Abstract
Objectives
Treatment of refractory/relapsed cutaneous T-cell lymphoma (CTCL) remains controversial, most studies included a few patients with a short follow-up. Previously, we performed two small studies employing interferon alpha 2b (IFN) combined with low doses of methotrexate (MTX) or retinoids. Thus, we conducted an open-label clinical trial to assess the benefit and toxicity of the two mentioned regimens in a large number of patients with a longer follow-up of the treatment of refractory/relapsed CTCL.
Patients and methods
Three-hundred and seventy-seven patients with refractory/relapsed, pathologically confirmed, CTCL, with advanced stages and at least treated with two previous effective regimens in CTCL, were randomized to receive IFN and low doses of MTX compared with IFN and all trans-retinoid acid during 6 months; if a complete response (CR) was not achieved, treatment was continued until 12 months in both arms. At this time, if patient achieves CR, MTX or retinoid was stopped, and the patient continues to receive IFN until progression disease or toxicity. One-hundred and eight patients received IFN for more than 5 years.
Results
Toxicity was minimal and well tolerated, no patients needed to modify the administration of IFN secondary to toxicity. The overall complete response was achieved 80% in both arms. Actuarial curves at 5 years showed that progression-free survival was 60% in the IFN/MTX group and 62% in the IFN/retinoids group (P = 0.8) that were not statistically different and overall survival (OS) rates were 70 and 67%, respectively (P = 0.03).
Discussion
Both present schedules showed good tolerance and an excellent OS at 5 years, which is better than the other, more expensive and toxic, regimens. Considering the indolent course of CTCL, we suggested that those regimens, mentioned in this paper, will be regarded as the standard therapy, for patients of this setting.
Conclusion
The use of IFN and retinoids or low dose of cytotoxic drugs will be preferred in patients with refractory/relapse CTCL, because OS is good and toxicity is minimal.
Introduction
Cutaneous T-cell lymphoma (CTCL) includes heterogeneous extranodal lymphoma arising in skin and separates by their clinical and T-cell phenotype characteristics. Mycosis fungoides (MF), the most common CTCL, is characterized by distinct clinical stages of cutaneous disease consisting of patches/plaques, tumor, and erithrodermia. For many years for CTCL, the pathology, diagnosis, definition of stage, identification of prognostic factors, and response criteria have been challenging and confusing. For these reasons, uniform criteria have been difficult to establish. Only recently these concepts have been established uniformly, and now, clinicians have adequate guidelines for CTCL diagnosis, prognosis, and management.Citation1–Citation6
CTCL is a sensitive disease and response has been observed through multiple therapeutics schedules, from topical therapies to high-dose chemotherapy and stem cell transplant. However, unfortunately, MF remains as an incurable disease. Complete response (CR) is common, but relapse/progression is the rule.Citation7–Citation17 Guidelines for untreated patients have been established,Citation2,Citation9,Citation10,Citation15,Citation16 but controversy persists in terms of treatment of refractory/progressive disease, and controlled clinical trials are limited. It is recommended that accounting the chronic evolution of MF, treatment during recurrences be considered to achieve the best response without compromise to patients’ quality of life. Most clinicians considered the use of chemotherapy with single agent or combined drugs, but excessive toxicities and poor performance status observed in these patients have limited their use. The use of new agents during the process of introduction into clinical use has been considered, but in most cases, the response is short: <1 year and improvement in survival rate has not been observed.Citation1,Citation5,Citation8,Citation13–Citation16,Citation18,Citation19 Interferon alpha 2b (IFN) is one of the most common drugs employed in this setting of patients, with most in combination with other agents, with a good number of responses, and adequate progression-free disease.Citation5,Citation7,Citation10,Citation12,Citation13,Citation19
Taking into account the preliminary results with the use of IFN and low doses of methotrexate (MTX) or retinoids in the treatment of refractory patients with MF,Citation20,Citation21 we developed an open-label, clinical trial to compare: IFN and retinoids or IFN and low doses of oral MTX. Considering the indolent curse of this neoplasm, we analyzed the long-term outcome for a large number of patients treated of these following the schedules. The end-points of the study were overall survival (OS) and safety of treatment.
