Annals of Oncology Advance Access originally published online on April 2, 2008
Annals of Oncology 2008 19(8):1387-1392; doi:10.1093/annonc/mdn066
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oncology practice |
Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features
1 Oncology Department, University Hospital del Mar, Barcelona, Spain
2 Klinika Onkologii Wojskowy Instytut Medyczny, Warszawa, Poland
3 Wyeth Research, Cambridge, MA, 02140 USA
* Correspondence to: Dr J. Bellmunt, Solid Tumor Oncology (Genitourinary & Gastrointestinal), Medical Oncology Service, Hospital del Mar, Paseo Maritimo 25–29, Barcelona 08003, Spain. Tel: +34-93-2483137; Fax: +34-93-2483366; E-mail: jbellmunt{at}imas.imim.es
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Abstract |
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Background: Temsirolimus, a novel inhibitor of mammalian target of rapamycin, has demonstrated prolonged overall survival and progression-free survival compared with interferon alfa (IFN) in patients with advanced renal cell carcinoma (RCC) and poor prognostic features. Adverse events (AEs) of any causality were previously reported, but AEs that were deemed temsirolimus related are of particular relevance for poor-risk patients and for defining mammalian target of rapamycin inhibitor-specific side-effects.
Patients and methods: Patients with advanced RCC, no prior systemic therapy, and three or more of six poor-risk factors were randomly assigned to one of three groups: (i) IFN s.c. up to 18 MU thrice weekly, (ii) temsirolimus i.v. 25 mg weekly, or (iii) temsirolimus i.v. 15 mg weekly plus interferon s.c. 6 MU thrice weekly.
Results: Among 208 patients, the most common temsirolimus-related grades 3–4 AEs were anemia (13%), hyperglycemia (9%), and asthenia (8%). Grades 3–4 hypercholesterolemia (1%), hypertriglyceridemia (3%), and hypophosphatemia (4%) were also seen. Although pneumonitis occurred infrequently, vigilance for its development is needed. Guidelines for management of toxic effects are presented on the basis of available clinical experience.
Conclusions: Temsirolimus-related grades 3–4 AEs were primarily metabolic in nature and easily controlled medically. In general, these did not negatively impact patient quality of life.
Key words: interferon, mammalian target of rapamycin (mTOR), renal cell carcinoma, safety, temsirolimus
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Temsirolimus is a potent, highly specific inhibitor of the mammalian target of rapamycin (mTOR), a central regulator of intracellular signaling pathways involved in tumor cell growth, proliferation, and response to hypoxic stress [1–4]. Temsirolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR and causes cell cycle arrest and tumor suppression [4, 5]. Inhibition of angiogenesis is also a consequence of mTOR inhibition and contributes to tumor regressions observed in xenograft models treated with temsirolimus [6].
Hudes et al. [7] reported results of the Global Advanced Renal Cell Carcinoma (ARCC) phase III trial (N = 626), which evaluated the efficacy and safety of single-agent temsirolimus, interferon alfa (IFN), or the combination of both as first-line treatment for patients with advanced renal cell carcinoma (RCC) and poor prognostic features. Patients in the temsirolimus arm received a mean weekly dose of 23 mg or 
92% of the planned maximum dose; in the IFN arm, patients received a mean weekly dose of 30.2 MU or 56% of the planned maximum dose. Temsirolimus significantly prolonged overall survival [hazard ratio 0.73; 95% confidence interval (CI), 0.58–0.92; P = 0.008] and progression-free survival (P < 0.001) compared with IFN. Combination therapy significantly improved progression-free survival (P < 0.007) but not overall survival relative to IFN.
The proportion of patients with grades 3–4 treatment-emergent adverse events (AEs) was significantly lower with temsirolimus than with IFN (67% versus 78%, P = 0.02). Mild-to-moderate rash, peripheral edema, stomatitis, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia occurred in more patients receiving temsirolimus or the combination than in those receiving IFN; asthenia occurred in more patients receiving IFN or the combination [7]. Patients treated with temsirolimus experienced significantly longer quality-adjusted survival (i.e. normalized time without symptoms of progression or grades 3–4 toxicity) versus IFN [8].
Whereas treatment-emergent AEs were previously reported [7], relatedness to treatment, as determined by investigators, has not been described. The study population in the Global ARCC trial comprised exceptionally ill patients with a high metastatic disease burden and laboratory abnormalities at baseline. In this setting, where treatment is not curative, concerns about toxicity and diminished quality of life (QoL) are of crucial relevance. To further characterize the safety profile of temsirolimus, the first mTOR inhibitor to be approved for treatment of advanced RCC patients (reviewed by M.E. Gore) [9], we report temsirolimus-related AEs from the Global ARCC trial, describe uncommon but potentially serious AEs, and discuss useful management strategies for this poor-risk patient population.
