Evidence based Dermatology - part 6 ppsx

the duration of response is short. However, patients recruited for this trial were heavily pretreated, suggesting that this is likely to be a useful additional therapy for CTCL patients with resistant disease, despite potential adverse effects. A randomised placebo-controlled trial in patients with stage IB/IIB/III mycosis fungoides who have undergone fewer than three previous treatments is ongoing. Ricin-labelled anti-CD5 immunoconjugate (H65-RTA) Efficacy A phase I trial of H65-RTA in 14 patients with resistant CTCL revealed a maximum tolerated dose of 0⋅33 mg/kg/day and PR in only four patients of short duration (3–8 months). 68 Drawbacks Acute hypersensitivity effects and vascular leak syndrome were noted. Radioimmunoconjugate (90Y-T101) Efficacy A phase I trial of this radioimmunoconjugate (which also targets CD5+ lymphocytes) in 10 patients (CD5+) with haematological malignancies, of whom eight patients had CTCL, showed PR in three CTCL patients with a median response duration of 23 weeks. 69 Biodistribution studies showed good uptake into skin and involved lymph nodes. Drawbacks Bone-marrow suppression was observed. T cells recovered within 3 weeks but B-cell suppression persisted after 5 weeks. Comments This is an interesting phase I study because CTCL is a radiosensitive tumour. Further studies are required. What are the effects of radiotherapy in mycosis fungoides/Sezary syndrome? Superficial radiotherapy Efficacy No systematic reviews or RCTs were identified. Dose–response studies have clearly established that localised superficial radiotherapy is an effective palliative therapy for individual lesions in mycosis fungoides. 70 A retrospective study of palliative superficial radiotherapy used to treat 191 lesions from 20 patients with mycosis fungoides showed CRs of 95% for plaques and small (<3 cm) tumours and a CR of 93% for large tumours (>3 cm), irrespective of dose. However in-field recurrences within 1–2 years were more common for those lesions treated with lower doses (42% for <1000 cGy, 32% for 1000–2000 cGy, 21% for 2000–3000 cGy and 0% for >3000 cGy). Drawbacks Superficial radiation is well tolerated. Mild erythema and occasional erosion have been reported. Use of low-dose/energy (400 cGy in 2–3 daily fractions at 80–150 Kv) is therapeutically effective and allows treatment of overlapping fields and lower limb sites. Comments CTCL is a highly radiosensitive malignancy, and localised superficial radiotherapy is an invaluable palliative therapy for patients with all stages of mycosis fungoides. Treatment should be palliative except for patients with solitary localised disease where “cure” is possible. Although in-field recurrence rates were very low for lesions treated with >3000 cGy, the number of lesions treated with this dose was very low compared with the other groups and this form of therapy is only palliative in mycosis fungoides because disease is multifocal. Therefore the use of high-dose fractionation regimens for individual 360 Evidence-based Dermatology lesions should be avoided in mycosis fungoides because CR rates are similar to those for low- dose regimens (see above) and recurrent disease adjacent to previously treated fields can be treated with overlapping fields if necessary. However, treatment of disease on the lower legs can be difficult in view of a higher risk of radiation necrosis with repeated treatments. Total skin electron beam therapy (TSEB) Efficacy A systematic review (meta-analysis) of open uncontrolled and mostly retrospective studies of TSEB as monotherapy for 952 patients with all stages of CTCL has established that the rate of CR is dependent on stage of disease, skin surface dose and energy, with CR rates of 96% in stage IA/IB/IIA disease, 36% in stage IIB disease and 60% in stage III disease. 71 Greater skin surface dose (32–36 Gy) and higher energy (4–6 MeV electrons) were significantly associated with a higher rate of CR; 5-year relapse-free survivals of 10–23% were noted. 71 An RCT has compared TSEB with topical mechlorethamine in 42 patients, with similar rates of CR and duration of response in both groups in early stages of disease but better ORs in later stages of disease with TSEB. 72 A retrospective study of TSEB (median dose 32 Gy; median treatment time 21 days) as monotherapy for 45 patients with erythrodermic CTCL (28 stage III, 13 stage IVA, 4 stage IVB) showed a 60% CR rate, with 26% disease free at 5 years. 