Photodynamic therapy with a 5-ALA patch does not increase the risk of conversion of actinic keratoses into squamous cell carcinoma: Results of a multicentre non-interventional study.

BACKGROUND: It is important to collect data about the risk of transformation of an actinic keratosis (AK) lesion into squamous cell carcinoma (SCC) after a single photodynamic therapy (PDT) with 5-ALA patch for a longer follow-up period under daily routine. QUESTIONS ADDRESSED: The purpose of this non-interventional study (NIS) was to collect data on the frequency of occurrence of SCCs in the treated area during an interval of 2 years after a single 5-ALA patch-PDT. EXPERIMENTAL DESIGN: This prospective observational case-only study included patients with mild AK lesions on the head and face treated with 5-ALA patch-PDT according to the Summary of Product Characteristics (SPC). RESULTS: In 370 patients, the risk of transformation of their treated AK lesion into SCC was 0.073% with its exact 95% confidence interval using the Poisson distribution of [0.009%, 0.262%]. The rate of complete clinical clearance on lesion basis after 3 months was 84.3%. CONCLUSION: The efficacy and the safety results show no observation of an increased risk for conversion of an AK into a SCC 2 years after a single 5-ALA patch-PDT. Additionally, the high clinical complete remission rate under routine conditions is comparable to the rates observed in the approval trials.

Survival after intratumoral interleukin-2 treatment of 72 melanoma patients and response upon the first chemotherapy during follow-up.

Systemic high-dose interleukin-2 (IL-2) treatment achieves long-term survival in a subset of advanced patients with melanoma. As we reported previously, intratumoral IL-2 induced complete local responses in more than 60% of melanoma patients. This study aimed to analyze the long-term outcome of 72 patients treated in two prior trials. Melanoma patients (49 stage III, 23 stage IV) with injectable metastases received intratumoral IL-2 injections thrice weekly at individually escalated doses (median duration, 6.5 weeks; median total IL-2 dose, 72 MIU; median number of injected metastases, 10). The observed 2-year overall survival rates were 95.5% for stage III patients with cutaneous metastases only (stage IIIB), 72% for those with combined cutaneous and lymph node involvement (stage IIIC), 66.7% for stage IV patients with disease limited to distant soft-tissue metastases (stage IV M1a), and 9.1% for those with visceral metastases (stage IV M1b and stage IV M1c). Thirty patients who reported recurrence of unresectable distant metastases subsequently received chemotherapy in the further course of disease and showed an overall response rate of 36.7% (16.7% complete responses, 20% partial responses). A high total dose of IL-2 and a dacarbazine/temozolomide-based chemotherapy regimen were variables correlated with a clinical response. In conclusion, patients with cutaneous metastasis without lymph node involvement in stage III and with soft-tissue metastasis without visceral involvement in stage IV showed unexpected favorable survival rates after intratumoral treatment with IL-2. Furthermore, the intratumoral IL-2 treatment seemed to be associated with increased complete and partial responses in subsequent chemotherapies.

A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal cell carcinoma.

OBJECTIVE: The present study was planned to evaluate the efficacy and tolerability of topical treatment with imiquimod in nodular basal cell carcinoma (nBCC). METHODS: One hundred two patients were randomized to receive thrice-weekly topical imiquimod for either 8 or 12 weeks. Twelve patients dropped out. A total of 90 patients were evaluated for tolerability and efficacy. Histologic clearance was controlled by excising the original tumor location with 3-mm margins and evaluating with permanent sections the cut-surgical margin, including the deep margin, and with serial step-sectioning the central portion of the tissue for tumor persistence. RESULTS: There were no significant differences between the treatment arms with respect to efficacy and tolerability. Of 90 evaluable patients, 70 had a complete clinical clearance (78%). Clinically visible tumor was still present in 20 patients (22%). A complete histopathological clearance was observed in 58 patients (64%). Tumor persisted in 32 patients (36%). In 12 patients, despite complete clinical clearance, tumor remnants were still detected in histopathological evaluation. Efficacy was better in nBCC that was less than 1 cm in diameter, showing 82% clinical and 72% histopathologic clearing. Adverse events were reported in 92% of the patients and were mainly classified as minor or moderate local inflammation. LIMITATIONS: Clinical follow-up was limited to the time period between end of treatment and final complete excision. CONCLUSION: Imiquimod applied thrice weekly for 8 and 12 weeks shows modest activity against small nBCC. Residual tumor was present in more than one third of treated patients. Clinical appearance after treatment does not accurately reflect the presence or absence of disease in nearly 1 of every 5 patients with nBCC. Since 17% of patients with clinical clearance still have pathologic evidence of disease, excisional biopsy of the treated site is still indicated.

