F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial.

AIM: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy. METHODS: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3-14 days before (pre-ICIT) and 21-28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu). RESULTS: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value. CONCLUSION: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value. TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT03426657.

Chemotherapeutic agents for GI tumor chemoradiotherapy overview of chemotherapeutic agents to be combined with radiotherapy in the GI tract and their potential as radiosensitizers.

In the treatment of gastrointestinal tumors, simultaneous radiochemotherapy plays an important role. It is one of the principles of simultaneous radiochemotherapy, applying only chemotherapeutic agents simultaneously to radiation, which are primarily effective in the treated tumor entity, therefore a lot of different agents, like antimetabolites, mostly 5-fluorouracil, platinum derivates (mostly cisplatinum and oxaliplatin), mitomycin C and taxanes are used in simultaneous radiochemotherapy. Most of these have also radiation-intensifying effects. The mechanisms and interactions with ionizing radiation are presented in the article.

Radiosensitizing effect of epothilone B on human epithelial cancer cells.

BACKGROUND: A combined modality treatment employing radiation and chemotherapy plays a central role in the management of solid tumors. In our study, we examined the cytotoxic and radiosensitive effect of the microtubule stabilizer epothilone B on two human epithelial tumor cell lines in vitro and its influence on the microtubule assembly. METHODS: Cancer cells were treated with epothilone B in proliferation assays and in combination with radiation in colony-forming assays. For the analysis of ionizing radiation-induced DNA damage and the influence of the drug on its repair a γH2AX foci assay was used. To determine the effect of epothilone B on the microtubule assembly in cells and on purified tubulin, immunofluorescence staining and tubulin polymerization assay, respectively, were conducted. RESULTS: Epothilone B induced a concentration- and application-dependent antiproliferative effect on the cells, with IC(50) values in the low nanomolar range. Colony forming assays showed a synergistic radiosensitive effect on both cell lines which was dependent on incubation time and applied concentration of epothilone B. The γH2AX assays demonstrated that ionizing radiation combined with the drug resulted in a concentration-dependent increase in the number of double-strand breaks and suggested a reduction in DNA repair capacity. Epothilone B produced enhanced microtubule bundling and abnormal spindle formation as revealed by immunofluorescence microscopy and caused microtubule formation from purified tubulin. CONCLUSION: The results of this study showed that epothilone B displays cytotoxic antitumor activity at low nanomolar concentrations and also enhances the radiation response in the tumor cells tested; this may be induced by a reduced DNA repair capacity triggered by epothilone B. It was also demonstrated that epothilone B in fact targets microtubules in a more effective manner than paclitaxel.

Chemoradiotherapy duration correlates with overall survival in limited disease SCLC patients with poor initial performance status who successfully completed multimodality treatment.

BACKGROUND AND PURPOSE: Limited data concerning treatment-related prognostic factors in limited disease (LD) small-cell lung cancer (SCLC) patients with poor initial performance status (PS) who successfully completed chemoradiotherapy (CRT) are available. PATIENTS AND METHODS: A total of 125 patients with initial PS WHO 2-3 who successfully completed CRT were retrospectively reviewed. Thoracic radiation therapy (TRT) was applied in the concurrent (group 1) or sequential (group 2) mode. Influence of treatment type, time from diagnosis to start of TRT, number of chemotherapy cycles, prophylactic cranial irradiation (PCI), occurrence of brain metastases (BMs), and duration of CRT on overall survival (OS) were analyzed. RESULTS: Median duration of CRT was 156 days in group 1 and 195 days in group 2 (p < 0.001). Median progression-free survival and OS were 11.6 (95% confidence interval (CI) 10-13.2) and 14.9 (95% CI 11.7-17.6) months with no difference between the groups. The 2- and 3-year survival rates were 37.9 ± 6.9% and 22.7 ± 6.3% in group 1 and 22.4 ± 4.9% and 15.2 ± 4.3% in group 2, respectively. Duration of CRT was only treatment-related factor predicting OS in the uni- (p < 0.014) and multivariate (p < 0.025) analyses. Short dose-dense CRT was associated with improved OS. CONCLUSION: Duration of CRT affects OS in LD SCLC patients with poor initial performance status who successfully completed multimodality treatment.

