Radiochemotherapy and interstitial brachytherapy for cervical cancer: clinical results and patient-reported outcome measures.

OBJECTIVE: To evaluate clinical results and long-term patient-reported outcome measures (PROMs) on quality of life in cervical cancer patients following radiochemotherapy (RCT) and brachytherapy (BT) as definitive treatment. MATERIALS AND METHODS: Between 2003 and 2023, a total of 132 patients with advanced cervical cancer were evaluated for possible treatment. Patients treated by postoperative RCT, palliative radiotherapy, and those treated for recurrent disease were excluded. Thus, 46 patients receiving standard RCT and BT as their curative treatment were included in this study. PROMs were assessed prospectively by patients' self-completion of the EORTC-QLQ-C30 and EORTC-QLQ-CX24 questionnaires. RESULTS: Five-year overall survival (OS), distant metastases-free survival (DMFS), and pelvic tumor-free survival rates (PTFS) were 53%, 54%, and 83%, respectively. A significant impact on OS was seen for FIGO (International Federation of Gynecologic Oncology) stage (IIB-IIIA: 79% vs. IIIB-IVA: 33%, p = 0.015), for overall treatment time (OTT; 50-65 d: 64% vs. > 65 d: 38%, p = 0.004), and for rectal D2cc (≤ 73 Gy: 50% vs. > 73 Gy: 38%, p = 0.046). The identical parameters were significantly associated with DMFS (FIGO stage: p = 0.012, OTT: p = 0.008, D2cc: p = 0.024). No parameters with a significant influence on PTFS were seen. In multivariate analysis, an impact of FIGO stage on OS (p = 0.05) and DMFS (p = 0.014) was detected, and of rectal D2cc on DMFS (p = 0.031). The overall QoL score was 63/100. Cognitive function was the least impaired (84/100), while role functioning was the worst (67/100). On the symptom scale, insomnia (46/100), fatigue (41/100), dyspnea (32/100), pain (26/100), and financial difficulties (25/100) were scored the worst. According to EORTC-QLQ-CX24, peripheral neuropathy (36/100) and lymphedema (32/100) occurred most frequently. Impaired sexual/vaginal functioning (32/100) and body image (22/100) were also frequently recorded. CONCLUSION: In patients with advanced cervical cancer, a combination of RCT and BT remains an excellent treatment option. In terms of patient-reported long-term quality of life, specific support is needed to alleviate symptoms including lymphedema, peripheral neuropathy, and impaired sexual activity.

Spinal and cervical nodal metastases in a patient with glioblastoma.

This article presents the rare case of a 54-year-old gentleman with primary glioblastoma developing multiple extracranial metastases 7 months after diagnosis. Initially, the patient complained of progressive headaches, confusion, and weakness of the left arm. Magnetic resonance imaging of the brain showed a right temporoparietal tumor with substantial surrounding subcortical edema and midline shift to the left. Two consecutive craniotomies resulted in complete microsurgical resection of the lesion. Histology was consistent with a World Health Organization grade IV, IDH-wildtype glioblastoma. Further treatment was standard chemoradiation including intensity-modulated radiotherapy with oral temozolomide chemotherapy. Seven months after diagnosis, the cranial lesion progressed, and the patient developed painful metastases in multiple bones and suspicious right-sided cervical lymph nodes. Immunohistochemistry and molecular signature supported the case of a metastatic glioblastoma. Further treatment was palliative radiotherapy of the spinal lesions along with symptomatic pain management. Extracranial metastasis of glioblastoma is a rare complication of which only a few cases have been reported in the literature. Little is known about the precise mechanisms of tumor dissemination and the appropriate treatment.

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial.

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.

Adenocarcinoma of the oesophagus: neoadjuvant chemoradiation and radical surgery : Long-term results.

