Prospects for online adaptive radiation therapy (ART) for head and neck cancer.

BACKGROUND: The aim of the present study is to examine the impact of kV-CBCT-based online adaptive radiation therapy (ART) on dosimetric parameters in comparison to image-guided-radiotherapy (IGRT) in consecutive patients with tumors in the head and neck region from a prospective registry. METHODS: The study comprises all consecutive patients with tumors in the head and neck area who were treated with kV-CBCT-based online ART or IGRT-modus at the linear-accelerator ETHOS™. As a measure of effectiveness, the equivalent-uniform-dose was calculated for the CTV (EUDCTV) and organs-at-risk (EUDOAR) and normalized to the prescribed dose. As an important determinant for the need of ART the interfractional shifts of anatomic landmarks related to the tongue were analyzed and compared to the intrafractional shifts. The latter determine the performance of the adapted dose distribution on the verification CBCT2 postadaptation. RESULTS: Altogether 59 consecutive patients with tumors in the head-and-neck-area were treated from 01.12.2021 to 31.01.2023. Ten of all 59 patients (10/59; 16.9%) received at least one phase within a treatment course with ART. Of 46 fractions in the adaptive mode, irradiation was conducted in 65.2% of fractions with the adaptive-plan, the scheduled-plan in the remaining. The dispersion of the distributions of EUDCTV-values from the 46 dose fractions differed significantly between the scheduled and adaptive plans (Ansari-Bradley-Test, p = 0.0158). Thus, the 2.5th percentile of the EUDCTV-values by the adaptive plans amounted 97.1% (95% CI 96.6-99.5%) and by the scheduled plans 78.1% (95% CI 61.8-88.7%). While the EUDCTV for the accumulated dose distributions stayed above 95% at PTV-margins of ≥ 3 mm for all 8 analyzed treatment phases the scheduled plans did for margins ≥ 5 mm. The intrafractional anatomic shifts of all 8 measured anatomic landmarks were smaller than the interfractional with overall median values of 8.5 mm and 5.5 mm (p < 0.0001 for five and p < 0.05 for all parameters, pairwise comparisons, signed-rank-test). The EUDOAR-values for the larynx and the parotid gland were significantly lower for the adaptive compared with the scheduled plans (Wilcoxon-test, p < 0.001). CONCLUSIONS: The mobile tongue and tongue base showed considerable interfractional variations. While PTV-margins of 5 mm were sufficient for IGRT, ART showed the potential of decreasing PTV-margins and spare dose to the organs-at-risk.

Respiration-controlled radiotherapy in lung cancer: Systematic evaluation of the optimal application practice.

Background and purpose: Definitive radiochemotherapy (RCT) for non-small cell lung cancer (NSCLC) in UICC/TNM I-IVA (singular, oligometastatic) is one of the treatment methods with a potentially curative concept. However, tumour respiratory motion during RT requires exact pre-planning. There are various techniques of motion management like creating internal target volume (ITV), gating, inspiration breath-hold and tracking. The primary goal is to cover the PTV with the prescribed dose while at the same time maximizing dose reduction of surrounding normal tissues (organs at risk, OAR). In this study, two standardized online breath-controlled application techniques used alternately in our department are compared with respect to lung and heart dose. Materials and methods: Twenty-four patients who were indicated for thoracic RT received planning CTs in voluntary deep inspiration breath-hold (DIBH) and in free shallow breathing, prospectively gated in expiration (FB-EH). A respiratory gating system by Varian (Real-time Position Management, RPM) was used for monitoring. OAR, GTV, CTV and PTV were contoured on both planning CTs. The PTV margin to the CTV was 5 mm in the axial and 6-8 mm in the cranio-caudal direction. The consistency of the contours was checked by elastic deformation (Varian Eclipse Version 15.5). RT plans were generated and compared in both breathing positions using the same technique, IMRT over fixed irradiation directions or VMAT. The patients were treated in a prospective registry study with the approval of the local ethics committee. Results: The PTV in expiration (FB-EH) was on average significantly smaller than the PTV in inspiration (DIBH): for tumours in the lower lobe (LL) 431.5 vs. 477.6 ml (Wilcoxon test for connected samples; p = 0.004), in the upper lobe (UL) 659.5 vs. 686.8 ml (p = 0.005). The intra-patient comparison of plans in DIBH and FB-EH showed superiority of DIBH for UL-tumours and equality of DIBH and FB-EH for LL-tumours. The dose for OAR in UL-tumours was lower in DIBH than in FB-EH (mean lung dose p = 0.011; lungV20, p = 0.002; mean heart dose p = 0.016). The plans for LL-tumours in FB-EH showed no difference in OAR compared to DIBH (mean lung dose p = 0.683; V20Gy p = 0.33; mean heart dose p = 0.929). The RT setting was controlled online for each fraction and was robustly reproducible in FB-EH. Conclusion: RT plans for treating lung tumours implemented depend on the reproducibility of the DIBH and advantages of the respiratory situation with respect to OAR. The primary tumour localization in UL correlates with advantages of RT in DIBH, compared to FB-EH. For LL-tumours there is no difference between RT in FB-EH and RT in DIBH with respect to heart or lung exposure and therefore, reproducibility is the dominant criterion. FB-EH is recommended as a very robust and efficient technique for LL-tumours.

