Ulrike Hoeller

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores

PURPOSE The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA) scores were compared in a group of breast cancer patients. The impact of the classification system on grading late effects was evaluated. MATERIALS AND METHODS Telangiectasia, skin pigmentation, and fibrosis were scored according to both LENT/SOMA and RTOG criteria. The results were compared with respect to up- or downgrading and correlated (Spearmans rho). Other side effects were recorded using LENT/SOMA criteria. Interobserver variability was calculated with Cohens kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent breast-conserving therapy between 1981 and 1995 were examined. The median dose of radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31 patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were used. Two doctors examined 45 patients jointly. RESULTS Of all patients, 20% had telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77% retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearmans rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy were observed in 226 patients using LENT/SOMA criteria. Interobserver variability was similar for both classification systems and ranged from Cohens kappa 0.3 (retraction) to 0.91 (telangiectasia). CONCLUSIONS LENT/SOMA criteria seem to be the better tool in grading and recording late radiation toxicity compared with the RTOG scale. There was some upgrading with the RTOG score when skin toxicity is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of the LENT/SOMA scoring system should be considered to standardize reporting of late radiation morbidity.

Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity

PURPOSE To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity. METHODS AND MATERIALS Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively. RESULTS Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32-3.55, p=0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity. CONCLUSIONS It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.

Individual Radiosensitivity Measured With Lymphocytes May Predict the Risk of Acute Reaction After Radiotherapy

PURPOSE We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy. METHODS AND MATERIALS Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions. RESULTS Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy. CONCLUSION Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.

Radiation-induced plexopathy and fibrosis: Is magnetic resonance imaging the adequate diagnostic tool?

Purpose:To investigate magnetic resonance imaging (MRI) features of radiation-induced plexopathy (RIP) and radiation-induced fibrosis frequently associated with RIP.Patients and Methods:Seven patients with late radiation sequelae in the supraclavicular region were examined with MRI after a median interval of 7 years (range, 5–18 years) following radiotherapy and 4–7 years after the onset of RIP. Four patients had RIP plus severe soft-tissue fibrosis, two RIP without soft-tissue fibrosis (n = 2/6), and one patient fibrosis without RIP. Patients underwent surgery of breast cancer (n = 6) or chest wall relapse (n = 1) and radiotherapy to the supraclavicular fossa with cobalt with an anterior portal in fractions of 1.7–2.6 Gy to 43–51.6 Gy in 3 cm depth. All patients were relapse-free at the time of MRI. Fibrosis and RIP were scored clinically (RTOG classification). Fibrosis of the supraclavicular and/or axillary region was marked in three and mild in two patients. RIP was mild, marked and severe in two patients each. MRI was performed with a 1.5-T unit including coronal STIR, coronal and transversal T2-weighted, transversal T1-weighted and fat-saturated post-contrast (gadolinium-DTPA) spin echo sequences.Results:The brachial plexus appeared normal in all patients, but subtle changes of adjoining tissue (slight, linear signal intensity in T2-weighted images or contrast enhancement surrounding the plexus) were detected in patients with RIP (n = 4/6) and the patient without RIP (n = 1). However, alterations of the soft tissue (marked signal intensity in T2-weighted sequences) correlated well with the clinical degree of fibrosis and were restricted to areas of marked to severe fibrosis (n = 3/3).Conclusion:Reliable MRI signs of RIP could not be identified. The severity of fibrosis closely corresponded to MRI features. The role of MRI in the diagnostic work-up of RIP is, therefore, the exclusion of tumor relapse.Ziel:Die Darstellung der radiogenen Schädigung des Plexus brachialis (RP) und der häufig mit der RP assoziierten Weichteilfibrose mit der Magnetresonanztomographie (MRT) wurde untersucht.Patienten und Methodik:Sieben Patientinnen mit ausgeprägten Strahlenreaktionen in der Supraklavikularregion wurden median 7 Jahre nach Therapie untersucht. Vier Patientinnen hatten eine RP und Fibrose, zwei Patientinnen eine RP ohne Fibrose und eine Patientin eine Fibrose ohne RP. Im Rahmen der Primärtherapie (n = 6) bzw. nach Exzision eines Brustwandrezidivs (n = 1) wurde die Supraklavikularregion mit 60Co in Einzeldosen von 1,7–2,6 Gy bis zu einer Gesamtdosis von 43–51,6 Gy in 3 cm Tiefe bestrahlt. Die Patientinnen waren seit mindestens 4 Jahren rezidivfrei. Fibrose und RP wurden klinisch nach RTOG klassifiziert. Die MRT-Untersuchung wurde an einem 1,5-T-Gerät mit koronaren und transversalen T2-gewichteten Sequenzen, koronaren STIR, transversalen T1-gewichteten Sequenzen und fettgesättigten Spinechosequenzen nach Kontrastmittelgabe (Gadolinium-DTPA) durchgeführt.Ergebnisse:Der Plexus brachialis selbst stellte sich unauffällig dar, aber die perineuralen Strukturen zeigten eine geringe lineare Hyperintensität in der T2-gewichteten Sequenz oder nach Kontrastmittelgabe (n = 4/6). Dagegen korrelierte die klinisch mäßiggradige und ausgeprägte Fibrose gut mit einer Hyperintensität des Fett- und Bindegewebes in den T2-gewichteten Sequenzen (n = 3/3).Schlussfolgerung:Zuverlässige Kriterien einer RP wurden nicht gefunden. Dagegen korrelierte der MRT-Befund mit dem klinischen Schweregrad der Fibrose. Das Ziel der MRT-Untersuchung ist der Ausschluss eines Tumorrezidivs als Ursache der Plexopathie.

