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Simple Summary: Primary concurrent platinum-based chemoradiation (CRT) is the standard-of-care treatment for locally advanced cervical cancer. However, persistent, recurrent or metastatic disease remains a substantial cause of mortality in women worldwide. Biomarker research can help identify the potential mechanisms of chemo- and radioresistance, improve risk stratification and ultimately translate into novel treatment strategies. We report here that elevated pretreatment levels of caspase-8 and cyclin-dependent kinase 9 (CDK9) are associated with significantly improved relapse-free, distant metastasis-free and cancer-specific survival, while, in contrast, higher levels of phosphorylated CDK9 predict an increased risk of recurrence and distant metastases, and inferior cancer-specific survival. Introduction: After primary platinum-based chemoradiation of locally advanced uterine cervical cancer, a substantial proportion of women present with persistent, recurrent or metastatic disease, indicating an unmet need for biomarker development. Methods: We evaluated the clinical records of 69 cervical cancer patients (Federation of Gynecology and Obstetrics, FIGO Stage > IB3) who were subjected to definitive CRT. Immunohistochemical scoring of caspase-8, cyclin dependent kinase 9 (CDK9) and phosphorylated (phospho-)CDK9 (threonine (Thr) 186) was performed on pretreatment samples and correlated with the histopathological and clinical endpoints, including relapse-free survival (RFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS) and overall survival (OS). Results: Lower levels of caspase-8 were more prevalent in patients with a higher T-stage (p = 0.002) and a higher FIGO stage (p = 0.003), and were significantly correlated with CDK9 expression (p = 0.018) and inversely with pCDK9 detection (p = 0.014). Increased caspase-8 levels corresponded to improved RFS (p = 0.005), DMFS (p = 0.038) and CSS (p = 0.017) in the univariate analyses. Low CDK9 expression was associated with worse RFS (p = 0.008), CSS (p = 0.015) and OS (p = 0.007), but not DMFS (p = 0.083), and remained a significant prognosticator for RFS (p = 0.003) and CSS (p = 0.009) in the multivariate analyses. Furthermore, low pCDK9 staining was significantly associated with superior RFS (p = 0.004) and DMFS (p = 0.001), and increased CSS (p = 0.022), and remained significant for these endpoints in the multivariate analyses. Conclusion: Increased caspase-8 and CDK9 levels correlate with improved disease-related outcomes in cervical cancer patients treated with CRT, whereas elevated pCDK9 levels predict worse survival in this patient population. [ABSTRACT FROM AUTHOR]

Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5‐FU‐based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO‐04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow‐up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease‐free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment‐induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5‐FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high‐level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies. What's new? Cancer often causes an inflammatory response, recruiting leukocytes and neutrophils to the tumor site where they hinder anti‐cancer treatments. Here, the authors asked how leukocytosis and neutrophilia affect outcomes in rectal cancer. Unlike previous studies, which have been retrospective, this study examined a large cohort of patients within a phase 3 clinical trial. They found that baseline leukocytosis and neutrophilia independently predicted poor outcomes, including distant metastasis and shorter survival. Treatment‐induced leukopenia, meanwhile, correlated with better outcomes. Adding oxaliplatin to standard chemoradiation improved disease‐free survival only in those patients with leukocytosis & neutrophilia. These findings could lead to improved personalized treatments. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT). Material and methods: Between 2003 and 2007, 45 patients were enrolled. After TUR-BT patients received radiotherapy (RT) of the bladder and regional lymph nodes with 50.4Gy, and a boost to the bladder of 5.4–9Gy. RCT was applied to 43/45 patients. RHT was administered once weekly. Response was re-evaluated 6weeks after RT by restaging-TUR. Toxicity was graded with the CTCAE, version 3.0. QoL was evaluated by a dedicated questionnaire. Results: The median follow-up was 34months (range 12–60). The median number of hyperthermia treatments was 5 (range 1–7). Acute toxicity grades 3 and 4 occurred in 20% (9/45) and 9% (4/45), respectively. Late toxicity grades 3/4 were seen in 24% (11/45). Complete response rate was 96% (43/45). Local recurrence-free survival was 85%, overall survival was 80%, disease-specific survival was 88%, metastasis-free survival was 89%, and the bladder-preserving rate was 96% (43/45) at 3years. Eighty percent (24/30) were at least mostly satisfied with their bladder function. Conclusions: The quadrimodal treatment was feasible and well tolerated. Local control and bladder-preserving rates were encouraging. [Copyright &y& Elsevier]

