Adjuvant Interferon Treatment Research Articles

Children with malignant melanoma: a single center experience from Turkey.

Aim:Malignant melanoma is the most frequent skin cancer in children and adolescents. It comprises 1–3% of all malignancies. In this study, we aimed to evaluate the clinical aspects, histopathologic features, and treatment outcomes of our patients with malignant melanoma.Material and Methods:Patients aged <15 years who were treated between 2003 and 2018 for malignant melanoma were retrospectively analyzed.Results:Seventeen patients (10 females, 7 males), with a median age of 7 years (range, 7 months-13 years) were evaluated. Five patients had congenital melanocytic nevi. All had cutaneous melanoma except one with mucosal (conjunctival) melanoma. The most frequent primary tumor site was the lower extremities (35%). Sentinel lymphoscintigraphy, sentinel node biopsy, and PET/CT were performed as the staging procedures at initial diagnosis. Localized disease was present in eight patients; nine had regional lymph node metastasis. The only treatment was surgery in localized disease; surgery and adjuvant interferon treatment was given in patients with regional lymph node metastasis. Three developed distant metastasis (bone, lung, brain) at a median of 9 months. A three-year-old patient received a BRAF inhibitor (vemurafenib), and a 13-year-old patient received a check point inhibitor (ipilimumab); both died of progressive disease. The median follow-up for all patients was 25 months. The 5-year overall survival was 76.6%.Conclusion:Although malignant melanoma is rare in children, prognosis is good if diagnosed early. Physicians should be aware of skin lesions and full-layer biopsy should be obtained in suspicious skin lesions. Patients with congenital melanocytic nevi should also be followed up cautiously.

Human Metapneumovirus Infection in Chronic Obstructive Pulmonary Disease: Impact of Glucocorticosteroids and Interferon

Human metapneumovirus (hMPV) infection is implicated in exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Research into the pathogenesis of infection is restricted to animal models, and information about hMPV replication and inflammatory and immune responses in human disease is limited. Human primary bronchial epithelial cells (PBECs) from healthy and asthmatic subjects and those with COPD were infected with hMPV, with or without glucocorticosteroid (GCS) exposure. Viral replication, inflammatory and immune responses, and apoptosis were analyzed. We also determined whether adjuvant interferon (IFN) can blunt hMPV infection in vitro and in a murine model. hMPV infected human PBECs and viral replication was enhanced in cells from patients with COPD. The virus induced gene expression of IFN-stimulated gene 56 (ISG56) and IFN-β, as well as IFN-γ-inducible protein 10 (IP-10) and regulated on activation, normal T cell expressed and secreted (RANTES), and more so in cells from patients with COPD. GCS exposure enhanced hMPV replication despite increased IFN expression. Augmented virus replication associated with GCS was mediated by reduced apoptosis via induction of antiapoptotic genes. Adjuvant IFN treatment suppressed hMPV replication in PBECs and reduced hMPV viral titers and inflammation in vivo. hMPV infects human PBECs, eliciting innate and inflammatory responses. Replication is enhanced by GCS and adjuvant IFN is an effective treatment, restricting virus replication and proinflammatory consequences of hMPV infections.

Association of immune-inflammation index with outcome of high-risk acral melanoma patients treated with adjuvant high-dose interferon.

e21070Background: High-dose interferon alfa-2b(IFN-α-2b) improves the survival of high-risk melanoma patients, especially acral melanoma patient. However, there is a significant number of patients fails to benefit from treatment because of the toxicities. In this study, we aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients with adjuvant high-dose interferon treatment. Methods: Pretreatment full blood counts, CD4+CD25+ regulatory T cells (CD4+Tregs),CD8+CD28-regulatory T cells(CD8+Tregs), CD8+CD28+cytotoxic T lymphocyte(CTL),serum lactate dehydrogenase (LDH), and clinical date were assessed in 113acral melanoma patients. 76 patients treated with 4-week IFN-α-2b (15*106 U/m2d1–5/w*4w) and 37 patients treated with1-year IFN-α-2b (15*106 U/m2 d1–5/w*4w + 9*106 U tiw*48w). Relapse free survival (RFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and multivariate Cox regression analysis were applied, adjusting for other prognostic fa...

Value of sentinel lymph node biopsy and adjuvant interferon treatment in thick (>4 mm) cutaneous melanoma: an observational study.

