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Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma
Version of Record online: 24 JUL 2003
Copyright © 2003 American Cancer Society
Volume 98, Issue 5, pages 993–1001, 1 September 2003
How to Cite
Wollina, U., Dummer, R., Brockmeyer, N. H., Konrad, H., Busch, J.-O., Kaatz, M., Knopf, B., Koch, H.-J. and Hauschild, A. (2003), Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer, 98: 993–1001. doi: 10.1002/cncr.11593
- Issue online: 20 AUG 2003
- Version of Record online: 24 JUL 2003
- Manuscript Accepted: 23 MAY 2003
- Manuscript Revised: 21 MAY 2003
- Manuscript Received: 10 APR 2003
- Essex Pharma, Munich, Germany
- cutaneous T-cell lymphoma;
- liposomal drug formulation;
- multicenter study
In single center studies and case reports, it was shown that pegylated liposomal doxorubicin (PEG-DOXO) was effective as second-line therapy for patients with cutaneous T-cell lymphoma (CTCL). The objective of this study was to evaluate the efficacy and toxicity of single-agent PEG-DOXO as second-line chemotherapy in patients with CTCL.
A retrospective, multicenter study was performed evaluating 34 patients (31 male patients and 3 female patients). Twenty-seven patients received PEG-DOXO 20 mg/m2, 5 patients received PEG-DOXO 20–30 mg/m2, and 2 patients received PEG-DOXO 40 mg/m2. PEG-DOXO was administered intravenously every 2 weeks in 6 patients, every 2–3 weeks in 4 patients, and every 4 weeks in 23 patients. One patient received only a single course of PEG-DOXO. Outcomes were evaluated, and adverse effects were recorded.
Thirty-four patients received at least 1 cycle of PEG-DOXO. Disease was classified as mycosis fungoides in 28 patients, mycosis fungoides with follicular mucinosis in 2 patients, small or medium-sized pleomorphic CTCL in 2 patients, Sèzary syndrome in 1 patient, and CD30 positive CTCL in 1 patient. Fifteen patients achieved a complete response (CR), including patients who achieved a CR and patients who achieved a CR defined by clinical criteria only with no biopsy (CRu), and 15 patients achieved a partial response (PR), resulting in a response rate (CRs, CRus, and PRs) of 88.2%. Two patients dropped out: one patient after a single PEG-DOXO infusion because of Grade 3 capillary leakage syndrome and one patient after two cycles because of a suicide attempt that was not related to treatment or to CTCL. All other patients received at least four cycles of PEG-DOXO. Overall survival was 17.8 months ± 10.5 months (n = 33 patients), event-free survival was 12.0 months ± 9.5 months, and disease-free survival was 13.3 ± 10.5 months (n = 16 patients). Adverse effects were seen in 14 of 34 patients (41.2%); they were temporary and generally mild. Only 6 patients had Grade 3 or 4 adverse effects.
This multicenter study provided evidence of high efficacy of PEG-DOXO monotherapy with a low rate of severe adverse effects compared with other chemotherapy protocols in patients with CTCL. Cancer 2003;98:993–1001. © 2003 American Cancer Society.