Prospective comparison of the impact on treatment decisions of whole-body magnetic resonance imaging and computed tomography in patients with metastatic malignant melanoma.

Patient management and treatment strategies for metastatic melanoma depend largely on the stage of metastatic disease. The aim of this study was to compare contrast-enhanced whole-body magnetic resonance imaging (wbMRI) and whole-body computed tomography (wbCT) to detect distant metastases for staging. A total of 43 patients (41 with completed wbCT and wbMRI examination) with known American Joint Committee on Cancer (AJCC) stage III-IV malignant melanoma were examined and 775 metastases were identified by both methods. Whole-body CT was able to detect 522 metastases, whereas wbMRI found 730 metastases. Whole-body CT identified 188 pulmonary metastases, compared with 143 metastases detected by wbMRI. In kidneys, adrenal glands and lymph nodes, respectively, wbCT and wbMRI detected the same number of lesions. Whole-body MRI detected more metastases than wbCT in liver (detection rate 122/199), spleen (26/54), subcutaneous tissue (39/61), muscle (4/11), bone marrow (23/132) and brain (15/25). Therapy was modified as a consequence of wbMRI findings in 10/41 (24%) patients. In conclusion, wbMRI detected clearly more malignant melanoma metastases in most organ systems with the exception of lung metastases. More accurate and complete staging by wbMRI has an impact on treatment strategy in about one-quarter of the patients.

Metastatic glucagonoma: treatment with liver transplantation.

Glucagonoma is a rare pancreatic endocrine tumor that is often both well developed and malignant at detection. In the case of metastatic spread the patient has a poor long-term prognosis. We hope to familiarize dermatologists and other specialists with this rare and potentially fatal disorder because early recognition of necrolytic migratory erythema, a clinical feature that may appear in patients with glucagonoma, can lead to possible cure, whereas delayed identification of the disease is associated with metastatic disease and a poor prognosis. We report the case of a 57-year-old patient with a metastatic glucagon-producing tumor; necrolytic migratory erythema was diagnosed and was successfully treated by a multimodal intervention including liver transplantation. Currently, 72 months after transplantation, our patient is in complete remission, which has been verified by somatostatin receptor scintigraphy monitoring, computed tomographic scanning and glucagon serum control. Increased awareness of the clinical symptoms and visible polymorphic mucocutaneous and nonspecific histopathologic features of glucagonoma syndrome is needed to avoid unnecessary delay in the diagnosis of this syndrome.

Fast whole-body assessment of metastatic disease using a novel magnetic resonance imaging system: initial experiences.

OBJECTIVE: The objective of this study was to investigate the clinical use of a novel whole-body magnetic resonance imaging (MRI) system for comprehensive assessment of tumor spread in clinical routine. MATERIAL AND METHODS: Sixty-five patients with different tumors with known metastatic disease and 6 healthy volunteers were included. High-resolution MRI from head to toe was performed using multiple phased-array surface coil elements, 24 independent receiver channels, and an integrated parallel acquisition technique (iPAT). A total room time of less than 60 minutes was required. Whole-body MRI and conventional spiral computed tomography (CT) were independently evaluated and compared in terms of feasibility, location/number of detected metastases, and therapeutic relevance. RESULTS: Whole-body MRI was successfully performed in 68 of 71 subjects. Compared with CT, more metastases were detected by MRI in 11 of 63 patients (17%), particularly in brain, liver, spleen, lymph nodes, bone marrow, muscle, and subcutaneous fat tissue. According to these findings, therapy had to be modified in 6 of 63 patients (10%). CONCLUSIONS: High-resolution whole-body MRI is feasible in clinical routine within 1 single examination and offers great potential for fast assessment of individual tumor spread and total tumor burden.

Imiquimod in the treatment of extensive recurrent lentigo maligna.

We report the case of a 70-year-old white male with an extensive recurrence of lentigo maligna in a skin-transplanted region. He was treated with imiquimod 5% cream topically applied 5 times a week for a total duration of 9 months. Clinically and histologically, a complete clearing of the lesion was observed after treatment. Topical treatment with imiquimod seems to be effective and safe in lentigo maligna.

High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma.