The role of sentinel lymph node biopsy and the benefit of immunotherapy with interferon in thick (>4 mm) melanomas remain uncertain. Our aim was to assess the value of both sentinel lymph node (SLN) biopsy and immunotherapy in the prognosis of thick melanomas. A retrospective study based on a computerized patient database in which patients have been prospectively collected since 2005 was performed. Age, sex, location, Breslow thickness, tumor ulceration, regression, Clark level, tumor infiltrating lymphocytes, tumor mitotic rate, microscopic satellite and vascular invasion were included in the analysis. Disease-free (DFS), disease-specific (DSS) and overall (OS) survivals were evaluated by the Kaplan-Meier method and Cox regression analysis. A series of 141 patients with melanomas thicker than 4 mm were included. Multivariate regression showed a worse prognosis in SLN-positive patients with respect to SLN biopsy-negative patients (DFS, hazard ratio [HR] 2, p = 0.04; DSS, HR 2.2, p = 0.002; OS, HR 2.4, p = 0.02). The observational group was shown to have a worse prognosis than the SLN-positive group but was very similar to the clinically positive group. Immunotherapy with high-dose interferon showed a protective effect (DFS, HR 0.5, p = 0.02; DSS, HR 0.3, p = 0.001; OS, HR 0.3, p = 0.001). Our data indicate that SLN biopsy and adjuvant interferon should be considered for patients with thick melanomas.

3323 The GERMELATOX DeCOG-trial: The attitude of German melanoma patients towards toxicity during adjuvant interferon treatment - Differences between the patient's and the physician's perspective

3323 The GERMELATOX DeCOG-trial: The attitude of German melanoma patients towards toxicity during adjuvant interferon treatment - Differences between the patient's and the physician's perspective

The GERMELATOX DeCOG-trial: Attitude of German melanoma patients towards toxicity during adjuvant interferon treatment—Differences between the patient's and the physician's perspective.

e20099 Background: Although trials of adjuvant interferon alfa-2b (IFNa-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), metaanalyses showed only a marginal ov...

Long-Term Outcomes and Prognostic Factors of High-Risk Malignant Melanoma Patients after Surgery and Adjuvant High-Dose Interferon Treatment: A Single-Center Experience

Background: Surgical excision constitutes an important part of the treatment of local advanced malignant melanoma. Due to the high recurrence risk, adjuvant high-dose interferon therapy is still the only therapy used in stage IIB and III high-risk melanoma patients. Methods: One hundred two high-risk malignant melanoma patients who received high-dose interferon-α-2b therapy were evaluated retrospectively. The clinicopathological features, survival times, and prognostic factors of the patients were determined. Results: The median disease-free and overall survival times were 25.2 and 60.8 months, respectively. Our findings revealed that male gender, advanced disease stage, lymph node involvement, lymphatic invasion, the presence of ulceration, and a high Clark level were significant negative prognostic factors. Conclusion: In light of the favorable survival results obtained in this study, high-dose interferon treatment as adjuvant therapy for high-risk melanoma is still an efficient treatment and its possible side effects can be prevented by taking the necessary precautions.

Social support decreases depressogenic effect of low-dose interferon alpha treatment in melanoma patients

ObjectiveThe most frequent serious psychological side effect of immune therapies is depression. In the present study, we tested whether social support, as a positive environmental effect, is able to moderate depression or anxiety symptoms in melanoma patients during adjuvant low-dose interferon treatment. MethodsHundred and twenty-seven melanoma patients with negative psychiatric history were included in our longitudinal study and followed up for one year. Depression and anxiety symptoms were measured six times during treatment: at baseline, at 1st, 3rd, 6th, 9th and 12th month of the therapy. In addition, social support was investigated with the Social Dimension Scale. ResultsDepressive symptoms significantly increased during the 12-month follow-up period (p<0.001). However, social support significantly moderated the depressogenic effect of low-dose interferon treatment (p<0.001). Patients with better social support showed attenuated increase of depression. Anxiety showed no significant changes during the low-dose interferon treatment (p=0.230). Social support had no moderating effect on anxiety symptoms (p=0.745) during the follow up. DiscussionOur data provide evidence that social support and interferon alpha treatment significantly interact in the development of depression. In addition, our study emphasises that enhancement of social support can reduce depressogenic side effects and increase compliance during adjuvant interferon treatment, and thus, psychological screening and psychooncological counselling should be incorporated in the treatment protocol.

