Martin Hellriegel

Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to [D-Lys6]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors.Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study

BACKGROUND Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.BACKGROUND Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): A subanalysis of the AGO ROBOT study

Background:Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure.Methods:Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS).Results:For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66–2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06–3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22–4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15–3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation.Conclusion:Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Modern therapy concepts for endometrial cancer

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.

Moderne Konzepte in der Behandlung des Endometriumkarzinoms

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.

Propensity Scoring after Multiple Imputation in a Retrospective Study on Adjuvant Radiation Therapy in Lymph-Node Positive Vulvar Cancer

Propensity scoring (PS) is an established tool to account for measured confounding in non-randomized studies. These methods are sensitive to missing values, which are a common problem in observational data. The combination of multiple imputation of missing values and different propensity scoring techniques is addressed in this work. For a sample of lymph node-positive vulvar cancer patients, we re-analyze associations between the application of radiotherapy and disease-related and non-related survival. Inverse-probability-of-treatment-weighting (IPTW) and PS stratification are applied after multiple imputation by chained equation (MICE). Methodological issues are described in detail. Interpretation of the results and methodological limitations are discussed.

Palliativmedizinische Konzepte beim Ovarialkarzinom

ZusammenfassungTrotz aller therapeutischen Fortschritte versterben die meisten Ovarialkarzinompatientinnen an dieser Erkrankung. Das Behandlungsteam muss rechtzeitig den Einsatz wenig bzw. nicht wirksamer Chemotherapien zurücknehmen und stattdessen professionell die sehr beeinträchtigenden Symptome der fortschreitenden Erkrankung hinauszögern bzw. behandeln. Zu diesen gehören u. a. Obstipation, Darmobstruktion, Erbrechen, Tenesmen, Anorexie, Aszites, Ödeme, Angst, Depression und Schmerzen. Eine enge und frühzeitige Kooperation zwischen gynäkologischen Onkologen und Palliativmedizinern ist hierfür die Voraussetzung.AbstractIn spite of all recent advances in the treatment of patients with ovarian cancer, most of these women ultimately die of the disease. The treatment team must revoke the treatment aims in a timely manner and avoid chemotherapy with limited or non-existing efficacy to improve the patient quality of life. Instead they should put the focus on the professional treatment of the impairing symptoms of the progressive disease, including obstipation, bowel obstruction, vomiting, tenesmus, anorexia, ascites, edema, fear, depression and pain. An early and close cooperation between gynecological oncologists and palliative care specialists is a prerequisite.

Palliativmedizinische Konzepte beim Mammakarzinom@@@Palliative medical concepts in breast cancer

ZusammenfassungDie Erstellung eines adäquaten palliativmedizinischen Konzepts beim metastasierten Mammakarzinom stellt höchste Anforderungen an die onkologisch tätigen Behandlungsteams und an die Patientin. Erstes Ziel ist der Erhalt der Lebensqualität. Es gilt, Symptome möglichst früh zu erfassen, nebenwirkungsarm und der Situation angepasst zu lindern und präventiv Komplikationen zu verhindern. Therapiestrategien müssen stadiengerecht in enger Kooperation interdisziplinär konzipiert werden, multimodal und flexibel sein. Im Entscheidungsprozess muss die Patientin von Anfang an aktiv eingebunden sein, um gemeinsam Therapieziele zu definieren. Psychosoziale, physiotherapeutische, pflegerische und komplementäre Maßnahmen müssen der Patientin aufgezeigt werden. Ansprechen, Wirkungen und Nebenwirkungen der Therapien, aber auch zuwartendes Verhalten müssen in regelmäßigen Abständen evaluiert werden. Kumulative Toxizitäten, abnehmende Wirksamkeiten und Resistenzen gegenüber medikamentösen Therapien sind im Verlauf zu berücksichtigen.AbstractThe construction of an adequate palliative medical concept in treating metastasized advanced breast cancer places highest demands on both the treating oncological team and the patient. The first target is to preserve the quality of life. For this it is necessary to recognize the symptoms as early as possible in order to alleviate side effects adapted to the situation and to prophylactically prevent complications. The strategies for therapy must be stage-dependent and designed in a close interdisciplinary cooperation and multimodal while being flexible. The patient must be actively involved in the decision-making process from the beginning in order to jointly define the aims of therapy. Psychosocial, physiotherapeutic, nursing and complementary measures must be explained to the patient. The response to, effects and side effects of treatment and also patiently waiting behavior must be evaluated at regular intervals. Cumulative toxicity, decreasing effectiveness and resistance to medication therapy must be taken into consideration during the course of therapy.

Moderne Konzepte in der Behandlung des Endometriumkarzinoms@@@Modern therapy concepts for endometrial cancer

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.