PURPOSE: To retrospectively evaluate long-term treatment results following neoadjuvant chemoradiation (CRT) and radical surgery in patients with advanced adenocarcinoma (AC) of the oesophagus. PATIENTS AND METHODS: Between 2005 and 2015, a total of 102 consecutive patients with a median age of 64 years (range, 44-86 years) and AC of the oesophagus were evaluated of whom 84 received a full CRT. A group of 51 patients was treated with neoadjuvant intent followed by radical surgery. A total dose of 50.4 Gy with mostly weekly paclitaxel/fluorouracil chemotherapy was administered. Six to eight weeks following CRT, a transthoracic subtotal oesophageal and proximal gastric resection was performed. Survival curves for overall survival and no evidence of disease (NED) survival (primary endpoints) were calculated according to Kaplan-Meier, and possible prognostic factors were evaluated by the log-rank test as well as by a Cox regression analysis. RESULTS: Median follow-up time of the surviving patients was 48 months (range, 14-134 months). Overall and NED survival rates for patients of the study group (n = 51) were 40 and 32%, respectively, at 5 years. Age (p = 0.04), ypT category (p = 0.1) and the development of distant metastases (p = 0.05) were identified as (marginally) independent prognostic variables with impact on survival. Median survival time for patients of the study group (n = 51) was 45 ± 18 months (95%CI 9-81 months). Clear resection margins were achieved in 46/51 patients (92%). Regression rates with complete regression rare residual cancer and increased number of residual cells, but predominantly fibrosis were 33, 41, and 10%, respectively. Patterns of failure revealed local with distant recurrence in 2/51 (4%), regional recurrence alone in 2/51 (4%), and distant metastases in 27/51 (53%) patients. CONCLUSION: Neoadjuvant CRT in patients with AC of the oesophagus followed by thoracoabdominal surgery is a locally very effective concept. A significant tumour regression in almost 75% of the patients may stimulate prospective trials on the omission of radical surgery for some elderly patients. Due to a high rate of distant metastases further investigations in terms of effective systemic therapy may be warranted.

Cardiac dose-sparing effects of deep-inspiration breath-hold in left breast irradiation : Is IMRT more beneficial than VMAT?

BACKGROUND: Given the reduction in death from breast cancer, as well as improvements in overall survival, adjuvant radiotherapy is considered the standard treatment for breast cancer. However, left-sided breast irradiation was associated with an increased rate of fatal cardiovascular events due to incidental irradiation of the heart. Recently, considerable efforts have been made to minimize cardiac toxicity of left-sided breast irradiation by new treatment methods such as deep-inspiration breath-hold (DIBH) and new radiation techniques, particularly intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). The primary aim of this study was to evaluate the effect of DIBH irradiation on cardiac dose compared with free-breathing (FB) irradiation, while the secondary objective was to compare the advantages of IMRT versus VMAT plans in both the FB and the DIBH position for left-sided breast cancer. METHODS: In all, 25 consecutive left-sided breast cancer patients underwent CT simulation in the FB and DIBH position. Five patients were excluded with no cardiac displacement following DIBH-CT simulation. The other 20 patients were irradiated in the DIBH position using respiratory gating. Four different treatment plans were generated for each patient, an IMRT and a VMAT plan in the DIBH and in the FB position, respectively. The following parameters were used for plan comparison: dose to the heart, left anterior descending coronary artery (mean dose, maximum dose, D25% and D45%), ipsilateral, contralateral lung (mean dose, D20%, D30%) and contralateral breast (mean dose). The percentage in dose reduction for organs at risk achieved by DIBH for both IMRT and VMAT plans was calculated and compared for each patient by each treatment plan. RESULTS: DIBH irradiation significantly reduced mean dose to the heart and left anterior descending coronary artery (LADCA) using both IMRT (heart -20%; p = 0.0002, LADCA -9%; p = 0.001) and VMAT (heart -23%; p = 0.00003, LADCA -16%; p = 0.01) techniques as compared with FB radiation. There were no significant changes in left lung dose by IMRT; however, with VMAT planning, mean dose to the left lung was reduced by -4% (p = 0.0004). In addition, DIBH significantly increased the mean dose to the contralateral breast with IMRT (+14%, p = 0.002) and significantly reduced the dose to the contralateral breast with VMAT planning (-9%, p = 0.003) compared with the FB position. Additionally, in comparison with VMAT, the IMRT technique reduced mean heart dose both in the FB and the DIBH-position by -30% (p = 0.0004) and -26% (p = 0.002), respectively. Furthermore, IMRT increased the mean dose to the left lung in both the FB and the DIBH position (+5%, p = 0.003, p = 0.006), respectively. There were no significant changes in dose to the right lung and contralateral breast either in the FB or DIBH position between IMRT and VMAT techniques. CONCLUSION: Left-sided breast irradiation is best performed in the DIBH position, since a considerable dose sparing to the heart and LADCA can be achieved by using either IMRT or VMAT techniques. A significant additional decrease in heart and LADCA dose by IMRT in both FB and DIBH irradiation was seen compared with VMAT.

