Evidence blocks for effective presentation of genomic findings at molecular tumor boards: Single institution experience.

Genomic profiling, or molecular profiling of the tumor, is becoming a key component of therapeutic decision making in clinical oncology, and is typically carried out via next generation sequencing. However, the interpretation of the results and evaluation of rationale for targeting the uncovered alterations is challenging and requires a deep understanding of cancer biology, genetics, genomics and oncology. Multidisciplinary molecular tumor boards represent a promising strategy in the facilitation of molecularly-informed therapeutic decisions, and usually consist of specialists with various fields of expertise. To effectively communicate the biological and clinical significance of genomic findings, as well as to make molecular tumor board discussions more productive, we developed and implemented evidence blocks into case discussions in our center. We found that this approach facilitated clinicians' understanding of the results of genomic profiling, and resulted in shorter yet more efficient case discussions within the molecular tumor board. Here, we discuss our experience with evidence blocks and how their implementation influenced the molecular tumor board practice.

Prognostic and predictive role of immune microenvironment in colorectal cancer.

Colorectal cancer (CRC) represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide. The traditional classification of CRC is based on pathomorphological and molecular characteristics of tumor cells (mucinous, ring-cell carcinomas, etc.), analysis of mechanisms of carcinogenesis involved (chromosomal instability, microsatellite instability, CpG island methylator phenotype) and mutational statuses of commonly altered genes (KRAS, NRAS, BRAF, APC, etc.), as well as expression signatures (CMS 1-4). It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC. According to the latest data, the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors. In this review, we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

Case Report: Progressive disease of BRCA2-mutant colon adenocarcinoma following talazoparib therapy.

Colorectal cancer (CRC) is currently one of the most common tumor types diagnosed worldwide. In the early stages, the disease responds well to surgical and chemotherapeutic treatment, but in the later stages when therapeutic options are exhausted, comprehensive genomic profiling can guide further treatment decisions. We present the case of a 46-year-old man of Ashkenazi Jewish ancestry who was diagnosed with KRAS-mutated metastatic colorectal cancer. After surgery and progression on standard FOLFOX/FOLFIRI + bevacizumab therapy, as well as on Trifluridine/Tipiracil, comprehensive genomic profiling was performed with the hope of expanding therapeutic options. Following comprehensive tumor molecular profiling via NGS, a discussion of the case was discussed at the local molecular tumor board in order to determine further treatment strategy. An activating variant of KRAS and PIK3CA, FLT3 and SRC amplification and damaging TP53 and APC variants were discarded by MTB as potential targetable biomarkers. The BRCA2 p.S1415fs*4 founder frameshift variant was of interest and the patient was included in the clinical trial investigating the efficacy of a PARP inhibitor talazoparib. Unfortunately, the disease progression was detected within one month of talazoparib treatment and the patient died during the 8th cycle of FOLFIRI + bevacizumab therapy rechallenge.

Precision oncology strategy in cetuximab-resistant ERRFI1-mutant colon cancer: case report of disease progression on afatinib.

Despite the existence of effective first and second line therapy options for patients with colorectal cancer, heavily treated patients have limited additional therapies. Genomic profiling is a promising tool for guiding subsequent treatment selection. Here, we describe the results of treating a colorectal cancer patient with molecularly-matched therapy based on the results of genomic profiling. The patient received a combination of afatinib and bevacizumab due to the presence of ERRFI1 variant. To our knowledge, this is the first report on the effect of EGFR inhibitors in patients with ERRFI1-altered RAS/BRAF wild-type colorectal adenocarcinoma.

Detecting Microsatellite Instability in Endometrial, Colon, and Stomach Cancers Using Targeted NGS.

