Rita Engenhart-Cabillic

Phase III Comparison of Preoperative Chemotherapy Compared With Chemoradiotherapy in Patients With Locally Advanced Adenocarcinoma of the Esophagogastric Junction

PURPOSE Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown. PATIENTS AND METHODS Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual. RESULTS The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26). CONCLUSION Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

Adjuvant Radiotherapy Versus Wait-and-See After Radical Prostatectomy: 10-year Follow-up of the ARO 96–02/AUO AP 09/95 Trial

BACKGROUND Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy. OBJECTIVE To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study. DESIGN, SETTING, AND PARTICIPANTS After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)--that is, 159 WS plus 148 ART men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease. RESULTS AND LIMITATIONS The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred. CONCLUSIONS Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe. PATIENT SUMMARY Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?

PURPOSE To compare retrospectively radiotherapy with neutrons, photons, and a photon/neutron mixed beam in patients with advanced adenoid cystic carcinoma of the head and neck. Local control, survival, distant failure, and complications were analyzed. MATERIALS AND METHODS Between 1983 and 1995, 75 patients with inoperable, recurrent, or incompletely resected adenoid cystic carcinoma of the head and neck received radiotherapy that consisted of either fast 14.1 MV DT neutrons (median dose 16 neutron Gy), linac-based photon irradiation (median dose 64 photon Gy), or both (median dose 8 neutron Gy and 32 photon Gy). Follow-up ranged from 1 to 160 months (median 51 months), and the surviving patients had a minimum follow-up of 3 years at the time of analysis. RESULTS The actuarial 5-year local control was 75% for neutrons, and 32% for both mixed beam and photons (P = 0.015, log-rank). This advantage for neutrons in local control was not transferred to significant differences in survival (P > 0.1). The survival is dictated by the tumor diseases due to distant metastases occurring in 29 (39%) of the 75 patients. Positive lymph nodes were the only significant factor (P = 0.001) associated with the development of distant metastases although negative lymph nodes did not predict absence of distant metastases, but predicted a delay of occurrence. In multivariate analysis postoperative radiotherapy (P = 0.003) and small tumor size (P = 0.01) were associated with high local control, while primary therapy (P = 0.006) and negative lymph nodes (P = 0.01) were associated with longer survival. While acute toxicity was similar in all three radiotherapy groups, severe late grade 3 and 4 toxicity tended to be more prevalent (P > 0.1) with neutrons (19%) than with mixed beam (10%) and photons (4%). CONCLUSION Fast neutron radiotherapy provides higher local control rates than a mixed beam and photons in advanced, recurrent or not completely resected adenoid cystic carcinoma of the major and minor salivary glands. Neutron radiotherapy can be recommended in patients with bad prognosis with gross residual disease (R2), with unresectable tumors, or inoperable tumors. The type of radiation does not impact survival, which is dominated by the high number of distant metastases.

Metastasis: the seed and soil theory gains identity

The metastatic spread of tumor cells to distant sites represents the major cause of cancer-related deaths. Cancer metastasis involves a series of complex interactions between tumor cells and microenvironment that influence its biological effectiveness and facilitate tumor cell arrest to distant organs. More than a century since Paget developed the theory of seed and soil, the enigma of tissue specificity observed in metastatic colonization of tumor cells begins to unfold itself. The advent of new technologies has led to the discovery of novel molecules and pathways that confer metastasis-associated properties to the cancer cells, mediating organ specificity and unique genetic signatures have been developed using microarray studies. Future clinical studies and new antimetastatic compounds aiming to improve survival of patients with metastasis will most probably be based on these signatures. This review summarizes the plethora of old and new molecules that are strongly correlated with organ-specific metastases and which provide now an identity to the theory of seed and soil.