Patients and methods
From 2000 to 2010, we enrolled consecutive patients diagnosed with refractory MF, into two schedules of treatment. Inclusion criteria were the diagnosis of MF, according to the criteria previously reported,Citation21 in all cases, tissue specimens were revised to confirm the diagnosis and a new biopsy for at least different anatomical sites was mandatory; immunohistochemistry was performed in all cases: CD2, CD3, CD5, CD7, CD20, CD25, and CD26: age >18 years without upper limit; no gender difference, performed status <3 according to the Eastern Cooperative Oncology Group (ECOG) criteria, negative for human immunodeficiency syndrome, and hepatitis B and C; absence of any morbid clinical condition that can limit the use of chemotherapy; and treatment with at least two therapeutic schedules, with proven effective action in MF. Clinical staging was performed including: careful physical examination, all skin lesions were measured in two dimensions, and the presence of a tumor was especially mentioned, any change in near skin was considered, also the presence, volume, and number of lymph nodes, and if necessary, nodal biopsy was performed. Complete blood counts, serum chemistry, and careful examination of blood smears were carried out by two observers. Serum determinations of lactic dehydrogenase and beta 2 microglobulin, HIV, and hepatitis B and C were also performed. Computed tomography of the thorax, abdomen and pelvis, and aspirate and biopsy of the bone marrow was also performed. After treatment, all the patients were carefully restaged that include studies of abnormalities secondary to the tumor, with the precise measures of the patches, the plaques, and the number and site of tumors, if there were suspicions, new biopsies were taken. Unfortunately, clonal rearrangements are not available in our institution.
The therapeutic decision was based on all-round meetings without the clinical department, at a basis 1:1, thus the study was balanced to avoid bias, and each group of patients was assigned to receive the following therapy:
Group A:
- IFN, 5.0 MU, subcutaneously, three times a week. During the first 3 weeks, patients received paracetamol to reduce acute toxicity;
- retinoids: all trans-retinoid acid 45 mg/m2, oral, biweekly.
Group B:
- IFN, as mentioned above, and
- MTX, 15 mg, oral, standard dose, two times a week. In both arms, drugs were administered for 6 months, at this time, restaging was performed, if CR was achieved, retinoids or MTX was stopped and IFN was continued until relapse, progression, or toxicity. If partial response or failure was observed, the treatment was continued for an additional 6 months. At 12 months of treatment, response was assessed again, and if CR or partial response was observed, again retinoids or MTX was stopped. IFN was continued until progression, death for any cause, or toxicity.
Taking into consideration that tumors have poor response to chemotherapy,Citation23–Citation26 we administered local radiotherapy (involved field) that includes the tumor and circumference of 3 cm to patients who present tumor mass. Doses range from 2.8 to 4.0 Gy, with a median of 3.45 Gy. Radiotherapy was administered at the same time that biological response modifiers were measured, without evidence of additional toxicity. Thus, response criteria were evaluated at the same time as systemic therapy.
Patients who did not achieve any response were considered failures, and were treated based on individual considerations, in most cases with single agents a low dose.
When the study began, standard criteria for response were not available, thus we applied the response criteria that were employed in the phase II studies of our institutionCitation20,Citation21 that was adjusted to the recent international criteria proposed by Olsen et al.Citation6
The primary end-points of the study were OS and safety of the treatment. Second end-points were achievement of CR, duration of response, and measurement of progression-free survival (PFS). Quality of life analysis was not performed, because we did not have the specialist in our institution.
Toxicity was grading according to the National Cancer Institute criteria. The study was approved by the Ethical and Scientific Committee of our institution (HO1999-11), and all the patients gave an informed consent to participate in the study.
