Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry.

(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23-0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1-2 HRadj: 0.61 95% CI: 0.4-0.93, p = 0.02, irAEs grade 3-4 HRadj: 0.55 95% CI 0.31-0.99, p = 0.04), but not with PFS (irAEs grade 1-2 HRadj: 1.21 95% CI: 0.91-1.79, p = 0.16, irAEs grade 3-4 HRadj: 1.14 95% CI 0.83-2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.

MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients.

BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.

Safety of shortened infusion times for combined ipilimumab and nivolumab.

BACKGROUND: Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates. AIM: To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent. PATIENTS AND METHODS: We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab. RESULTS: Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR. CONCLUSIONS: Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

The need for psycho-oncological support for melanoma patients: Central role of patients' self-evaluation.

Despite an increasing number of promising treatment options, only a limited number of studies concerning melanoma patients' psycho-oncological distress have been carried out. However, multiple screening tools are in use to assess the need for psycho-oncological support. This study aimed first to identify parameters in melanoma patients that are associated with a higher risk for being psycho-oncologically distressed and second to compare patients' self-evaluation concerning the need for psycho-oncological support with the results of established screening tools.We performed a cross-sectional study including 254 melanoma patients from the Center for Dermatooncology at the University of Tuebingen. The study was performed between June 2010 and February 2013. Several screening instruments were included: the Distress Thermometer (DT), Hospital Anxiety and Depression Scale and the patients' subjective evaluation concerning psycho-oncological support. Binary logistic regression was performed to identify factors that indicate the need for psycho-oncological support.Patients' subjective evaluation concerning the need for psycho-oncological support, female gender, and psychotherapeutic or psychiatric treatment at present or in the past had the highest impact on values above threshold in the DT. The odds ratio of patients' self-evaluation (9.89) was even higher than somatic factors like female gender (1.85), duration of illness (0.99), or increasing age (0.97). Patients' self-evaluation concerning the need for psycho-oncological support indicated a moderate correlation with the results of the screening tools included.In addition to the results obtained by screening tools like the DT, we could demonstrate that patients' self-evaluation is an important instrument to identify patients who need psycho-oncological support.

Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry.

For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96-1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients.

Impact of 18F-FDG-PET/CT on surgical management in patients with advanced melanoma: an outcome based analysis.

PURPOSE: To evaluate the influence of 18F-FDG-PET/CT on clinical decision making and outcome in advanced melanoma patients planned for radical metastasectomy. METHODS AND MATERIALS: A cohort of 333 patients with mainly stage III/IV melanoma having a PET/CT for clinical reasons was prospectively enrolled in our oncologic PET/CT registry between 2013 and 2015. Referring physicians completed questionnaires regarding their intended management for each patient before and after PET/CT. Management changes after PET/CT were classified as major and minor changes. A subgroup of 107 patients (stage I, N = 5; stage II, N = 3; stage III, N = 42; stage IV, N = 57) was planned for complete metastasectomy initially, based on conventional imaging. Management changes and outcome were evaluated by linkage with the information obtained from patients' medical records. RESULTS: In 28 of 107 patients (26%), the surgical treatment plan remained unchanged after PET/CT. In 24 patients (22%), minor changes were performed, such as enlargement or reduction of the surgical field. In 55 patients (51%, 95% CI 42%-61%) major changes of the intended treatment plan occurred; of those, 20 patients (19%) were classified to be tumor-free with PET/CT, 32 patients (30%) were found to have multiple previously unrecognized metastases and had to be treated by systemic therapy, three patients (3%) had to be changed to palliative radiotherapy or isolated extremity perfusion. The 1-year and 2-year overall survival (OS) in patients with complete metastasectomy (N = 52) was 90% and 79%, respectively. Systemically treated patients (N = 32) resulted in 1-year OS of 72% and 2-year OS of 61%. Eleven of 32 patients (34%) with systemic therapy experienced a complete response. Until December 2016, all 20 patients classified as tumor-free by PET/CT were alive. CONCLUSION: The study confirms the high impact of PET/CT on clinical management in patients with advanced melanoma planned for radical metastasectomy. PET/CT resulted in frequent management changes, preventing futile surgery in half of the patients.

Prognostic impact of tumour burden measured by quantitative real-time PCR from sentinel lymph nodes of melanoma patients: data from 10-year follow-up.

BACKGROUND: Sentinel node (SN) biopsy is regarded as standard of care for patients (pts) with cutaneous melanoma ≥1.0 mm of thickness. In the recent AJCC classification, findings in the SN are simply classified as positive or negative. In our analyses, we were interested whether quantitative real-time PCR (qRT-PCR) is able to predict disease-free survival (DFS) and overall survival (OS) depending on tumour burden in the SN. METHODS: One hundred and forty-five pts were analysed using qRT-PCR for tyrosinase. Results were analysed using accelerated failure time survival model and cox proportional hazards models using the R statistics framework. RESULTS: Forty-one pts (28%) were positive according to qRT-PCR. In total, 12 of 41 pts showed tumour deposits in the SN using S100 and/or HMB-45-labelled immunohistochemistry as well. One patient had micrometastases detected by immunohistochemistry staining but failed in the qRT-PCR. After 10 years of follow-up, 34 patients recurred and 27 patients died. Significant differences for DFS and OS were detected for sex, increasing tumour thickness, ulceration of the primary tumour, and metastatic spread in the SN determined by histology as well as qRT-PCR. CONCLUSION: Quantitative analyses showed a logarithmic correlation between tumour burden and prognosis. However, as multivariate analyses reveal qRT-PCR was not superior compared to classical histology or immunohistology.

Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR).

BACKGROUND: During 2011 and 2014, new treatment modalities like tyrosine kinase inhibitors and checkpoint inhibitors were introduced into the therapy of metastatic melanoma. This study addresses the question whether overall survival (OS) of metastatic melanoma patients has already been improved in 441 patients diagnosed with metastatic melanoma between 2011 and 2014 in the real-world setting at the University Hospital Tuebingen. METHODS: All patients were documented with their different therapies by the CMMR and followed up until March 2016. Survival probabilities were calculated by Kaplan-Meier estimators, and log-rank tests were used to evaluate significances. Hazard ratios were estimated by Cox regression analysis for survival probabilities and prognostic factors in stage IV melanoma. RESULTS: Best OS was observed in patients (n = 93) treated by metastasectomy as primary treatment with the intention to completely excise all metastases (3-year OS 61%). OS for patients with first-line systemic treatment (n = 258) was unfavorable in general (3-year OS 23%). Of those, the most favorable outcome was observed in patients without brain metastasis and treated with immunotherapy (mostly ipilimumab), as first-line treatment (median OS 35 months, 3-year OS 43%). In case of brain metastases, patients with targeted therapy had a better OS (median 14 months) than patients with ipilimumab treatment (median 7 months). Among all patients with first-line systemic treatment, outcome of patients diagnosed in the years 2013/2014, compared to 2011 and 2012, showed an improved survival. Three-year OS for patients that entered stage IV in 2013/2014 was 37% compared to those that entered stage IV in 2011 (18%) and 2012 (20%). CONCLUSION: The analysis of real-world data of treatment of metastatic melanoma showed an improvement of OS with both immunotherapy and targeted therapy. In case of cerebral metastasis, patients treated with targeted therapy showed a longer median OS than patients treated with ipilimumab.

Influence of (18)F-FDG PET/CT on therapy management in patients with stage III/IV malignant melanoma.

PURPOSE: To evaluate the influence of (18)F-FDG PET/CT in comparison to CT alone on treatment decisions in patients with advanced melanoma and to analyse the 5-year survival data in comparison to literature data. METHODS: Therapy management in 64 consecutive patients (primary staging n = 52; surveillance n = 12) with stage III/IV melanoma who underwent (18)F-FDG PET/CT between 2004 and 2005 in our department was retrospectively analysed. Treatment decisions were made by two dermatooncologists for each patient twice, first based on the CT results and then based on the PET/CT results. Therapy changes based on the PET/CT results were classified as "major" (e.g. change from metastasectomy to systemic therapy) or "minor" (e.g. change from first to second line chemotherapy). The 5-year survival data of different patient cohorts were calculated. RESULTS: In the 52 patients in the primary staging group, the results of (18)F-FDG PET/CT led to therapy change in 59% and a major therapy change in 52%. (18)F-FDG PET/CT led to the avoidance of futile operations in 13 patients with suspicious lesions on CT that were deemed nontumorous on PET/CT. In the 12 patients in the surveillance group, the results of (18)F-FDG PET/CT led to therapy change in 33% and a major change in 17%. The 5-year survival rates were 30% in the entire cohort, 34% in the primary staging group, and 17% in the surveillance group. A significant overall survival benefit was observed in patients in whom (18)F-FDG PET/CT excluded metastases or in whom metastases could be completely removed compared with patients who were not eligible for surgery (41% vs. 10%). CONCLUSION: Primary staging of patients with stage III/IV melanoma should be performed with (18)F-FDG PET/CT, leading to higher diagnostic accuracy and enabling individualized therapeutic management, especially optimal patient selection for metastasectomy. This strategy may extend long-term survival even in patients with advanced disease.

Serum S100B, lactate dehydrogenase and brain metastasis are prognostic factors in patients with distant melanoma metastasis and systemic therapy.

BACKGROUND: Prognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH) and the type of treatment on survival in advanced patients receiving systemic treatment. PATIENTS AND METHODS: We analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: In univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral), the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy) were associated with overall survival (all p<0.001). In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3-2.1]; p<0.001), S100B (HR 1.6 [1.2-2.1]; p<0.001) and the presence of brain metastases (HR 1.5 [1.1-1.9]; p = 0.009), but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup. CONCLUSION: Serum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.

Melanoma patients with unknown primary site or nodal recurrence after initial diagnosis have a favourable survival compared to those with synchronous lymph node metastasis and primary tumour.