BACKGROUND: Systemic high-dose interleukin-2 (IL-2) achieved long-term survival in a subset of patients with advanced melanoma. The authors reported previously that intratumorally applied IL-2 induced complete local responses of all metastases in >60% of patients. The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response. METHODS: Patients with melanoma who had a median of 12 injectable metastases received intratumoral IL-2 treatments 3 times weekly until they achieved clinical remission. The initial dose of 3 million international units was escalated, depending on the individual patient's tolerance. RESULTS: Forty-eight of 51 patients were evaluable. Only grade 1/2 toxicity was recorded. A complete response that lasted >/=6 months was documented in 70% of all injected metastases. A complete local response of all treated metastases was achieved in 33 patients (69%), including 11 patients who had between 20 and 100 metastases. Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease. No objective responses of distant untreated metastases were observed. The 2-year survival rate was 77% for patients with stage IIIB/IIIC disease and 53% for patients with stage IV disease. Efficacy and survival did not differ between patients who had >/=20 lesions and patients who had <20 lesions. CONCLUSIONS: Intratumoral IL-2 treatment elicited complete local responses in a high percentage of patients. Further studies will be required to investigate the mode of action of this treatment and its impact on survival.

Adjuvant treatment with vindesine in comparison to observation alone in patients with metastasized melanoma after complete metastasectomy: a randomized multicenter trial of the German Dermatologic Cooperative Oncology Group.

To evaluate the efficacy and safety of vindesine in patients with metastatic melanoma after complete metastasectomy. One hundred and forty-two patients with metastatic spread to regional sites, lymph nodes, and distant sites after complete metastasectomy were randomized to receive either treatment with vindesine for 2 years or observation alone. Vindesine 3 mg/m intravenously was administered biweekly for the first 26 weeks following 3-week intervals for an additional 26 weeks and thereafter every 4 weeks for 52 weeks. One hundred and thirty-nine patients were eligible for intent-to-treat analysis. Median follow-up time was 46 months. Median recurrence free survival was 7.9 months in the vindesine group and 7.6 months in the observational group (P=0.40). Three-year overall survival rate was 54.9% (37 patients) for patients receiving vindesine in comparison to 43.6% (31 patients) in the observation arm (P=0.07). No grade IV toxicity was observed. The two major side effects in the vindesine group were alopecia and peripheral neuropathy. Ten patients went off treatment because of grade III toxicity. Adjuvant treatment with vindesine did not significantly prolong disease free or overall survival in high-risk melanoma patients. Thus, this randomized trial did not confirm earlier reports of beneficial effects of adjuvant vindesine and can therefore not be recommended.

[Experiences with the new American Joint Committee on Cancer (AJCC) classification of cutaneous melanoma]. / Erfahrungen mit der neuen American Joint Committee on Cancer (AJCC)-Klassifikation des kutanen malignen Melanoms.

A new AJCC/UICC staging classification of malignant melanoma was published in 2001 and has been in use since then. Compared to the TNM classification used for the previous 15 years, the new classification contains fundamental changes. The classification of the primary tumor is now based on newly defined classes for Breslow's tumor thickness (0 - 1.0 mm; 1.01 - 2.0 mm, 2.01 - 4.0 mm; > 4.0 mm). Histopathologically diagnosed ulceration is the second prognostic factor in primary melanoma and its presence leads to upstaging into the next higher T category. Clark level of invasion is now only relevant for tumors up to 1 mm thick; levels IV and V are also reasons for upstaging. Classification of regional lymph node metastasis distinguishes between microscopic metastasis only as detected with sentinel lymph node biopsy and clinically detectable macroscopic metastasis. Additionally, the number of metastatic nodes and the presence of satellite and in-transit metastasis are prognostic factors for classification of regional lymph node metastasis. In distant metastasis, the kind of organ involvement has a role for classification (only skin and lymph nodes vs. lung vs. other organs) and an elevated LDH value leads to upstaging. A critical analysis of data of the German Central Malignant Melanoma Registry did not confirm the strong role of histopathological ulceration of the primary tumor in all T- and N-stages. Furthermore, there is an inconsistency of the classification as stage IIC displays a significantly worse prognosis as compared to stage IIIA. In spite of these drawbacks the new staging classification should used particularly in clinical trials in order to make data internationally comparable.

Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials.

We undertook a systematic review of 41 randomised studies in disseminated melanoma, identified by a comprehensive search. We aimed to investigate rates of response to various treatment modalities and the outcome for the patients. We analysed seven studies that compared polychemotherapy with single-agent dacarbazine, six that compared different chemotherapeutic schedules with each other, five on the addition of tamoxifen to a reference therapy, and six that included non-specific immunostimulators. In 17 studies, the addition of interferon alfa, interleukin 2, or both, to a reference therapy was investigated, including trials with biochemotherapy. Many trials had small sample sizes and did not report a power analysis; not all were analysed by intention to treat. Although some treatment regimens, especially polychemotherapeutic schedules, seem to increase response rates, none of the treatment schedules was proven to prolong overall survival. Patients with disseminated melanoma should be treated with well-tolerated drug regimens, such as single-agent treatments or in combination with interferon alfa. Systemic treatments should preferably be investigated in randomised trials so that the potential benefits of new treatment concepts can be thoroughly examined.