Dose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial.

BACKGROUND: This prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year. METHODS: Eligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1-6, 8-13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals. RESULTS: Between 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48-66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59-100], 53% [34-83], 41% [23-73], and 29% [14-61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40-88], 35% [19-67], and 29% [14-61], corresponding cumulative incidences of loco-regional progressions were 18% [4-39%], 35% [14-58%], and 41% [17-64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%). CONCLUSIONS: Dose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound. Trial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE ) and authorized to proceed on 2006-09-25.

Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus.

The aim of this study was to retrospectively analyze the long-term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. Patients received high-dose external beam radiotherapy and concurrent cisplatin-based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin-based induction chemotherapy before definitive chemoradiation. Fifty-five patients (46 men, 9 women, median age 58 years, range 35-72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50-70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long-term survivors were observed with a follow-up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty-four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long-term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long-term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer.

Accelerated hyperfractionated radiotherapy within trimodality therapy concepts for stage IIIA/B non-small cell lung cancer: Markedly higher rate of pathologic complete remissions than with conventional fractionation.

BACKGROUND: Radiation dose escalation within definitive radiochemotherapy (RTx/CTx) was not successful for stage III non-small cell lung cancer (NSCLC) using conventional fractionation (CF). Accelerated-hyperfractionation (AHF) counteracts tumour cell repopulation. In this observational study, the effects of neoadjuvant RTx/CTx using AHF or CF were studied by histopathology and using the survival end-point. METHODS: Data from all consecutive lung cancer patients treated with neoadjuvant RTx/CTx and thoracotomy between 08/2000 and 06/2012 were analysed. Patients received induction chemotherapy (cisplatin-doublets) followed by concurrent RTx/CTx using AHF (45 Gy/1.5 Gy bid) or CF-RTx (46 Gy/2 Gy qd). For estimating the AHF versus CF treatment effects, multivariate analysis (MA), propensity score weighting (PS), and instrumental variable analysis (IV) were used. FINDINGS: 239 patients were treated, median age 58 (34-78)years, stage II/IIIA/B: 19/88/132, squamous cell/adenocarcinomas/other: 98/107/34; AHF/CF-RTx 112/127 patients. No significant differences between both groups, in tumour related factors (age, gender, Charlson comorbiditiy score, lactate dehydrogenase (LDH), haemoglobin, stage, histopathology and grading), existed. Crude rates of pathologic complete responses (pCR) in AHF and CF groups were 37% and 24% respectively. The dose fractionation effect on pCR was significant (p ⩽ 0.006, PS and IV analyses). There was a significant dependence of pCR on biologically effective dose. pCR also depended on treatment time (MA, p = 0.04; PS, p = 0.0004). Median treatment time was 22 d or 31 d using AHF or CF (p<0.0001), respectively. Adenocarcinomas had lower pCR rates in comparison to other histologies. Five-year survival of patients with pCR was 65%, independent of the fractionation. INTERPRETATION: This large monoinstitutional analysis demonstrates an increased effect of AHF on pCR of lung cancer which modifies overall survival.

Neoadjuvant treatment improves capsular integrity and the width of the fibrous capsule of high-grade soft-tissue sarcomas.