Abstract: Adjuvant radiotherapy with or without chemotherapy has been used widely in an attempt to improve outcome in rectal cancer. For locally advanced disease, postoperative radiochemotherapy significantly improved both local control and overall survival when compared with surgery alone or surgery plus irradiation. This prompted a National Cancer Institute Consensus Conference in the United States in 1990 to recommend postoperative radiochemotherapy for patients with TNM stage II and III rectal cancer as standard treatment. In Europe, several randomized studies tested preoperative radiotherapy in comparison to surgery alone and showed lower local failure rates. A recent meta-analysis concluded that the combination of preoperative radiotherapy and surgery, as compared with surgery alone, significantly improves local control and overall survival. These results are, however, challenged by more recent reports of extraordinarily low local failure rates following improved surgical techniques, including total mesorectal excision. Evidently, the current monolithic approaches to either apply the same schedule of postoperative radiochemotherapy to all patients with stage II/III rectal cancer or to give preoperative intensive short-course radiation according to the Swedish concept for all patients with resectable rectal cancer irrespective of tumor stage and treatment goal (e.g. sphincter preservation), need to be questioned. [Copyright &y& Elsevier]

Purpose: To address the value of neck dissection (ND) in patients with advanced head and neck cancer following primary radiochemotherapy and to specifically analyse its impact on locoregional tumour control, survival and toxicity.Patients and methods: Between 1987 and 1997 (9335), a total of 142 patients (pts) were treated by primary radiochemotherapy (RCT) according to prospective protocols. There were 64 pts with involvement of the hypopharynx, 57 pts with oropharyngeal and 21 with oral cavity carcinoma. UICC (1997) stages included: 16 pts in stage III, 113 pts in stage IV A, 13 pts in stage IV B. All pts received platin-based RCT up to a median total dose of 70 Gy (range, 60–72 Gy). Six weeks after RCT, pts with complete response of the primary tumour (N=97) were offered a uni- or bilateral ND depending on the initially diagnosed nodal disease as part of a strict institutional policy. Fifty-six pts consented to ND and 41 refused. These two groups were analysed in terms of characteristics, local and regional tumour control, survival and long-term side effects. Median follow-up was 37 months (range, 22–124 months).Results: Among the 56 pts receiving ND, a total of 13 (23%) was found to have residual tumour in the neck specimen. The rates of positive histology according to clinical N category after RCT were: yN0 (2/22[9%]), yN1 (2/10[20%]), yN2a-b (2/10[20%), yN2c-3 (7/14[54%]). Five-year overall survival and disease-specific survival rates for pts with ND were 44 and 55%, for pts without ND 42 and 47%, respectively (P=0.9). No difference was seen for long-term local and regional control between the two patient groups. Comparing the group of patients with and without ND, a trend towards higher subjective morbidity of grade 3 and 4 (LENT-SOMA), i.e. pain recording (24% vs. 17%), dysphagia (48% vs. 35%) and hoarseness (20% vs. 9%) was evident in patients with ND.Conclusion: No clear evidence for routine clinical use of ND after RCT in advanced head and neck tumours can be derived from these data. ND may be contemplated in selected cases with multiple residual nodes only. [Copyright &y& Elsevier]