Association of single nucleotide polymorphisms in the genes ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with risk of severe erythema after breast conserving radiotherapy

PurposeTo examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position −509), XPD (codon 751), and XRCC1 (codon 399) with the risk of severe erythema after breast conserving radiotherapy.Methods and materialsRetrospective analysis of 83 breast cancer patients treated with breast conserving radiotherapy. A total dose of 50.4 Gy was administered, applying 1.8 Gy/fraction within 42 days. Erythema was evaluated according to the Radiation Therapy Oncology Group (RTOG) score. DNA was extracted from blood samples and polymorphisms were determined using either the Polymerase Chain Reaction based Restriction-Fragment-Length-Polymorphism (PCR-RFL) technique or Matrix-Assisted-Laser-Desorption/Ionization –Time-Of-Flight-Mass-Spectrometry (MALDI-TOF). Relative excess heterozygosity (REH) was investigated to check compatibility of genotype frequencies with Hardy-Weinberg equilibrium (HWE). In addition, p-values from the standard exact HWE lack of fit test were calculated using 100,000 permutations. HWE analyses were performed using R.ResultsFifty-six percent (46/83) of all patients developed erythema of grade 2 or 3, with this risk being higher for patients with large breast volume (odds ratio, OR = 2.55, 95% confidence interval, CI: 1.03–6.31, p = 0.041). No significant association between SNPs and risk of erythema was found when all patients were considered. However, in patients with small breast volume the TGFB1 SNP was associated with erythema (p = 0.028), whereas the SNP in XPD showed an association in patients with large breast volume (p = 0.046). A risk score based on all risk alleles was neither significant in all patients nor in patients with small or large breast volume. Risk alleles of most SNPs were different compared to a previously identified risk profile for fibrosis.ConclusionsThe genetic risk profile for erythema appears to be different for patients with small and larger breast volume. This risk profile seems to be specific for erythema as compared to a risk profile for fibrosis.