73 Overall median survival was 3⋅4 years, which was associated significantly with an absence of peripheral blood involvement (stage III disease). Higher rates of CR (74%) and disease-free progression (36%) were noted in those patients receiving a more intense regimen (32–40 Gy and 4–6 MeV). A retrospective study of 66 CTCL patients (1978–96) treated with 30 Gy in far fewer fractions (12 fractions over 40 days) showed a CR rate of 65% with progression-free survival of 30% at 5 years and 18% at 10 years. 74 Responses and specifically 5-year OS were highest in those with early-stage disease (79–93% for IA/IB/III compared with 44% for IIB/IVA/B). Although it has been recommended that TSEB can only be given once in a lifetime, several reports have described multiple courses in CTCL. 75,76 A retrospective analysis of 15 patients (1968–90) with mycosis fungoides who received two courses of TSEB reported a mean dose of 32⋅6 Gy for the first course and 23⋅4 Gy for the second, with a mean interval of 41⋅3 months. No additional toxicities were noted but the CR rate for the second course was lower (40% compared with 73%). 75 A further retrospective study of 14 patients with CTCL revealed a mean dose of 36 Gy for the first (93% CR) and 18 Gy for the second course (86% CR). 76 In this series five patients received a third course (total dose 12–30 Gy). The median duration of response was 20 months for the first and 11⋅5 months for the second course. No additional toxicities were reported. In both of these studies the fractionation regimens employed may have been critical for tolerability (1 Gy per day at 6 MeV over 9–12 weeks). Combination TSEB regimens An RCT in 103 CTCL patients comparing TSEB and multi-agent chemotherapy (CAVE) with sequential topical therapy including superficial radiotherapy and phototherapy revealed a higher CR rate in the TSEB/chemotherapy group (38% compared with 18%; P = 0⋅032) but after a median follow up of 75 months DFS and OS did not differ significantly. 77 A retrospective non-randomised study comparing TSEB (32–40 Gy) alone with TSEB followed by 361 Primary cutaneous T-cell lymphoma ECP (given 2 days monthly for a median of 6 months) in 44 patients with erythrodermic CTCL (57% stage III, 30% stage IVA, 13% stage IVB/overall 59% had haematological involvement B1) has reported an overall CR rate of 73% after TSEB, with a 3-year DFS of 49% for 17 patients who received only TSEB (OS 63%) and 81% for 15 patients who received TSEB followed by ECP (OS 88%). 78 A multivariate analysis suggested that the combination of TSEB and ECP was significantly associated with a prolonged disease-free and cause-specific survival when corrected for peripheral blood involvement (B1) and stage of disease. Drawbacks Adverse effects of TSEB include radiation- induced secondary cutaneous malignancies, telangiectasia, pigmentation, anhidrosis, pruritus, alopecia and xerosis. Treatment is generally only given once in a lifetime, but several reports suggest that multiple therapies may be tolerated (see above). Comments Although these studies are uncontrolled and mostly retrospective, the response rates indicate that TSEB is highly effective for CTCL. The lack of a long-term response in early-stage disease suggests that TSEB should be reserved for later stages of disease, particularly as an RCT has indicated that responses are similar for TSEB and topical mechlorethamine. Meta-analysis of observational data indicates that higher dosage regimens are more effective (32–40 Gy with 4–6 MeV). Although an RCT in CTCL indicates that combined TSEB and chemotherapy is no more effective than sequential skin-directed therapy, a further trial comparing TSEB alone with TSEB and chemotherapy in late stages of disease (stage IIB) would be helpful. The current data on long-term DFS and OS in erythrodermic CTCL suggest that TSEB is effective, particularly if combined with ECP, but this requires confirmation in an RCT. What are the effects of single-agent chemotherapy in mycosis fungoides/Sezary syndrome? Single-agent chemotherapy regimens Efficacy No RCTs have been reported. A systematic review of uncontrolled open studies of single- agent regimens in 526 CTCL patients (1988–1994) revealed OR rates of 62%, with a CR rate of 33% and median response durations of 3–22 months. 