Involved-Node Radiotherapy in Early-Stage Hodgkin’s Lymphoma

Background and Purpose:Radiotherapy of Hodgkin’s lymphoma has evolved from extended-field to involved-field (IF) radiotherapy reducing toxicity whilst maintaining high cure rates. Recent publications recommend further reduction in the radiation field to involved-node (IN) radiotherapy; however, this concept has never been tested in a randomized trial. The German Hodgkin Study Group aims to compare it with standard IF radiotherapy in their future HD17 trial.Patients and Methods:All patients must be examined by the radiation oncologist before the start of chemotherapy. At that time, patients must have complete staging CT scans. For patients with IN radiotherapy, a radiation planning CT before and after chemotherapy with patients in the treatment position is recommended. Fusion techniques, allowing the overlapping of the pre- and postchemotherapy CT scans, should be used. Usage of PET-CT scans with patients in the treatment position is recommended, whenever possible.Results:The clinical target volume encompasses the initial volume of the lymph node(s) before chemotherapy and incorporates the initial location and extent of the disease taking the displacement of the normal tissues into account. The margin of the planning target volume should be 2 cm in axial and 3 cm in craniocaudal direction. If necessary, it can be reduced to 1–1.5 cm. To minimize lung and cardiac toxicity, the target definition in the mediastinum is different.Conclusion:The concept of IN radiotherapy has been proposed as a means to further improve the therapeutic ratio by reducing the risk of radiation-induced toxicity, including second malignancies. Field sizes will further decrease compared to IF radiotherapy.Hintergrund und Ziel:Die Strahlenbehandlung des Hodgkin-Lymphoms entwickelte sich von der Extended-Field- zur Involved-Field-(IF-)Radiotherapie bei anhaltend hohen Heilungsraten. Kürzlich erschienene Publikationen empfehlen die weitere Reduktion der Bestrahlungsvolumina hin zur Involved-Node-(IN-)Radiotherapie. Allerdings ist dieses Vorgehen bislang nicht innerhalb randomisierter klinischer Studien geprüft worden. Daher wird die Deutsche Hodgkin-Lymphom-Studiengruppe in der zukünftigen HD17-Studie die IF- mit der IN-Radiotherapie vergleichen (Abbildung 1).Patienten und Methodik:Alle Studienpatienten müssen vor dem Start der Chemotherapie vom Radioonkologen untersucht werden. Zu diesem Zeitpunkt muss ein vollständiges bildgebendes Staging vorliegen. Für Patienten, die eine IN-Radiotherapie erhalten, wird ein Planungs-CT in Bestrahlungsposition vor und nach der Chemotherapie empfohlen. Die Überlagerung (Matching) des prätherapeutischen Planungs-CT mit dem Planungs-CT nach Chemotherapie ist wünschenswert. Steht eine prätherapeutische PET-CT zur Verfügung, sollte diese in die Zielvolumendefinition im Rahmen der IN-Radiotherapie einbezogen werden.Ergebnisse:Das klinische Zielvolumen (CTV) umfasst die initial als befallen gewerteten Lymphknoten. Es berücksichtigt die initiale Ausdehnung der Erkrankung inklusive der Verlagerung von Normalgeweben. Der Sicherheitssaum des Planungszielvolumens (PTV) sollte in axialer Ausdehnung 2 cm, in kraniokaudaler Ausrichtung 3 cm betragen (Abbildung 2). Er kann in axialer Ausdehnung auf 1–1,5 cm reduziert werden, um Organtoxizitäten möglichst gering zu halten. Um die pulmonale und kardiale Toxizität gering zu halten, wird im Mediastinum ein anderes Vorgehen empfohlen (Abbildung 3).Schlussfolgerung:Das Konzept der IN-Radiotherapie soll das Auftreten radiogener Toxizitäten inklusive Zweitneoplasien weiter minimieren. Die Feldgrößen werden im Vergleich zur IF-Radiotherapie weiter abnehmen (Abbildung 4).

