Lutz Kretschmer

Temozolomide in Combination With Interferon-Alfa Versus Temozolomide Alone in Patients With Advanced Metastatic Melanoma: A Randomized, Phase III, Multicenter Study from the Dermatologic Cooperative Oncology Group

PURPOSE Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. PATIENTS AND METHODS Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week). RESULTS Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001). CONCLUSION In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection.

For patients with melanoma metastasis to a sentinel lymph node, subsequent complete regional lymph node dissection (CLND) is currently regarded to be the surgical standard. This approach, however, has not been confirmed by controlled studies, so that surgical morbidity is of primary importance. Using clinical examination and a questionnaire, we determined morbidity in 315 patients with axillary or inguinal lymph node excision on whom 275 sentinel lymphonodectomies (SLNEs) and 90 CLNDs were performed. The overall incidence of at least one complication following SLNE was 13.8%. The short-term complication rate was 11.3% (allergic reaction to blue dye 0%, wound breakdown 0%, haematoma 2.5%, wound infection 3.6%, seroma 6.9%). The incidence of long-term complications was 4.1% (persistent tattoo 0.4%, functional deficit 0.4%, nerve dysfunction/pain 0.7% or swelling 2.5%). All complications were mild. Significantly, the complication rate was not higher for patients aged 70 years or older. After CLND, the overall complication rate was significantly higher (65.5%, P<0.000001). The incidence of short-term complications was 50% (haematoma 0%, wound breakdown 6.7%, wound infection 24.7% or seroma 34.8%). The incidence of long-term complications was also 50% (nerve dysfunction/pain 8.9%, functional deficit 16.8%, swelling 37.1%). Overall, inguinal lymph node excision was burdened by a higher complication rate (P=0.015). Age and sex did not influence postoperative morbidity. No deaths linked to either procedure were noted. Complication rates after SLNE are low and most complications are minor and short-lasting. In contrast, CLND has been demonstrated to be a major and potentially morbid surgical procedure. This highlights the importance of testing the therapeutic value that CLND adds to the sentinel lymph node procedure.

Dynamic lymphoscintigraphy and image fusion of SPECT and pelvic CT-scans allow mapping of aberrant pelvic sentinel lymph nodes in malignant melanoma

To date, there are no reliable criteria to identify those patients with melanoma-infiltrated sentinel lymph nodes (SLNs) of the groin who might benefit from an extended lymphadenectomy, including the pelvic lymph nodes. We hypothesised that there are pelvic lymph nodes that receive lymph directly from the primary tumour, thus being at an increased risk for metastasis. In order to determine the frequency of radioactively labelled pelvic lymph nodes and the kinetics of their appearance, we introduce here a combination of dynamic lymphoscintigraphy, single photon emission computed tomography (SPECT) and image fusion of SPECT and pelvic Computed Tomography (CT)-scans. By dynamic lymphoscintigraphy and intraoperative gamma probe detection, superficially located inguinal SLNs (median 2 nodes) could be identified in all of the 51 patients included in this analysis. The histological search for micrometastases was positive in 16 patients (median Breslow thickness of the primary melanoma 2.5 mm). In 29 patients, SPECT and the image fusion technique were additionally performed. Radioactively labelled pelvic lymph nodes were detected in 20 individuals, 6 of them presenting aberrant pelvic SLNs that, on dynamic lymphoscintigraphy, had appeared simultaneously with the superficial SLN(s). Of the 6 patients in whom radioactive pelvic lymph nodes were excised together with the superficial SLN(s), only one had positive superficial SLNs. In this patient, the aberrant pelvic SLN proved to be tumour-positive. In 9 patients, there was no radiotracer uptake in the pelvic lymph nodes at all. Image fusion of SPECT and pelvic CT-scans is an excellent tool to localise exactly the pelvic tumour-draining nodes. The significance of radioactively labelled pelvic lymph nodes for the probability of pelvic metastases should be analysed further.

Sentinel lymph node status is the most important prognostic factor for thick (≥ 4 mm) melanomas

Background: The value of the status of the sentinel lymph node (SLN) in patients with thick melanomas (Breslow thickness ≥ 4 mm) is controversial.

