide, and dacarbazine, but was cured by vimentin and cytokeratin. It was negative for all other subsequent treatment with PLD and resection of one markers tested, including gastrointestinal stromal tumor remaining nodule. One could question exactly what it and smooth muscle markers. Given the presence in the means to be “doxorubicin resistant/refractory.” Techni- bladder and co-expression of keratin and vimentin, it was cally, we did not demonstrate tumor growth while the possible that this represented a urothelial or a urachal patient was receiving doxorubicin. However, the patient remnant-based carcinoma with sarcomatoid differentia - was treated with 3 cycles of a doxorubicin containing tion. However, the location of the tumor (posterior dome, regimen starting at a time when there was no tumor per imaging), lack of associated mucosal lesion, positive detectable by CT imaging. Three months after stop - calretinin stain, and lack of reactivity for urothelial mark- ping the doxorubicin containing regimen, CT imaging ers such as GATA3, p63, and CK5/6 were unusual for revealed a sizable tumor burden. One must conclude the above diagnosis. The diffuse calretinin reactivity, in that either the tumor was not inhibited by the doxoru- conjunction with co-expression of keratin and vimentin, bicin containing regimen or that it kept residual tumor raised the possibility of mesothelial differentiation/ori - cells dormant until it was stopped and then those gin. While the morphology was not incompatible with a tumor cells grew very rapidly, or alternatively, some Savani et al. Clin Sarcoma Res (2019) 9:1 Page 5 of 7 Table 1 Summary of clinical trial results of PLD in sarcoma Study Disease Dosing regimen Organizer/sponsor # of patients Responses and toxicities References Phase 2 STS (many patients had poor PLD 50 mg/m every 4 weeks 13 None Garcia et al. [13] prognostic features, including low- Treatment responses possibly grade tumors affected by poor prognostic features Phase 2 Advanced and/or metastatic STS PLD 30–50 mg/m every 3 weeks 25 3 PRs, 4 minor responses, and 17 Toma et al. [22] Patients were previously treated with patients with SD an anthracycline-based chemo- therapy Phase 2 randomized Advanced STS, with a high propor- PLD 50 mg/m every 4 weeks EORTC Soft Tissue 94 (50 PLD, PLD had equivalent activity as doxo- Judson et al. [6] tion of gastrointestinal stromal Doxorubicin 75 mg/m every and Bone Sarcoma 44 doxoru- rubicin with an improved toxicity tumors 3 weeks Group bicin) profile, including lower incidence of myelosuppression and alopecia. However, a higher incidence of palmar-plantar erythrodysesthesia was noted in the cohort receiving PLD Phase 2 Previously treated sarcomas or PLD 55 mg/m with subsequent 47 3 CR or PR and 15 clinical benefit Skubitz [10] sarcomas considered unresponsive dose adjustment Treatment was generally well toler- to chemotherapy ated, and mucositis and hand-foot syndrome were the dose-limiting toxicities Phase 2 Advanced leiomyosarcoma of the PLD 50 mg/m every 4 weeks 31 CR in 1, PR in 4, and SE in 10 patients Sutton et al. [21] uterus Retrospective analysis Metastatic STS Initial PLD 40–60 mg/m every 11 PR in 6 with extended time to pro- Grenader et al. [14] 4 weeks gression, SD in 2, and PD in 3 (One patient was progression free for 60 months after receiving seven cycles of PLD) Savani et al. Clin Sarcoma Res (2019) 9:1 Page 6 of 7 tumor cells were killed by the doxorubicin containing initiation of bolus doxorubicin to reduce long-term car- regimen, but the remaining cells grew very rapidly over diotoxicity, this is not required with administration of 3  months. In any of these cases, it seems very unlikely PLD, eliminating any concern that dexrazoxane might that it would have been possible to cure the patient decrease anti-tumor activity. with further doxorubicin if 3 cycles starting with no PLD is a different formulation of doxorubicin with residual tumor detectable did not, especially given the different pharmacologic properties and different toxici - size of the tumor burden and the issue of dose related ties than bolus free doxorubicin. In addition to reduced cardiotoxicity. cardiotoxicity, PLD has markedly reduced nausea, alo- PLD is a unique formulation of doxorubicin in that pecia, and myelosuppression, and no anti-emetics or the agent is contained in liposomes coated with hydro- other pre-medications or growth factors are usually philic methoxypoly (ethylene glycol), that diminishes needed. A small number of patients experience an infu- uptake of the agent by the reticuloendothelial system sion reaction in the