PURPOSE: To develop a method for testing the MSI based on targeted NGS. METHODS: Based on the results of previous studies, 81 microsatellite loci with high variability in MSI-H tumors were selected, and a method for calculating the MSI score was developed. Using the MSI score, we defined the MSI status in endometral (162), colon (153), and stomach (190) cancers. Accuracy of the MSI scores was evaluated by comparison with MMR immunohistochemistry for 137 endometrium (63 dMMR and 74 pMMR), 76 colon (29 dMMR and 47 pMMR), and 81 stomach (8 dMMR and 73 pMMR) cancers. RESULTS: Classification of MSS and MSI-H tumors was performed with AUC (0.99), sensitivity (92%), and specificity (98%) for all tumors without division into types. The accuracy of MSI testing in endometrial cancer was lower than for stomach and colon cancer (0.98, 87%, and 100%, respectively). The use of 27 loci only, the most informative for endometrial cancer, increased the overall accuracy (1.00, 99%, and 99%). Comparison of MSI score values in 505 tumors showed that MSI score is significantly higher in colon (p < 10-5) and stomach (p = 0.008) cancer compared with endometrial cancer. CONCLUSION: The MSI score accurately determines MSI status for endometrial, colon, and stomach cancers and can be used to quantify the degree of MSI.

Risk Factors for Relapse in Nonseminomatous Testicular Cancer After Postchemotherapy Retroperitoneal Lymph Node Dissection With Viable Residual Cancer.

PURPOSE: No consensus exists on the management of men with nonseminoma and viable nonteratomatous germ cell tumor in the postchemotherapy retroperitoneal lymph node dissection (pcRPLND) specimen after first-line chemotherapy. We analyzed surveillance versus different adjuvant chemotherapy regimens and the influence of time to pcRPLND on oncologic outcomes. METHODS: Data on 117 men treated with cisplatin-based first-line chemotherapy between 1990 and 2018 were collected from 13 institutions. All patients had viable nonteratomatous germ cell tumor in the pcRPLND specimen. Surgery was performed after a median of 57 days, followed by either surveillance (n = 64) or adjuvant chemotherapy (n = 53). Primary end points were progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: After controlling for International Germ Cell Cancer Cooperative Group risk group and percent of viable malignant cells found at RPLND, no difference was observed between men managed with surveillance or adjuvant chemotherapy regarding PFS (hazard ratio [HR], 0.72 [95% CI, 0.32 to 1.6]; P = .4), CSS (HR, 0.69; 95% CI, 0.20 to 2.39; P = .6), and OS (HR, 0.78 [95% CI, 0.25 to 2.44]; P = .7). No statistically significant differences for PFS, CSS, or OS were observed on the basis of chemotherapy regimen or in men treated with pcRPLND ≤57 versus >57 days after first-line chemotherapy. Residual disease with <10% versus ≥10% viable cancer cells were associated with a longer PFS (HR, 3.22 [95% CI, 1.29 to 8]; P = .012). Relapse in the retroperitoneum was observed in 34 (29%) men. CONCLUSION: Men with a complete resection at pcRPLND and <10% viable cells have favorable outcomes without further treatment. Complete retroperitoneal resection seems more important than early pcRPLND.

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy.

Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.

Risk of residual cancer after complete response following first-line chemotherapy in men with metastatic non-seminomatous germ cell tumour and International Germ Cell Cancer Cooperative Group intermediate/poor prognosis: A multi-institutional retrospective cohort study.

INTRODUCTION: Current guidelines recommend surveillance in metastatic non-seminomatous germ cell tumour patients treated with first-line-chemotherapy and a complete clinical response (normalisation of serum tumour markers and residual masses <1 cm). However, this recommendation is based on a series including patients with good prognosis according to International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and a complete clinical response after first-line-chemotherapy. MATERIAL & METHODS: This is a retrospective study of men with intermediate/poor IGCCCG-PG, who had a complete clinical response after first-line chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy retroperitoneal lymph node dissection (pcRPLND). RESULTS: Between 2009 and 2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median a 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom seven (6%) had a retroperitoneal-only relapse versus 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p-value = 0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3-9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%). CONCLUSIONS: While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups.