Dynamic Changes in Nevi of a Patient With Melanoma Treated With Vemurafenib: Importance of Sequential Dermoscopy

BACKGROUND Therapy with vemurafenib, an inhibitor of mutated BRAF, yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation. As an adverse effect of vemurafenib, proliferative disorders of keratinocytes, including squamous cell carcinoma, have been described. Low concentration of vemurafenib as present in the epidermis were found to activate wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. OBSERVATION We present the case of a patient with dynamic changes of melanocytic nevi well documented by sequential digital dermoscopy during vemurafenib therapy. A variety of dermoscopic changes were observed. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. Second, preexisting nevi increased in size, and pigmentation that rendered them atypical. Such lesions were flat and showed a predominant reticular pattern at baseline. Third, multiple new nevi occurred. One example of each of the latter 2 categories was excised and showed wild-type BRAF. CONCLUSION Our findings of changing nevi in a patient treated with vemurafenib highlight the need for sequential skin examinations, including dermoscopy.

Hybrid cell vaccination in metastatic melanoma: clinical and immunologic results of a phase I/II study.

Hybrid cell vaccination with cell fusion products (CFPs) of autologous tumor cells and mature allogenic MHC II bearing dendritic cells has been described to induce cytotoxic T lymphocyte (CTL)-mediated immune responses. The aim of this study was to assess safety, antitumor activity, and immune responses of a CFP-vaccine in patients with disseminated malignant melanoma. In a phase I/II study, we treated 11 patients by monthly intracutaneous or subcutaneous application of a CFP vaccine generated by electrofusion of autologous melanoma cells with mature allogenic dendritic cells. In addition, patients received subcutaneous low-dose interleukin-2 injections for 6 days after each vaccination. No serious adverse effects were observed. Ten patients showed progressive disease and one patient had a short-lasting stable disease. None of the patients developed a positive delayed-type hypersensitivity reaction against irradiated autologous melanoma cells. In 2 patients, who were monitored in more detail, we found no evidence of induction of a specific antimelanoma T-cell response by analyzing the proliferation, cytokine secretion, and cytotoxicity of their T cells toward autologous melanoma cells. No unequivocal beneficial effects of the used CFP vaccine could be demonstrated.

Factors Predicting the Risk of In-Transit Recurrence After Sentinel Lymphonodectomy in Patients With Cutaneous Malignant Melanoma

BackgroundIn-transit metastasis is an important morbidity factor after sentinel lymphonodectomy (SLNE). So far, factors posing an increased risk after SLNE have not been adequately analyzed.MethodsUsing Kaplan-Meier estimations and the Cox proportional hazards model, we analyzed the risk of developing in-transit metastases after SLNE for 328 consecutive patients (median tumor thickness, 2.0 mm; median follow-up period, 40 months).ResultsThe 5-year probability of developing in-transit metastases as a first recurrence was 11.2%. After negative and positive SLNE, the probabilities were 6.3% and 24%, respectively. Patients in whom satellite metastases were excised concurrently with the primary tumor had a probability of recurrence with in-transit metastases of 41%. In sentinel lymph node (SLN)-negative patients with primary tumors having a thickness of more than 4 mm, the probability was 22.1%. Among the group of SLN-positive patients, significantly increased in-transit probabilities were observed in those with primary tumors that were thicker than 4 mm (41.8%), with tumors located on the distal extremities (42.1%), and with penetration of the nodal metastasis of >1 mm into the SLN (36%) and in patients with capsular breakthrough (63.3%). By using multifactorial analysis, the SLN status (P = .005), Breslow thickness (P = .0009), and extremity location of the primary melanoma (P = .005) significantly predicted the risk of in-transit recurrence. Satellite metastasis (P < .089), Clark level, and ulceration did not reach significance.ConclusionsSubgroups of patients can be identified who seem to have an increased risk of developing in-transit metastases as a first recurrence after SLNE. Individualized therapeutic strategies should be developed for these patients.

