Krzysztof Urbański

Influence of overall treatment time and radiobiological parameters on biologically effective doses in cervical cancer patients treated with radiation therapy alone.

The aim of the study was to examine the influence of overall treatment time (OTT) on the value of calculated biological effective doses (BEDs) for different biological variables. These variables were: tumour proliferation rate, different cell radiosensitivity (α=0.2, 0.3, and 0.4 /Gy), and different start time for repopulation (Tk=21, 28, and 35 days). Also the influence of age (≤50 years >), Hb level (≤116 g/l>), tumor proliferation rate (bromodeoxyuridine labelling index; BrdUrdLI), and DNA ploidy on survival after shorter (≤60 days) or longer (>60 days) OTT was investigated. The study included 229 patients with cervix carcinoma treated entirely by standard radiotherapy (RT) (external beam RT plus low-medium dose-rate (LDR/MDR) brachytherapy (BT) at the Center of Oncology in Krakow. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill. BEDs 10 (for tumours) were calculated with consideration of OTT for each patient and tumour proliferation rate (standardized potential doubling time; standardized Tpot) based on BrdUrdLI assessed on biopsy material before RT. Median OTT was 90 days (range 30–210). The mean calculated total BED for point A for tumour and ‘early reactions’ was equal to 103.0 Gy10. The longest median survival time—52 months—was seen for patients treated with OTT ≤60 days. If OTT exceeded 90 days to more than 120 days, loss in BED10 for relatively radiosensitive tumours (α=0.3–0.4/Gy and Tk=28 days) was equal to 0.37–0.26 Gy/day. However, for radioresistant tumours (α=0.2/Gy) it was 0.6 Gy/day. For fast proliferating tumours (BrdUrdLI >8.8%) BED loss was 1.4 Gy/day and for slowly proliferating tumours (BrdUrdLI ≤8.8%) it was 0.2 Gy/day. Assuming shorter (21 days) or longer (35 days) periods for Tk and relatively radiosensitive tumours similar BED loss of 0.38 Gy/day was observed. Kaplan–Meier analysis revealed that OTT ≤60 days was a significant prognostic factor for overall survival (OS) (p=0.019), disease-free survival (DFS) (p=0.0173), and local control (LC) (p=0.011). BED10 had significant influence on survival (p=0.047). Cox multivariate analysis revealed that for OTT shorter than 60 days the only favourable significant parameters were: age >50 years (p=0.003) and high Hb level (>116 g/l) (p=0.041). For longer treatments (OTT >60 days) the unfavourable parameters were: age ≤50 years (p=0.037), BrdUrdLI ≤8.8% (p=0.003), tumour aneuploidy (p=0.043), and BED10 ≤103 Gy (p=0.017). The examined tumour biological parameters should be taken into account for RT and provide a basis for adjuvant RT.

Low-dose radiation response of primary keratinocytes and fibroblasts from patients with cervix cancer

Abstract Słonina, D., Biesaga, B., Urbański, K. and Kojs, Z. Low-Dose Radiation Response of Primary Keratinocytes and Fibroblasts from Patients with Cervix Cancer. Radiat. Res. 167, 251–259 (2007). The aim of the present study was to examine, using the micronucleus (MN) assay, the low-dose radiation response of normal skin cells from cancer patients and to determine whether the hyper-radiosensitivity (HRS)-like phenomenon occurs in cells of these patients. Primary skin fibroblasts and keratinocytes derived from 40 patients with cervix cancer were studied. After in vitro γ irradiation with single doses ranging from 0.05 to 4 Gy, MN induction was assessed. For each patient, the linear-quadratic (LQ) model and the induced repair (IR) model were fitted over the whole data set. In fits of the IR model, an HRS-like response after low doses (seen as the deviation over the LQ curve) was demonstrated for the fibroblasts of two patients and for the keratinocytes of four other patients. The αs/αr ratio for the six patients ranged from 2.7 to 15.4, whereas the values of the parameter dc ranged from 0.13 to 0.36 Gy. No relationship was observed between chromosomal radiosensitivity of fibroblasts and keratinocytes derived from the same donor in the low-dose (0.1–0.25 Gy) region. In conclusion, the fact that low-dose chromosomal hypersensitivity was observed for cells of only six of the patients studied suggests that it is not a common finding in human normal cells and can represent an individual characteristic.

Tumour cell kinetics as a prognostic factor in squamous cell carcinoma of the cervix treated with radiotherapy.