Utility of public knowledge bases for the interpretation of comprehensive tumor molecular profiling results.

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma.

Adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) represent a heterogeneous group of diseases with distinct etiology, clinical features, treatment approaches, and prognosis. Studies are ongoing to isolate molecular genetic subtypes, perform complete biological characterization of the tumor, determine prognostic groups, and find predictive markers to the effectiveness of therapy. Separate molecular genetic classifications were created for esophageal adenocarcinoma [The Cancer Genome Atlas (TCGA)], stomach cancer (TCGA, Asian Cancer Research Group), and colon cancer (Colorectal Cancer Subtyping Consortium). In 2018, isolation of TCGA molecular genetic subtypes for adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) highlighted the need for further studies and clinical validation of subtyping of gastrointestinal adenocarcinomas. However, this approach has limitations. The aim of our work was to critically analyze integration of molecular genetic subtyping of gastrointestinal adenocarcinomas in clinical practice.

The prognostic significance of lactate dehydrogenase levels in seminoma patients with advanced disease: an analysis by the Global Germ Cell Tumor Collaborative Group (G3).

PURPOSE: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. METHODS: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). RESULTS: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. CONCLUSIONS: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.

Epstein-Barr virus-associated gastric cancer: disease that requires special approach.

Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.

Human chorionic gonadotropin-positive seminoma patients: A registry compiled by the global germ cell tumor collaborative group (G3).

BACKGROUND: The prognostic role of human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH) serum levels in seminoma patients remains uncertain. This observational study evaluates the prognostic impact of tumour marker levels, and other clinicopathological findings, in hCG-positive seminoma patients. METHODS: Seminoma patients with serum hCG levels above normal at first diagnosis were eligible for recruitment. Statistical analysis, including multivariate regression, was performed to identify risk factors. Primary end-points were overall survival (OS) and recurrence-free survival (RFS). RESULTS: We recruited 1031 hCG-positive patients (stage I: n = 586; stage II + III: n = 427) diagnosed between 1981 and 2018. In metastatic disease, LDH levels ≥3 above upper normal limit (UNL) pre- (n = 109) or post-orchiectomy (n = 73) and patients aged ≥40 years (n = 187) were associated with poor prognosis: 5-year OS rates of 84% (LDH ≥3 UNL pre-orchiectomy) versus 92% (<3 UNL pre-orchiectomy) (hazard ratio [HR]: 3.155, [95% confidence interval {CI}: 1.28-7.75], P = 0.012), 82% (≥3 UNL post-orchiectomy) versus 92% (<3 UNL post-orchiectomy) (HR: 6.877, [95% CI: 1.61-29.34]; P = 0.009) and 86% (≥40 years) versus 91% (<40 years) (HR: 6.870, [95% CI: 1.45-13.37], P = 0.009), respectively. A subset of patients with hCG levels ≥2000 IU/l pre-orchiectomy (n = 17) exhibited a poor prognosis, with 5-year OS rates of 73% (≥2000 IU/l) versus 94% (<2000 IU/l) (HR: 3.936, [95% CI: 1.02-12.61], P = 0.047). CONCLUSIONS: Age and LDH levels are significantly associated with poor prognosis in hCG-positive seminoma patients. A small number of patients, with levels of hCG ≥2000 IU/l, may represent a separate prognostic subgroup associated with impaired survival rates.

Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies.

The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with pancreatic cancer (PC). We performed PubMed and Embase database queries. We included 4 studies into the meta-analysis and 16 studies in the systematic review. Our systematic analysis showed that the average weighted median overall survival (OS) in patients with HRD with advanced PC was 19.8 and 15.6 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 23.8 and 17.1 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 8.3 and 12.0 months in patients without HRD. For resected PC, our meta-analysis demonstrated that HRD status did not affect the prognosis (HR 1.03, 95% CI 0.46 to 2.33), but results were rather heterogeneous (I2=83%, p=0.003). Our systematic analysis showed that the average weighted median OS in patients with HRD was 34.6 and 27.0 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 46.1 and 36.3 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 24.2 and 42.9 months in patients without HRD. Results of our meta-analysis and systematic review support the idea of platinum use in patients with HRD both in resected and metastatic PCs, although a randomised trial is warranted to make a more reliable conclusion. PROSPERO REGISTRATION NUMBER: CRD42019121914.