59 These therapies included alkylating agents (chlorambucil and cyclophosphamide), antimetabolites (methotrexate), vinca alkaloids and topoisomerase II inhibitors. Drawbacks As with all chemotherapy regimens, infection and myelosuppression are significant risks. Comments The lack of controlled studies makes interpretation difficult but single-agent regimens may have similar efficacy to combination regimens (see below) but with lower toxicity and therefore may be preferable as palliative therapy in late stages of mycosis fungoides and Sezary syndrome, especially as durable responses and cures are rarely, if ever, achieved. RCTs are urgently required. Methotrexate Efficacy No RCTs were identified. A retrospective report of low-dose methotrexate in 29 patients with erythrodermic CTCL (III/IVA) has shown a 41% 362 Evidence-based Dermatology complete remission rate, with an OR of 58%. 79 Median freedom from treatment failure was 31 months and OS was 8⋅4 years. Weekly doses ranged from 5 to 125 mg for a median duration of 23 months. A majority (62%) of patients satisfied criteria for a diagnosis of Sezary syndrome. Drawbacks Adverse effects included reversible abnormalities of liver function, mucositis, cutaneous erosions, reversible leucopenia and thrombocytopenia, nausea, diarrhoea and, in one case, pulmonary fibrosis. Comments Although these data are uncontrolled, the OS in this cohort is surprisingly good. A randomised study comparing methotrexate with other single- agent chemotherapies in erythrodermic CTCL would be worthwhile. Purine analogues Efficacy No RCTs were found. A systematic review of purine analogues in CTCL (1988–94) revealed overall and CR rates, respectively, of 41% and 6% for deoxycoformycin (n = 63), 41% and 19% for 2-chlorodeoxyadenosine (n = 27), and 19% and 3% for fludarabine (n = 31). 59 Most of these studies included some patients with peripheral T-cell lymphomas. No comparative studies were available. A prospective open study of deoxycoformycin in 28 heavily pretreated patients, of whom 21 had CTCL (14 Sezary syndrome, seven stage IIB) revealed an OR rate of 71%, with 25% CR and 46% PR (OR: 10/14 patients with Sezary syndrome; four CR, and 4/7 stage IIB patients; one CR). Response was short lived (median duration of 2 months for stage IIB disease and 3⋅5 months for Sezary syndrome) except in two cases of Sezary syndrome with remissions for 17 and 19 months. The regimen consisted of starting doses of 3⋅75–5⋅0mg/m 2 /day for 3 days every 3 weeks. A dose escalation to 6⋅25 mg/m 2 /day was rarely possible because of toxicity. 80 Two recent open studies of deoxycoformycin in CTCL (27 mycosis fungoides and 37 Sezary syndrome) patients have shown OR rates ranging from 35% to 56%, with CR rates from 10% to 33% and a reported median disease-free interval of 9 months in one of the studies. 81,82 Interestingly, responses were better in Sezary syndrome than mycosis fungoides. The usual schedule for deoxycoformycin consists of a once-weekly intravenous dose of 4 mg/m 2 for 4 weeks and then every 14 days for either 6 months or until maximal response. Combination therapy consisting of deoxycoformycin and alfa interferon in CTCL has shown OR and CR rates of 41% and 5%, respectively. 83 A recent phase II trial of 2-chlorodeoxyadenosine in 21 refractory CTCL patients (mycosis fungoides IIB/IV and Sezary syndrome) revealed an OR rate of 28%, with 14% CR (median duration of 4⋅5 months) and 14% PR (median duration of 2 months). 84 Drawbacks Side-effects include nausea, infections (especially herpetic), CD4 lymphopenia, renal toxicity, hepatotoxicity and myelosuppression (especially for 2-chlorodeoxyadenosine and fludarabine). Comments Purine analogues are attractive therapeutic candidates for CTCL because they are potent inhibitors of the enzyme adenosine deaminase, 363 Primary cutaneous T-cell lymphoma which preferentially accumulates in lymphoid cells, such that these drugs are selectively lymphocytotoxic independently of cell division. Although efficacy in CTCL is moderate, most of these patients were heavily pretreated and relatively chemoresistant. Patients with Sezary syndrome appear to respond better than those with late stages of mycosis fungoides. Purine analogues are appropriate as monotherapy, especially in Sezary syndrome, but response duration may be short. Comparative trials with other single-agent regimens in Sezary syndrome are required. Gemcitabine Efficacy A phase II prospective trial (1200 mg/m 2 weekly for 3 weeks each month for a total of three cycles) in 44 previously treated patients with CTCL (30 mycosis fungoides patients with stage IIB or III disease) reported a PR rate of 59% and a CR rate of 12%, with median durations of 10 and 15 months, respectively. 