first few minutes of the first treat - and consequently increases the half-life of the drug in ment, that manifests as shortness of breath or low back blood to approximately 50–60 h [7, 9, 20]. PLD localizes pain. It has been suggested that the symptoms of the to tumors due to increased vascular permeability, result- infusion reaction, which are associated with transient ing in greater drug concentration in tumor in compari- neutropenia, reflect neutrophil sludging in the micro - son to free doxorubicin [9, 16–18]. A number of trials vasculature as observed with hemodialysis neutropenia have demonstrated activity of PLD in a variety of tumors, [15]. Pre-medications have not been shown to prevent including sarcomas (Table  1) [6, 10, 13, 14, 21, 22]. A this reaction, which usually only occurs with the first phase II trial by the EORTC Soft Tissue and Bone Sar- treatment. The main toxicities of PLD are mucositis, coma Group compared the results of 50 patients treated hand-foot syndrome, and mild fatigue. Notably, not all with PLD at 50  mg/m every 4  weeks and 44 patients liposomal formulations are the same; non-pegylated treated with doxorubicin at 75  mg/m every 3  weeks liposomal anthracyclines have different pharmacologic for advanced STS; they found that PLD had equivalent properties and lack some of the favorable properties of activity as doxorubicin with an improved toxicity pro- PLD. file, including lower incidence of myelosuppression and While some early studies used doses of PLD as high alopecia. However, a higher incidence of palmar-plantar as 55 mg/m , this dose is usually too high for a monthly erythrodysesthesia was noted in the cohort receiving treatment schedule; a more typical monthly starting PLD [6]. This study had a high proportion of gastrointes - dose is 45  mg/m . When dose-limiting toxicities are tinal stromal tumors. They also concluded that further seen, the next dose should be delayed until there is studies of PLD in combination with other drugs should no pain from mucositis or hand-foot syndrome. Car- be considered. diotoxicity is rare, and there is no study demonstrating In addition to its activity in STS, PLD has an that monitoring the EF as a predictor of cardiotoxicity improved toxicity profile as compared with free doxo - is useful [10, 12, 24, 25]. In conclusion, PLD has a more rubicin. An important limiting toxicity of doxorubicin favorable toxicity profile, including reduced incidences is cardiotoxicity. In contrast, PLD has much less car- of cardiotoxicity, nausea, myelosuppression, and alope- diotoxicity [10, 12, 20, 23–25]. A recent retrospective cia. As a result no pre-medications or growth factor is study [12] showed no definitive doxorubicin-induced required [6–15, 20, 24, 25]. Furthermore, PLD results in clinical heart failure (HF) in 56 patients receiving a higher concentrations of drug in tumor than free dox- cumulative dose of free doxorubicin and PLD compa- orubicin [9, 16–18]. Our case highlights that PLD can rable or higher than the dose our case received (PLD: cure a patient with a doxorubicin-resistant tumor, dem- 2 2 595  mg/m and free doxorubicin: 196  mg/m ). In this onstrating that in some cases PLD is more efficacious retrospective study, 56 patients received a cumula- than free doxorubicin with a more favorable toxicity tive dose of free doxorubicin and PLD of > 450  mg/ profile. As with all drugs, individual adjustment of dose 2 2 m , 49 patients received > 500  mg/m , 14 > 1000  mg/ and treatment interval is important. 2 2 m and 5 > 1400  mg/m . While modest changes in EF were noted over time in the absence of clinical signs Abbreviations or symptoms of HF, EF was not considered a useful PLD: pegylated-liposomal doxorubicin; STS: soft-tissue sarcoma; EF: ejection predictor of doxorubicin-induced cardiotoxicity, at fraction; HF: heart failure. least in the case of PLD [12]. Our case’s EF remained Authors’ contributions within or above the normal range before, during, and Conception and design: KS; Manuscript writing: MS, PM, and KS; Final approval: after PLD treatment for the 20-year follow-up period. MS, PM, and KS; Pathological explorations: PM; Patient’s management: KS. All authors read and approved the final manuscript. While dexrazoxane is occasionally employed during Savani et al. Clin Sarcoma Res (2019) 9:1 Page 7 of 7 Author details 8. Gabizon AA, Barenholz Y, Bialer M. Prolongation of the circulation time Department of Medicine, University of Minnesota Medical School, Office of doxorubicin encapsulated in liposomes containing a polyethylene Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455, USA. glycol-derivatized phospholipid: pharmacokinetic studies in rodents and 2 3 Masonic Cancer Center, Minneapolis, MN, USA. Department of Laboratory dogs. Pharm Res. 1993;10(5):703–8. Medicine and Pathology, University of Minnesota Medical School, Minneapo- 9. Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman lis, MN, USA. M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor Acknowledgements localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J We thank Michael Franklin for editorial assistance, and support from the Kevin Clin Pharmacol. 1996;36(1):55–63. Franklin family and the James Dinnerstein family. 10. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Invest. 2003;21(2):167–76. Competing interests 11. Northfelt DW, Dezube BJ, Thommes JA, Levine R, Von Roenn JH, Dosik The authors declare that they have no competing interests. GM, Rios A, Krown SE, DuMond C, Mamelok RD. Efficacy of pegylated- liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma Availability of data and materials after failure of standard chemotherapy. J Clin Oncol. 1997;15(2):653–9. Not applicable. 12. Skubitz KM, Blaes AH, Konety SH, Francis GS. Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxoru- Consent for publication bicin: use of left ventricular ejection fraction is of unproven value. Cancer Written informed consent was obtained from the patient for publication of Chemother Pharmacol. 2017;80(4):787–98. this Case report and any accompanying images. 13. Garcia AA, Kempf RA, Rogers M, Muggia FM. 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Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure

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Springer Journals
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Copyright © 2019 by The Author(s)
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
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2045-3329
DOI
10.1186/s13569-018-0111-0
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Abstract

Background: Doxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposo- mal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma. Case presentation: In this report, we describe a patient with high-grade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Second-line treat- ment with PLD resulted in long-term disease remission during a 20-year follow-up period. Mucositis and hand-foot syndrome were controlled by adjustment of dose and treatment interval. Conclusions: This case illustrates the curative potential of PLD after failure of free doxorubicin and the absence of long term cardiotoxicity with PLD. As with all drugs, individual adjustment of dose and treatment interval is important. Keywords: Pegylated-liposomal doxorubicin, Doxorubicin, Sarcoma Background toxicity obviates the need for premedication [6, 9–14]. The median survival of patients with metastatic soft tis - PLD’s main toxicities are hand-foot syndrome, low risk of sue sarcomas (STS) is only 12–15  months [1]. Doxo- infusion reaction, and some fatigue [6, 9–11, 13, 14]. It rubicin is one of the most active drugs available for has been hypothesized that the symptoms of the infusion treatment of STS [2–6], although cardiotoxicity can be reaction, which are associated with transient neutrope- dose-limiting. Pegylated-liposomal doxorubicin (PLD) is nia, reflect neutrophil sludging in the microvasculature a formulation of doxorubicin in which the doxorubicin as observed with hemodialysis neutropenia [15]. We do is encapsulated in liposomes coated with methoxypoly not routinely pre-medicate patients receiving PLD. In (ethylene glycol). Unlike doxorubicin, PLD’s uptake by addition, PLD has been shown to localize to implanted the reticuloendothelial system is decreased, resulting in tumors in animals [16] and deliver more doxorubicin different pharmacologic properties, including a longer to the tumor than free doxorubicin in Kaposi sarcoma, half-life in blood and different toxicities [ 7–10]. PLD is prostate cancer, and breast cancer [9, 17, 18]. While PLD associated with less cardiotoxicity, nausea, alopecia, and has a better toxicity profile than free doxorubicin, there myelosuppression than free doxorubicin; this reduced is no consensus on the relative efficacy of PLD and free doxorubicin in STS because of the small number of trials directly comparing these two agents. In this report, we describe a patient with high-grade *Correspondence: skubi001@umn.edu Department of Medicine, University of Minnesota Medical School, Office metastatic STS with rapid recurrence after adjuvant Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN 55455, USA treatment with free doxorubicin, cisplatin, ifosfamide, Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Savani et al. Clin Sarcoma Res (2019) 9:1 Page 2 of 7 and dacarbazine. The patient’s treatment was changed to immunoprofile were thought to represent an undifferen - PLD, and no recurrence was observed during a follow- tiated pleomorphic sarcoma (UPS). up period of more than 20 years. This case illustrates the Two months after resection of the intra-abdominal curative potential of PLD after treatment failure with free mass, the tumor recurred (Fig.  1). He underwent resec- doxorubicin and the absence of long-term cardiotoxicity tion of multiple masses in the falciform ligament, left with PLD. pelvic side wall, small bowel, mesentery, and retroperito- neum. Multiple lymph nodes were also resected. Patho- logical examination was again thought to be consistent Case presentation with leiomyosarcoma. A 37-year-old white man with a past medical history of After recovery from surgery the patient received three mitral valve prolapse and gastritis presented with abdom- courses of adjuvant chemotherapy with cisplatin, ifos- inal pain. A computed tomography (CT) scan revealed an famide, dacarbazine, and doxorubicin. This involved 2 2 18 cm × 17  cm × 11 cm colonic flexure mass. The patient 50  mg/m of cisplatin on day 1; doxorubicin 65  mg/m underwent a resection of the intraabdominal mass with on day 1; dacarbazine 300 mg/m on days 1, 2 and 3; and partial small bowel resection, resection of distal trans- ifosfamide 2.5 grams/m a day by continuous infusion for verse and descending colon with enteroenterostomy, as 3 days. This treatment was well tolerated, aside from neu - well as colocolostomy, appendectomy and gastrostomy tropenic fevers requiring hospitalization. (Fig. 1). Pathology was thought to be consistent with leio- Three months later, however, a CT scan revealed myosarcoma, grade 3/3. a 4-cm metastatic lesion in the left lobe of the liver. The gastric wall tumor showed a high-grade spindle The patient underwent a partial left hepatectomy and cell neoplasm with focal epithelioid features (Fig.  2B). cholecystectomy. Numerous atypical mitotic figures were noted. The back - Three months later, a CT revealed multiple 2–3  cm ground showed moderate amounts of  chronic inflam - lesions along the margin of the previous partial left hepa- matory infiltrate. The tumor was originally thought to tectomy. At the time, the patient noted night sweats and represent a gastrointestinal leiomyosarcoma. Subsequent low-grade fevers of 99–100  °F, but good appetite and no studies performed 20 years later (Fig. 2) included immu- significant weight loss. The tumor doubled in size during nohistochemical stains showing patchy reactivity for the next 5  weeks and imaging revealed multiple lesions vimentin, cytokeratin AE1/AE3 and cytokeratin 7, while throughout the remaining left lobe. He subsequently other markers tested, including gastrointestinal stro- underwent a complete left hepatectomy and excision of mal tumor and smooth muscle markers were negative. perigastric lymph nodes. Pathological examination was Notably, calretinin was also negative. This histology and thought to confirm metastatic grade 3 leiomyosarcoma Fig. 1 Timeline of treatment Savani et al. Clin Sarcoma Res (2019) 9:1 Page 3 of 7 Fig. 2 A, C, and E (bladder wall tumor): A highly cellular epithelioid (top right) and spindle cell (bottom left) malignancy involving the outer wall of the urinary bladder (A) (H&E ×100). The cells demonstrate round to oval nuclei with variably prominent nucleoli, moderate eosinophilic cytoplasm and indistinct borders (C) (H&E ×400). Immunohistochemistry shows diffuse reactivity for cytokeratin AE1/AE3 and calretinin (inset) (E) (IHC ×100). B, D, and F (remote abdominal tumor): A moderately cellular malignancy with intermixed spindled and epithelioid cells involving the outer gastric wall (B) (H&E ×200). The cells demonstrate irregular nuclei with prominent multiple eosinophilic nucleoli, abundant eosinophilic cytoplasm and indistinct borders (D) (H&E ×400). Immunohistochemistry shows reactivity for cytokeratin AE1/AE3 and negative calretinin (inset) (F) (IHC ×100) of the liver. No extrahepatic involvement or lesions in the PLD, CT imaging revealed multiple metastases in the right lobe were noted by intraoperative ultrasound. remaining left lobe of the liver, the largest being 4 × 4 cm, Five weeks later, the patient noted right upper abdomi- and one spleen nodule. The left ventricular ejection frac - nal fullness and pain, left shoulder