BACKGROUND: Neoadjuvant treatment is thought to improve resection with margin-negative surgery in locally advanced soft-tissue sarcomas (STS). Treatment-induced alterations of the tumor peripheryhave not yet been microscopically evaluated. OBJECTIVE: This histopathological study compared limb STS with primary resection and those that had undergone neoadjuvant treatment, emphasizing microscopic changes of the fibrous capsule (FC) and reactive zone (RZ) after neoadjuvant treatment. PATIENTS AND METHODS: Patients with primary high-grade limb sarcomas (N = 76) which have not previously been treated were included. Of those, 37 were primarily resected and 39 were treated with one of the following neoadjuvant treatment modalities: 7x chemotherapy (CTX), 3x radiotherapy (RT), 15x isolated limb perfusion (ILP), 8x CTX + RT, and 6x CTX + ILP. Sizes of the FC and RZ were microscopically measured, and FC-integrity was documented. Histopathologic regression was expressed as a percent. RESULTS: Only 35.1% of untreated sarcomas showed an intact FC. We observed significantly higher capsular integrity after treatment (76.9%). Additionally, the average width of the FC (0.21 mm vs. 0.61 mm) and RZ (0.67 mm vs. 1.48 mm) increased significantly. The extent of histopathologic regression showed a correlation with capsular integrity and width. The combination of two treatment modalities (CTX + RT or ILP) showed strongest effects at the tumor periphery. CONCLUSIONS: Neoadjuvant treatment stabilizes the tumor periphery in STS (e.g., the capsule). Concerning local treatment strategies, these novel histopathologic insights might significantly influence the decision as to whether primary resection is advisable in advanced local soft-tissue sarcoma.

Therapy response assessment in radiotherapy of lung cancer.

Radiotherapy represents an important therapeutic modality in the treatment of lung cancer. Treatment response assessment after high-dose radiotherapy with or without concurrent chemotherapy using conventional imaging methods is limited since normal tissue appearance might resemble tumour recurrence very close. Positron emission tomography (PET) based imaging has been introduced in this situation with great enthusiasm and provides useful additional information on the biologic characteristics of the irradiated region, be it tumour or healthy lung tissue, provided some marginal conditions are taken into account. Furthermore, biologic imaging seems highly appealing for treatment guidance especially during treatment protocols including multimodality approaches with neoadjuvant intent. Treatment response might not only serve as a surrogate marker for pathological remission but for overall prognosis as well. Within this context, the optimal time point and the best parameter to evaluate remain issues of continuing debate. This review is aimed to give an overview of the current state of the scientific knowledge.

[Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in locally advanced nasopharyngeal carcinomas]. / Lokal fortgeschrittene Nasopharynxkarzinome. Hyperfraktioniert-akzelerierte Radiotherapie mit simultaner Chemotherapie.

BACKGROUND: The excellent results yielded by hyperfractionated and accelerated radiotherapy associated with concurrent chemotherapy in locally advanced oropharyngeal and hypopharyngeal carcinomas led to investigation of this therapeutic regimen in nasopharyngeal carcinomas also. METHODS: Thirty-five patients with stage III and IV nasopharyngeal carcinomas received accelerated hyperfractionated radiotherapy with concurrent chemotherapy (5-FU, mitomycin C + leucovorin). In the first 3 weeks of treatment five 2-Gy doses per week were delivered to the primary tumour and regional lymph nodes. The fractionation was then accelerated, with 1.4 Gy given twice daily until a total dose of 72 Gy had been administered. RESULTS: The overall objective response rate was 100%. The median follow-up period was 71 months. Salvage surgery of the lymph nodes was performed in 10 patients, revealing vital tumour tissue in 6 of these. The actuarial 5-year local control rate was 64% (95%CI: 47-81%), while overall actuarial survival at 5 years was 70% (95%CI: 53-86%). CONCLUSION: Hyperfractionated accelerated radiotherapy with concurrent chemotherapy is effective and feasible in locally advanced nasopharyngeal carcinoma.

Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour.

The traditional treatment of Pancoast tumour with local approaches (surgery, radiotherapy or a combination of both) leads to a poor outcome due to the high rate of incomplete resection and the lack of systemic control. The aim of the present prospective feasibility study was to determine whether a trimodality approach improves local control and survival. Patients with stage IIB-IIIB Pancoast tumour received induction chemotherapy (three courses of split-dose cisplatin and etoposide or paclitaxel) followed by concurrent chemoradiotherapy (a course of cisplatin/etoposide combined with 45 Gy hyperfractionated accelerated radiotherapy). After restaging, eligible patients underwent surgery 4-6 weeks post-radiation. A total of 31 consecutive patients with T3 (81%) or T4 (19%) Pancoast tumour were enrolled in the study. Induction chemoradiotherapy was completed in all patients without treatment-related deaths. Grade 3-4 toxicity was observed in 32% of cases. In total, 29 (94%) patients were eligible for surgery. Complete resection was achieved in 94% of patients. The post-operative mortality rate was 6.4% and major complications arose in 20.6% of the patients. The median survival was 54 months with 2- and 5-yr survival rates of 74 and 46%, respectively. In conclusion, this intensive multimodality treatment of Pancoast tumour is feasible and improves local resectability rates and long-term survival as compared with historical series.

Staging laparoscopy in gastric cancer.

BACKGROUND: As patients with gastric cancer are offered choices between surgical resection, neoadjuvant or palliative chemotherapy, or symptomatic relief alone, the need for accurate preoperative staging becomes apparent. Laparoscopy has been suggested as an appropriate staging modality in a variety of upper gastrointestinal malignancies. METHODOLOGY: Staging laparoscopy was performed in 45 patients with potentially resectable gastric cancer as determined by physical examination, gastroscopy, endosonography, transcutaneous ultrasonography and current generation computed tomography. Conventional clinic staging and laparoscopic staging according to the Tumor-Node-Metastases classification of the International Union against Cancer were registered separately on a database. Results were then compared to evaluate the agreement of both staging procedures. RESULTS: Compared to conventional staging, laparoscopy resulted in up staging of 23 patients (51.1%). In 10 patients of them peritoneal seeding was first found during laparoscopy, whereas additional liver metastases were detected in 3 patients and Krukenberg's tumor in one. As a consequence, the therapy planning was changed and laparotomy was avoided in 14 of these patients as the first operative procedure. Sensitivity of clinical staging was especially poor for stage IV tumors (5.3%) and for the majority of stage IIIB tumors (42.9%). Cytologic examination of peritoneal fluid had no additional information in our series. CONCLUSIONS: The value of laparoscopy in staging patients with gastric carcinoma could be demonstrated in this study. It is a safe and effective staging modality, helping to avoid unnecessary laparotomies and providing new means of directing appropriate treatment strategy.

New targeted treatments in lung cancer--overview of clinical trials.

Combination chemotherapy has been established as the cornerstone of systemic treatment for advanced lung cancer in the last ten to fifteen years. However, improvements with new drug combinations in recent years have been rather small and a general outcome plateau has been reached with one-year survival rates of about 40% and two-year survival rates of less than 15%. Survival over three to four years is still a rare event in this disease, and more and more efforts are being made to develop innovative systemic treatment strategies with mechanisms of action different from conventional cytotoxic drugs. These molecular targeted agents have made a strong move forward in the management of this disease since Gefitinib--a small molecule EGF-receptor tyrosine kinase inhibitor--was registered in 2003 by the FDA and a number of further countries for the third-line treatment of non-small-cell lung cancer. Since then, every month findings have been reported about new cellular targets on lung-cancer cells and, consequently, new agents aiming at these molecular targets are being developed, preclinically. Some of these agents have already been tested in the clinics within phase-I, phase-II and some even within randomised phase-III trials. In this review we will try to summarise the current knowledge and data on the clinical activity of these new drugs in lung cancer and to give a perspective on the future for these new treatment principles. The most promising strategies have been aiming at the EGF-receptor family, serum-VEGF and the VEGF-receptor family (VEGF-1 and -2, respectively). Results from pivotal registration trials are expected within the next one or two years for a number of these new drugs, and the standards of care for advanced lung cancer may change dramatically, comparable to what we have seen in other solid tumours such as metastasised breast and colon cancer.

Prophylactic cranial irradiation as a component of intensified initial treatment of locally advanced non-small cell lung cancer.

Patients with locally advanced non-small cell lung cancer are threatened by the concurrent risks of local, regional and distant failure. By improving local and regional control with multimodality protocols, the brain becomes one of the major sites of relapse. PCI has a high potential to reduce the risk of brain metastases. Long-term toxicity is presently poorly defined and represents an important potential risk. The value of PCI as an adduct to present aggressive multimodality protocols and the optimal total dose with conventional fractionation will be investigated within clinical studies by two study groups in the future. As the best dose and fractionation still remains undefined, the integration of PCI into multimodality protocols.

[Significance of pulmonary lymph node metastases in locally advanced non-small cell lung cancer]. / Bedeutung der pulmonalen Lymphknotenmetastasierung bei lokal fortgeschrittenen, nicht-kleinzelligen Bronchialkarzinomen.