Cutaneous T-cell lymphomas (CTCL) are neoplasias of malignant T-lymphocytes that usually present a helper/inducer phenotype. Characteristically, CTCL shows a skin specific homing in which adhesion molecules, such as cutaneous lymphocyte antigen, chemokine/chemokine receptor, and lectin/lectin binding site interactions are involved.1–3 The most common CTCL is mycosis fungoides. The 5-year survival rate of patients with mycosis fungoides is approximately 87%.4 The prognosis for patients with advanced-stage disease is poor, with a median survival of approximately 40 months.5–7
Doxorubicin is an anthracycline with antineoplastic activity in patients with non-Hodgkin lymphoma as a part of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen or its modifications.8–10 Conversely, the therapeutic index of doxorubicin is low, and hematotoxicity is a common and dose dependent side effect. Severe neutropenia develops in nearly all patients who receive doxorubicin doses > 120 mg/m2. Gastrointestinal side effects, palmoplantar erythrodysesthesia (PPE), and reversible alopecia are common. Anthracycline-induced cardiomyopathy may lead to congestive heart failure. To prevent this irreversible side effect, the cumulative life-time dose of doxorubicin should not exceed 450–550 mg/m2.8
Liposomal-encapsulated cytotoxic drugs offer potential advantages over the corresponding unencapsulated agents. The liposome prolongs the half-life of the drug in the circulation and alters its biodistribution pattern such that drug deposition is increased in tumor tissue and decreased in dose-limiting normal tissues: Doxil/Caelyx® is comprised of doxorubicin encapsulated in a small, unilamellar vesicle with a mean dimension 96 nanometers (nm). The liposome matrix is comprised of hydrogenated soybean phosphatidylcholine (56.2%), cholesterol (38.3%), and N-(carbamoyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phospho-ethanolamine sodium salt (5.3%). These liposomes are modified further by attachment to polyethylene glycol (pegylation). Pegylation improves pharmacokinetics and pharmacodynamics.11
Recently, the first data on the efficacy and safety of pegylated liposomal doxorubicin (PEG-DOXO) were published for patients with CTCL.12–14 The response rate in a group of 10 patients with CTCL was 80%.13 The current report provides what to our knowledge are the first multicenter data concerning the safety, efficacy, and disease-free survival of patients with recurrent or recalcitrant CTCL who were treated with PEG-DOXO.
MATERIALS AND METHODS
Patient Eligibility Criteria
Only patients with histologic proof of CTCL who had recurrent disease, were unresponsive to previous treatments, or had rapid disease progression after confirmation of diagnosis were eligible. Patients younger than 18 years; female patients who were pregnant or lactating; patients with severe or untreated heart disease, active infection, allergy to anthracyclines, previous anthracycline doses > 200 mg/m2; or who had received radiotherapy or chemotherapy within 4 weeks before PEG-DOXO treatment were excluded. There was no additional selection of patients.
Pretreatments included phototherapy (selective ultraviolet [UV] therapy [SUP], UVA-photochemotherapy with 8 methoxypsoralen [PUVA], or extracorporeal photochemotherapy [ECP]; n = 24 patients); immunotherapy with interferon α2a or α2b (n = 8 patients); radiotherapy (Grenz rays or electron beam; n = 7 patients); and chemotherapy regimens, including polychemotherapy (n = 8 patients). Patients had been informed in detail about the treatment, the study objectives and limitations, and side effects in accordance with the Declaration of Helsinki (June 1964) as amended by the 41st World Medical Assembly, Hong Kong (September 1989), and in compliance with the principals of good (clinical) research practice.15
A complete medical history, including previous treatments for CTCL, was taken; and a physical examination, including performance status, concurrent nonmalignant disease, and staging of disease, was done for each patient. In patients with T3 tumors, a transformation was ruled out by biopsy. Four patients with Stage IIB or higher disease underwent bone marrow biopsies.
Patients had chest X-rays and lymph node and abdominal sonographic images taken. Routine laboratory examinations were performed. Fluorescent-activated cell sorter analysis of peripheral blood and repeated differential blood counts were performed in 10 patients. Patients with one of the following parameters present at pretreatment evaluations were excluded: a leukocyte count < 2.0 × 109/L, granulocyte count < 1.0 × 109/L, hemoglobin < 10 g/dL, platelet count < 75.0 × 109/L, serum transaminase level > 2.5 times the upper limit of normal, and creatinine level > 2.0 mg/dL1. Histologic examination was performed on a biopsy of a typical CTCL lesion. Immunohistology was available in 25 patients. T-cell receptor polymerase chain reaction and Southern blot gene rearrangement validated clonality in nine of nine patients and in two of two patients, respectively.
