Long-term survival in patients with brain metastases-clinical characterization of a rare scenario.

PURPOSE: This study aimed to assess clinical, treatment, and prognostic features in patients with brain metastases (BM) from solid tumors achieving long-term survival (LTS). Further, the accuracy of diagnosis-specific Graded Prognostic Assessment scores (ds-GPA) to predict LTS was evaluated. METHODS: Patients admitted for radiotherapy of BM between 2010 and 2020 at a large tertiary cancer center with survival of at least 3 years from diagnosis of BM were included. Patient, tumor, treatment characteristics and ds-GPA were compiled retrospectively. RESULTS: From a total of 1248 patients with BM, 61 (4.9%) survived ≥ 3 years. In 40 patients, detailed patient charts were available. Among LTS patients, median survival time from diagnosis of BM was 51.5 months. Most frequent primary tumors were lung cancer (45%), melanoma (20%), and breast cancer (17.5%). At the time of diagnosis of BM, 11/40 patients (27.5%) had oligometastatic disease. Estimated mean survival time based on ds-GPA was 19.7 months (in 8 cases estimated survival < 12 months). Resection followed by focal or whole-brain radiotherapy (WBRT) was often applied (60%), followed by primary stereotactic radiotherapy (SRT) (20%) or WBRT (20%). 80% of patients received systemic treatment, appearing particularly active in specifically altered non-small lung cancer (NSCLC), melanoma, and HER2-positive breast cancer. Karnofsky performance score (KPS) and the presence of oligometastatic disease at BM diagnosis were persisting prognostic factors in LTS patients. CONCLUSION: In this monocentric setting reflecting daily pattern of care, LTS with BM is heterogeneous and difficult to predict. Effective local treatment and modern systemic therapies often appear crucial for LTS. The impact of concomitant diseases and frailty is not clear.

[Skull base metastases with cranial nerve deficits : Clinical profile of a severe disease]. / Schädelbasismetastasen mit Hirnnervenaffektionen : Klinischer Steckbrief einer schwerwiegenden Erkrankung.

BACKGROUND AND PURPOSE: Skull base metastases are a severe complication of various malignant tumors. If cranial nerves are involved even small lesions can cause significant symptoms. Specific clinical characteristics like neurological symptoms, associated primary tumors, prognosis and optimal treatment are poorly defined and are systematically described in this article. METHODS: In a monocentric retrospective study patients with skull base metastases and cranial nerve deficits who received treatment between 2006 and 2018 were analyzed concerning clinical characteristics at initial diagnosis, treatment and course of the disease. RESULTS: In this study 45 patients with skull base metastases and cranial nerve deficits were included. The most frequent primary tumors were prostate cancer (27%), breast cancer (22%) and multiple myeloma (16%). The most involved cranial nerves were trigeminal nerve (42%), oculomomotor nerve (33%) and facial nerve (27%). Of the patients 84% had additional bone metastases outside the skull base. Dural infiltration or meningeal carcinomatosis were each observed in 13% of the patients. After radiotherapy cranial nerve deficits remained stable in 61% of all cases and in 22% symptoms improved. Median overall survival from treatment was 8 months (range 0.4-51 months). Patients with dose-escalated radiotherapy appeared to live longer (16.4 months vs. 4.7 months). This effect persisted in a multivariate analysis including the Karnofsky index, number of metastases, primary tumor and radiation dose (HR 0.37, p = 0.02). CONCLUSION: Skull base metastases with cranial nerve deficits are complex diseases with poor prognosis. Precise diagnosis and treatment are required. Further research is needed to improve treatment.

[Organ preservation in advanced laryngeal/hypopharyngeal carcinoma: lessons from the DeLOS-II trial]. / Organerhalt beim fortgeschrittenen Larynx­/Hypopharynxkarzinom: Erfahrungen aus der DELOS-II-Studie.