BACKGROUND: The locally advanced (T3 - 4) non-small cell lung cancer with pulmonary lymph node metastases (N1) is a mixture of different subgroups of disease with varying pattern of tumor extension and long-term survival rates. PATIENTS AND METHODS: We retrospectively reviewed hospital records and follow-up data of 181 patients operated on between 1990 and 1995 with pathological stage IIIA-pT3N1 and IIIB-pT4N1. Median age was 62 years (range 34 - 80). RESULTS: The operative mortality was 3.7 %. The analysis was carried out on the 181 hospital survivors. The operative procedure was a pneumonectomy in 110 cases (60.8 %) and a lobectomy/bilobectomy in 71 (39.26 %). The pathological stage according to the UICC TNM-Classification of 1997 was T3N1 in 128 (70.7 %) and T4N1 in 53 (29.3 %). We observed a metastatic involvement of the hilar, interlobar and lobar lymph nodes in 44 (24.3 %), 17 (9.4 %), and 27 (14.9 %) patients, respectively, whereas a direct infiltration in 93 patients (51.4 %). The actuarial overall 3-, 5- and 10-year survival rates for N1 hilar was 23 %, 13 % and 8 %, for N1 interlobar was 18 %, 6 % and 0 %, for N1 lobar was 48 %, 37 % and 22 %, and for N1 direct was 32 %, 27 % and 21 %, respectively. The involvement of hilar lymph nodes correlates with a worse prognosis (p =.0366). CONCLUSIONS: Metastases to the hilar lymph nodes in locally advanced NSCLC can be considered an initial N2-disease and should be treated correspondingly. Lymph node involvement by direct invasion is associated with a relatively more favourable prognosis for the patients.

Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages IIIa/IIIb): a pilot phase I/II trial.

BACKGROUND: Overall prognosis of patients with locally advanced non-small-cell lung cancer (LAD-NSCLC) is still unfavourable. Different attempts to improve treatment results have been made using combinations of chemotherapy and radiotherapy. The aim of this pilot phase I/II investigation was to test the feasibility and toxicity of a definitive multimodality protocol in patients with irresectable NSCLC stages IIIA (N2) and IIIB. PATIENTS AND METHODS: Thirty LAD-NSCLC patients (stages IIIA/IIIB: 3/27; median age: 54 years, range 34-70; male/female: 17/13) who were consecutively enrolled onto our ongoing neoadjuvant multimodality protocol from October 1996 to February 1999 remained inoperable after induction treatment. Three cycles of cisplatin/etoposide (PE) were followed by hyperfractionated accelerated radiotherapy (HF-RTx: 1.5 Gy bid up to a total dose of 45 Gy in 3 weeks) concurrent with one cycle of PE. Definitive local treatment was completed with a small volume boost of 20 Gy (qd), adding up to a total dose of 65 Gy to the primary. Patients were routinely offered prophylactic cranial irradiation (PCI; 30 Gy; 2 Gy qd). RESULTS: Overall toxicity of the definitive CTx/RTx protocol-the main endpoint of this investigation-turned out to be acceptable (oesophagitis grade 3/4: 6/4 patients; pneumonitis grade 3/4: 0/1 patients; no treatment-related deaths). Actuarial survival at 2 years was 31% with a loco-regional control rate of 21%. CONCLUSIONS: This regimen turned out to be feasible with acceptable toxicity and will serve as a reference arm in a planned randomised trial in stage IIIB NSCLC, testing the value of surgery in this setting: preoperative induction CTx/RTx followed by surgery versus definitive CTx/RTx.

The role of prophylactic cranial irradiation in the treatment of lung cancer.

Patients with lung cancer face concurrent risks of their disease by local, regional as well as distant failure. The brain is one of the major sites of distant relapse and the prevention of cerebral metastasis has therefore gained rising interest. A recent meta-analysis has confirmed the benefit of prophylactic cranial irradiation in patients with limited disease small-cell lung cancer in complete remission following induction therapy. In non-small-cell lung cancer, aggressive multimodality therapy regimens including surgery have achieved locoregional control rates of 50% and higher. In these patient groups the relatively high incidence of brain relapses as a site of first failure causes substantial morbidity and worsens the prognosis. Given the proven efficacy of prophylactic cranial irradiation (PCI) to prevent metastases to the brain, the introduction of PCI into the treatment of non-small cell lung cancer in the curative setting seems promising.

Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice.

PURPOSE: The effect of recombinant human erythropoietin (Epo) on the radiosensitivity of human tumour xenografts growing in anaemic nude mice was studied. METHODS AND MATERIALS: Anaemia was induced by total body irradiation (TBI) of mice prior to tumour transplantation. The development of anaemia was prevented by Epo (1000 U/kg s.c.) given 3 times weekly starting 2 weeks prior to TBI (5 Gy). Epo treatment did not influence the growth rate of the tumours, which were transplanted into the subcutis of the hind leg of mice. Thirteen days after TBI (tumour volume of approx. 40 mm3), a single-dose irradiation (12 Gy) of the tumour was performed resulting in a growth delay with subsequent regrowth of the tumours. RESULTS: In Epo-treated animals the tumour growth delay was significantly longer compared to anaemic mice. However, the radiosensitivity of tumours in non-anaemic animals' (non-Epo-treated) tumours could not fully be restored. CONCLUSION: These data give evidence for restored radiosensitivity after correction of anaemia with Epo.