85 Drawbacks Treatment was well tolerated and only mild haematological toxicity was noted. Comments Gemcitabine is a new pyrimidine antimetabolite which appears to be well tolerated in heavily pretreated patients with advanced stages of mycosis fungoides. Further trials are required. Doxorubicin Efficacy An open study of pegylated liposomal doxorubicin, 20 mg/m 2 monthly to a maximum of 400 mg or eight cycles, in 10 patients with various stages of mycosis fungoides revealed a CR in six and PR in two patients, with a median response duration of 15 months. 86 Drawbacks Mild haematological toxicity was reported. Comments An EORTC phase II trial in advanced stages of mycosis fungoides (>IIB) is due to start enrolment shortly. What are the effects of multiagent chemotherapy regimens in mycosis fungoides/Sezary syndrome? Combination chemotherapy Efficacy An RCT in 103 CTCL patients comparing TSEB and multiagent chemotherapy (CAVE) with sequential topical therapy including superficial radiotherapy and phototherapy revealed a higher CR rate in the TSEB/chemotherapy group (38% compared with 18%; P = 0⋅032 with OR rates of 90% and 65%, respectively) but after a median follow up of 75 months there was no significant difference in DFS or OS. 77 A systematic review of all systemic therapy in CTCL (mycoses fungoides and Sezary syndrome, 1988–94) showed an OR rate of 81% in 331 patients treated with various different combination chemotherapeutic regimens, with a CR rate of 38% and response duration ranging from 5 to 41 months, with no documented cures for patients with late stages of disease (IIB–IVB). 59 Recent prospective non-randomised studies of different multiagent chemotherapy regimens have revealed similar OR rates. A third- generation anthracycline (idarubicin) was used in combination with etoposide, cyclophosphamide, vincristine, prednisolone and bleomycin (VICOP-B) to treat 25 CTCL patients (eight stage IIB, 13 IVA, four stage IVB) for 12 weeks. OR rates of 80%, with 36% CR, were documented, although 364 Evidence-based Dermatology 10 patients had not received any previous therapy. The two patients with Sezary syndrome did not respond and the median duration of response in patients with mycoses fungoides was 8⋅7 months. Stage IIB patients had a median duration of response of 22 months but four previously untreated patients received additional TSEB therapy after completion of chemotherapy. 87 A combination of etoposide, vincristine, doxorubicin, cyclophosphamide and prednisolone (EPOCH) was used to treat 15 patients with advanced, refractory CTCL (six with Sezary syndrome; four with stage-IVB mycoses fungoides, one with adult T-cell lymphoma and four with large cell anaplastic lymphoma). After a median of five cycles, 27% had a CR and 53% achieved a PR (OR rate 80%) with an overall median survival of 13⋅5 months. 88 Drawbacks Multi-agent chemotherapy regimens are associated with very high rates of toxicity and considerable morbidity, including nausea, anorexia, infection, hepatotoxicity and myelosuppression. Patients with CTCL are at high risk of septicaemia, and therapy-related mortality with combination chemotherapy is a significant risk. Comments Patients with late stages of CTCL (IIB–IVB) will require treatment with a chemotherapy regimen, although response duration is short. In the RCT, 77 OS/DFS was similar to that in those treated with skin-directed therapy although in this study patients with early stage disease were also included. The individual patient’s quality of life should always be considered before embarking on very toxic regimens with limited efficacy. Single-agent regimens (see above) appear to have similar efficacy, although