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patients and methods |
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Study design and complete inclusion and exclusion criteria were previously described [7]. Patients had advanced RCC with three or more of six poor prognostic features, including more than one organ site of metastasis, lactate dehydrogenase >1.5x upper limit of normal, hemoglobin below lower limit of normal, corrected serum calcium >10 mg/dl, <1 year from diagnosis to randomization, and Karnofsky performance status of 60 or 70. Baseline assessments included complete blood count, serum cholesterol and triglyceride levels, and renal and hepatic function, with blood counts, serum chemistries, vital signs, and AEs (National Cancer Institute—Common Toxicity Criteria, version 3.0) assessed weekly.
Patients in the IFN arm received 3 MU s.c. thrice weekly for week 1; dose was escalated as tolerated to 9 MU thrice weekly for week 2, then 18 MU thrice weekly for study duration. Patients in the temsirolimus arm received i.v. 25 mg temsirolimus (ToriselTM, Wyeth Pharmaceuticals, Philadelphia, PA) weekly as a 30- to 60-min infusion, plus diphenhydramine i.v. 25–50 mg or similar H1 blocker 30 min preinfusion. Patients in the combination arm received IFN 3 MU thrice weekly during week 1; beginning on week 2, IFN 6 MU was administered thrice weekly, with temsirolimus 15 mg weekly. Treatment continued until disease progression, symptomatic deterioration, or intolerable AEs. Treatment was held for grades 3–4 AEs and restarted at a reduced dose after recovery to grade 2 or lower. Dose reduction was not required with AEs that could be adequately managed with supportive therapy.
Causal relationship between drug treatment and an AE was determined by investigators as definitely, probably, possibly, probably not, or definitely not related to treatment. In our analysis, drug-related AEs were reported as definitely, probably, or possibly related to treatment. Statistical analyses were carried out using SAS version 9.1. The number and percentage of patients with AEs were summarized on the basis of type and grade, and pairwise comparisons across treatment groups were calculated using Fisher's exact test.
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results |
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Analysis of AEs was on the basis of the safety population of 616 patients who received treatment: IFN (n = 200), temsirolimus (n = 208), and temsirolimus plus IFN (n = 208). Grades 3–4 AEs were reported as drug related in 50% of patients receiving IFN, 48% receiving temsirolimus, and 72% receiving combination therapy (Table 1).
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5%)The nature of drug-related grades 3–4 AEs was consistent with events reported overall [7]. In patients receiving temsirolimus, anemia (13%) and hyperglycemia (9%) were the most common drug-related grades 3–4 AEs; with IFN, asthenia (20%) was the most common. In all three groups, the greatest difference between reports of all-causality and drug-related AEs was observed for anemia, dyspnea, and pain (Table 1).
Most patients who reported drug-related hematologic and metabolic AEs had grades 1–2 events (Table 2). Anemia was the predominant grades 3–4 temsirolimus-related hematologic AE, whereas grades 3–4 anemia and neutropenia (both 7%) were those most commonly reported as IFN related.
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Temsirolimus was also associated with metabolic AEs, including high serum glucose, triglycerides, and/or cholesterol (Table 2). Preexisting laboratory abnormalities were present in many patients in this study. At baseline, 42% had grades 1–2 elevated serum glucose and one patient (0.5%) had grades 3–4. Additionally, 35% of patients had grades 1–2 high total cholesterol/lipid levels at baseline. Regardless of causality, 26% of patients on temsirolimus had increased cough versus 15% on IFN (P = 0.006). However, the percentage of patients with drug-related increased cough was similar for the temsirolimus and IFN groups (7% and 4%, respectively; Table 2). Beginning on study weeks 9–41, four patients in the temsirolimus group had drug-related pneumonitis of differing severity and consequences (Table 3): grade 1 (asymptomatic radiographic finding) with no dose interruption (n = 1); grade 2 with dose delay and reduction from 25 to 20 mg (n = 1); grade 2 progressing to grade 3 with discontinuation of treatment (n = 1); and grade 3 progressing to grade 4 to 5 with dose delay, then reduction from 15 to 10 mg, and finally treatment discontinuation (n = 1). One patient whose pneumonitis progressed was treated with antibiotics. One patient in the IFN group (Table 3) developed drug-related grade 2 pneumonitis on study week 28, received prednisone, and then discontinued treatment. In the temsirolimus group, cough was associated with pneumonitis grade 2 or higher; dyspnea was associated with pneumonitis that progressed in severity. Cough and dyspnea also were associated with grade 2 pneumonitis in the patient in the IFN group. A 48-year-old patient who progressed from grade 3 to 4 to 5 pneumonitis had dyspnea with right lower lobe airspace disease and a pleural-based mass at baseline and received temsirolimus until week 40, when he was hospitalized for grade 3 dyspnea and pneumonitis. The pneumonitis increased in severity and he died shortly thereafter, with cause of death reported as progressive disease, yet the persistent pneumonitis may have contributed to the patient's death.