[Radiotherapy as therapeutic option for primary localised orbital lymphomas of low malignancy]. / Die Strahlentherapie als Therapieoption bei primären lokalisierten niedrig malignen orbitalen Lymphomen.

PURPOSE: The aim of this study was to assess the efficacy of radiotherapy as first line therapy for the treatment of primary localised orbital lymphomas of low malignancy (St IE) based on our cases. METHODS: 7 patients with histologically proven primary localised orbital lymphomas of low malignancy treated with radiotherapy were retrospectively reviewed. The dose was 40 Gy for unilateral and 36 Gy for bilateral lymphoma. The follow-up period was 12 - 60 months after the end of the therapy (mean follow-up period: 36 months). RESULTS: Complete regression was achieved in 6 patients 12 - 24 months after the end of radiotherapy. In one patient an increase of tumour mass was observed 3 months after radiotherapy. Chemotherapy was subsequently performed and the patient was free of disease 2 years later. In 2 cases cataract surgery had to be performed for post-radiotherapy cataract formation. CONCLUSION: The majority of orbital lymphomas are localised St. IE tumours of low malignancy. Radiotherapy is the first-line therapy in these cases. Success rates of > 90 % are reported in the literature.

Impact of comorbidity and age on the outcome of patients with inoperable NSCLC treated with concurrent chemoradiotherapy.

BACKGROUND: The value of concurrent chemoradiotherapy (CRT) for treatment of locally advanced non-small cell lung cancer (NSCLC) in elderly and multimorbid patients is generally disputed due to the assumed lack of toxicity compensation or the limited prognosis of the accompanying morbidity. AIM: We investigated correlation between impaired organ function, age, tumor-associated symptoms, social factors and acute toxicity as well as survival following CRT. PATIENTS AND METHODS: Retrospective data collection and analysis were performed on the variables age, functional parameters: FEV1, VC, DLCO, LVEF, creatinine clearance, age, several categories of comorbidities, WHO performance status, alcohol and nicotine habits, toxicity according CTC-criteria and survival of all patients (n=66) with inoperable NSCLC suffering substantial comorbidities or advanced age (>70 years) treated with an CRT consisting of two cycles cisplatin or carboplatin plus vinorelbine and a conventionally fractionated radiotherapy up to 63Gy. RESULTS: Median survival of all patients was 13 months (10.6-15.4 months, 95% confidence interval). Univariate analyses showed significantly poorer survival (12 months vs. 15 months) in patients with LVEF<50% compared with LVEF> or = 50% (P=0.022, in log-rank test). All other variables did not exhibit any significant correlation to survival. Multivariate analyses revealed significantly inferior survival in patients suffering from cardiac or pulmonary dysfunction (P=0.039, hazard ratio [HR]: 2.18; 95% CI of HR [1.04-4.59]). Elderly patients (>70 years) had a higher prevalence of hematotoxicity of higher degree than younger patients (< or = 70 years), but without significant impact on the feasibility of both treatment modalities. CONCLUSION: Our results suggest that cardiac and pulmonary dysfunction may be associated with a reduced survival in elderly or poor-risk patients with inoperable NSCLC after CRT.

Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study.

The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4 + 5.4) Gy. Concurrently, irinotecan 40 mg m(-2) once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m(-2) twice daily were administered. Surgery was performed 4-6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand-foot syndrome at the 825 mg m(-2) dose level. The maximum tolerated dose of capecitabine was 750 mg m(-2). Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer.

Concurrent chemoradiotherapy and adjuvant chemotherapy with Topotecan for patients with glioblastoma multiforme.