PEG-DOXO (Caelyx®; Essex Pharma GmbH, Munich, Germany) was administered intravenously during a 2-hour infusion at a dose of 20 mg (n = 28 patients), 20–30 mg (n = 4 patients), or 40 mg/m2 (n = 2 patients). The frequency in the induction phase was once per month (n = 19 patients) or twice per month (n = 6 patients). Eight patients received the infusion every 2–3 weeks. The objective was to induce a complete response (CR). Two patients who developed recurrent disease after the first course of 8 cycles were given a second course that was limited to 10 cycles. Most patients received 4–8 mg ondansetron (Zofran®; Glaxo Wellcome GmbH, Hamburg, Germany) orally or before the PEG-DOXO infusion as an antiemetic approach. No other chemotherapy or radiotherapy was given. Topical steroids were allowed. Adjuvant, systemic interferon α treatment was given to two patients. All other patients received PEG-DOXO as a monotherapy.
Classification of Patients and Assessment of Response
CTCL subtypes were classified according to the European Organization for Research and Treatment of Cancer (EORTC) criteria.4 Erythrodermic CTCL was classified into Sèzary syndrome, erythrodermic mycosis fungoides, and erythrodermic CTCL not otherwise defined.16 CTCL stages were defined according to the EORTC Cutaneous Lymphoma Project Group17 as follows: Stage IA (T1N0M0), Stage IB (T2N0M0), Stage IIA (T1-T2N1PB0M0), Stage IIB (T3N0M0), Stage III (T4N0-N1M0), Stage IVA (T1-T4N2-N3M0), and Stage IVB (T1-T4N0-N3M1).
Response criteria18 were applied and controlled by clinical, radiologic, and skin pathology criteria within 4 weeks after PEG-DOXO therapy: A CR was defined as the absence of clinically detectable residual disease for at least 1 month. Postinflammatory hyperpigmentation was not classified as residual disease. A CR that was defined by clinical criteria only without a biopsy was called a CRu. A partial response (PR) was defined as a decrease > 50% in the size of preexisting lesions for at least 1 month. A classification of PR was also made if > 50% nodular or plaque-like lesions became macules without evidence of internal involvement. Stable disease (SD) was defined as any response that did not meet the criteria for a CR, PR, or disease progression. Progressive disease (PD) was defined as the appearance of new lesions, an increase > 25% in previously existing lesions, a change from macular to plaque-like or nodular in > 25% of previously existing lesions, or any evidence of developing internal manifestation.
Monthly efficacy evaluations included evaluation of tumor response and assessment of quality of life according to Karnofsky performance status. Patients were withdrawn from the treatment due to profound and persistent neutropenia, anemia or thrombocytopenia, biochemical abnormalities (≥ Grade 3), intercurrent illness, pregnancy, patient request, capillary leak syndrome, or proven evidence of cardiotoxicity.
Determination of Endpoints
The following major endpoints were determined: Overall survival and failure free survival were measured from the onset of treatment with PEG-DOXO until death from any cause or until death or progression of disease. Progression-free survival was measured from the time of entry into treatment with PEG-DOXO until disease progression or death from CTCL. Disease-free survival was measured for patients who achieved a CR from the first assessment that documented the response to the date of disease progression. Response duration was measured for all patients who achieved a CR or a PR from the first documentation of response to the time of disease recurrence or progression.18
Thirty-four patients with CTCL were treated. Their demographics are given in Table 1. The patient population included mycosis fungoides (n = 28 patients); mycosis fungoides with follicular mucinosis (n = 2 patients); pleomorphic small or medium-sized CTCL (n = 2 patients); Sèzary syndrome (n = 1 patient); and anaplastic, CD30 positive, large cell CTCL (n = 1 patient). The TNM status and tumor stage for all patients are shown in Table 1. Details on 10 patients were published previously in connection with a multicenter trial.13 Herein, their follow-up data have been enlarged as far as possible.