This article briefly summarizes clinically relevant new aspects of the recently published German, Austrian, and Swiss Onkopedia guideline for the treatment of locally advanced rectal cancer. Main aspects comprise (i) the use of total neoadjuvant therapy for rectal cancers with high-risk features, (ii) treatment with neoadjuvant chemotherapy for patients with a low risk for local recurrence, (iii) immunotherapy using dostarlimab in patients with MSI high/dMMR rectal cancer, as well as (iv) the implementation of organ sparing treatment concepts. The availability of several evidence-based treatment options requires intensive discussion within the multidisciplinary team as well as dedicated information for patients about treatment goals, options, and risks of individual treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Intra-tumoral CD8 + T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of cisplatin-based chemoradiation (CDDP-CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may guide the development of CRTX-ICI combinations. Methods: Comprehensive immune transcriptome analysis was applied to a training set of tumor specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients treated with CDDP-CRTX in the ARO-0401 phase III study (n = 33). A composite immune signature risk score (ISRS) for survival prediction was developed, and subsequently validated in two independent OPSCC cohorts treated with either CDDP-CRTX (n = 36) or mitomycin-based CRTX (MMC-CRTX, n = 31). Further validation of the ISRS was performed in the OPSCC subset (n = 79) of the TCGA HNSCC cohort. Potential interference between immune signatures and HPV status was evaluated in multivariate Cox regression models. Results: Significant differences according to the 3-y OS status in the abundance of tumor-infiltrating T- and B-cells, and the expression levels of 51 immune-related genes were observed. A risk score based on 13 differentially expressed genes involved in cytokine signaling, T-cell effector functions and the TNFR pathway was established as robust predictive factor of OS. Its predictive power was superior to the 6-gene interferon-gamma signature of ICI efficacy and independent of the HPV status. Conclusions: This study further elucidates the complex interaction of the tumor immune microenvironment with the efficacy of CDDP-CRTX in OPSCC. The results suggest immune markers for selection of patients treated with CRTX-ICI combinations. [ABSTRACT FROM AUTHOR]

Objective To compare six HPV detection methods in pre-treatment FFPE tumour samples from patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received postoperative ( N  = 175) or primary ( N  = 90) radiochemotherapy. Materials and methods HPV analyses included detection of (i) HPV16 E6/E7 RNA, (ii) HPV16 DNA (PCR-based arrays, A-PCR), (iii) HPV DNA (GP5+/GP6+ qPCR, (GP-PCR)), (iv) p16 (immunohistochemistry, p16 IHC), (v) combining p16 IHC and the A-PCR result and (vi) combining p16 IHC and the GP-PCR result. Differences between HPV positive and negative subgroups were evaluated for the primary endpoint loco-regional control (LRC) using Cox regression. Results Correlation between the HPV detection methods was high (chi-squared test, p  < 0.001). While p16 IHC analysis resulted in several false positive classifications, A-PCR, GP-PCR and the combination of p16 IHC and A-PCR or GP-PCR led to results comparable to RNA analysis. In both cohorts, Cox regression analyses revealed significantly prolonged LRC for patients with HPV positive tumours irrespective of the detection method. Conclusions The most stringent classification was obtained by detection of HPV16 RNA, or combining p16 IHC with A-PCR or GP-PCR. This approach revealed the lowest rate of recurrence in patients with tumours classified as HPV positive and therefore appears most suited for patient stratification in HPV-based clinical studies. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The CAO/ARO/AIO-94 phase-III-trial demonstrated a significant improvement of preoperative chemoradiotherapy (CRT) versus postoperative CRT on local control for UICC stage II/III rectal cancer patients, but no effect on long-term survival. In this add-on evaluation, we investigated the association of gender and age with acute toxicity and outcome. Patients and methods: According to actual treatment analyses, 654 of 799 patients had received pre- (n =406) or postoperative CRT (n =248); in 145 patients postoperative CRT was not applied. Gender, age and clinicopathological parameters were correlated with CRT-associated acute toxicity and survival. Results: The 10-year survival was higher in women than in men, with 72.4% versus 65.6% for time to recurrence (p =0.088) and 62.7% versus 58.4% for overall-survival (OS) (p =0.066), as expected. For patients receiving CRT, women showed higher hematologic (p <0.001) and acute organ toxicity (p <0.001) in the entire cohort as well as in subgroup analyses according to pre- (p =0.016) and postoperative CRT (p <0.001). Lowest OS was seen in patients without acute toxicity (p =0.0271). Multivariate analyses for OS showed that acute organ toxicity (p =0.034) was beneficial while age (p <0.001) was associated with worse OS. Discussion: Female gender is significantly associated with CRT-induced acute toxicity in rectal cancer. Acute toxicity during CRT may be associated with improved long-term outcome. [Copyright &y& Elsevier]

Purpose: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. Methods and Materials: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients. Results: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. Conclusions: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates. [Copyright &y& Elsevier]