PURPOSE: The prognosis for patients with glioblastoma multiforme remains poor. Phase II studies, meta-analyses and a phase III study show that concurrent chemoradiotherapy has an advantage over irradiation alone. In this study the effectiveness of concurrent chemoradiotherapy with Topotecan and an adjuvant chemotherapy with Topotecan was investigated. PATIENTS AND METHOD: Forty-two patients with predominantly unfavourable prognosis factors were included in the study and treated as follows: hyperfractionated accelerated radiotherapy (2x1.75Gy to 45.5 + 12.25 Gy (RP)) with a concurrent, continuous infusion of Topotecan (0.5 mg/m(2)/d, days 1-21). On day 28 the adjuvant chemotherapy (three courses) was begun according to the same scheme. RESULT: Haematological toxicities were 13/42 (30%) grade III leucopenia, 2/42 (4%) grade IV, as well as 5/42 (10%) grade III thrombopenias and 1/42 (2%) grade IV. 30/42 (71%) patients showed improvement or stabilisation of an existing neurological symptomatic complex. The median time to progression was 7.2 (+/- 0.8) months, the median total survival was 10 (+/- 1.2) months, the 2 year survival rate 4.7 (+/- 0.3)%. Prognostic factors were age, surgical radicality, performance status and the tumour volume before therapy. SUMMARY: Concurrent chemoradiotherapy and an adjuvant chemotherapy with Topotecan is feasible at acceptable toxicity levels also for patients with a moderate performance status. The patients benefit from the improvement of the clinical symptomatic complex and, even with unfavourable prognosis factors, have a higher median survival in comparison to data published on similar groups of patients given only radiotherapy.

Minimally invasive and local treatment for mucosal early gastric cancer.

BACKGROUND: Early gastric cancer (EGC) can present an indication for local resection procedures under pertain circumstances. Especially endoscopic mucosal resections (EMRs) and laparoscopic resections or those combined with endoscopy have been made possible in recent years. METHODS: From 1996 to 2004, of a total of 425 patients with gastric cancer, 58 patients with EGC (13.6%) were prospectively analyzed and observed. Of these, 35 patients had preoperatively diagnosed submucosal infiltration and subsequently underwent gastrectomy and standard lymphnodectomy. Of the 23 patients with intramucosal EGC, 22 underwent local resection. One patient displayed lymph node and liver metastasis at the time of diagnosis and received chemotherapy following staging laparoscopy. RESULTS: Among the 23 patients with intramucosal EGC, 13 were female and 10 male. The average age of the patients was 77.4 years (range: 69-86). The rate of lymph node metastasis was 12.5% (n = 35) for submucosal EGC and 4.3% (n = 23) for intramucosal EGC. Twenty-two patients with intramucosal EGC underwent local resection (four EMR, six laparoscopic intragastric resection, 12 laparoscopic wedge resection). The average tumor size was 1.2 cm (range 0.3-2.3). The definitive histological findings yielded in all patients tumor-free resection margins without venous or lymphangic infiltration. In 10 of 18 patients undergoing laparoscopic resection a simultaneous sentinel lymph node sampling (4 +/- 3 LN) was performed. There were no metastases detected. Method-specific complications did not occur. The morbidity of this patient group was 13.6% (three of 22). Mortality was zero. The average postoperative hospital stay was 6.5 days (range 2-12). In the median follow-up of 30.3 months (range 1-86) no recurrences have yet been diagnosed. Four patients died within the observation period of non-cancer-related causes. CONCLUSIONS: Minimally invasive local resection of intramucosal EGC represents a favorable option when strict determination of indication has taken place.

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer.

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.

Phase I/II clinical trial of concurrent radiochemotherapy in combination with topotecan for the treatment of brain metastases.