Glucocorticosteroids enhance replication of respiratory viruses: effect of adjuvant interferon.

Glucocorticosteroids (GCS) are used on a daily basis to reduce airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). This treatment is usually escalated during acute disease exacerbations, events often associated with virus infections. We examined the impact of GCS on anti-viral defences and virus replication and assessed supplementary interferon (IFN) treatment. Here, we report that treatment of primary human airway cells in vitro with GCS prior to rhinovirus (RV) or influenza A virus (IAV) infection significantly reduces the expression of innate anti-viral genes and increases viral replication. Mice given intranasal treatment with GCS prior to IAV infection developed more severe disease associated with amplified virus replication and elevated inflammation in the airways. Adjuvant IFN treatment markedly reduced GCS-amplified infections in human airway cells and in mouse lung. This study demonstrates that GCS cause an extrinsic compromise in anti-viral defences, enhancing respiratory virus infections and provides a rationale for adjuvant IFN treatment.

The GERMELATOX DeCOG-trial: German melanoma patients and their attitude toward toxicity during adjuvant interferon treatment.

TPS9113^ Background: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), a metaanalysis could only show ...

Intermittent intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: Pooled analysis of two randomized phase III trials (NCT00226408 and ISRCTN75125874) with 980 patients.

e20028 Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts) with malignant melanoma (MM) consists of 4 weeks intravenous (IV) induction with 20 MU/m² interferon (IFN) alpha 2b followed by 11 months of 10 Mio IU/m² IFN subcutaneously (sc). It is unclear whether both parts of the regimen are mandatory for the efficacy of HDI treatment. The adjuvant phase III trials DeCOG MM-ADJ-5 and the Italian Melanoma Intergroup (IMI) trial evaluated intermittent IV HDI (iHDI) regimens as compared to standard HDI. In both trials, the experimental arm consisted of iHDI for 3 or 4 cycles, respectively. To gain more insight into the role of iHDI in the adjuvant setting we performed a pooled analysis of both trials. Methods: Based on the intent-to-treat populations, the German DeCOG trial contributed data on 627 MM pts. with stage III (AJCC 2002) resected intransit or lymph node metastasis. From the Italian IMI trial 330 pts. with stage III regional lymph node metastasis excluding intransit metastasis were evaluable. We performed a combined analysis with respect to relapse free survival (RFS) and overall survival (OS), and toxicity using Cox regression models. Results: Median follow-up was 4.6 years in the DeCOG trial and 7.2 years in the IMI trial. There were 320 relapses in the DeCOG trial (51%) and 179 relapses in the IMI trial (54%) resulting in a combined hazard ratio (HR) for RFS of 1.11 (95% CI 0.93; 1.33) comparing iHDI vs.conventional HDI. OS was similar for iHDI vs. conventional HDI (HR 1.04; 95% CI 0.84; 1.29). There was no significant heterogeneity comparing different substages (IIIA vs. IIIB vs. IIIC) or ulcerated versus non-ulcerated primary tumors. In both studies more patients discontinued treatment due to toxicity or impairment of quality of life with conventional HDI as compared to iHDI (DeCOG: 31.0% vs. 16.7%; IMI: 31.2% vs. 23.8%). Conclusions: The pooled analysis of the two pulsed adjuvant HDI treatments showed no significant differences for RFS or OS as compared to conventional HDI. There is a favorable safety profile and less overall toxicity in the pulsed regimens.

A systematic review and meta‐analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis‐related hepatocellular carcinoma