Statistical analysis
We calculated the duration of OS, from the date of enrollment until the time of death or last follow-up (March 2013). The duration of PFS was calculated from the date of enrollment until the date of progression or last follow-up. We used the Kaplan–Meier method to determine the probability of OS and PFS. Patients characteristics were compared by means of Fisher's exact tests for dichotomous variables and by means of the Wilcoxon's rank sum for continuous variables. All values were two-tailed. The median following was calculated from the date of enrollment through the date of last update (June 2013).
Results
A total of 506 patients were diagnosed with CTCL; 129 cases were excluded, 39 were of B-cell origin, 64 were Sèzary syndrome, 12 were skin malignancies non-lymphoma, and in 14 cases, pathological materials were not available for revision. Thus, 377 patients were enrolled in the present study. Clinical and laboratory characteristics are given in .
Table 1. Clinical and laboratory characteristics
Male predominance was observed, advances stages and increase a number of tumor sites were more frequent. The number of patients with elevated levels of lactid dehydrogenase (LDH), even in advance stages, was low. Previously, all the patients received at least two lines of effective treatment. The time between primary diagnosis and the arrival at our hospital was 56.4 months (range 22–84 months). Previously, the diagnosis of CTCL was not correctly performed and many received multiple therapies for misdiagnosed cutaneous pathology, including benign diseases. Although, the study was not randomized, the baseline characteristics were balanced, and statistical differences were not observed.
provides the response types: the response in CTCL was low, especially CR at 6 months. However, at 12 months, the rate of CR increased to 80%, in both arms. No statistical differences were observed between the two groups (P = 0.81). Patients whose were considered a failure were treated according to their clinical condition, the presence of comorbidities, performance status, and lymphoma activity.
Table 2. Response type and outcome
The median follow-up was 78.9 months (range from 48 to 165 months).Thirty-four patients relapsed in the IFN/MTX arm (22 %) and another 34 patients in the IFN/retinoids group, thus, actuarial curves of progression-free survival were not statistically significant (). Causes of death are given in . Most patients die secondary to tumor progression; and five patients developed second neoplasia (lung cancer – two, prostate cancer – one, breast cancer – one, and bladder cancer). A relationship between second neoplasm and treatment could not be established. Eighty patients died in IFN/MTX (38%) and 84 in the IFN/retinoids group (42%), thus actuarial curves at 5-years were 70 and 67%, respectively (P = 0.03).
Table 3. Cause of death
shows the toxicity profile. Flu-like syndrome secondary to IFN administration was the most common, 84 patients (22%), in all cases, were grade I or II, and was well controlled, generally during the first 4 weeks of administration; no dose modification or treatment stoppage was necessary. Note, IFN was administered to 108 patients for more than 5 years and to 56 for more than 10 years without any evidence of late toxicity. When granulocytopenia was observed, secondary to IFN administration, the drug was stopped for 1–2 weeks, when the drug was continued, no hematological toxicity was observed. During the follow-up, 23 patients developed viral infections, but they were mild and treatment modification was not necessary. Increase in triglycerides was observed, secondary to retinoid administration, in only seven patients, diet and exercise were sufficient to control it.
Table 4. Toxicity
Neither patient was dropped for the study during the initial treatment or during follow until now, because we are the unique tertiary national center for our institution for the treatment of this type of patients. Our institute has a national coverage, with a population of 58,600,000 people (December 2012).
Discussion
Greater advances have been achieved in CTCL; unified pathological criteria classification, employment of biological markers to improve diagnosis, introduction of a classification based in prognostic factors to define better treatment , and unified response criteriaCitation1,Citation6; The introduction of multiple new drugs in the treatment of this disease has also improved prognosis.Citation5,Citation9,Citation10,Citation14,Citation15
However, CTCL remains an incurable disease, in patients newly diagnosed CR can be achieved in >80% of patients, with a median OS of >8 years, but eventually, most patients die secondary to tumor progression or toxicity secondary to treatments. Thus, clinical approaches will be focused on improving OS and quality of life.