|Patient||Gender||Age (yrs)||Diagnosis||History (months)||TNPBMa||Stage||Pretreatment(s)||Result||Caelyyx dosage (in mg/m2)||Interval (weeks)|
|1||M||59||MF||24||T3N0PB0M0||IIB||ECP, IFN, radiation||PR||20||4|
|2||F||71||MF||160||T3N0PB0M0||IIB||PUVA, ECP, radiation||PD||20||4|
|3||M||78||MF||96||T3N0PB0M0||IIB||ECP, IFN, MTX||PD||20||4|
|5||M||66||Large cell anaplastic CD30 + CTCL||7||T2N1PB0M0||IIA||—||—||20||4|
|6||M||71||MF||50||T3N0PB0M0||IIB||ECP, IFN, COP||PD||20||3|
|8||M||71||Small/medium-sized pleomorphic CTCL||12||T4N0PB0M0||III||IFN||PD||20||4|
|9||M||62||MF||42||T4N1PB0M0||IVA||PUVA, corticosteroids, IFN, radiation||PD||20||4|
|11||M||66||MF||1||T3N0PB0M0||IIB||PUVA, IFN, radiation||PR||40||4|
|14||M||56||Small/medium-sized pleomorphic CTCL||36||T1N0PB0M0||IA||Radiation||PD||20||2|
|15||M||62||MF||18||T3N1PB0M0||IVA||PUVA; leukeran, corticosteroids||PD||20||2|
|16||M||57||MF with mcinosis||12||T2N0PB0M0||IB||Radiation||PD||20||2|
|18||M||65||MF||156||T2N0PB0M0||IB||Leukeran, corticosteroids, IFN, radiation, mitoxantron, clorambucil||PD||20||2|
|20||M||71||MF with mucinosis||86||T3N0PB0M0||IIB||ECP, IFN||PD||20||4|
|21||M||68||MF||38||T1N0PB0M0||IA||PUVA, acitretin, ECP||PR||20||4|
|27||M||65||MF||20||T2N0PB0M0||IIA||ECP, IFN, fludarabin||PR||20||3–2|
|29||F||85||MF||16||T2N1PB0M0||IVA||PUVA, IFN, MTX||PD||20||3|
|31||M||53||MF||49||T3N1PB0M0||IVA||IFN, acitretin, ECP, fludarabin||PD||30–20||3–2|
|32||M||73||Sèzary syndrome||14||T4N1PB0M0||IVA||PUVA, IFN, fludarabin||PR||30–20||2–3|
|34||M||45||MF||15||T3N0PB0M0||IIB||PUVA, IFN, radiation||PD||20||4|
A clinical response was seen during the first three infusions. Fourteen patients achieved a CR (with 1 additional patient who achieved a CRu in Stage IA), 15 patients achieved a PR, 2 patients had SD, and 2 patients had PD during the first course. No internal involvement developed during the treatment. Two patients with recurrent disease were referred for a second course of PEG-DOXO and had a PR as their best response. Their final outcome was a PR and SD, respectively (Table 2).
|Patient||Response||KPS||Overall survival (mos)||Event-free survival (mos)||Progression-free survival (mos)||Recurrence-free survival (mos)||Disease-free survival (mos)||Response duration (mos)||Time to next Rx (mos)||Cause-specific death (mos)||Next Rx||Drop out|
|1||PR||70||24||8||8||0||—||8||5||24||Second Caelyx course||—|
|3||PR||90||33+||24+||24+||0||—||24+||—||—||IFN 2 × 5 mioU/week||—|
|7||PR||90||36+||34+||34+||34+||—||34+||1||—||IFN 3 × 3 mioU/week||—|
|8||PR||70||21+||4+||4+||4+||—||4+||1||—||Pegylated IFN 50 μg/week||After 7 cycles|
|16||CR||100||12+||12||12||12||12||12||15||—||Caelyx every 6 weeks||—|
|17||CR||100||12+||12||12||12||12||12||1||—||Caelyx every 6 weeks||—|
|20||CR||90||28+||23||23||23||23||28+||3||—||Second Caeylx course||—|
|23||SD||30||6+||—||—||—||—||—||1||—||Bleomycin, vincristine, prednisolone||Capillary leak syndrome|
|26||PR||100||10+||10+||10+||10+||—||10+||1||—||IFN 3 × 9 mioU/week||—|
Patients with Stage I-II CTCL had better survival, with 22.9 months ± 12.4 months (mean ± standard deviation) compared with patients who had Stage III-IV CTCL (14.6 months ± 8.6 months; 31 patients received at least 4 cycles of PEG-DOXO; P < 0.001). However, comparing all patients who had Stage IA-IIA disease with patients who had Stage IIB-IVB disease, the difference in overall survival was not significant (17.0 months ± 12.2 months vs. 17.9 months ± 10.4 months).