The efficacy of adjuvant interferon treatment for the management of patients with viral hepatitis-related hepatocellular carcinoma (HCC) following curative treatment is controversial. We have conducted a systematic review with meta-analysis to assess the effects of adjuvant interferon therapy on survival outcomes. Randomized and nonrandomized studies (NRSs) comparing adjuvant interferon treatment with the standard of care for viral hepatitis-related HCC after curative treatment were included. CENTRAL, Medline, EMBASE and the Science Citation Index were searched with complementary manual searches. The primary outcomes were recurrence-free survival (RFS) and overall survival (OS). Nine randomized trials and 13 NRSs were included in the meta-analysis. These nine randomized trials included 942 participants, of whom, 490 were randomized to the adjuvant interferon treatment group and 452 to the control group. The results of meta-analysis showed unexplained heterogeneity for both RFS and OS. The 13 NRSs included 2214 participants, of whom, 493 were assigned to the adjuvant interferon treatment group and 1721 to the control group. The results of meta-analysis showed that, compared with controls, adjuvant interferon treatment significantly improved the RFS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.52-0.84, I(2) = 29%] and OS (HR 0.43, 95% CI 0.34-0.56, I(2) = 0%) of patients with hepatitis C virus-related HCC following curative treatment. There was little evidence for beneficial effects on patients with hepatitis B virus-related HCC. Future research should be aimed at clarifying whether the effects of adjuvant interferon therapy are more prominent in hepatitis C patients with sustained virological responses.

Prevalence, Treatment, and Outcomes of Coexistent Ocular Surface Squamous Neoplasia and Pterygium

The purpose of this study was to determine the prevalence of ocular surface squamous neoplasia (OSSN) coexisting with pterygia in South Florida and to study the treatment and related outcomes. Noninterventional retrospective study. A total of 2005 patients with surgically excised pterygia at the Bascom Palmer Eye Institute from 2000 to 2010. Pathology reports of patients with pterygia were reviewed for evidence of OSSN. Patients were divided into the following groups: pterygium and no OSSN (group 1), clinically suspected OSSN with pterygium (group 2), and unexpected OSSN with pterygium found on histopathology (group 3). Clinical charts of patients in groups 2 and 3 were reviewed. Period prevalence, treatment, and outcome. In surgically excised pterygia, the prevalence of coexistent OSSN was 1.7% (n = 34), of which 41% (n = 14) were clinically suspected preoperatively (group 2) and 59% (n = 20) were unexpectedly found on histopathology (group 3). Clinically suspected OSSN with pterygia was generally treated with wide surgical margins and cryotherapy, whereas unexpected OSSN with pterygia was treated with simple excision, followed by adjuvant interferon treatment in 30% (n = 6). After a mean follow-up of 2 years, there were no recurrences in the suspected OSSN group and 2 recurrences in the unexpected OSSN group. The recurrence rate in the latter group was 11% at 1 year and 24% at 2 years. Ocular surface squamous neoplasia is uncommonly found to coexist with pterygium. The prognosis in suspected OSSN cases is excellent, with no recurrences noted despite positive margins in 50% of cases. The recurrence rates of unexpected OSSN mirrors that of OSSN not associated with pterygium, and thus vigilance for recurrence is important.

Advances and perspectives in immunotherapy of melanoma

Immunotherapy using unspecific modulators has a long tradition in the adjuvant treatment of stage II/III melanoma. Interferon has shown a consistent effect on relapse-free survival independent of interferon dosage and duration. The results of the american Joint Committee on Cancer (AJCC) Melanoma Staging Database analysis led to a strict inclusion of additional prognostic risk factors such as ulceration of the primary and microscopic lymph node involvement explored by the sentinel node biopsy in the revised 2009 AJCC classification. These factors are now being increasingly included as stratification factors into clinical trials and yield a new hypothesis that primarily patients with both characteristics benefit from adjuvant interferon treatment. In the metastatic situation, interleukin-2 is the only immunotherapeutic agent approved by the Food and Drug administration. In combination with interferon and/or with various chemotherapeutic agents, IL-2 is associated with substantial toxic effect and poor efficacy that does not improve overall survival (OS). Ipilimumab is a fully human, monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 and has recently been approved for metastatic melanoma based on two independent randomized phase III studies both demonstrating an improved OS rate after 1, 2, and 3 years compared with the control group. Based on this major step in treating metastatic melanoma, novel adjuvant strategies in stage III and combination therapies with targeted agents in stage IV are currently being explored.

Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: Final analysis of a randomized phase III DeCOG-trial (NCT00226408).