Patients with locoregionally advanced laryngeal and hypopharyngeal squamous cell carcinomas (LHSCC) comprise two broad groups: those who are candidates for functional larynx preservation (LP) with avoidance of ablative surgery and those who are not. Currently, treatment depends on the patient's needs and wishes, the experience and recommendation of the surgeon, the philosophy of the institution, etc. The milestone VA trial established non-surgical LP in advanced LHSCC in the 1990s using induction chemotherapy (IC) with PF (cisplatin, P, plus 5­fluorouracil, F) followed by irradiation (IC + RT) as an appropriate alternative treatment to total laryngectomy (TL). Even though the findings of the VA trial were verified by the EORTC 24891 trial, a debate persists regarding the best protocol for balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options for larynx preservation, only IC + RT or primary concurrent platin-based chemoradiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is exclusively recommended as the best curative protocol. With regards to long-term survival with functional organ preservation and persistently high failure rates, there is current discussion on the necessity of improving patient selection based on the current literature and the recently published data of the DeLOS-II trial.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1).

BACKGROUND: Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for locally advanced head and neck cancer. This phase II study investigated the effectivity of a split-dose TPF ICT before surgery for locally advanced resectable (stage III/IVA) oral and oropharyngeal cancer. PATIENTS AND METHODS: Patients received TPF split on two dosages on days 1 and 8 per cycle (30 mg/m2 docetaxel, 40 mg/m2 cisplatin, 2000 mg/m2 fluorouracil per week). Responders (reduction tumor volume ≥30% after first cycle) received three 3-week cycles and non-responders only one cycle before surgery and postoperative radio(chemo)therapy (RCT). The primary endpoint was progression-free survival rate after 24 months. Secondary endpoints were amongst others overall survival, histopathological response to ICT, toxicity, quality of life and swallowing function. RESULTS: Fifty-four patients (91% stage IVA, 87% male, 72% oropharyngeal cancer, 70% responders) were eligible for a per-protocol analysis. The progression-free survival rate after 24 months was 88.5% for responders and 60.6% for non-responders (P = 0.005). The overall survival rate after 24 months was 97.3% for responders and 73.7% for non-responders (P = 0.032). The rate of histopathological complete remission of the primary tumor was higher in responders (P = 0.015). High-risk classification for postoperative RCT was lower in responders (P < 0.0001). The most common grade 3+ adverse event was neutropenia in 26% of patients during ICT and mucositis in 13% during postoperative RCT. During treatment and follow-up quality of life and swallowing function was not different between responders and non-responders. CONCLUSION: Patients with oral and oropharyngeal cancer responding to split-dose TPF before surgery and postoperative RCT show good oncological results. The tri-modal treatment regime was well tolerated. ICT using tumor response as criterion for duration of ICT before surgery of oral and oropharyngeal cancer merits additional investigation in a phase III study. CLINICAL TRIAL NUMBER: NCT01108042.

[Head and Neck Cancer in Pregnancy - Recommendations for Diagnosis and Therapy With Case Report]. / Kopf-Hals-Krebs in der Schwangerschaft ­ Empfehlungen zu Diagnostik und Therapie mit Fallbericht.

Objective: The diagnosis of cancer in pregnancy is rare, but might become more relevant even for head and neck cancer patients due to a shift of age of primipara towards the last third of reproductive years. Unsureness exists about the risk and benefit of diagnostic and therapeutic cancer modalities for the unborn and established recommendations are still missing. But, according to recent data, even multimodal therapeutic approaches (e. g. surgery, radiation, chemotherapy) seem possible in face of pregnancy and should be traded against the risk of prematurity. Material and Methods: Our findings are discussed on the basis of a case report of a pregnant woman with advanced carcinoma of the outer ear canal and therapy options are formulated. Results: Sufficient performed diagnostic modalities do not reach imperilling uterus dosages. A growing number of case reports und studies did not detect any developmental disadvantage of children of prenatal exposed mothers by radiation or chemotherapy, whereas long-term impairments of premature infants are proven. Conclusion: In cancer in pregnancy, an immediate start of well-established therapy modalities like surgery and/or cisplatin-based chemoradiation seems to be possible without unjustifiable risks for the unborn.

Role of choline PET/CT in guiding target volume delineation for irradiation of prostate cancer.