The follow-up after the first course was 2–44 months (17.8 months ± 10.5 months). During this time, three patients died. One patient had a CR after PEG-DOXO and died because of a lung embolism unrelated to CTCL or treatment 12 months later without evidence of CTCL recurrence. The second patient died 19 months after the first course of PEG-DOXO with advanced tumor stage. The third patient died after 4 months due to disease progression (see Table 2).
Clinical and laboratory data were available for all patients. In general, the treatment was tolerated well (Table 3). Adverse effects ≥ Grade 1 were noted in 41.2% of all patients. We did not observe any nausea, emesis, stomatitis, constipation, diarrhea, or alopecia. One patient had Grade 4 anemia during the second course, leading to a blood transfusion. One patient developed a Grade 3 capillary leak syndrome of with a 4-week delay after 1 infusion (drop-out) with weight gain, generalized edema, and central nervous involvement. Grade 3 hematologic side effects were present in 3 patients (3 episodes of lymphopenia, 2 episodes of anemia, and 1 episode of leucopenia) only once during treatment.
|Patient||Adverse effects||Supportive therapy|
|5||Lymphopenia Grade 3, anemia Grade 3, leukopenia Grade 3, prolongation of partial thromboplastin time Grade 1||—|
|6||Leukopenia Grade 1, thrombopenia Grade 1||—|
|7||Lymphopenia Grade 3, increase of serum transaminases Grade 1||—|
|9||Lymphopenia Grade 1||—|
|11||Stenocardia Grade 1||Metoclopramide|
|13||PPE Grade 3||Pyridoxin|
|14||PPE Grade 2||Pyridoxin|
|20||Weight loss Grade 1||—|
|22||Stenocardia Grade 1||—|
|24||Capillary leak syndrome Grade 3||Diuretics, intensive care unit|
|25||Anemia Grade 3, lymphopenia Grade 3, increase of serum transaminases Grade 1||—|
|26||Anemia Grade 4||Blood transfusion|
|27||Stomatitis Grade 2||—|
|29||Nausea Grade 2||Ondansetron|
|31||Pancytopenia Grade 2, creatinin increase Grade 2||G-CSF|
|32||Leukopenia Grade 2||G-CSF|
|34||PPE Grade 2||—|
PPE was observed in 2 patients (Grade 2 and 3) who were on a 2-week schedule for PEG-DOXO. One of the patients with longer treatment intervals (3–4 weeks) developed Grade 2 PPE. Other symptoms of skin toxicity, such as diffuse follicular rash, intertrigo-like eruption, or new formation of melanocytic macules, were not recorded. Grade 1 side effects included stenocardia in two patients; increased transaminases in two patients; and prolonged partial thromboplastine time, loss of weight, leukopenia, lymphopenia, and thrombopenia in one patient each.
Supportive therapy for drug-induced adverse effects was necessary in five patients (Table 3). One patient received blood transfusions because of Grade 4 anemia, and 1 patient needed hospitalization and intensive care treatment because of capillary leak syndrome. Two patients received pyridoxine 300 mg per day because of PPE. Another patient who complained of stenocardia received metoclopramide because he had evidence of gastric reflux: His complaints resolved.