8505 Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts) with malignant melanoma (MM) usually consists of 4 weeks initial intravenous (iv) infusion of 20 MU/m² IFNa2b followed by 11 months of 10 MU/m² subcutaneously (sc). It is still unclear, whether both components are necessary for the efficacy of HDI in high-risk MM pts. The adjuvant phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, tolerability and quality of life (QoL) of an intermittent (pulsed) high-dose iv IFNa2b regimen as compared to standard HDI. Methods: Patients with stage III (AJCC 2002) resected intransit or lymph node metastasis from cutaneous malignant melanoma were randomly assigned to receive either standard HDI regimen (Arm A), or 3 courses of IFNa2b 20 MU/m² iv on 5 days a week for 4 weeks repeated every 4 months (Arm B). Distant metastasis free survival (DMFS) was the primary endpoint for efficacy analysis. The EORTC QLQ C30 questionnaire was used before and during the study in a standardized way (weeks 0, 4, 16, 24, 40). In addition, patients completed a diary containing global QoL measures every week. Results: Out of 649 patients who were enrolled, 22 patients had to be excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between both arms according to sex, age, and stage. Median follow-up was similar in both groups (55.4 vs. 55.3 months). Distant metastasis occurred in 138 (Arm A; 44%) vs. 145 (Arm B; 47%) patients without statistical significance (p=0.46). Survival was not significantly different for DMFS (HR 1.1; p=0.39) or OS (HR=1.0; p=0.85). Termination of treatment due to adverse events or QoL related reasons occurred significantly more often in arm A than in arm B (26.0% vs. 14.8%; p&lt;0.001). The pulsed schedule resulted in less cumulative toxicity as compared to the standard regimen, in particular regarding fatigue and neuropsychiatric side effects. Conclusions: The final analysis of pulsed adjuvant HDI treatment showed no significant DMFS or OS differences in comparison to conventional HDI. There is a clearly favorable safety and QoL profile of the pulsed regimen.

Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity?

Ulceration of a primary cutaneous melanoma has for many years been recognized as a very important prognostic factor associated with increased risk for recurrence and mortality. Patients with an ulcerated melanoma do much worse than patients with a nonulcerated melanoma with the same breslow thickness. Ulceration may indicate a separate biologic entity. Gene profiling studies of fresh frozen melanoma samples indicated that ulcerated melanomas have a very different profile. Analysis of the results of the two largest adjuvant interferon (IFN) trials ever conducted in 2644 patients [European Organization for Research and Treatment of Cancer (EORTC) 18952 and 18991], which used ulceration of the primary as a stratification factor, indicated that ulceration was not only a very strong prognostic factor, but more importantly a significant predictive factor for outcome of adjuvant IFN treatment. Only in patients with an ulcerated primary, was a similar and significant impact on disease-free survival, distant metastasis-free survival and overall survival observed. As a more general finding, in trials independent of ulceration used as a stratification factor, this IFN sensitivity of ulcerated melanomas has been reported in a meta-analysis in more than 3000 patients. It was also identified as a predictive factor of outcome in the Sunbelt adjuvant IFN trial in the USA. These important findings regarding ulceration need biologic studies to identify the differences between ulcerated and nonulcerated melanoma at the molecular level. Moreover, the importance of ulceration will be assessed prospectively in the EORTC 18081 trial in patients with primary ulcerated melanomas more than 1 mm.

Expression of the Stem Cell Markers Nestin and CD133 on Circulating Melanoma Cells

Different molecular markers have been identified for melanoma-initiating cells including CD133 and nestin. Assuming that metastasis requires a dissemination of tumor-initiating cells, presence of circulating tumor-initiating cells should be associated with worse patient outcome. In this study, 20 ml blood was collected from 32 consecutive patients affected by metastatic melanoma and blood was enriched for circulating melanoma cells (CMCs) by CD45 depletion of the non-melanoma cell fraction. Multiparameter cytometry was carried out to co-stain with combinations of CD133 and nestin (NES). Six tissue samples from metastatic lesions of six different patients were stained with the same antibodies by immunohistochemistry. Percentage of NES-positive CMCs correlated with tumor burden and number of metastatic sites. Cox regression analysis revealed levels of lactate dehydrogenase (LDH; hazard ratio: 12.8 (1.35-121.5); P=0.02), number of metastatic sites (hazard ratio 3.87 (1.66-9.03); P=0.02), tumor burden (hazard ratio 5.72 (1.57-20.9); P=0.01), and percentage of NES-expressing CMCs ≥ 35% (hazard ratio 5.73 (1.66-19.7); P=0.006) to be factors related to shorter overall survival. CD133- and NES-expression profiles on CMCs were similar to matched metastatic tissue. These findings show that CMCs expressed stem cell-associated markers NES and CD133. Higher expression of NES on CMCs might represent an index of poor prognosis.