Choline PET/CT has shown limitations for the detection of primary prostate cancer and nodal metastatic disease, mainly due to limited sensitivity and specificity. Conversely in the restaging of prostate cancer recurrence, choline PET/CT is a promising imaging modality for the detection of local regional and nodal recurrence with an impact on therapy management. This review highlights current literature on choline PET/CT for radiation treatment planning in primary and recurrent prostate cancer. Due to limited sensitivity and specificity in differentiating between benign and malignant prostatic tissues in primary prostate cancer, there is little enthusiasm for target volume delineation based on choline PET/CT. Irradiation planning for the treatment of single lymph node metastases on the basis of choline PET/CT is controversial due to its limited lesion-based sensitivity in primary nodal staging. In high-risk prostate cancer, choline PET/CT might diagnose lymph node metastases, which potentially can be included in the conventional irradiation field. Prior to radiation treatment of recurrent prostate cancer, choline PET/CT may prove useful for patient stratification by excluding distant disease which would require systemic therapy. In patients with local recurrence, choline PET/CT can be used to delineate local sites of recurrence within the prostatic resection bed allowing a boost to PET-positive sites. In patients with lymph node metastases outside the prostatic fossa and regional metastatic lymph nodes, choline PET/CT might influence radiation treatment planning by enabling extension of the target volume to lymphatic drainage sites with or without a boost to PET-positive lymph nodes. Further clinical randomized trials are required to assess treatment outcomes following choline-based biological radiation treatment planning in comparison with conventional radiation treatment planning.

[Radiation-related caries: etiology and possible preventive strategies. What should the radiotherapist know?]. / Radiogene Karies: Ätiologie und Möglichkeiten der Prävention. Was sollte der Strahlentherapeut wissen?

BACKGROUND: After radiation treatment of head-and-neck cancer, the impairment of patient's quality of life still remains an issue. After completion of the treatment course, a substantial number of patients develop so-called radiation caries. In addition, almost 50% of all cases of infectious osteoradionecrosis (iORN) of the jaws are directly associated with radiation caries. This review addresses our current knowledge on the etiology and pathogenesis of radiation caries including possible preventive strategies. MATERIALS AND METHODS: A PubMed search using the terms "radiation caries" ("radiation related caries", "radiation related damage to dentition") and "radiogenic caries" ("postradiation caries", "dental complications and radiotherapy") was performed. The analysis of its content focused on the etiology, the pathogenesis, and the available knowledge on prophylaxis as well as treatment of radiation caries. RESULTS: For this review, 60 publications were selected. As main causal factors for radiogenic caries, either indirect impairment, resulting from alterations in the oral environment (e.g., radiation-induced xerostomia) or direct radiation-induced damage in teeth hard tissues are discussed. Radiation caries remains a lifelong threat and, therefore, requires permanent prevention programs. CONCLUSION: To enable optimal medical care of the patients during the time course of radiotherapy as well as afterwards, close interdisciplinary cooperation between radiotherapists, oral surgeons, otorhinolaryngologists, and dentists is absolutely essential.

Survival of patients with head and neck cancer. Impact of physical status and comorbidities.

BACKGROUND: Prognostic factors (e.g., gender, tumor stage, and hypoxia) have an impact on survival in patients with head and neck cancer. Thus, the impact of physical status and comorbidities on treatment decision and survival were evaluated. PATIENTS AND METHODS: A total of 169 primary, inoperable patients with squamous cell cancer of the head and neck were retrospectively investigated. Patients were treated with hyperfractionated accelerated radio(chemo)therapy (HARcT) or hypofractionated radio(chemo)therapy (HypoRcT). Depending on the individual patient's situation (Karnofsky Performance Index, KPI), treatment for patients with a KPI of 80-100% was generally radiochemotherapy and for patients with a KPI ≤ 70% treatment was radiotherapy alone. In addition, all comorbidities were evaluated. Uni- and multivariate proportional hazards model were used, and overall survival (OS) was estimated by the Kaplan-Meier method. RESULTS: Treatment consisted of HARcT for 76 patients (45%), HART for 28 patients (17%), HypoRcT for 14 patients(8%), and HypoRT for 51 patients (30%). Of the patients, 107 patients (63%) presented with a KPI of 80-100%. OS (20%) was significantly better for patients with a KPI of 80-100%, while the OS for patients with a KPI ≤ 70% was 8% (p < 0.001). Good KPI, total irradiation dose (> 70 Gy), and chemotherapy were significant prognostic factors for better OS. CONCLUSION: Our retrospective analysis shows that performance status with dependency on comorbidities was an independent risk factor for OS.

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1.

Chronic lymphocytic leukemia (CLL) has a high prevalence in western countries and remains incurable to date. Here, we provide evidence that the multikinase inhibitor sorafenib induces apoptosis in primary CLL cells. This strong pro-apoptotic effect is not restricted to any subgroup of patients, based on Binet stage and the expression of ZAP70 or CD38. Mechanistically, sorafenib-induced cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy.

Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN. PATIENTS AND METHODS: Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/m² initial dose on day -7 of HART, followed by 250 mg/m² weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m² using a classical 3 + 3 dose escalation algorithm. RESULTS: Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%). CONCLUSIONS: The combination of cisplatin with cetuximab and HART is active, well tolerated and merits additional investigation. The recommended weekly dose of cisplatin for phase II studies is 40 mg/m².

[Principles of radiation therapy for malignant tumors of the orbit and the periorbital area]. / Prinzipien der Strahlentherapie bei malignen orbitalen und periorbitalen Raumforderungen.

Primary malignant tumors of the orbit and the orbital adnexal area are rare, variform and in the majority of cases need an interdisciplinary treatment. According to tumor entity, tumor localization, and tumor extent the complete spectrum of radiotherapeutic therapy options is necessary. In the majority of malignant tumors, such as those of the eyelids, lachrymal glands, orbit, metastases, sarcoma or lymphoma, radiotherapy is used as a high energy therapy by means of medical linear accelerators as so-called teletherapy. In addition, new therapy methods, such as stereotactic highly conformal radiation or intensity-modulated radiation therapy (IMRT) were developed to achieve a higher local tumor control by a better configuration of the radiotherapy fields to the tumor borders and to contribute to a reduction of acute and chronic side effects in normal tissue by blurring of the dose. The application of ionizing radiation sources, such as so-called interstitial brachytherapy can also be just as carefully as effectively used. Particle beam radiotherapy is limited only to specially licensed centers and light hydrogen ions as proton therapy or carbon ions as heavy ion radiotherapy are in use. This overview will show the options as well as important progress in the field of radiotherapy in the treatment of tumors of the orbit and periorbital area.

[Radiotherapy of eye and orbit tumors]. / Radiotherapie von Augen- und Orbitatumoren.

Malignant diseases of the orbit are multifaceted and require in the majority of the cases an interdisciplinary treatment. Advances in radiotherapy, surgery and chemotherapy make a high cure rate possible, especially in children's tumors. In adults these tumors reach a tumor control rate of nearly 90 %, even with preservation of the eye in most of the cases. There are only two curative therapy options for tumors in this region: radiotherapy and surgery. The therapy for tumors of the eye and the orbit require the total spectrum of the radiotherapeutic techniques depending on the tumor entity, its spread and localization. In a prevailing number of malignant tumors (tumors of the eyelids, tear glands, orbit, metastases) the application of the radiotherapy as an external, fractionated radiotherapy is standard practice, if necessary in combination with operation and/or chemotherapy. Particularly in the therapy for ocular tumors brachytherapy with radionuclides (e. g., ruthenium) is possible and in a few centers world-wide proton therapy is available. As an alternative procedure in special modalities, stereotactic radiotherapy may be considered. Altogether the new radiotherapy techniques permit a dose increase in the tumor region and/or a reduction of the doses to healthy tissues and lead so to a better local tumor control rate and a decrease in acute and chronic side effects.

[Radiotherapy for Graves' ophthalmopathy]. / Radiotherapie der endokrinen Orbitopathie.