There were two drop-outs after one or after two PEG-DOXO infusions. One male patient developed a capillary leak syndrome after the first infusion. Another male patient made a suicide attempt that was not considered treatment-related by the physician. He responded with a CR after only two cycles of PEG-DOXO but was hospitalized in a psychiatric clinic and was lost to follow-up.
The current study provides the first multicenter data on PEG-DOXO in the treatment of patients with CTCL. The study covered 34 patients with recurrent or recalcitrant CTCL (Stage I-IV) who received PEG-DOXO as monochemotherapy, including data on 10 patients that were published in a previous report.13 Two patients received adjuvant, low-dose interferon α (3 × 3 million units per week subcutaneously).
Responders usually showed a clinical improvement during the first 3 months of treatment with PEG-DOXO. The best response was seen between one infusion and eight infusions. The outcome after 1 course of treatment was CR or CRu in 15 patients (2 patients with Stage IA disease, 5 patients with Stage IB disease, 2 patients with Stage IIA disease, 3 patients with Stage IIV disease, and 3 patients with Stage IVA disease), PR in 11 patients (2 patients with Stage IIA disease, 5 patients with Stage IIB disease, 1 patient with Stage III disease, and 7 patients with Stage IVA disease), SD in 2 patients (1 patient with Stage IIA disease and 1 patient with Stage IVA disease), and PD in 2 patients (1 patient with Stage IIA disease and 1 patient with Stage IVA disease). In the two patients who received a second course of PEG-DOXO, a PR was noted as the best response: Their final outcomes were a PR and SD, respectively. The distribution of CRs among patients who had tumors classified from Stage IA to Stage IVA provided no evidence of a stage-related response pattern.
Patients who achieved a CR during the first course of treatment had a disease-free interval of ≥ 1–44 months (mean ± standard deviation: 13.3 months ± 10.5 months). Ten patients had a disease-free interval ≥ 12 months.14 Prolonged treatment with PEG-DOXO some patients received or the introduction of patients to a second course of PEG-DOXO did not result in increased rates of unwanted side effects; in particular, there were no cardiac adverse reactions, supporting earlier data on patients with cumulative doses of PEG-DOXO > 400 mg.21, 22
PEG-DOXO therapy resulted in a response rate of 88.2% and seemed to be more effective compared with ECP (50% response) compared with and antitumor treatment with methotrexate, cyclophosphamide, and cisplatin (60–70% response rate).23–25 We observed an event-free survival of 12.0 months ± 9.5 months and an overall survival of 17.8 months ± 10.5 months with a maximum survival of > 44 months. CHOP chemotherapy has been defined as a standard treatment for patients with advanced-stage, intermediate-grade, or high-grade non-Hodgkin lymphoma.7 Patients with advanced CTCL who were treated with the CHOP regimen or with cyclophosphamide, vincristine, and prednisone achieved an objective response rate of 40% and a disease-free interval of 5.7 months.24 In a Phase II study with the EPOCH regimen (etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisolone) in 15 patients with refractory CTCL (including patients with Sèzary syndrome and anaplastic, CD30 positive, large-cell CTCL), 27% of patients achieved a CR, and 53% of patients achieved a PR, resulting in a total response rate of 80%. The median progression-free interval was 8 months, and the median overall survival was 13.5 months. Grade 3 or 4 hematotoxicity occurred in 61% of patients.26
Pentostatin, a purine analogue, also has been evaluated in patients with cutaneous CTCL. Of 22 patients with mycosis fungoides and 21 patients with Sèzary syndrome who were treated on a Phase II trial with pentostatin 4 mg/m2, the response rates were 22.7% and 33.4%, respectively, with mild-to-moderate toxicity.27 Findings from two single-center studies supported these results.28, 29 Gemcitabine, a novel pyrimidine antimetabolite, was investigated at 2 centers in a Phase II trial at a dosage of 1.2 g/m2 in 44 patients with Stage IIB–IV CTCL. The outcome was CR in 11.5% of patients and PR in 26% of patients, with a median duration of 15 months and 10 months, respectively.30
Oral bexarotene, a retinoid that has been approved for patients with all stages of refractory CTCL, has achieved an overall response rate of approximately 50% at a dosage ≥ 300 mg/m2.31 In a multicenter trial in 94 patients with Stage IIB–IVG CTCL, the overall response rate was 45% for patients who received the 300 mg/m2 bexarotene dose and 55% for patients who received a bexarotene dose > 300 mg/m2.32 However, patients require monitoring for hypertriglyceridemia and hyperthyroidism, which are reversible and manageable with concomitant medication.