Adjuvant interferon therapy for malignant melanoma:the debate

Based on the results of the Kirkwood high-dose interferon alpha-2b (HDI) adjuvant therapy trial of the Eastern Cooperative Oncology Group 1684, the US Food and Drug Administration (FDA) approved HDI as the postoperative adjuvant therapy for high-risk melanoma. Unfortunately, controversies continue regarding the use of interferon (IFN) as adjuvant therapy for melanoma owing to the inconsistent results of subsequent trials. Numerous trials of adjuvant interferon therapy demonstrated a benefit in terms of relapse-free survival (RFS), but without confirmed significant effect on overall survival (OS). The optimal timing, dose, and type of interferon are not yet defined. Therefore, adjuvant interferon treatment is preferentially applied in the randomized clinical trials in specialized centers. Decisions about the appropriateness of adjuvant interferon alfa-2b treatment for patients should be made on an individual basis, after discussion with the patient, including an explanation of the potential benefits and side effects of interferon therapy. Moreover, we also need to use available regimens reasonably, seek feasible and predictable prognostic factors to serve patients with individualized therapy.

Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma

Using tissue microarrays assembling 465 nevi, primary melanomas and metastases, we investigated whether expression of methylthioadenosine phosphorylase (MTAP), a recently suggested biomarker of malignant melanoma, has prognostic significance and may predict responsiveness to adjuvant interferon therapy in patients with melanoma. Because of its association with MTAP activity and interferon signalling pathways, signal transducer and activator of transcription 1 (STAT1) immunohistochemistry was analysed, too. MTAP expression was significantly reduced in melanomas and metastases compared with nevi (P < 0.001); STAT1 expression significantly increased. In melanomas, loss of MTAP expression was significantly related to Clark level (P < 0.05) and tumor thickness (P < 0.01); whereas STAT1 immunoreactivity was significantly related to gender (p < 0.05) and tumor thickness (P < 0.05). Interestingly, subgroup analysis of patients with a tumor thickness of 1.5-4.0 mm revealed a significant survival benefit from adjuvant interferon treatment regarding recurrence-free survival (RFS; P < 0.05) if MTAP expression was observed in the primary melanoma. Patients with STAT1-positive melanomas also tended to benefit from interferon concerning RFS (P = 0.074) and showed a significant benefit concerning overall survival (OS; P < 0.05). According to Cox analysis, MTAP expression in contrast to STAT1 was an independent positive prognostic marker for RFS and OS. In conclusion, MTAP represents a highly promising immunohistochemical marker for prognosis and interferon response of patients with malignant melanoma.

Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study)

Aim To evaluate the prognostic and predictive importance of detection of melanoma cells in peripheral blood using reverse transcriptase polymerase chain reaction (RT-PCR) in stage III cutaneous melanoma patients after sentinel or regional lymph node dissection. Patients and methods Serial testing for tyrosinase and Mart-1/Melan-A transcripts in peripheral blood was performed every 6 months over a maximum period of 60 months in a subset of patients enrolled in EORTC 18991 phase 3 trial, comparing pegylated interferon-α-2b with observation. Univariate and multivariate analyses were performed to estimate the role of RT-PCR as prognostic and predictive factor for distant metastasis-free survival (DMFS). Results Among 299 patients who underwent RT-PCR analyses, 109 (36.5%) had at least one positive sample, either at time of randomisation ( N = 17) or subsequently ( N = 92). The cumulative rate of positive results was similar in the two treatment groups, as the DMFS from first RT-PCR positivity. RT-PCR result, positive versus negative, at a given time point, had no prognostic impact on subsequent DMFS. Cox time-dependent analysis indicated a significantly higher risk of developing distant metastasis in patients with a positive sample as compared to those with a negative one: hazard ratio (HR) of 2.23 (95% confidence interval (CI), 1.40–3.55; p < .001). These results were comparable in the 2 treatment groups, indicating that RT-PCR assessment was not predictive for treatment outcome. Conclusion Detection of circulating tumour cells by RT-PCR for tyrosinase and Mart-1/Melan-A was a time-dependent moderate prognostic factor for subsequent development of distant metastasis in stage III melanoma patients.