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Although renal AEs were common, patients in this study were predisposed to nephrotoxicity because 67% had undergone prior nephrectomy. Drug-related renal events in the temsirolimus arm (25%) were approximately two times greater than the IFN arm (12%). Drug-related creatinine increase in the temsirolimus arm (11%) was approximately three times greater than the IFN arm (4%).
Drug-related rash (mostly low grade) and acne (all low grade) occurred in 34% and 10%, respectively, of patients receiving temsirolimus versus 4% and 0.5% in those receiving IFN. Temsirolimus-related rash was mainly maculopapular in nature. Mucositis-type AEs were reported as drug related in all three treatment groups. Among patients on temsirolimus, 20% reported stomatitis, 19% mucositis, 4% aphthous stomatitis, and 3% mouth ulceration. Almost all mucositis-type AEs were low grade and manageable with supportive measures.
Allergic reactions, mostly low severity, occurred in 10 (5%) patients receiving temsirolimus, despite premedication with an antihistamine. Four of these patients experienced two or more allergic symptoms on drug administration day; two experienced edema, vasodilation, dizziness, and dyspnea, which were reported as possibly indicative of hypersensitivity to the drug.
A similar percentage in the temsirolimus and IFN arms had drug-related cardiovascular events (19% and 18%, respectively). The percentage of patients with drug-related chest pain was low and similar for temsirolimus (2%) and IFN (1%). Drug-related hypokalemia occurred approximately twice as often in temsirolimus patients (4%) than IFN patients (2%), but was not associated with an increase in arrhythmias.
Among deaths during the study, most were attributable to disease progression; 10 were attributed to AEs, seven of which were in patients receiving combination treatment. In the temsirolimus arm, two deaths were considered possibly treatment related by investigators: a 61-year-old woman with mainly grades 1–2 AEs except for grade 3 hyperglycemia had a fatal cardiac arrhythmia secondary to electrolyte abnormalities, and a 69-year-old man hospitalized for grade 3 diarrhea was subsequently diagnosed with and died from acute renal failure. One death in the IFN arm was considered possibly treatment related: a 55-year-old man died of cerebral vascular disorder after experiencing grade 1 AEs except for grade 3 anemia.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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To better characterize the safety profile of temsirolimus in poor-risk patients, a population particularly ill with disease-related symptoms, it is important to consider both overall treatment-emergent AEs, as reported by Hudes et al [7], and temsirolimus-related AEs. The AEs in phase III clinical trials are often all inclusive, regardless of causality, rather than in relation to a drug or treatment because it can be difficult to exclude an effect of the drug and could result in underreporting of AEs. In the Global ARCC trial, treatment-emergent grades 3–4 AEs of any causality occurred in 139 (67%) patients in the temsirolimus group [7]. Investigators deemed that 99 (48%) patients had grades 3–4 AEs related to temsirolimus. Because temsirolimus is a novel mTOR inhibitor, the types of AEs deemed temsirolimus related by investigators provides insight into potential effects of this new class of anticancer agents.
Drug relatedness of AEs is determined by investigators, and each investigator's ability to determine drug relatedness depends on experience with the drug. The types of temsirolimus-related grades 3–4 AEs in the Global ARCC trial were consistent with those reported in a phase II study of temsirolimus in patients with cytokine-refractory advanced RCC [10]. In that study (n = 110), the most frequent temsirolimus-related grades 3–4 AEs were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%).
Dosage interruption and medication guidelines are available for cases of grades 3–4 AEs that do not resolve with medical management or supportive care [11]. Temsirolimus should be held if the absolute neutrophil count is <1000/µl, the platelet count is <75 000/µL, or a grades 3–4 AE occurs. Once toxic effects have resolved to grade 2 or lower, temsirolimus may be restarted with the dose reduced by 5 mg/week to no lower than 15 mg/week. Concomitant use of strong CYP3A4 inhibitors should be avoided because of increased potential for temsirolimus-related side-effects, but a temsirolimus dose reduction to 12.5 mg/week is recommended if coadministration is necessary.
