Franziska Eckert

Re-surgery and chest wall re-irradiation for recurrent breast cancer - a second curative approach

BackgroundRepeat radiation is a rarely used treatment strategy that must be performed with caution. The efficacy and toxicity of a second curative radiotherapy series was investigated in cases of recurrent breast cancer.MethodsForty-two patients treated from 1993 to 2003 with resection (n = 30) and postoperative re-irradiation or definitive re-irradiation (n = 12) for recurrent breast cancer were enrolled in the study. Concurrent hyperthermia was performed in 29 patients. The median age was 57 years. The median pre-radiation exposure was 54Gy. Re-irradiation was conventionally fractionated to a median total dose of 60Gy.ResultsAfter a median follow-up of 41 months (range 3-92 months) higher graded late toxicity > G3 according to CTC 3.0 and LENT-SOMA was not observed. The estimated 5-year local control rate reached 62%. The estimated 5-year overall survival rate was 59%. Significantly inferior survival was associated with recurrence within two years (40 vs. 71%, p < ([0-9]).01) and presence of macroscopic tumour load (24 vs. 75%, p = 0.03).ConclusionsRepeat radiotherapy for recurrent breast cancer with total radiation doses of 60 Gy and the addition of hyperthermia in the majority of patients was feasible, with acceptable late morbidity and improved prognosis, particularly in patients with previous resection of recurrent tumours.

Ionizing radiation, ion transports, and radioresistance of cancer cells

The standard treatment of many tumor entities comprises fractionated radiation therapy which applies ionizing radiation to the tumor-bearing target volume. Ionizing radiation causes double-strand breaks in the DNA backbone that result in cell death if the number of DNA double-strand breaks exceeds the DNA repair capacity of the tumor cell. Ionizing radiation reportedly does not only act on the DNA in the nucleus but also on the plasma membrane. In particular, ionizing radiation-induced modifications of ion channels and transporters have been reported. Importantly, these altered transports seem to contribute to the survival of the irradiated tumor cells. The present review article summarizes our current knowledge on the underlying mechanisms and introduces strategies to radiosensitize tumor cells by targeting plasma membrane ion transports.

Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer

BackgroundAs dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy.MethodsAcute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions.ResultsFrom eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks.ConclusionsThis prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. Trial registration: German Clinical Trials Register DRKS00003273.

Small cell carcinoma of vulva: curative multimodal treatment in face of resistance to initial standard chemotherapy.

Background and Purpose:Extrapulmonary small cell carcinoma (EPSCC) is a rare disease, which has a slightly better prognosis than small cell lung cancer, but still dismal. Gynecologic small cell malignancies tend to show a better survival than similar histologies of other regions. However, of five reported cases of vulvar manifestation only one patient was disease-free at the time of publication with limited follow-up.Case Report:The authors describe a case of locally advanced small cell vulva carcinoma infiltrating the anal sphincter and urethra with spread to inguinal lymph nodes treated by radiochemotherapy and regional hyperthermia. After three cycles of carboplatin/ etoposide, computed tomography and magnetic resonance imaging indicated only little regressive transformations but overall stable disease. Surgical options were excluded. Therefore, curative radiotherapy to a total dose of > 65 Gy to macroscopic tumor, chemotherapy with cisplatin weekly, and regional hyperthermia were performed. Acute severe toxicity was limited to skin reactions. Despite the disadvantageous situation with inguinal lymph node metastases and chemoresistance, the multimodal therapy yielded a 5-year disease-free survival.Conclusion:Thus, the trimodal regimen of radiochemotherapy plus regional hyperthermia offered a curative chance in spite of resistance to the standard chemotherapy for irresectable, locally advanced small cell carcinoma of the vulva. Therefore, this approach merits further evaluation for limited disease of EPSCC.ZusammenfassungHintergrund und Ziel:Extrapulmonale kleinzellige Karzinome (EPSCC) sind eine seltene Tumorentität, die eine etwas bessere Prognose als kleinzellige Bronchialkarzinome besitzt. Innerhalb dieser Entität zeigen gynäkologische Tumoren ein etwas besseres Überleben. Allerdings war von den fünf beschriebenen Fällen kleinzelliger Vulvakarzinome zum Zeitpunkt der Auswertung nur eine Patientin mit kurzer Nachsorge tumorfrei.Fallbericht:Die Autoren beschreiben den Fall einer Patientin mit lokal fortgeschrittenem kleinzelligen Vulvakarzinom, welches den Sphincter ani, die Urethra und die inguinalen Lymphknoten involvierte. Nach der initialen Chemotherapie mit Carboplatin/ Etoposid zeigten sich leichte regressive Veränderungen, aber messtechnisch keine relevante Größenabnahme im Sinne einer „stabilen Erkrankung“. Operative Behandlungsmöglichkeiten bestanden nicht. Daher wurde als kurative Modalität eine definitive Radiochemotherapie mit > 65 Gy auf den makroskopischen Tumor mit simultaner wöchentlicher Cisplatingabe plus lokoregionaler Tiefenhyperthermie durchgeführt (Abbildung 1). Höhergradige Akuttoxizitäten beschränkten sich auf die Haut. Trotz der ungünstigen Ausgangssituation mit lymphogener Metastasierung und fehlendem Ansprechen auf die initiale Chemotherapie konnte mit der multimodalen Therapie ein krankheitsfreies Überleben von 5 Jahren erreicht werden (Abbildung 2).Schlussfolgerung:Die trimodale Therapie mit Radiotherapie, Chemotherapie und Hyperthermie eröffnete trotz der initialen Resistenz gegenüber der Standardchemotherapie einen kurativen Ansatz bei einem inoperablen, lokal fortgeschrittenen kleinzelligen Vulvakarzinom. Dieses Ergebnis kann einen Ausgangspunkt für die Diskussion der Therapieoptionen von lokal begrenzten EPSCC bilden.