Purpose: The objectives of this study were to investigate the expression of survivin in tumor samples from patients with high-risk T1 bladder cancer and to correlate its expression with clinicopathologic features as well as clinical outcomes after initial transurethral resection (TURBT) followed by radiotherapy (RT) or radiochemotherapy (RCT). Methods and Materials: Survivin protein expression was evaluated by immunohistochemistry on tumor specimen (n = 48) from the initial TURBT, and was correlated with clinical and histopathologic characteristics as well as with 5-year rates of local failure, tumor progression, and death from urothelial cancer after primary bladder sparring treatment with RT/RCT. Results: Survivin was not expressed in normal bladder urothelium but was overexpressed in 67% of T1 tumors. No association between survivin expression and clinicopathologic factors (age, gender, grading, multifocality, associated carcinoma in situ) could be shown. With a median follow-up of 27 months (range, 3–140 months), elevated survivin expression was significantly associated with an increased probability of local failure after TURBT and RCT/RT (p = 0.003). There was also a clear trend toward a higher risk of tumor progression (p = 0.07) and lower disease-specific survival (p = 0.10). Conclusions: High survivin expression is a marker of tumor aggressiveness and may help to identify a subgroup of patients with T1 bladder cancer at a high risk for recurrence when treated with primary organ-sparing approaches such as TURBT and RCT. [Copyright &y& Elsevier]

Purpose: Standard treatment for superficial bladder cancer is transurethral resection of the bladder tumor (TURBT) followed by intravesical therapy. Little is known about the biologic behavior and treatment response of superficial disease within an irradiated bladder. We specifically analyzed patients who developed superficial recurrence after TURBT and radiotherapy or radiochemotherapy. Patients and Methods: Between 1982 and 2006, a total of 531 consecutive patients with invasive bladder cancer were treated by using various bladder-sparing protocols at our institution. Of these, 389 (76%) achieved a complete response after TURBT and radiotherapy/radiochemotherapy. During follow-up, 68 of 389 patients (17%) developed a superficial local relapse (≤T1) and form the subject of this study. Results: Sixty-four of 68 patients underwent conservative TURBT with or without intravesical treatment (4 patients underwent immediate cystectomy): 31 of 64 patients (48%) had no further bladder recurrence, 21 (33%) experienced additional superficial recurrences, and 12 (19%) ultimately progressed to muscle-invasive disease. Disease-specific survival rates were 87% and 72% at 5 and 10 years, respectively. Compared with 255 patients without local bladder relapse after primary treatment, no significant difference was found for disease-specific survival rates (72% after superficial vs. 79% without local relapse at 10 years, p = 0.78). However, significantly fewer patients with a superficial relapse survived with their native bladder (50% after superficial vs. 76% without local relapse at 10 years, p < 0.001). Conclusion: A further bladder-sparing approach with TURBT and intravesical therapy is reasonable for patients with superficial relapse after combined-modality treatment without compromising survival. However, these patients are at greater risk of requiring late cystectomy. [Copyright &y& Elsevier]

Purpose: To give an update on the long-term outcome of an intensified protocol of combined radiochemotherapy (RCT) with 5-fluorouracil (5-FU) and cisplatin after initial transurethral resection of bladder tumor (TURBT) with selective organ preservation in bladder cancer. Methods and Materials: One hundred twelve patients with muscle-invading or high-risk T1 (G3, associated Tis, multifocality, diameter >5 cm) bladder cancer were enrolled in a protocol of TURBT followed by concurrent cisplatin (20 mg/m2/day as 30-min infusion) and 5-FU (600 mg/m2/day as 120-h continuous infusion), administered on Days 1–5 and 29–33 of radiotherapy. Response to treatment was evaluated by restaging TURBT 4–6 weeks after RCT. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Results: Ninety-nine patients (88.4%) had no detectable tumor at restaging TURBT; 71 patients (72%) have been continuously free from local recurrence or distant metastasis. Superficial relapse occurred in 13 patients and muscle-invasive recurrence in 11 patients. Overall and cause-specific survival rates for all patients were 74% and 82% at 5 years, respectively. Of all surviving patients, 82% maintained their own bladder, 79% of whom were delighted or pleased with their urinary condition. Hematologic Grade 3/4 toxicity occurred in 23%/6% and Grade 3 diarrhea in 21% of patients. One patient required salvage cystectomy due to a shrinking bladder. Conclusion: Concurrent RCT with 5-FU/cisplatin has been associated with acceptable acute and long-term toxicity. Overall and cause-specific survival rates are encouraging. More than 80% of patients preserved their well-functioning bladder. [Copyright &y& Elsevier]