Radiation-Induced Plexopathy and Fibrosis

Purpose:To investigate magnetic resonance imaging (MRI) features of radiation-induced plexopathy (RIP) and radiation-induced fibrosis frequently associated with RIP.Patients and Methods:Seven patients with late radiation sequelae in the supraclavicular region were examined with MRI after a median interval of 7 years (range, 5–18 years) following radiotherapy and 4–7 years after the onset of RIP. Four patients had RIP plus severe soft-tissue fibrosis, two RIP without soft-tissue fibrosis (n = 2/6), and one patient fibrosis without RIP. Patients underwent surgery of breast cancer (n = 6) or chest wall relapse (n = 1) and radiotherapy to the supraclavicular fossa with cobalt with an anterior portal in fractions of 1.7–2.6 Gy to 43–51.6 Gy in 3 cm depth. All patients were relapse-free at the time of MRI. Fibrosis and RIP were scored clinically (RTOG classification). Fibrosis of the supraclavicular and/or axillary region was marked in three and mild in two patients. RIP was mild, marked and severe in two patients each. MRI was performed with a 1.5-T unit including coronal STIR, coronal and transversal T2-weighted, transversal T1-weighted and fat-saturated post-contrast (gadolinium-DTPA) spin echo sequences.Results:The brachial plexus appeared normal in all patients, but subtle changes of adjoining tissue (slight, linear signal intensity in T2-weighted images or contrast enhancement surrounding the plexus) were detected in patients with RIP (n = 4/6) and the patient without RIP (n = 1). However, alterations of the soft tissue (marked signal intensity in T2-weighted sequences) correlated well with the clinical degree of fibrosis and were restricted to areas of marked to severe fibrosis (n = 3/3).Conclusion:Reliable MRI signs of RIP could not be identified. The severity of fibrosis closely corresponded to MRI features. The role of MRI in the diagnostic work-up of RIP is, therefore, the exclusion of tumor relapse.Ziel:Die Darstellung der radiogenen Schädigung des Plexus brachialis (RP) und der häufig mit der RP assoziierten Weichteilfibrose mit der Magnetresonanztomographie (MRT) wurde untersucht.Patienten und Methodik:Sieben Patientinnen mit ausgeprägten Strahlenreaktionen in der Supraklavikularregion wurden median 7 Jahre nach Therapie untersucht. Vier Patientinnen hatten eine RP und Fibrose, zwei Patientinnen eine RP ohne Fibrose und eine Patientin eine Fibrose ohne RP. Im Rahmen der Primärtherapie (n = 6) bzw. nach Exzision eines Brustwandrezidivs (n = 1) wurde die Supraklavikularregion mit 60Co in Einzeldosen von 1,7–2,6 Gy bis zu einer Gesamtdosis von 43–51,6 Gy in 3 cm Tiefe bestrahlt. Die Patientinnen waren seit mindestens 4 Jahren rezidivfrei. Fibrose und RP wurden klinisch nach RTOG klassifiziert. Die MRT-Untersuchung wurde an einem 1,5-T-Gerät mit koronaren und transversalen T2-gewichteten Sequenzen, koronaren STIR, transversalen T1-gewichteten Sequenzen und fettgesättigten Spinechosequenzen nach Kontrastmittelgabe (Gadolinium-DTPA) durchgeführt.Ergebnisse:Der Plexus brachialis selbst stellte sich unauffällig dar, aber die perineuralen Strukturen zeigten eine geringe lineare Hyperintensität in der T2-gewichteten Sequenz oder nach Kontrastmittelgabe (n = 4/6). Dagegen korrelierte die klinisch mäßiggradige und ausgeprägte Fibrose gut mit einer Hyperintensität des Fett- und Bindegewebes in den T2-gewichteten Sequenzen (n = 3/3).Schlussfolgerung:Zuverlässige Kriterien einer RP wurden nicht gefunden. Dagegen korrelierte der MRT-Befund mit dem klinischen Schweregrad der Fibrose. Das Ziel der MRT-Untersuchung ist der Ausschluss eines Tumorrezidivs als Ursache der Plexopathie.

Hyperfractionated-accelerated radiotherapy followed by radical surgery in locally advanced tumors of the oral cavity.