Definitive radiotherapy and Single-Agent radiosensitizing Ifosfamide in Patients with localized, irresectable Soft Tissue Sarcoma: A retrospective analysis

Background and PurposeStandard therapy for soft-tissue sarcomas remains complete resection. For primary radiotherapy local control rates of 30-45% have been reported. We analyzed retrospectively 11 cases of radiochemotherapy with single-agent ifosfamide in patients with macroscopic soft-tissue sarcomas.Patients and MethodsThe patients were treated in irresectable high risk situations. Radiation therapy was performed with median 60 Gy. During the first and fifth week the concomitant chemotherapy with ifosfamide was added. Two patients received trimodal therapy with additional regional hyperthermia.ResultsThe therapy was completed in 73% of the patients. Average local control time was 91 months, median disease-free-survival/overall-survival was 8/26 months. Five-year rates for local control/disease free survival/overall survival were 70%/34%/34%. The limited prognosis is mainly caused by systemic treatment failure.ConclusionsThe data strongly suggest a better outcome of radiochemotherapy with ifosfamide compared to radiotherapy alone and radiotherapy in combination with other radiosensitizers.

Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data

Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

Role of ion channels in ionizing radiation-induced cell death

Neoadjuvant, adjuvant or definitive fractionated radiation therapy are implemented in first line anti-cancer treatment regimens of many tumor entities. Ionizing radiation kills the tumor cells mainly by causing double strand breaks of their DNA through formation of intermediate radicals. Survival of the tumor cells depends on both, their capacity of oxidative defense and their efficacy of DNA repair. By damaging the targeted cells, ionizing radiation triggers a plethora of stress responses. Among those is the modulation of ion channels such as Ca2+-activated K+ channels or Ca2+-permeable nonselective cation channels belonging to the super-family of transient receptor potential channels. Radiogenic activation of these channels may contribute to radiogenic cell death as well as to DNA repair, glucose fueling, radiogenic hypermigration or lowering of the oxidative stress burden. The present review article introduces these channels and summarizes our current knowledge on the mechanisms underlying radiogenic ion channel modulation. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Small Cell Carcinoma of Vulva