studies involving a comparison between single-agent and multi-agent regimens, with or without TSEB, are required. To date there have been no studies assessing the use of biochemotherapy in CTCL although subsequent treatment with immunotherapy for patients achieving a response with chemotherapy should be considered. Myeloablative chemotherapy with autologous/allogeneic peripheral blood/bone-marrow stem-cell transplantation Efficacy No systematic reviews or RCTs were identified. Most studies were based on small numbers of patients. High-dose chemotherapy with TSEB and total-body irradiation (TBI) in four and three patients with mycoses fungoides (two patients had both TSEB and TBI) followed by autologous bone marrow transplantation in six patients (three stage IIB, one stage IVA, two stage IVB) produced five complete clinical responses but disease relapse occurred within 100 days in three patients. 89 The other two patients, who had both received a combination of carmustine- etoposide-cisplatin chemotherapy, were disease free at almost 2 years (666 and 631 days post-transplant). High-dose chemotherapy combined with either TSEB or TBI and followed by autologous peripheral blood stem cell transplantation in patients with stage IIB/IVA mycosis fungoides revealed CRs in eight patients and durable clinical responses in four patients (median DFS 11 months). 90 Isolated case reports of high-dose chemotherapy with TBI followed by allogeneic bone-marrow or stem-cell transplantation have shown excellent long-term complete remissions in stage IIB mycosis fungoides (CR for total of 17 months at time of report) and Sezary syndrome. 91,92 365 Primary cutaneous T-cell lymphoma Drawbacks Myeloablative therapy is associated with a high incidence of toxicity and systemic infections. Significant mortality, especially with allogeneic transplantation, occurs. Comments Controlled trials comparing autologous transplantation with standard chemotherapy in late stages of mycosis fungoides are required, as conducted in systemic follicular B-cell lymphoma. The mortality rate associated with allogeneic transplantation makes this a less attractive approach but the use of mini- allogeneic procedures to induce a graft-versus- tumour effect would be worth investigating. Key points Implications for practice • Although there are few well-designed RCTs in CTCL, there is convincing evidence that several skin-directed therapies have a significant therapeutic effect. However, there is a fundamental lack of data on the impact of different therapies on DFS and OS, which will only become clearer when the results of key RCTs in different stages of disease become available. • In addition, patients with early-stage disease can have a normal life expectancy, and so aggressive therapies with a significant mortality and morbidity should be avoided in these patients, especially when the chance of a cure is very low. • Patients with early-stage disease (IA/IB/IIA) should be offered skin-directed therapies such as topical mechlorethamine, phototherapy, PUVA and superficial radiotherapy. Alfa interferon should be considered for patients with persistent or recurrent stage IB/IIA disease. Some patients with stage IA disease may not require any specific therapy. Recommendations for the future • New topical therapies should be assessed in the context of well-designed clinical trials comparing them with topical mechlorethamine. • The role of new immunotherapies and retinoids in early stage (IB/IIA) disease should involve comparative RCTs with standard therapies such as PUVA. • TSEB therapy with or without adjuvant immunotherapy and chemotherapy should be reserved for patients with late stages of disease, preferably in the context of clinical trials. • There is an urgent need for more effective therapy for late-stage disease and this should be based on appropriate RCTs involving new immunotherapies, adjuvants, single- and multi-agent chemotherapies and both (mini)allogeneic and autologous transplants in selected individuals. References 1. Willemze R, Kerl H, Sterry W et al . EORTC classification for primary cutaneous lymphomas A proposal from the cutaneous lymphoma study group of the European organisation for research and treatment of cancer. 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