Purpose:To evaluate the outcome of hyperfractionated-accelerated radiotherapy and subsequent planned primary tumor resection and radical neck dissection in locally advanced tumors of the oral cavity.Patients and Methods:This retrospective analysis evaluates 126 subsequent patients who were treated between 1988 and 1997 for locally advanced tumors of the oral cavity (with extension into the oropharynx in 17 patients), 34 (27%) AJCC stage III and 92 (73%) stage IV. Primary tumor and nodal metastases were irradiated with 1.4 Gy bid to a median total dose of 72.8 Gy (range 58.8–75.6 Gy). Then, planned radical surgery of the primary site according to the initial tumor extent and cervical nodes was performed. Median follow-up of living patients was 6 years (range 1–11 years).Results:4 weeks after radiotherapy, 14 patients (11%) had complete tumor remission, 92 (73%) partial remission, 15 (12%) no change, and five (4%) progressive disease. Complete resection was achieved in 117 (93%) patients (nine incomplete resections). 5-year locoregional control rate was 62 ± 9%, overall survival 36 ± 9%. Surgery-related morbidity occurred in 42 patients (33%; mainly delayed wound healing and fistulae), overall severe treatment-related morbidity in 46 patients (36%). 24/84 relapse-free patients (29%) required a percutaneous gastrostomy or nasal tube ≥ 1 year after therapy.Conclusion:In this study, the outcome of combined curative radiotherapy and planned surgery of the primary tumor and neck nodes was comparable to reported results of hyperfractionated radiotherapy with or without salvage surgery of the neck nodes with respect to locoregional control and overall survival. Planned surgery carries a substantial risk of morbidity and seems to offer no benefit in comparison to salvage surgery of the neck nodes only. Therefore, salvage surgery is preferred.Ziel:Das Ergebnis einer hyperfraktioniert-akzelerierten Strahlentherapie, gefolgt von geplanter Resektion des Primärtumors und einer zervikalen Lymphknotendissektion bei fortgeschrittenen Mundhöhlentumoren wurde untersucht.Patienten und Methodik:Retrospektiv wurde das Therapieergebnis von 126 Patienten analysiert, die von 1988 bis 1997 wegen lokal fortgeschrittener, potentiell operabler Mundhöhlentumoren (mit Ausdehnung bis in den Oropharynx bei 17 Patienten)—34 Tumoren (27%) im AJCC-Stadium III und 92 (73%) im Stadium IV—behandelt wurden. Primärtumor und Lymphknotenmetastasen wurden mit 1,4 Gy zweimal täglich, Wochendosis 12,6 Gy, Gesamtdosis 72,8 Gy (Spanne 58,8–75,6 Gy), bestrahlt. Anschließend wurden eine radikale Tumor- und Lymphknotenresektion durchgeführt. Die mediane Nachbeobachtungszeit lebender Patienten beträgt 6 Jahre (Spanne 1–11 Jahre).Ergebnisse:4 Wochen nach Strahlentherapie hatten 14 Patienten (11%) eine komplette Tumorremission, 92 (73%) eine partielle Tumorremission, 15 (12%) Status idem und fünf (4%) einen progredienten Tumor. Eine komplette Tumorresektion war bei 117/126 Patienten (93%) möglich. Die lokale 5-Jahres-Kontrollrate betrug 62 ± 9%, das Gesamtüberleben 36 ± 9%. Operationsassoziierte Morbidität, vor allem verzögerte Wundheilung und Fisteln, trat bei 42 Patienten (33%) auf. Insgesamt wurden gravierende Therapiefolgen bei 46 Patienten (36%) beobachtet. 24/84 rezidivfreie Patienten (29%) hatten ≥ 1 Jahr nach Therapie eine PEG (perkutane endoskopische Gastrostomie).Schlussfolgerung:In diesem Patientenkollektiv waren die lokale Kontrollrate und die Gesamtüberlebenszeit mit den publizierten Ergebnissen von hyperfraktioniert-akzelerierten Studien mit und ohne „salvage surgery“ der Lymphknoten vergleichbar. Die elektive Resektion des Primärtumors und der zervikalen Lymphknoten („in den alten Grenzen“) wies ein deutliches Morbiditätsrisiko auf. Ihr Nutzen im Vergleich zu ausschließlicher hyperfraktioniert-akzelerierter Strahlentherapie ist wahrscheinlich gering, so dass die Resektion auf inkomplett zurückgebildete Lymphknotenmetastasen beschränkt werden sollte.

Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

Background and purposeThe aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity.Materials and methodsPatients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted.ResultsWith one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance.ConclusionFunctional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.ZusammenfassungHintergrund und ZielFür ein SNP-Netzwerk („single nucleotide polymorphism“, Einzelnukleotidpolymorphismus), welches im ROS-Signalweg, an der DNA-Reparatur und im TGFB1-Signalweg involviert ist, sollen die Bedeutung für die akute und späte Toxizität sowie die individuelle Strahlenempfindlichkeit bestimmt werden.Material und MethodenNach Strahlentherapie wurden Brustkrebspatientinnen entweder hinsichtlich des Erythems (n = 83), einer Fibrose (n = 123) oder der individuellen Strahlenempfindlichkeit (n = 123) untersucht. Die 17 untersuchten SNPs sind entweder am ROS-Pathway (GSTP1, SOD2, NQO1, NOS3, XDH), bei der DNA-Reparatur (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) oder dem TGFB Signalling (SKIL, EP300, APC, AXIN1, TGFB1) beteiligt. Die Assoziation mit biologischen und klinischen Endpunkten wurde für einzelne, aber insbesondere für Kombinationen von SNPs untersucht, wobei angenommen wurde, dass ein SNPs sowohl von Vorteil als auch von Nachteil sein kann und auch gewichtet werden sollte.ErgebnisseMit einer Ausnahme wurde für einen einzelnen SNP keine signifikante Assoziation identifiziert. Ebenfalls keine signifikante Assoziation wurde gefunden, wenn alle SNPs in einem Wert zusammengefasst werden, unter der Annahme, dass ein SNP immer nachteilig ist. Im Gegensatz dazu ergeben sich signifikante Assoziationen, wenn davon ausgegangen wird, dass ein SNP entweder nachteil- oder vorteilhaft sein kann. Diese Assoziationen werden noch stärker, wenn die SNPs individuell gewichtet werden. Eine detaillierte Analyse des Netzwerks ergibt, dass das Erythem und die individuelle Strahlenempfindlichkeit insbesondere durch SNPs in der DNA-Reparatur und dem TGFB1-Signalweg bestimmt werden, während SNPs im ROS-Signalweg ohne große Bedeutung sind.SchlussfolgerungFunktionale SNP-Netzwerke können genutzt werden, um einen Risikoscore zu bilden, der es erlaubt das Risiko für akute und späte Toxizität vorherzusagen und die zugrundeliegenden Mechanismen aufzuklären.

A patient questionnaire for radiation-induced brachial plexopathy.

We analyzed the usefulness of a symptom questionnaire to screen for radiation-induced brachial plexopathy (RIBP) after breast cancer treatment. Four questions addressed distal and proximal paresis: impaired hand functions, problems raising the arm, carrying weights, and lifting objects from a high shelf. Eighty-one relapse-free patients were neurologically examined. Treatment was mastectomy (51%) or breast-conserving surgery (49%), radiotherapy to the supraclavicular ± axilla with median 60 Gy maximum dose. Sixty-five subsequent control patients had breast-conserving surgery and radiotherapy to the breast only with 55 Gy median dose. Median follow up was 10 and 7.4 years, respectively. Sixteen patients had RIBP, 7 had Radiation Therapy Oncology Group (RTOG) grade 1, 4 grade 2, 3 grade 3, and 2 grade 4 RIBP. Thirty-seven patients had fibrosis and 32 had arm edema. Four patients with RIBP had no fibrosis (n = 2) or fibrosis of the axilla only (n = 2). Specificity of the question “impaired hand functions” for RIBP was 0.66 (95% confidence interval [CI], 0.51–0.78); sensitivity was 0.80 (95% CI, 0.52–0.96). Specificity of the question “raising the arm” was 0.98 (95% CI, 0.9–0.99) and sensitivity was 0.18 (95% CI, 0.04–0.45); the rate of false-positive control patients was 3%. In multivariate analysis, “impaired hand functions” and fibrosis were independent indicators of RIBP (P <0.005). Patients with breast irradiation only stated moderate/pronounced impaired hand functions; and problems carrying weights and lifting objects from a high shelf in 38%, 58%, and 77%, not significantly different from patients with RIBP or the patients with supraclavicular radiation. RIBP is not necessarily associated with fibrosis. The aim of the questionnaire was screening of a population at risk for RIBP. In this group, the question “problems raising the arm” detected severe RIBP with high specificity. Negation of “impaired hand functions” excludes RIBP. Both questions should be included in follow-up questionnaires.

Sex-specific aspects of tumor therapy.

There is increasing evidence that sex-specific differences in toxicity profiles and outcome after radiotherapy are accumulating in medical oncology, and that treatment strategies may require some modification. Furthermore, sex-specific differences in the sensitivity to genotoxic and therapeutical agents are also of general concern for risk estimation. This review is focussed on the specific influence of sex on these endpoints covering both a clinical and a biological point of view. In this paper, the literature was systematically reviewed with respect to sex-specific differences in tumor and normal tissue sensitivity after exposure to ionizing radiation, as well as to the relevant underlying molecular and cellular mechanisms. Although a number of data on sex-specific differences are available and remarkable differences on clinical, molecular, and cellular levels have been reported, a firm conclusion on any existing sex-specific differences is not yet possible. Future studies are required and should be focussed on this aspect of individual radiosensitivity.