Aflibercept Plus FOLFIRI for Second-line Treatment of Metastatic Colorectal Cancer: Observations from the Global Aflibercept Safety and Health-Related Quality-of-Life Program (ASQoP).

BACKGROUND: The objectives of this study were to evaluate the safety profile of aflibercept and health-related quality of life (HRQL) in patients with metastatic colorectal cancer (mCRC) provided with aflibercept access before marketing authorization. PATIENTS AND METHODS: Patients received aflibercept followed by FOLFIRI (fluorouracil, leucovorin, irinotecan) on day 1 of a 2-week cycle until disease progression, unacceptable toxicity, death, or patient/investigator decision to discontinue. Treatment-emergent adverse events (TEAEs) were evaluated, and HRQL was assessed at baseline, cycle 3, and every other cycle using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29, and EuroQol 5-Dimensions 3-Levels questionnaires (NCT01571284). RESULTS: Overall, 779 adult patients with mCRC, who received ≥ 1 prior oxaliplatin-based regimen and had disease progression during or following their last administration of oxaliplatin-based chemotherapy, were enrolled. At data cutoff, all patients had discontinued treatment, mainly owing to disease progression (51.7%). The most common TEAEs of any grade were diarrhea (61.6%), hypertension (48.4%), and nausea (43.3%). The most common grade 3/4 TEAEs were hypertension (24.1%), neutropenia (23.1%), and diarrhea (15.3%). Clinically meaningful changes in HRQL were reported for all measures. Most patients either had an improvement in their HRQL scores or remained stable during the treatment period based on patient-reported outcomes. CONCLUSION: The data from this study support the tolerability of the combination of aflibercept and FOLFIRI in a setting that more closely approximates real life in patients with mCRC who failed to respond to oxaliplatin-based chemotherapy, and also suggest an improvement in HRQL.

Intratumoral Heterogeneity of SMAD4 Immunohistochemical Expression and Its Role in Prediction of Recurrence Pattern in Patients with Resectable Pancreatic Cancer.

BACKGROUND: The aim of our study was to evaluate consistency of SMAD4 expression in different tumor areas and its correlation with recurrence pattern in patients after resection for pancreatic cancer (PC). METHODS: Records of patients who underwent resection for nonmetastatic PC between 2001 and 2015 were analyzed. Formalin-fixed, paraffin-embedded tissue sections from different areas of primary tumor and lymph node metastases were analyzed immunohistochemically (IHC) for SMAD4 expression using TMA technology. RESULTS: SMAD4 expression was assessed in 356 tissue sections obtained from 91 patients. SMAD4 expression was positive in all assessed tumor slides only in 7 of 26 patients (26.9%). There were 54 recurrences (9 locoregional, 41 distant, and 4 both local and distant) with median follow-up of 21.7 months. There was no correlation between SMAD4 expression and locoregional recurrence pattern (p = 0.30). SMAD4 status influenced neither distant recurrence-free survival (p = 0.99) nor overall survival (p = 0.13). CONCLUSIONS: Different areas inside primary tumor and lymph node metastases express SMAD4 heterogeneously. SMAD4 IHC expression is not a biomarker of the recurrence pattern after surgical resection for PC.

Questioning the Value of Fluorodeoxyglucose Positron Emission Tomography for Residual Lesions After Chemotherapy for Metastatic Seminoma: Results of an International Global Germ Cell Cancer Group Registry.