The prognosis of patients with brain metastases is very poor. In this phase I/II study we tested the feasibility, dosage, toxicity and tumour efficacy of a concurrent radiochemotherapy regimen including topotecan. Twenty patients were recruited between July 1998 and February 2000 (9 women, 11 men) and treated with a whole-brain irradiation of 40 Gy (some patients were also given a boost) in combination with topotecan given as a 21-day continuous infusion in a dosage of 0.4 to 0.6 mg/m2/day. The median survival was five months (95% Confidence Interval (CI): 2-8 months). In 13 of 20 patients, it was possible to evaluate the remission with computed tomography (CT) scans or magnetic resonance scans. We detected four complete responders (CRs), two partial responders (PRs), and one progressive disease (PD). 6 patients had stable disease (SD). An intracerebral recurrence was experienced in 3 patients, 3 patients experienced spinal lesions. Systemic progression of cancer outside the central nervous system (CNS) was dominant in 9 of 20 patients. A reversible, non-cumulative haematological toxicity mainly occurring from a dose of 0.5 mg/m2/day and above was dose-limiting for this type of therapy. Combined concurrent radiochemotherapy with topotecan is feasible in spite of various pretreatments. Myelosuppression was the dominant toxicity, which was reversible and manageable. We recommend a dose of 0.4 mg/m2/day of topotecan as a 21-day continuous infusion therapy in combination with radiotherapy.

[The multimodality therapy of advanced inoperable esophageal carcinoma. A retrospective analysis]. / Multimodale Therapie des fortgeschrittenen inoperablen Osophaguskarzinoms. Eine retrospektive Analyse.

BACKGROUND: The records of 161 patients with inoperable esophageal carcinoma were reviewed to determine the influence of concurrent radiochemotherapy and brachytherapy on overall survival. PATIENTS AND METHODS: From 1984 to 1999 161 patients suffering from advanced esophageal carcinoma Stage II to IV were treated with radiotherapy alone (131) or radiochemotherapy (30). In 48 patients additional brachytherapy was given. Median follow-up was 8 months (1 to 64 months), the median external beam doses was 51 Gy (18 to 66.6 Gy) and the median brachytherapy dose was 10 Gy (4 to 25 Gy). Chemotherapy consisted of cisplatin and 5-fluorouracil. RESULTS: Median survival for all patients was 10 months, 3-year survival rate 13% and the 5-year survival 5.2%. In univariate analysis the best results were achieved by concurrent radiochemotherapy with a median overall survival of 13 months, a 4-year survival of 18% (p = 0.0368), the combination of external radiotherapy and additional brachytherapy with a median overall survival of 14 months, a 4-year survival of 12.2% (p = 0.0008). After combination of concurrent radiochemotherapy and brachytherapy the 2-year survival rate is 58%. Multivariate analysis revealed simultaneous radiochemotherapy, external beam dose and additional brachytherapy as prognostic factors. Combination of concurrent radiochemotherapy and brachytherapy was possible without significant increase of local toxicity. CONCLUSIONS: Our retrospective analysis demonstrates that concurrent radiochemotherapy and additional brachytherapy are effective treatment schedules without significant increase of toxicity and may improve overall survival of patients with inoperable carcinoma of the esophagus. According to the results of this retrospective study, it would be appropriate to conduct a randomized trial to evaluate the benefit of combination of concurrent radiochemotherapy and brachytherapy.

[Endoscopic pretherapeutic clipping for gastrointestinal tumors. A method for exact definition of the target volume]. / Endoskopische prätherapeutische Clipmarkierung von Tumoren im Gastrointestinaltrakt. Eine Methode zur exakteren Definition von Zielvolumina.