Although initial therapies have been defined according to prognosis classification, the treatment of refractory disease has not been defined. The use of new drugs has been proved to be used with CR >50%, but the median duration of response <2 years, with a median OS of <3 years.Citation10,Citation14–Citation16 The goal of the mentioned treatments has been focused on achieving a quick response, but without improvement in OS, and without long-term follow-up to enable observation of longer response or late toxicity.
IFN is one the most commonly used drugs alone or in combination, in the treatment of CTCL.Citation17,Citation18,Citation26 The use of retinoids adding to IFN was based on basic studies that demonstrate that retinoids can increase the production of interferon gamma that is cytotoxic against T-cells, also MTX has been proved to be effective as monodrug as palliative therapy in patients with T-cell malignancies, and previously, we demonstrated in two small studies, the clinical efficacy of both agents combined with IFN.Citation20,Citation21 . In this paper, we reported an analysis of two schedules that incorporate two drugs to IFN, both have been reported to be useful in CTCL: retinoids and MTX. The response rate and CR were similar in both arms, and improvement has been observed in both groups, when compared with other studies. Moreover, acute and late toxicities were minimal, and we did not need to modify the dosage or the schedule, even in patients that received the medication for >5 years. We did not perform specific studies to evaluate quality of life, but all the patients improved their functional status and could have life without severe limitations. The use of IFN, in combination with retinoids or MTX, does no need for hospitalization and is less expensive than modern drugs.
Radiation therapy occupied the primordial site in the treatment of CTCL, used as an initial therapy or in patients with limited cutaneous tumor presentation,Citation24–Citation26 and the introduction of new strategies in radiotherapy has diminished the presence of severe toxicities. Patients with CTCL and tumor presentation have a poor response in the tumor site when they are treated with systemic therapy, thus radiotherapy is employed as the treatment of choice. In our patients, that have tumor involvement, we added limited (involved field) radiation therapy, during systemic therapy, and 85% of patients showed response, with 68% considered as CR in the tumor site. No additional toxicities were observed during the use of radiation.
Our policy in the treatment of chronic neoplasm, as CTCL, is to employ drugs that have been proved effective against tumor cells, but that the profile of toxicity showed that it will be mild, and in most cases it has not been associated with lethal events. In addition, in a country with limited resources, the treatment will be considered less expensive.
The results presented herein showed that both regimens are effective in this special setting of patients, because an improvement in CR rate and OS has been shown. The treatment of CTCL takes time, as shown in our patients, needing 1 year to achieve an effective response. Considering that both regimens are effective, the use of IFN+MTX could be suggested, as the treatment of choice in CTCL, because it is less expensive.
However, it is evident that the treatment of refractory CTCL remains to be defined, because relapse/progression continues to be the rule. It is probably that microscopic foci of tumor cells, that will be transformed or resistant to treatment, will be considered the cause of this problem. Dummer et al.Citation27 analyzes the possibility of adding a maintenance regimen to prolong progression-free disease, without excessive toxicity. In this report, we did not plan to prolong the treatment, but when patients achieved CR, and toxicity was mild, the group decided to continue the treatment with IFN until disease progression or toxicity. However, when patients continued CR at 5 years, we decide to stop treatment. Surprisingly, we observed that relapse/progression did not occur (only 17 cases), thus we planned a study to randomize patients to treatment of continued IFN for 3, 5, and 7 years.
Disclaimer statements
Contributors No other contributors.
Funding The work was performed with the owner resources of the Mexican Institute of Social Security, the national institute for social and health of all workers people in the country and did not received any funds or support from any source.
Conflicts of interest All authors disclose any conflict of interest.
Ethics approval None.
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