Background and Purpose:Extrapulmonary small cell carcinoma (EPSCC) is a rare disease, which has a slightly better prognosis than small cell lung cancer, but still dismal. Gynecologic small cell malignancies tend to show a better survival than similar histologies of other regions. However, of five reported cases of vulvar manifestation only one patient was disease-free at the time of publication with limited follow-up.Case Report:The authors describe a case of locally advanced small cell vulva carcinoma infiltrating the anal sphincter and urethra with spread to inguinal lymph nodes treated by radiochemotherapy and regional hyperthermia. After three cycles of carboplatin/ etoposide, computed tomography and magnetic resonance imaging indicated only little regressive transformations but overall stable disease. Surgical options were excluded. Therefore, curative radiotherapy to a total dose of > 65 Gy to macroscopic tumor, chemotherapy with cisplatin weekly, and regional hyperthermia were performed. Acute severe toxicity was limited to skin reactions. Despite the disadvantageous situation with inguinal lymph node metastases and chemoresistance, the multimodal therapy yielded a 5-year disease-free survival.Conclusion:Thus, the trimodal regimen of radiochemotherapy plus regional hyperthermia offered a curative chance in spite of resistance to the standard chemotherapy for irresectable, locally advanced small cell carcinoma of the vulva. Therefore, this approach merits further evaluation for limited disease of EPSCC.ZusammenfassungHintergrund und Ziel:Extrapulmonale kleinzellige Karzinome (EPSCC) sind eine seltene Tumorentität, die eine etwas bessere Prognose als kleinzellige Bronchialkarzinome besitzt. Innerhalb dieser Entität zeigen gynäkologische Tumoren ein etwas besseres Überleben. Allerdings war von den fünf beschriebenen Fällen kleinzelliger Vulvakarzinome zum Zeitpunkt der Auswertung nur eine Patientin mit kurzer Nachsorge tumorfrei.Fallbericht:Die Autoren beschreiben den Fall einer Patientin mit lokal fortgeschrittenem kleinzelligen Vulvakarzinom, welches den Sphincter ani, die Urethra und die inguinalen Lymphknoten involvierte. Nach der initialen Chemotherapie mit Carboplatin/ Etoposid zeigten sich leichte regressive Veränderungen, aber messtechnisch keine relevante Größenabnahme im Sinne einer „stabilen Erkrankung“. Operative Behandlungsmöglichkeiten bestanden nicht. Daher wurde als kurative Modalität eine definitive Radiochemotherapie mit > 65 Gy auf den makroskopischen Tumor mit simultaner wöchentlicher Cisplatingabe plus lokoregionaler Tiefenhyperthermie durchgeführt (Abbildung 1). Höhergradige Akuttoxizitäten beschränkten sich auf die Haut. Trotz der ungünstigen Ausgangssituation mit lymphogener Metastasierung und fehlendem Ansprechen auf die initiale Chemotherapie konnte mit der multimodalen Therapie ein krankheitsfreies Überleben von 5 Jahren erreicht werden (Abbildung 2).Schlussfolgerung:Die trimodale Therapie mit Radiotherapie, Chemotherapie und Hyperthermie eröffnete trotz der initialen Resistenz gegenüber der Standardchemotherapie einen kurativen Ansatz bei einem inoperablen, lokal fortgeschrittenen kleinzelligen Vulvakarzinom. Dieses Ergebnis kann einen Ausgangspunkt für die Diskussion der Therapieoptionen von lokal begrenzten EPSCC bilden.

Ion Channels in Brain Metastasis

Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation.

SCLC extensive disease – treatment guidance by extent or/and biology of response?

In extensive disease of small cell lung cancer a doubling of the one-year-survival rate was reported in August 2007 by prophylactic cranial irradiation applied to patients who experienced any response to initial chemotherapy. We discuss the treatment concept of extensive disease in the face of the latest results and older studies with additional thoracic irradiation in this subgroup. A randomized trial with prophylactic cranial irradiation published in 1999 demonstrated an improvement of 5-year-overall-survival for complete responders (at least at distant levels) receiving additional thoracic radiochemotherapy compared to chemotherapy alone (9.1% vs. 3.7%). But, these results were almost neglected and thoracic radiotherapy was not further investigated for good responders of extensive disease. However, in the light of current advances by prophylactic cranial irradiation these findings are noteworthy on all accounts. Considering both, a possible interpretation of these data could be a survival benefit of local control by simultaneous thoracic radiochemotherapy in the case of improved distant control due to chemotherapy and prophylactic cranial irradiation. Furthermore the question arises whether the tumor biology indicated by the response to chemotherapy should be integrated in the present classification.