PURPOSE: Residual lesions after chemotherapy are frequent in metastatic seminoma. Watchful waiting is recommended for lesions < 3 cm as well as for fluorodeoxyglucose (FDG) positron emission tomography (PET)-negative lesions ≥ 3 cm. Information on the optimal management of PET-positive residual lesions ≥ 3 cm is lacking. PATIENTS AND METHODS: We retrospectively identified 90 patients with metastatic seminoma with PET-positive residual lesions after chemotherapy. Patients with elevated α-fetoprotein or nonseminomatous histology were excluded. We analyzed the post-PET management and its impact on relapse and survival and calculated the positive predictive value (PPV) for PET. RESULTS: Median follow-up time was 29 months (interquartile range [IQR], 10 to 62 months). Median diameter of the largest residual mass was 4.9 cm (range, 1.1 to 14 cm), with masses located in the retroperitoneum (77%), pelvis (16%), mediastinum (17%), and/or lung (3%). Median time from the last day of chemotherapy to PET was 6.9 weeks (IQR, 4.4 to 9.9 weeks). Post-PET management included repeated imaging in 51 patients (57%), resection in 26 patients (29%), biopsy in nine patients (10%) and radiotherapy in four patients (4%). Histology of the resected specimen was necrosis in 21 patients (81%) and vital seminoma in five patients (19%). No biopsy revealed vital seminoma. Relapse or progression occurred in 15 patients (17%) after a median of 3.7 months (IQR, 2.5 to 4.9 months) and was found in 11 (22%) of 51 patients on repeated imaging, in two (8%) of 26 patients after resection, and in two (22%) of nine patients after biopsy. All but one patient who experienced relapse were successfully treated with salvage therapy. The PPV for FDG-PET was 23%. CONCLUSION: FDG-PET has a low PPV for vital tumor in residual lesions after chemotherapy in patients with metastatic seminoma. This cautions against clinical decisions based on PET positivity alone.

Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute complications in nonseminomatous germ cell tumor patients with ultra high tumor markers and/or poor performance status.

PURPOSE: Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established. METHODS: We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as α-fetoprotein ≥ 100,000 ng/ml or human chorionic gonadotropin ≥ 200,000 mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration. RESULTS: From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26). CONCLUSIONS: Dose reduction of the first EP cycle by 40-60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival.

Concurrent paclitaxel, capecitabine, mitomycin C and pelvic radiation therapy for patients with squamous cell anal carcinoma.

PURPOSE: The goals of this study were to assess safety and efficacy of triplet chemoradiotherapy (CRT) with paclitaxel for squamous cell anal carcinoma (SCAC). METHODS: Patients with stage I-IIIB SCAC were enrolled and received 52-58 Gy intensity-modulated radiotherapy (IMRT) (with dose based on the T stage) in consecutive daily 1.8-2.2 Gy fractions. The concurrent chemotherapy consisted of paclitaxel 45 mg/m2 days 3, 10, 17, 24, 31, capecitabine 625 mg/m2 bid on treatment days and mitomycin C 10 g/m2 on day 1. Primary endpoints were complete clinical response at 26 weeks and protocol compliance; secondary endpoints included toxicity, overall survival (OS) and progression-free survival (PFS). RESULTS: Thirty-eight patients were enrolled. The percentage of patients with stage I, II, IIIA, and IIIB disease were 1 (2.6%), 5 (13.2%), 15 (39.5%), and 17 (44.7%), respectively. 32 patients (84.2%) completed CRT without significant alterations. Grade 3-4 toxicity occurred in 23 (60.5%) patients. 33 (86.8%) patients had complete clinical response at 26 weeks. Median follow-up was 25.6 months. Seven (18.4%) patients experienced disease progression: four patients had residual tumor after CRT, 2 patients developed distant metastases and 1 patient developed a local recurrence 12 months after CRT. Two-year OS was 93.6%, 2-year PFS was 83.9%. CONCLUSIONS: Investigated treatment scheme is feasible despite high toxicity profile, and may be beneficial for patients with advanced SCAC. Further research is warranted.