BACKGROUND: In many cases it is not possible to exactly define the extension of carcinoma of the gastrointestinal tract with the help of computertomography scans made for 3-D-radiation treatment planning. Consequently, the planning of external beam radiotherapy is made more difficult for the gross tumor volume as well as, in some cases, also for the clinical target volume. PATIENTS AND METHODS: Eleven patients with macroscopic tumors (rectal cancer n = 5, cardiac cancer n = 6) were included. Just before 3-D planning, the oral and aboral border of the tumor was marked endoscopically with hemoclips. Subsequently, CT scans for radiotherapy planning were made and the clinical target volume was defined. Five to 6 weeks thereafter, new CT scans were done to define the gross tumor volume for boost planning. Two investigators independently assessed the influence of the hemoclips on the different planning volumes, and whether the number of clips was sufficient to define the gross tumor volume. RESULTS: In all patients, the implantation of the clips was done without complications. Start of radiotherapy was not delayed. With the help of the clips it was possible to exactly define the position and the extension of the primary tumor. The clinical target volume was modified according to the position of the clips in 5/11 patients; the gross tumor volume was modified in 7/11 patients. The use of the clips made the documentation and verification of the treatment portals by the simulator easier. Moreover, the clips helped the surgeon to define the primary tumor region following marked regression after neoadjuvant therapy in 3 patients. CONCLUSIONS: Endoscopic clipping of gastrointestinal tumors helps to define the tumor volumes more precisely in radiation therapy. The clips are easily recognized on the portal films and, thus, contribute to quality control.

[First results of neoadjuvant simultaneious radiochemotherapy in advanced rectal carcinoma]. / Erste Ergebnisse der neoadjuvanten simultanen Radiochemotherapie bei fortgeschrittenen Rektumkarzinomen.

PURPOSE: In locally advanced rectal cancer tumor-negative margins often cannot be obtained by surgery alone. Nevertheless only patients with complete tumor resection can be cured. Due to the poor prognosis of patients with R1/R2 resection the "Deutsche Krebsgesellschaft" recommends concurrent preoperative radiochemotherapy for patients with locally advanced rectal cancer. PATIENTS AND METHODS: Between May 1997 and November 1999 22 patients were treated with preoperative radiochemotherapy. A total dose of 45 Gy with a small-volume boost of 5.4 Gy was delivered in conventional fractionation (single dose 1.8 Gy). On days 1 to 5 and 29 to 33 patients received concurrently 5-fluorouracil (5-FU) as continuous infusion of 1,000 mg/m2. If there was any sign of cardiac toxicity chemotherapy was changed to 5-FU/folinic acid or ralitrexed. RESULTS: Surgery following radiochemotherapy was performed in 19/22 patients. Resections with negative margins were achieved in 16/19 (84%) patients. Sphincter-conserving surgery was possible in 9/19 (47%) patients. A downstaging of at least 1 T category was found in 12/19 (63%) patients. With a median follow-up of 16 months no locoregional recurrences occurred in patients who underwent surgery. Two-year disease-free survival of resected patients is 62%, 2-year overall survival is 89%, of the whole population 76%. CONCLUSION: Preoperative radiochemotherapy followed by surgery is able to achieve clear resection margins in more than 70% of patients with locally advanced rectal cancer and may improve the rate of sphincter-conserving surgery.

A new microwave applicator with integrated cooling system for intracavitary hyperthermia of vaginal carcinoma.

An improved design of a previously described intracavitary microwave hyperthermia applicator is presented. The applicator consists of a coaxial choke antenna designed to be positioned into a perspex obturator. The antenna can be fitted in the obturator in three defined positions depending on the specific clinical situation: the selected median, paramedian or lateral position can each provide differently directed heating patterns. This feature combined with the additional axial variability of the antenna position within the obturator can lead to a highly targeted heating of tumours and a reduced risk of unwanted heating of normal tissues. Various phantom studies were conducted using both liquid and solid phantoms. The saline phantom was used to check the typical action of the choke of the antenna where it was found that the antenna choke is efficiently working resulting in a heating pattern which is dependent of the insertion depth of the antenna. The solid phantom was used to measure the typical specific absorption rate (SAR) distribution of each antenna/obturator configuration.