Most temsirolimus-related AEs can be managed medically or with supportive care. Close patient monitoring and early intervention is recommended (Table 4) [11]. Hyperglycemia may manifest as excessive thirst or increased urination (volume or frequency), and may require a dose increase or initiation of insulin and/or oral hyperglycemic agent. Serum cholesterol and triglyceride levels should be tested before and monitored during treatment. Hypertriglyceridemia and hypercholesterolemia associated with temsirolimus were generally manageable with lipid-lowering agents.
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Patients receiving temsirolimus should also be monitored for clinical respiratory symptoms indicative of interstitial lung disease. Rare fatal cases of nonspecific interstitial pneumonitis have been reported in phase I and II trials in advanced RCC patients on temsirolimus [12]. In this phase III trial, patients who developed interstitial lung disease were managed with antibiotics and/or steroids and/or temsirolimus dose reductions or discontinuation (Table 4). The indication for respiratory tests was variable among treating physicians. In affected patients, a decrease in diffusing capacity of the lung to carbon monoxide measurement on pulmonary function tests was consistently observed. Among patients with symptoms and compatible radiology, some received an approximated dose of 1 mg/kg prednisone, and a decrease in steroid dose was dictated by results of sequential pulmonary function tests (written communication, I. Duran, August 2007). In patients with only radiologic alterations but without symptoms, temsirolimus treatment was continued without change.
Hypersensitivity reactions occurred during i.v. temsirolimus infusion despite premedication with diphenhydramine. If a hypersensitivity reaction occurs, administration should be stopped and the patient observed for 30–60 min. At the physician's discretion, temsirolimus may be resumed 30 min after administration of a histamine H2-receptor antagonist, such as famotidine i.v. 20 mg or ranitidine i.v. 50 mg. Infusion rate may be slowed to 60 min.
The widest clinical experience with mTOR inhibitors has been with the use of sirolimus and everolimus as immunosuppressant agents in organ transplantations. Classic side-effects of sirolimus, an active metabolite of temsirolimus [13, 14], include hematologic effects (anemia, leukopenia, thrombocytopenia), hypercholesterolemia, and arthralgias (reviewed by Buhaescu et al. [15]). Because sirolimus-induced anemia is independent of the drug's antiproliferative effects and is not associated with features of inflammation-related anemia, anemia is thought to be attributable to a direct effect on iron homeostasis [16, 17]. Because anemia, the most frequent grades 3–4 temsirolimus-related AE in patients with RCC and poor prognostic factors, can impair QoL, further study is critical to understand the mechanism of temsirolimus-associated anemia and to define appropriate management in this population.
With increased use of mTOR inhibitors in the transplantation setting, postmarketing studies have revealed a number of unforeseen AEs, including impaired wound healing and renal pathologies and possibly proteinuria, edema, pneumonitis, and thrombotic microangiopathy [18]. Although a relatively infrequent, rarely severe temsirolimus-related AE in this study, edema will likely have higher recognition as a potential temsirolimus-related AE in future studies. Renal insufficiency was also a rare temsirolimus-related AE but should be considered because many RCC patients have only one kidney and reduced renal function. Nephropathologies observed with mTOR inhibitors in transplant recipients [19, 20] may be due to suppression of compensatory renal cell proliferation and survival/repair processes [19].
In patients with RCC, the AE profile of temsirolimus is primarily metabolic in nature, with minimal impact on QoL compared with the commonly seen side-effects with oral multikinase inhibitors. Hypertension and hand–foot syndrome are class-type toxic effects of sunitinib [21] and sorafenib [22] that sometimes limit their use; these events are not associated with temsirolimus. The different types of toxic effects between temsirolimus and multikinase inhibitors reflect the distinct targeted mechanisms. Its high level of specificity for mTOR likely contributes to the tolerability of temsirolimus.
In conclusion, laboratory abnormalities associated with temsirolimus sometimes require medical management but generally do not negatively impact patients’ QoL. Anemia, mucositis, asthenia, and rash are temsirolimus-related AEs that can negatively affect QoL and should be managed promptly. The most concerning albeit infrequent AE is pneumonitis. Patients receiving temsirolimus should therefore be monitored for clinical respiratory symptoms indicative of interstitial lung disease. Overall, temsirolimus has a manageable safety profile and is well tolerated as first-line treatment for advanced RCC patients with poor prognostic features.
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Wyeth Pharmaceuticals.
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The authors wish to recognize the contributions of the investigators for the Global Advanced Renal Cell Carcinoma trial, listed in Hudes et al. N Engl J Med 2007; 356: 2271–2281. The authors thank Peloton Advantage for assistance with manuscript preparation.
Received for publication October 11, 2007. Revision received January 7, 2008. Accepted for publication February 20, 2008.
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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