Graves' ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease, an autoimmune disorder of the thyroid, whereas the precise pathogenesis still remains unclear. In Hashimoto's thyroiditis the occurrence of proptosis is an extremely rare event. The therapy for middle and severe courses of GO shows in partly disappointing results, although several therapy modalities are possible (glucocorticoid therapy, radiotherapy, antithyroid drug treatment, surgery). All these therapies lead in only 40 - 70 % to an improvement of the pathogenic symptoms. An intensive interdisciplinary cooperation is necessary to satisfy the requirements for the treatment of Graves' ophthalmopathy. As a consequence of the very different results of the few of clinical studies that were accomplished with reference to this topic, treatment by radiotherapy in the management of the disease is presently controversially discussed. In the German-speaking countries the radiotherapy is, however, firmly established as a therapy option in the treatment of the moderate disease classes (class 2-5 according to NO SPECS), especially if diplopia is present. This article describes the sequences, dosages and fractionation schemes as well as the risks and side effects of the radiotherapy. Altogether, radiotherapy is assessed as an effective and sure method. The administration of glucocorticoids can take place before the beginning of or during the radiotherapy. For the success of treatment the correct selection of patients who may possibly profit from a radiotherapy is absolutely essential. By realising that GO proceeds normally over a period of 2-5 years, which is followed by a period of fibrotic alteration, the application of the radiotherapy in the early, active phase is indispensable. A precise explanation for the effects of radiotherapy in treatment of the GO does not exist at present. The determination of the most effective irradiation doses was made from retrospectively evaluated collectives. Recently the results of a national survey of all German RT departments were published, initiated by the working group of the DEGRO (German Society of Radiooncology). In the most of the German radiooncology departments irradiation with 8 to 10 x 1.8-2.0 Gy 5 x weekly to 16 or 20 Gy is standard. Two recently published prospective German studies pointed out the equivalence of the effectiveness of a short therapy in low dose ranges up to 2.4 Gy as well as of a low proportioned irradiation during a longer period in relation to a standard therapy with 20 Gy. That is why at the moment it is not possible to give a definite recommendation with reference to dosages or the fractionation schemes. In 2003 the first European group (European Group on Graves ' Orbitopathy Experience -- EUGOGO) was founded for pursuing investigations of GO in multi-centric studies, mainly to improve therapy results.

Tumor hypoxia and systemic levels of vascular endothelial growth factor (VEGF) in head and neck cancers.

BACKGROUND: Hypoxia is the most important stimulus for the up-regulation of vascular endothelial growth factor (VEGF), one of the key cytokines for angiogenesis. We have investigated the possible relationship between tumor hypoxia and systemic levels of VEGF. PATIENTS AND METHODS: 56 patients with head and neck cancers underwent measurement of tumor volume (pretreatment CT scans), tumor oxygenation (pO2 histography) and serum levels of VEGF. The hemoglobin level ranged from 9.1 to 16 g/dl. The absolute amount of hypoxic tumor (hypoxic tumor volume) was determined as the product of the absolute tumor volume and the relative frequency of hypoxic (< 5 mm Hg) measurements in the pO2 histography. RESULTS: The serum VEGF levels in the 56 head and neck cancer patients ranged from 102 to 1699 pg/ml (median 405 pg/ml, mean 527 +/- 396 pg/ml). Elevated serum-VEGF levels (> 700 pg/ml) were found in 14/56 patients (25%). Serum-levels of VEGF were significantly and independently correlated with hypoxic tumor volume (R2 = 0.63, p < 0.001), but also with total tumor volume, hemoglobin levels, platelet counts and tumor hypoxia. There was no correlation with T and N category, histological grading, and age. CONCLUSIONS: The strong and independent impact of the hypoxic tumor volume on systemic VEGF levels suggests that the absolute amount of hypoxia within a tumor represents the most important stimulus for up-regulation of angiogenesis. Anemia acts as a co-factor via worsening of tumor tissue oxygenation.

[No association between p53 overexpression and polarographically measured tumor oxygenation in patients with head and neck carcinomas]. / Keine Assoziation zwischen p53-Uberexpression und polarographisch gemessener Tumoroxygenierung bei Patienten mit Kopf-Hals-Karzinomen.

PURPOSE: Clinical investigation of a potential relationship between the polarographically measured tumor oxygenation and the p53 status in patients with squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: In 99 patients with mostly advanced, histologically proven squamous cell carcinoma of the head and neck we estimated the classical tumor parameters (TNM stage, histological grading) the immunohistochemical p53-overexpression (DO-7) and the tumor oxygenation status (Eppendorf pO2 Histograph). The tumor volume and the hemoglobin concentration were evaluated simultaneously. RESULTS: No statistically significant difference could be detected between immunohistological p53-positive (p53 > or = 10% stained cells) and p53-negative tumors (p53 < 10% stained cells) regarding both the median pO2 and the relative frequency of values < or = 5 mm Hg. Moreover, no statistically relevant differences could be seen between both p53-groups considering the hemoglobin concentration, the TNM stage, the histological grading and the tumor volume. CONCLUSION: Our data imply that there is no association between p53-overexpression and tumor hypoxia in head and neck carcinomas. However, this is not necessarily in contradiction to experimental or clinical data that confirmed a relationship between hypoxia and p53-mediated increased malignancy of tumor cells in other tumor entities. The comparable oxygenation status of p53-positive and p53-negative tumors in our study is associated with an analogous clinical tumor aggressiveness of both groups. That could be caused by a hypoxia related but p53-independent selection of tumor cells with a more malignant phenotype in head and neck carcinomas. However, further research is needed to prove this possible relationship.

Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas.

PURPOSE: To investigate the relationship between tumor oxygenation and the blood hemoglobin (Hb) concentration in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: A total of 133 patients with SCCHN underwent pretreatment polarographic pO2 measurements of their tumors. In 66 patients measurements were also made in sternocleidomastoid muscles. The patients were divided into three groups according to their Hb concentration-severe anemia (Hb < 11.0 g/dl), mild anemia (female: Hb 11.0-11.9 g/dl; male: Hb 11.0-12.9 g/dl), and normal Hb concentration (female: Hb > or =12.0 g/dl; male: > or =13.0 g/dl). RESULTS: No significant difference in tumor oxygenation could be detected between mildly anemic patients and patients with a normal Hb level. However, the tumor oxygenation in the severely anemic group was significantly below that of each of the other two groups (p < 0.0001). There was no significant difference between the Hb groups in oxygenation of sternocleidomastoid muscles. In a multivariate analysis including Hb group, tumor volume, smoking habits, gender, T-stage, N-stage, and histologic grade a Hb level < 11 g/dl was found to be the strongest predictor for a poor tumor oxygenation. Smoking also had a marginal influence on median pO2. CONCLUSION: Our data suggest that a low Hb concentration and cigarette smoking contribute to inadequate oxygenation of SCCHN and thus for increased radioresistance. Consequently, Hb correction and abstinence from smoking may significantly improve tumor oxygenation.

Acute radiation reaction and local control in breast cancer patients treated with postmastectomy radiotherapy.

BACKGROUND: We have investigated the variation of acute radiation reactions in medium-risk patients with postmastectomy radiotherapy with regard to a possible correlation between radiation reaction of normal tissues and local tumor control. MATERIAL AND METHODS: From 1985 through 1991, a total number of 194 patients received postmastectomy radiotherapy for breast cancer pT1-2pN0-2M0 at the University of Halle-Wittenberg. The lymphatics were irradiated by an anterior 9-MV photon field and the chest wall by an individually shaped anterior field with 9-MV electrons. Both fields received single doses of 2 Gy 5 times weekly up to a total dose of 44 Gy to the chest wall and 50 Gy to the lymphatics. All patients were routinely evaluated once weekly during radiotherapy for acute side effects by one examiner. Skin erythema was classified as mild, moderate or severe, esophagitis as being present in form of dysphagia or not and pneumonitis, if present, as asymptomatic (visible only on repeated chest X-rays) or clinically symptomatic. A differential blood count was also carried out once weekly. For this analysis, the records of all patients were retrospectively reviewed. The median follow-up at the time of analysis was 4.2 years. RESULTS: Of the patients, 98 (51%) had a mild, 53 (27%) moderate and 43 (22%) a severe erythema. Furthermore, 38 patients (20%) had signs of esophagitis, 13 (7%) had asymptomatic and 26 (13%) symptomatic pneumonitis. Patients with severe erythema or erythema plus esophagitis and pneumonitis had a more pronounced decrease in lymphocyte count during treatment than patients with mild erythema: the lymphocyte nadir was 0.14 vs 0.73 Gpt/l in patients with severe vs mild erythema, and 0.36 vs 0.69 Gpt/l in patients with erythema plus esophagitis plus pneumonitis vs patients with erythema only, p < 0.05. Of the patients, 44 (22%) developed chronic side effects, mostly arm edema. There was no correlation between acute and late effects. An overall number of seven local recurrences (3.6%) occurred. The risk of developing a local recurrence within 5 years after treatment was 0% in patients with severe erythema or erythema plus esophagitis/pneumonitis vs 7% in patients with mild erythema only; this difference was marginally significant, p = 0.055. CONCLUSIONS: This analysis showed a trend towards better local control in patients with severe acute radiation reaction of normal tissue. The data support a recent publication by Dahl and coworkers showing a linkage between acute radiation reaction of normal tissue and tumor response in patients with preoperative radiotherapy for rectal cancer. The correlation between acute normal tissue reaction and local control might be explained by interindividual variations in the intrinsic, genetically determined radiosensitivity. However, local factors might also be involved, e.g. induction of a cytokin cascade in cases of acute reactions in normal tissues.