BACKGROUND: A direct comparison of prognosis between patients with regional lymph node metastases (LNM) detected synchronously with the primary melanoma (primary LNM), patients who developed their first LNM subsequently (secondary LNM) and those with initial LNM in melanoma with unknown primary site (MUP) is missing thus far. PATIENTS AND METHODS: Survival of 498 patients was calculated from the time point of the first macroscopic LNM using Kaplan Meier and multivariate Cox hazard regression analysis. RESULTS: Patients with secondary LNM (HR = 0.67; p = 0.009) and those with initial LNM in MUP (HR = 0.45; p = 0.008) had a better prognosis compared to patients with primary LNM (median survival time 52 and 65 vs. 24 months, respectively). A high number of involved nodes, the presence of in-transit/satellite metastases and male gender had an additional independent unfavourable effect. CONCLUSIONS: Survival of patients with LNM in MUP and with secondary LNM is similar and considerably more favourable compared to those with primary LNM. This difference needs to be considered during patient counselling and for stratification purposes in clinical trials. The assumption of an immune privilege of patients with MUP which is responsible for rejection of the primary melanoma, and results in a favourable prognosis is not supported by our data.

Prognostic factors of melanoma patients with satellite or in-transit metastasis at the time of stage III diagnosis.

BACKGROUND: Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma. PATIENTS AND METHODS: We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis. RESULTS: Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival. CONCLUSION: Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or in-transit metastases.

Effective combination of photodynamic therapy and imiquimod 5% cream in the treatment of actinic keratoses: three cases.

BACKGROUND: The therapy for actinic keratoses includes photodynamic therapy (PDT) and imiquimod 5% cream. The sequential use of both could result in better clinical outcomes. OBJECTIVES: To enhance efficacy of therapies while improving tolerability, convenience, and patient adherence with a scheme combining two concomitant or sequential AK treatments. METHODS: All patients underwent one session of conventional PDT. Two weeks after, the PDT imiquimod 5% cream was applied to the treatment area once daily for three days per week. One course continued for four weeks followed by a clinical evaluation and decision about further treatment. Patients who had not cleared all of their AK lesions in the treatment area in course 1 participated in a second 4-week course of treatment. Limitations. Small size of population. RESULTS: Three participants were enrolled. Two patients showed complete clinical clearance of AKs. The effect was also noted after long-term followup, at months seven and eleven. No subject discontinued for an adverse event. There were severe local skin reactions in two participants which were severe erythema, scaling, and crusting. One patient showed no response to the therapy. CONCLUSIONS: Photodynamic therapy followed by imiquimod was well tolerated and improved reduction of actinic keratoses. This initial proof-of-concept should be studied in larger clinical 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.

Melanoma staging: facts and controversies.

The value of staging examinations remains controversial for the initial staging in melanoma patients at the time of the primary diagnosis and for surveillance. Issues concerning tumor recurrences and progression must be discussed separately for different risk groups. For low-risk patients (stage IA; tumor thickness less than 1 mm), staging examinations like sentinel lymph node biopsy (SLNB), blood tests, or imaging can generally be abandoned. Baseline staging with simple techniques is at the discretion of the physician. In intermediate-risk patients (stages IB and IIA), an initial staging examination involving SLNB and computed tomography (CT) scans is recommended. Further follow-up may be restricted to physical examinations, blood tests of tumor marker protein S100beta, and to lymph node ultrasonography. If findings are suspicious, further imaging procedures may be involved. In high-risk patients (stages IIB to III), an initial staging examination with CT is recommended, and regular follow-up every 6 months with whole body imaging by CT or magnetic resonance imaging seems useful. Physical examinations, blood tests of tumor marker protein S100beta, and lymph node ultrasound imaging should be routine. This intense follow-up may enable surgical treatments with complete removal of all recognizable metastases in about 15% to 25% of patients and improve their prognosis. The risk of recurrence or tumor progression is very high in stage IV patients, and their management is individualized.

Incisional biopsy and melanoma prognosis: Facts and controversies.

Facing the increasing number of melanoma patients is the controversial question of whether an incisional biopsy is associated with an unfavorable patient prognosis. Results of nine studies that occurred during the last four decades were reviewed. One of these studies was a large, prospective randomized controlled trial. Evidence from this trial and from most other studies is that incisional biopsies were not associated with an unfavorable prognosis for melanoma patients. Incisional biopsies are currently recommended for the histopathologic diagnosis of large tumors in facial, mucosal, and acral locations. Complete excisional biopsies are the generally recommended standard for melanoma surgery. Incisional biopsies of malignant melanoma do not negatively influence prognosis. Complete excision of primary melanoma is still the recommended standard of care and is a precondition for accurate histopathologic diagnosis.

Excision guidelines and follow-up strategies in cutaneous melanoma: Facts and controversies.

The ongoing increase in melanoma incidence throughout Caucasian populations worldwide raises the question of an economic and efficient management of primary melanoma and follow-up. The primary treatment of a cutaneous melanoma is surgical excision. An excision biopsy is recommended, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for a higher tumor thickness should be applied at the primary excision or in a two-step procedure. When dealing with facial, acral, or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. Whereas the treatment for primary melanoma is accepted world wide, follow-up strategies for melanoma patients are discussed controversially, and so far, no international consensus has been reached.