Hypofractionated Stereotactic Reirradiation of Recurrent Glioblastomas

Background and Purpose:Recurrent malignant gliomas have a very poor prognosis. This trial aimed to evaluate the benefits of reirradiation in case of recurrent glioblastoma multiforme (GBM) using hypofractionated stereotactic radiotherapy (hFSRT) after primary high-dose percutaneous irradiation.Patients and Methods:Between 1998 and 2008, 53 patients with recurrent GBM were treated by hFSRT based on CT and MR imaging. At the time of recurrence, a median total dose of 30 Gy (20–60 Gy) was delivered in median fractions of 3 Gy/day (2–5Gy).Results:The reirradiation was well tolerated (no acute or late toxicity > grade 2), despite the relatively large median tumor volume (35.01 ml). Karnofsky Performance Score was the strongest predictor for survival after reirradiation (p = 0.0159). Tumor volume (p = 0.4690), patient age (p = 0.4301), second operation (p = 0.6930), and chemotherapy (p = 0.1466) at the time of reirradiation did not affect survival. After hFSRT, the median survival was 9 months, and the 1-year progression-free survival (PFS) amounted to 22%.The median overall survival from initial diagnosis was 27 months. 1-year survival from first diagnosis was 83%, 2-year survival 45%. The median time to progression from the end of initial irradiation to recurrence was 12 months. 1-year PFS before reirradiation was 40%.Conclusion:hFSRT as a secondary treatment of recurrent GBM is a feasible and effective treatment option. Only minor side effects were observed with prolonged life expectancy of 9 months.Hintergrund und Ziel:Die Prognose im Rezidivfall eines malignen Glioms ist schlecht. Diese Studie hatte zum Ziel, den Stellenwert einer hypofraktionierten stereotaktischen Rebestrahlung (hFSRT) bei rezidiviertem Glioblastom (GBM) nach perkutaner hochkonformaler Radiotherapie zu evaluieren.Patienten und Methodik:Zwischen 1998 und 2008 wurden 53 Patienten mit einem rezidivierten GBM stereotaktisch rebestrahlt. Die mediane Gesamtherddosis betrug 30 Gy (20–60 Gy), die mediane Einzelherddosis 3 Gy/Tag (2–5 Gy).Ergebnisse:Trotz großer Tumorvolumen von median 35,01 ml wurde nach hFSRT keine Akut- oder Spättoxizität > Grad 2 beobachtet. Der Karnofsky-Perfomance-Score war der einzige determinante Faktor hinsichtlich des Gesamtüberlebens nach hFSRT (p = 0,0159). Hingegen beeinflussten Tumorvolumen (p = 0,4690), Patientenalter (p = 0,4301), Zweitoperationen (p = 0,6930) oder Chemotherapie (p = 0,1466) das Gesamtüberleben nach hFSRT nicht. Das mediane Gesamtüberleben nach hFSRT betrug 9 Monate, das progressionsfreie 1-Jahres-Überleben (PFS) 22%. Das mediane Gesamtüberleben nach initialer Diagnosestellung eines GBM lag bei 27 Monaten, das 1- bzw. 2-Jahres-Gesamtüberleben bei 83% bzw. 45%. Der mediane Zeitpunkt bis zum ersten Rezidiv nach initialer Bestrahlung betrug 12 Monate, das 1-Jahres-PFS nach initialer Bestrahlung bis zum ersten Rezidiv 40%.Schlussfolgerung:Die hFSRT ist eine geeignete und effektive Behandlungsoption für rezidivierte GBM. Das mediane Gesamtüberleben nach hFSRT konnte bei geringer Nebenwirkungsrate um 9 Monate verlängert werden.

Ion beam radiobiology and cancer: Time to update ourselves

High-energy protons and carbon ions exhibit an inverse dose profile allowing for increased energy deposition with penetration depth. Additionally, heavier ions like carbon beams have the advantage of a markedly increased biological effectiveness characterized by enhanced ionization density in the individual tracks of the heavy particles, where DNA damage becomes clustered and therefore more difficult to repair, but is restricted to the end of their range. These superior biophysical and biological profiles of particle beams over conventional radiotherapy permit more precise dose localization and make them highly attractive for treating anatomically complex and radioresistant malignant tumors but without increasing the severe side effects in the normal tissue. More than half a century since Wilson proposed their use in cancer therapy, the effects of particle beams have been extensively investigated and the biological complexity of particle beam irradiation begins to unfold itself. The goal of this review is to provide an as comprehensive and up-to-date summary as possible of the different radiobiological aspects of particle beams for effective application in cancer treatment.

Stereotactic radiotherapy of meningiomas: symptomatology, acute and late toxicity.