Liposomal pegylated formulations of antitumor drugs are capable of improving safety and efficacy compared with conventional chemotherapy. In particular, PEG-DOXO is less cardiotoxic and nephrotoxic compared with doxorubicin HCl.33, 34 The ability of PEG-DOXO to ameliorate the familiar side effects of unencapsulated doxorubicin also has been reported widely. Nausea and emesis,35, 36 alopecia,35, 36 local tissue vesicant activity,37 and doxorubicin-induced cardiomyopathy22 all are reduced significantly by encapsulation of the drug in pegylated liposomes. However, the administration of repeated doses of PEG-DOXO can be associated with PPE or hand-foot syndrome, which manifests as painful swelling and inflammation of the hands and feet, intertriginous areas, and sites of trauma.20, 38 A similar mucosal toxicity associated with superficial mouth ulcers also occurs. These mucocutaneous adverse effects, as discussed above, are dose dependent, and it has been shown that they are dose-limiting. A number of attempts have been made to define therapies to limit this toxicity, including the use of pyridoxine39 and topical dimethyl sulfoxide.40 Such interventions may offer the prospect of safely administering larger doses of PEG-DOXO, although, to date, no interventions have demonstrated effectiveness in a randomized study.
The tolerability of PEG-DOXO was very good. Only two drop-outs were noted, one because of a capillary leakage syndrome that developed with a 4-week delay after the first infusion and another because of a suicide attempt that was not related to treatment.
Toxicity was low to moderate. Adverse effects were reported in 41.2% of patients and was mostly Grade ≤ 2. Monitoring of toxicity revealed temporary Grade 4 events (anemia in 1 patient) and Grade 3 events (anemia and lymphopenia in 4 patients, PPE in 1 patient) but no neutropenia. PPE occurred in only two patients who received PEG-DOXO twice per months and in only one patient who received PEG-DOXO at longer intervals (i.e., 3–4 weeks). This may argue for the initial suggestion of once-monthly treatment (cf. Gordon et al.38).
The current study did not provide evidence for improved efficacy with dose increases (20 mg/m2 vs. 40 mg/m2) or increases in the frequency of application (once per month vs. twice per month). There is a lack of data regarding adjuvant treatment and the best (if any) treatment after patients achieve a CR. Current data support the use of PEG-DOXO as a monochemotherapy given once per month at a dose of 20 mg/m2.
Because no curative treatment has been established and because the more aggressive treatments, although they have a better initial response rate, do not improve the prognosis of patients with CTCL,5, 7 limiting toxicity is a rational approach for the development of effective new treatments. The treatment schedule in the current study with PEG-DOXO was less toxic than most of the established chemotherapy regimens but was effective, suggesting this treatment as a promising second-line alternative. Randomized, prospective, multicenter studies are needed to confirm our observations.
- 10CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol. 1998; 16: 27–34., , , et al.
- 15EEC. Good clinical practice for trials on medicinal products in the European Community. 11/3976/88-EN. Brussels: European Commission, 1991.
- 17Classification and staging. In: BurgG, SterryW, editors. EORTC/BMFT Cutaneous Lymphoma Project Group: recommendations for staging and therapy of cutaneous lymphomas. Berlin: Springer, 1987: 1–10., .
- 34Pharmacological-toxicological expert report: Caelyx® (Stealth® liposomal doxorubicin HCl). Hum Exp Toxicol. 1996; 15: 752–785., .