pain, and presented to tion (EF) was 58% by multi-gated acquisition (MUGA). our clinic. Pathology review of the earlier resections at The patient began treatment with PLD at 55  mg/m our institution and at another large sarcoma center in the monthly. After 2 cycles of PLD a CT scan showed regres- US agreed with the diagnosis of leiomyosarcoma. A CT sion of tumor nodules. Because of mucositis and hand- scan showed multiple metastases in the right lobe of the foot syndrome the dose was reduced 10% for cycles 2–4 liver and splenic metastases. Immediately before starting and 50% for cycle 5; thereafter, the dose was increased to Savani et al. Clin Sarcoma Res (2019) 9:1 Page 4 of 7 30.8  mg/m monthly starting with cycle 6 and the treat- poorly differentiated biphasic mesothelioma, the overall ment interval lengthened to every 6  weeks starting with clinical presentation, lack of serosal continuity and non- cycle 7. The left ventricular EF was 61% by MUGA before reactivity for ancillary mesothelial markers (WT1, D2-40 cycle 12. After 14 cycles the EF was 62% by MUGA and a and CK 5/6) precluded a definitive diagnosis of the same. CT scan showed a persistent lesion in the spleen. At this The morphology and immunohistochemical staining point, after 14 cycles of PLD, CT imaging revealed no vis- patterns of the remote gastric lesion were compared to ible disease in the liver and the spleen nodule that was that of the bladder neoplasm. Both were poorly differ - unchanged in size but had a lower density. Thus, while entiated neoplasms, but the high magnification cytology a complete response by RECIST criteria was evident in and calretinin reactivity were dissimilar; there was no the liver, the stable size of the spleen nodule indicated a clear evidence that the tumor on the bladder wall repre- partial response to PLD by RECIST. A splenectomy was sented a recurrence of the remote malignancy. His hospi- performed revealing some viable tumor cells in a necrotic tal course was complicated by Citrobacter urinary tract nodule. The patient received 3 more cycles of PLD for a infections and intraabdominal abscesses requiring three total PLD dose of 595 mg/m and a total dose of free dox- intraabdominal drains and intravenous antibiotics. EF orubicin of 196  mg/m . CT imaging revealed no tumor by ultrasound was normal at 55–60%. He subsequently and MUGA showed an EF of 70%. The patient was fol - underwent neoadjuvant gemcitabine and cisplatin fol- lowed with interval imaging with no recurrence. lowed by total cystectomy; the cystectomy specimen Twenty-two years later, the patient experienced sev- showed no evidence of residual tumor. He continues eral months of scrotal pain radiating to his urethra and to do well 4  months after surgery, with no evidence of localized to his right testicle. An ultrasound showed a tumor recurrence. 2.8  cm × 1.6  cm × 0.8  cm mass on the outer surface of the bladder. Fine needle aspiration of the mass showed Discussion and conclusions poorly differentiated carcinoma that was CK7+/CD20+ Doxorubicin remains one of the most active agents and histologically compatible with urothelial origin. A with therapeutic activity against advanced STS [2–6]. PET-CT revealed an intense hypermetabolic pelvic mass Numerous phase II and III trials have been conducted contiguous with the right side of the bladder. An explora- showing superior response rates using a combination of tory laparotomy, intraabdominal mass resection, and doxorubicin and other agents in the treatment of meta- partial cystectomy were performed. static STS, though demonstration of a clear survival Pathologic examination of the bladder wall tumor benefit has been elusive. A phase III trial conducted by showed a 5.5  cm high-grade malignancy with epithe- Judson et  al. found no statistically significant improve - lioid and sarcomatoid features (Fig.  2A). Margins were ment in overall survival with the addition of ifosfamide negative on the perivesical soft tissue mass, and 16 of to doxorubicin for palliative treatment of advanced STS 16 lymph nodes were negative for malignancy. Mitotic [19]. However, this study did show a higher response activity was high, and the background showed moderate rate (26% vs 14%) and longer median progression-free chronic inflammation. It appeared predominantly located survival (7.4 months vs 4.6 months) in the combination in the outer half of the bladder wall, involving the mus- cohort, raising the argument in favor of adding ifosfa- cularis propria and perivesical fat. No mucosal involve- mide to doxorubicin [2, 19]. Our case failed adjuvant ment or in  situ urothelial carcinoma was identified. The treatment with a combination of doxorubicin, cispl- tumor was diffusely and strongly positive for calretinin, atin, ifosfamide, and dacarbazine, but was cured by vimentin and cytokeratin. It was negative for all other subsequent treatment with PLD and resection of one markers tested, including gastrointestinal stromal tumor remaining nodule. One could question exactly what it and smooth muscle markers. Given the presence in the means to be “doxorubicin resistant/refractory.” Techni- bladder and co-expression of keratin and vimentin, it was cally, we did not demonstrate tumor growth while the possible that this represented a urothelial or a urachal patient was receiving doxorubicin. However, the patient remnant-based carcinoma with sarcomatoid differentia - was treated with 3 cycles of a doxorubicin containing tion. However, the location of the tumor (posterior dome, regimen starting at a time when there was no tumor per imaging), lack of associated mucosal lesion, positive detectable by CT imaging. Three months after stop - calretinin stain, and lack of reactivity for urothelial mark- ping the doxorubicin containing regimen, CT imaging ers such as GATA3, p63, and CK5/6 were unusual for revealed a sizable tumor burden. One must conclude the above diagnosis. The diffuse calretinin reactivity, in that either the tumor was not inhibited by the doxoru- conjunction with co-expression of keratin and vimentin, bicin containing regimen or that it kept residual tumor raised the possibility of mesothelial differentiation/ori - cells dormant until it was stopped and then those gin. While the morphology was not incompatible with a tumor cells grew very rapidly, or alternatively, some Savani et al. Clin Sarcoma Res (2019) 9:1 Page 5 of 7 Table 1 Summary of clinical trial results of PLD in sarcoma Study Disease Dosing regimen Organizer/sponsor # of patients Responses and toxicities References Phase 2 STS (many patients had poor PLD 50 mg/m every 4 weeks 13 None Garcia et al. [13] prognostic features, including low- Treatment responses possibly grade tumors affected by poor prognostic features Phase 2 Advanced and/or metastatic STS PLD 30–50 mg/m every 3 weeks 25 3 PRs, 4 minor responses, and 17 Toma et al. [22] Patients were previously treated with patients with SD an anthracycline-based chemo- therapy Phase 2 randomized Advanced STS, with a high propor- PLD 50 mg/m every 4 weeks EORTC Soft Tissue 94 (50 PLD, PLD had equivalent activity as doxo- Judson et al. [6] tion of gastrointestinal stromal Doxorubicin 75 mg/m every and Bone Sarcoma 44 doxoru- rubicin with an improved toxicity tumors 3 weeks Group bicin) profile, including lower incidence of myelosuppression and alopecia. However, a higher incidence of palmar-plantar erythrodysesthesia was noted in the cohort receiving PLD Phase 2 Previously treated sarcomas or PLD 55 mg/m with subsequent 47 3 CR or PR and 15 clinical benefit Skubitz [10] sarcomas considered unresponsive dose adjustment Treatment was generally well toler- to chemotherapy ated, and mucositis and hand-foot syndrome were the dose-limiting toxicities Phase 2 Advanced leiomyosarcoma of the PLD 50 mg/m every 4 weeks 31 CR in 1, PR in 4, and SE in 10 patients Sutton et al. [21] uterus Retrospective analysis Metastatic STS Initial PLD 40–60 mg/m every 11 PR in 6 with extended time to pro- Grenader et al. [14] 4 weeks gression, SD in 2, and PD in 3 (One patient was progression free for 60 months after receiving seven cycles of PLD) Savani et al. Clin Sarcoma Res (2019) 9:1 Page 6 of 7 tumor cells were killed by the doxorubicin containing initiation of bolus doxorubicin to reduce long-term car- regimen, but the remaining cells grew very rapidly over diotoxicity, this is not required with administration of 3  months. In any of these cases, it seems very unlikely PLD, eliminating any concern that dexrazoxane might that it would have been possible to cure the patient decrease anti-tumor activity. with further doxorubicin if 3 cycles starting with no PLD is a different formulation of doxorubicin with residual tumor detectable did not, especially given the different pharmacologic properties and different toxici - size of the tumor burden and the issue of dose related ties than bolus free doxorubicin. In addition to reduced cardiotoxicity. cardiotoxicity, PLD has markedly reduced nausea, alo- PLD is a unique formulation of doxorubicin in that pecia, and myelosuppression, and no anti-emetics or the agent is contained in liposomes coated with hydro- other pre-medications or growth factors are usually philic methoxypoly (ethylene glycol), that diminishes needed. A small number of patients experience an infu- uptake of the agent by the reticuloendothelial system sion reaction in the first few minutes of the first treat - and consequently increases the half-life of the drug in ment, that manifests as shortness of breath or low back blood to approximately 50–60 h [7, 9, 20]. PLD localizes pain. It has been suggested that the symptoms of the to tumors due to increased vascular permeability, result- infusion reaction, which are associated with transient ing in greater drug concentration in tumor in compari- neutropenia, reflect neutrophil sludging in the micro - son to free doxorubicin [9, 16–18]. A number of trials vasculature as observed with hemodialysis neutropenia have demonstrated activity of PLD in a variety of tumors, [15]. Pre-medications have not been shown to prevent including sarcomas (Table  1) [6, 10, 13, 14, 21, 22]. A this reaction, which usually only occurs with the first phase II trial by the EORTC Soft Tissue and Bone Sar- treatment. The main toxicities of PLD are mucositis, coma Group compared the results of 50 patients treated hand-foot syndrome, and mild fatigue. Notably, not all with PLD at 50  mg/m every 4  weeks and 44 patients liposomal formulations are the same; non-pegylated treated with doxorubicin at 75  mg/m every 3  weeks liposomal anthracyclines have different pharmacologic for advanced STS; they found that PLD had equivalent properties and lack some of the favorable properties of activity as doxorubicin with an improved toxicity pro- PLD. file, including lower incidence of myelosuppression and While some early studies used doses of PLD as high alopecia. However, a higher incidence of palmar-plantar as 55 mg/m , this dose is usually too high for a monthly erythrodysesthesia was noted in the cohort receiving treatment schedule; a more typical monthly starting PLD [6]. This study had a high proportion of gastrointes - dose is 45  mg/m . When dose-limiting toxicities are tinal stromal tumors. They also concluded that further seen, the next dose should be delayed until there is studies of PLD in combination with other drugs should no pain from mucositis or hand-foot syndrome. Car- be considered. diotoxicity is rare, and there is no study demonstrating In addition to its activity in STS, PLD has an that monitoring the EF as a predictor of cardiotoxicity improved toxicity profile as compared with free doxo - is useful [10, 12, 24, 25]. In conclusion, PLD has a more rubicin. An important limiting toxicity of doxorubicin favorable toxicity profile, including reduced incidences is cardiotoxicity. In contrast, PLD has much less car- of cardiotoxicity, nausea, myelosuppression, and alope- diotoxicity [10, 12, 20, 23–25]. A recent retrospective cia. As a result no pre-medications or growth factor is study [12] showed no definitive doxorubicin-induced required [6–15, 20, 24, 25]. Furthermore, PLD results in clinical heart failure (HF) in 56 patients receiving a higher concentrations of drug in tumor than free dox- cumulative dose of free doxorubicin and PLD compa- orubicin [9, 16–18]. Our case highlights that PLD can rable or higher than the dose our case received (PLD: cure a patient with a doxorubicin-resistant tumor, dem- 2 2 595  mg/m and free doxorubicin: 196  mg/m ). In this onstrating that in some cases PLD is more efficacious retrospective study, 56 patients received a cumula- than free doxorubicin with a more favorable toxicity tive dose of free doxorubicin and PLD of > 450  mg/ profile. As with all drugs, individual adjustment of dose 2 2 m , 49 patients received > 500  mg/m , 14 > 1000  mg/ and treatment interval is important. 2 2 m and 5 > 1400  mg/m . While modest changes in EF were noted over time in the absence of clinical signs Abbreviations or symptoms of HF, EF was not considered a useful PLD: pegylated-liposomal doxorubicin; STS: soft-tissue sarcoma; EF: ejection predictor of doxorubicin-induced cardiotoxicity, at fraction; HF: heart failure. least in the case of PLD [12]. Our case’s EF remained Authors’ contributions within or above the normal range before, during, and Conception and design: KS; Manuscript writing: MS, PM, and KS; Final approval: after PLD treatment for the 20-year follow-up period. MS, PM, and KS; Pathological explorations: PM; Patient’s management: KS. All authors read and approved the final manuscript. While dexrazoxane is occasionally employed during Savani et al. Clin Sarcoma Res (2019) 9:1 Page 7 of 7 Author details 8. Gabizon AA, Barenholz Y, Bialer M. 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