Age as a key factor influencing metastasizing patterns and disease-specific survival after sentinel lymph node biopsy for cutaneous melanoma.

In our study, we investigated the impact of the constitutional factor age on the clinical courses of melanoma patients with sentinel lymph node (SLN) biopsy. Descriptive statistics, Kaplan‐Meier estimates, logistic regression analysis and the Cox proportional hazards model were used to study a population of 2,268 consecutive patients from three German melanoma centers. Younger age was significantly related to less advanced primary tumors. Nevertheless, patients younger than 40 years of age had a twofold risk of being SLN‐positive (p < 0.000001). Of the young patients with primary melanomas with a thickness of 0.76 mm to 1.0 mm, 19.7% were SLN‐positive. Using multivariate analysis, younger age, increasing Breslow thickness, ulceration and male sex were significantly related to a higher probability of SLN‐metastasis. During follow‐up, older patients displayed a significantly increased risk of in‐transit recurrences (p = 0.000002) and lymph node recurrences (p = 0.0004). With respect to melanoma specific overall survival the patients age was highly significant in the multivariate analysis. The unfavorable effect of being older was significant in the subgroups with positive and negative SLNs. Age remained also significant for the survival after the onset of distant metastases (p = 0.002). In conclusion, the patients age is a strong and independent predictor of melanoma‐specific survival in patients with localized melanomas, in patients with positive SLNs and after the onset of distant metastases. Younger patients have a better prognosis despite their higher probability of SLN metastasis. Older patients are less frequently SLN‐positive but have a higher risk of loco‐regional recurrence.

Standardized axillary lymphadenectomy improves local control but not survival in patients with palpable lymph node metastases of cutaneous malignant melanoma

Abstract.Background: The aim of the present study was to investigate whether consistent application of standard surgical techniques contributes to improved local control or improved survival in melanoma patients with palpable lymph node metastases to the axilla. Method: Using Kaplan-Meier estimations and the Cox proportional hazards model, 120 axillary dissections were assessed. The data from 63 patients who had received standardized axillary lymphadenectomy were compared to those of 57 patients operated on before the introduction of standardized lymphadenectomy. Results: The introduction of standardized axillary lymphadenectomy led to a significant decrease in 5-year local recurrence probability from 43.1% to 13.1% (P=0.0008). Using multifactorial analysis, the standardized operative procedure resulted in a significantly lower risk of recurrence in the dissected axilla (P=0.009). The development of intransit metastases was also related to recurrence in the nodal basin (P=0.03). No significance was accorded to the number of metastatic lymph nodes, tumor thickness, epidermal ulceration, site of primary melanoma, age, sex, or adjuvant chemotherapy. Notably, no differences in the survival rates were observed between the two treatment groups. Conclusion: In patients with palpably enlarged axillary lymph node metastases, the introduction of a complete lymphadenectomy, standardized according to the currently acknowledged principles of oncological surgery, improves local disease control without improving overall survival.

Schimmelpenning-Feuerstein-Mims Syndrome with Hypophosphatemic Rickets

The Schimmelpenning-Feuerstein-Mims syndrome (SFM syndrome) is a rare and variable multisystem defect consisting of congenital, extensive linear nevus sebaceus and associated abnormalities in different neuroectodermal organ systems. We present the history of a 52-year-old female patient with disproportionate hyposomia and asymmetric constitution. From birth she suffered from a right-sided, extensive nevus sebaceus following Blaschko’s lines extending on the scalp, neck, right arm and trunk. At the age of 5 years, she developed a generalized growth retardation, along with deformations of bones. At the age of 11, hypophosphatemic rickets was diagnosed causing this growth retardation. Moreover, the patient developed a precocious puberty at the age of 9 years. When we saw the patient 40 years after the diagnosis had been made, phosphaturia had returned to normal. Specific therapy of hypophosphatemic rickets is straightforward and efficient in preventing late complications like growth retardation. We suggest to conduct appropriate laboratory tests in early childhood in patients with an extensive systematized sebaceous nevus or with additional signs of growth retardation or skeletal involvement, in order to exclude hypophosphatemic rickets associated with SFM syndrome.