Background and Purpose:Stereotactic radiosurgery (SRS) is well established in the treatment of skull base meningiomas, but this therapy approach is limited to small tumors only. The fractionated stereotactic radiotherapy (SRT) offers an alternative treatment option. This study aims at local control, symptomatology, and toxicity.Patients and Methods:Between 1997–2003, 224 patients were treated with SRT (n = 183), hypofractionated SRT (n = 30), and SRS (n = 11). 95/224 were treated with SRT/SRS alone. 129/224 patients underwent previous operations. Freedom from progression and overall survival, toxicity, and symptomatology were evaluated systematically. Additionally, tumor volume (TV) shrinkage was analyzed three-dimensionally within the planning system.Results:The median follow-up was 36 months (range, 12–100 months). Overall survival and freedom from progression for 5 years were 92.9% and 96.9%. Quantitative TV reduction was 26.2% and 30.3% 12 and 18 months after SRT/SRS (p < 0.0001). 95.9% of the patients improved their symptoms or were stable. Clinically significant acute toxicity (CTC III°) was rarely seen (2.5%). Clinically significant late morbidity (III°–IV°) or new cranial nerve palsies did not occur.Conclusion:SRT offers an additional treatment option of high efficacy with only few side effects. In the case of large tumor size (> 4 ml) and adjacent critical structures (< 2 mm), SRT is highly recommended.Hintergrund und Ziel:Die stereotaktische Radiochirurgie (SRS) ist in der Behandlung von Schädelbasismeningeomen fest etabliert. Ihr Einsatz ist jedoch auf kleine Tumoren begrenzt. Die stereotaktisch fraktionierte Radiotherapie (SRT) bietet eine Behandlungsalternative an. Ziel dieser Untersuchung war, die lokale Kontrolle, Symptomatologie und die Toxizität zu evaluieren.Patienten und Methodik:Zwischen 1997 und 2003 wurden 224 Patienten stereotaktisch fraktioniert (n = 183), stereotaktisch hypofraktioniert (n = 30) und radiochirurgisch (n = 11) behandelt. 95/224 wurden primär bestrahlt, 129/224 waren voroperiert. Progressionsfreies und Gesamtüberleben, Toxizität und Symptomatologie wurden systematisch erfasst. Zusätzlich wurde die Tumorvolumenreduktion quantitativ mit dem Planungssystem ermittelt.Ergebnisse:Die mediane Nachbeobachtungszeit betrug 36 Monate (12–100 Monate). Das 5-Jahres-Gesamtüberleben lag bei 92,9%, das progressionsfreie Überleben bei 96,9%. Die quantitative Tumorvolumenreduktion betrug 12 und 18 Monate nach SRT/SRS 26,2% und 30,3% (p < 0,0001). Bei 95,9% der Patienten waren die Symptome kontrolliert oder gebessert. Klinisch signifikante Akuttoxizität (CTC III°) trat selten auf (2,5%). Klinisch signifikante Spättoxizität (III°–IV°) oder neu aufgetretene neurologische Defizite wurden nicht beobachtet.Schlussfolgerung:Die SRT ist eine effektive und nebenwirkungsarme Therapie. Im Fall eines großen Tumorvolumens (> 4 ml) und nahegelegener Risikostrukturen (< 2 mm) ist eine SRT empfehlenswert.

Expectations and quality of life of cancer patients undergoing radiotherapy.

Summary Expectations, real or false, affect the way patients respond to their illnesses. We assessed therapy-related expectations in relation to global quality of life in 55 cancer patients before and after radiotherapy. Factor analysis indicated that therapy-related expectations come into three broad categories—pain/emotional control, healing and tumour/symptom control. 35 patients expected ‘healing’ even though curative treatment was intended in only 19 and all patients had been fully informed. The expectation of healing was associated with high quality of life, and the same was true of perception of healing after radiotherapy. In the group as a whole, quality of life was little altered by radiotherapy, but it became substantially worse in those patients who had expected healing but perceived that this had failed, even though physician-assessed Karnofsky status did not change. These findings indicate that the expectation of healing, in cancer patients, is a component of a good global quality of life, whereas more limited expectations (pain control, tumour control) relate to lower quality of life. Patients’ expectations deserve further study as a novel approach to improving care.

Decreased mitochondrial DNA content in blood samples of patients with stage I breast cancer

BackgroundAlterations of mitochondrial DNA (mtDNA) have been implicated in carcinogenesis. We developed an accurate multiplex quantitative real-time PCR for synchronized determination of mtDNA and nuclear DNA (nDNA). We sought to investigate whether mtDNA content in the peripheral blood of breast cancer patients is associated with clinical and pathological parameters.MethodsPeripheral blood samples were collected from 60 patients with breast cancer and 51 age-matched healthy individuals as control. DNA was extracted from peripheral blood for the quantification of mtDNA and nDNA, using a one-step multiplex real-time PCR. A FAM labeled MGB probe and primers were used to amplify the mtDNA sequence of the ATP 8 gene, and a VIC labeled MGB probe and primers were employed to amplify the glyceraldehyde-3-phosphate-dehydrogenase gene. mtDNA content was correlated with tumor stage, menstruation status, and age of patients as well as lymph node status and the expression of estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu protein.ResultsThe content of mtDNA in stage I breast cancer patients was significantly lower than in other stages (overall P = 0.023). Reduced mtDNA was found often in post menopausal cancer group (P = 0.024). No difference in mtDNA content, in regards to age (p = 0.564), lymph node involvement (p = 0.673), ER (p = 0.877), PR (p = 0.763), and Her-2/neu expression (p = 0.335), was observed.ConclusionEarly detection of breast cancer has proved difficult and current detection methods are inadequate. In the present study, decreased mtDNA content in the peripheral blood of patients with breast cancer was strongly associated with stage I. The use of mtDNA may have diagnostic value and further studies are required to validate it as a potential biomarker for early detection of breast cancer.