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. METHODS: In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. INTERPRETATION: Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial.

BACKGROUND: In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS). RESULTS: The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48% (A) and 52% (B, P = 0.81) and (y)pN0 was 30% (A) vs. 39% (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). CONCLUSION: This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.

Critical role of spatial interaction between CD8⁺ and Foxp3⁺ cells in human gastric cancer: the distance matters.

PURPOSE: In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer. MATERIALS AND METHODS: Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years). RESULTS: High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 µm) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively. CONCLUSION: Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 µm of CD8(+) T cells to positively impact on prognosis.

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under "Real World" Conditions?

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients' characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471-0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245-4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.

PD-1 and PD-L1 expression predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma.

Background and purpose: PD-1 and PD-L1 are involved in anticancer immunosurveillance, and their expression may be predictive for therapeutic effectiveness of specific antibodies. Their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC) remains to be defined. Materials and methods: Between 10/2004 and 06/2018, complete pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of CD8, PD-1 and PD-L1 in pre-treatment specimens to determine their influence on tumour regression grade and survival. PD-1 and PD-L1 expression were considered positive (+) if ≥1% of all cells were stained positive, otherwise negative (-); densities of CD8+ cells were categorized as being high (Hi) or low (Lo) according to the median. Results: A negative PD-L1 expression in peritumoural cells predicted a poor tumour regression (RD 0.24 [95% CI 0.03-0.44], p = 0.023). A positive PD-1 expression in intra- as well as peritumoural cells was identified as an unfavourable prognostic factor (HR 0.52 [95% CI 0.29-0.93], p = 0.028; HR 0.50 [0.25-0.99], p = 0.047, respectively). With respect to CD8+ infiltration, positive PD-1 and PD-L1 expressions attenuated its favourable prognostic effect in intratumoural area (LoCD8/PD1 + vs. HiCD8/PD1-: HR 0.25 [0.09-0.69], p = 0.007; LoCD8/PDL1+ vs. HiCD8/PDL1-: HR 0.32 [0.12-0.89], p = 0.028) and were associated with negative outcome when seen in peritumoural area (HiCD8/PD1+ vs. LoCD8/PD1-: HR 0.29 [0.11-0.74], p = 0.010); HiCD8/PDL1+ vs. LoCD8/PDL1-: HR 0.33 [0.12-0.90], p = 0.031). Conclusions: PD-1 and PD-L1 expression were identified to be of predictive and prognostic value in patients with OAC, particularly when considering CD8+ infiltration. Further validation by a large size dataset is required.

Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial.

IMPORTANCE: Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. OBJECTIVE: To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. INTERVENTIONS: Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. MAIN OUTCOMES AND MEASURES: The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. RESULTS: Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. CONCLUSIONS AND RELEVANCE: This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02363374.

Adenocarcinoma of the esophagogastric junction: neoadjuvant radiochemotherapy and radical surgery : early results and toxicity.

PURPOSE: To retrospectively evaluate treatment results and toxicity following a combined approach consisting of neoadjuvant radiochemotherapy and radical surgery in advanced adenocarcinoma of the esophagus and gastroesophageal junction. PATIENTS AND METHODS: Between 2005 and 2009, a total of 41 consecutive patients with newly diagnosed nonmetastatic adeno-carcinoma of the esophagus and the esophagogastric junction were evaluated, of whom 23 received neoadjuvant radiochemo-therapy (RCT). A total dose of 50.4 Gy with 2 cycles of simultaneous cisplatin/5-fluorouracil (FU) or Taxol/FU-chemotherapy were applied. A radical transthoracic subtotal esophageal and proximal gastric resection through a right thoracoabdominal laparotomy with intrathoracic anastomosis was performed 6-8 weeks following RCT. This was combined with a two-field lymphadenectomy of mediastinal and abdominal lymph nodes. Standard histopathological evaluation included the application of regression grading according to Werner and Höfler. Toxicity was recorded on the basis of CTC criteria; survival curves were calculated according to Kaplan-Meier. V10, V15, and V20 data were correlated with pulmonary toxicity. RESULTS: Overall survival for all 23 patients was 61% at 3 years. Of the original 23 patients, 18 (78%) patients proceeded to radical surgery. Reasons for no surgery included advanced age of 79, 82, and 86 years (n = 3), severe comorbidity (n = 1), and progression during radiochemotherapy (n = 1). Surgical morbidity (grade 3-4) and mortality rates were 35% and 6%, respectively. Resurgery was necessary in 3 cases (18%). Clear resection margins were achieved in 17 of 18 patients (94%). Twelve of 18 (67%) patients initially diagnosed with T3 tumors and 3 of 3 patients with T4 tumors experienced downstaging. The ypN0 rate was 12 of 18 patients (67%). Out of a total of 18 patients, regression grading revealed < 10% viable cells in 8 (44%) including 3 cases (17%) with complete regression, 10-50% viable cells in 9 (50%) and > 50% viable cells in 1 patient. During the postoperative course or thereafter, 8 of 23 (35%) patients experienced pulmonary complications including pneumonia and/or pneumonitis. V10 > 20% (p = 0.019), V15 > 13% (p = 0.008), and V20 > 10% (p = 0.008) were associated with a significant increase in the rate of pulmonary toxic effects. CONCLUSION: Neoadjuvant radiochemotherapy in patients with advanced adenocarcinoma of the esophagogastric junction followed by thoracoabdominal surgery is a feasible concept. Significant tumor regression in 44% of the patients and an ypN0 rate in 67% of the patients may favor this approach due to its high efficacy. However, to avoid toxic pulmonary effects constraints for low-dose radiation volume parameters need specific attention.

Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial.

BACKGROUND: The CAO/ARO/AIO trial has shown that oxaliplatin added to preoperative chemoradiotherapy and postoperative chemotherapy significantly improved disease-free survival in locally advanced rectal cancer (LARC). Here, we present a post-hoc analysis of quality of life (QoL) in disease-free patients. PATIENTS AND METHODS: Between 2006 and 2010, 1236 patients with LARC were randomly assigned either to preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy (N = 623) or combined with oxaliplatin (N = 613). QoL questionnaires (EORTC QLQ-C30, colorectal module CR38) were completed at baseline, after postoperative chemotherapy and during follow-up. Analysis was performed according intent-to-treat. RESULTS: Available questionnaires (baseline) were 82% (N = 512) in the control and 84% (N = 513) in the investigational group. Response rates were 49% (533 of 1086) at 1 year and 43% (403 of 928) at 3 years. Global health status (GHS) for disease-free patients was stable in both groups (range 0-100). At baseline: standard arm 62.0 (mean, SD 21.6; N = 491) versus oxaliplatin arm 63.2 (mean, SD 22; N = 503); at 3 years: 69.4 (SD 19.3; N = 187) versus 65.4 (SD 22.2; N = 202). After treatment and at 3 years, no significant differences (≥10 points) between groups were found in QoL subscales. Disease-free patients experiencing neurotoxic side-effects (grade 1-4) showed reduced GHS at 3 years versus patients without neurotoxicity (mean 59.2 versus 69.3; P < 0.001), while grade 3-4 rate was low. CONCLUSION: The addition of oxaliplatin was not associated with worse overall QoL. This information is of interest to patients in many ongoing rectal cancer trials. TRIAL REGISTRATION INFORMATION: NCT00349076.

[Geriatrics and radiation oncology. Part 1: How to identify high-risk patients and basic treatment principles]. / Geriatrie und Radioonkologie. Teil 1: Identifikation des Risikopatienten und Grundsätzliches zur Behandlung.

BACKGROUND: Until the mid of this century, 33% of the Western population will be > or = 65 years old. The percentage of patients being > or = 80 years old with today 5% will triple until 2050. Therefore, radiation oncologists must be familiar with special geriatric issues to meet the increasing demand for multidisciplinary cooperation and to offer useful and individual treatment concepts. PATIENTS AND METHODS: This review article will provide basic data on the definition, identification and treatment of geriatric cancer patients. RESULTS: The geriatric patient is defined by typical multimorbidity (15 items) and by age-related increased vulnerability. Best initial identification of geriatric patients will be provided by assessment including the Barthel Index evaluating self-care and activity in daily life, by the Mini-Mental Status Test that will address cognitive pattern, and by the Timed "Up&Go" Test for evaluation of mobility. As for chemotherapy, standard treatment was associated with increased toxicity, consequently, dose modifications and supportive treatment are of special importance. CONCLUSION: Geriatric cancer patients need to be identified by special assessment instruments. Due to increased toxicity following chemotherapy, supportive measures seem important. Radiation treatment as a noninvasive and outpatient-based treatment remains an important and preferable option.