PURPOSE Proliferative rate and DNA ploidy status were evaluated by flow cytometry in cervical cancer patients, prior to radiotherapy, to assess their importance as prognostic factors to predict survival rates. MATERIAL AND METHODS Between 1987 and 1995, a total of 260 patients with squamous cell carcinoma (SCC) of the cervix, FIGO stages IB-IIIB were analysed. Tumour samples were incubated with bromodeoxyuridine (BrdUrd) in vitro to measure their total labelling index (totLI) and LI (totLI for diploid and anLI for aneuploid tumours). Proliferation was also assessed by S-phase fraction (SPF) analysis of the DNA profile. Patients had intracavitary therapy (three applications, each of 16 Gy to point A) and XRT of 40-50 Gy given over 4-5 weeks. RESULTS The cervical tumours were characterized by a high proliferation rate which varied within each clinical stage of disease. The totLI ranged from 1.1 to 33.1% with median value of 9.6% whilst the LI ranged from 1.1 to 37.1% with a median value of 10.9%. Univariate analysis identified patients age (cut-offpoint < or = 50&greater; years) and to a lesser extent proliferation (cut-off point, median totLI=9.6%) as significant prognostic factors for 5-year survival. The median survival time for younger patients ( < or = 50 years) with tumours of low proliferation (totLI < or = 9.6%) tumours was 17.5 months compared with 56 months in the faster proliferating tumours (P=0.0354). In the older patient sub-group, proliferation rate had no influence on survival. The median LI value was not a useful parameter in survival. Cox multivariate analysis showed that patient age ( < or = 50 years) and low proliferation of the tumour cells (totLI < or = 9.6) were unfavourable prognostic factors for cervical cancers treated with radiotherapy. DNA ploidy was not significant in this series. CONCLUSIONS These data suggest that further improvements in therapy might be gained by selection of alternative treatments strategies such as neoadjuvant chemotherapy or radiation sensitizers in younger patients with more slowly proliferating tumours.

The response of primary keratinocytes and fibroblasts from cancer patients to multiple low-dose irradiations.

Abstract Słonina, D., Biesaga, B., Urbański, K. and Kojs, Z. The Response of Primary Keratinocytes and Fibroblasts from Cancer Patients to Multiple Low-Dose Irradiations. Radiat. Res. 168, 631–636 (2007). In our previous study, using the micronucleus (MN) assay, a hyper-radiosensitivity (HRS)-like phenomenon was observed after single low doses for fibroblasts from two and keratinocytes from four of the 40 patients studied. In this paper, we report the response of primary keratinocytes from 23 and fibroblasts from 21 of these cancer patients to multiple low-dose irradiations and answer the question regarding whether the patients with an HRS-like response after single low doses also demonstrate chromosomal hypersensitivity after multiple low doses. The cells were irradiated with three doses of 0.25 Gy separated by 4-h intervals, and MN induction was compared with that after the same total dose given as a single fraction of 0.75 Gy. Similarly, the effect of three doses of 0.5 Gy was compared with that of a single dose of 1.5 Gy. For fibroblasts from two and keratinocytes from four patients who demonstrated a single-dose HRS-like response, a significant inverse effect of fractionation (greater MN induction after three doses of 0.25 Gy than after a single dose of 0.75 Gy) was observed, which suggests a repeated hypersensitive response after each dose of 0.25 Gy. Such an effect was not seen for the cells from 19 patients who were single-dose HRS-like negative. In conclusion, an inverse fractionation effect for MN induction that was observed in fibroblasts from two and keratinocytes from four patients after three doses of 0.25 Gy (but not 3 × 0.5 Gy) reflects the chromosomal hyper-radiosensitivity seen in the same patients in response to single low doses.

Hematogenous Metastases in Patients with Stage I or II Endometrial Carcinoma

AimsThe aim of this study was to present the characteristics, methods of treatment, and the survival of patients with hematogenous metastases from endometrial carcinoma, free from local and other distant recurrences.Patients and MethodsIn 1,610 endometrial carcinoma patients managed with surgery and postoperative radiotherapy, we defined hematogenous metastases as a tumor spread to the lung or other sites via hematogenous routes.ResultsA total of 110 patients with stage I and II endometrial carcinoma, presenting with 134 metastases sites (69 in the lungs, 32 in the liver, 23 in the bones, and 10 in the brain), were observed. Progestin and combination chemotherapy were the most commonly used therapies. Primary treatment consisted of surgery in patients with solitary metastases to the lung (30 patients), liver (2 patients), and brain (2 patients). Radiotherapy was performed in 32 patients with metastases to the brain and bones. Presenting with a 36-month survival rate were 11.6% (8/69) of patients with metastases to the lungs, 6.3% (2/32) of patients with metastases to the liver, 8.7% (2/23) of patients with metastases to the bones, and 20.0% (2/10) of patients with metastases to the brain.ConclusionsHormonal therapy and chemotherapy play a major role in the palliative management of patients with hematogenous metastases from endometrial carcinoma to the liver, lungs, and bones. Radical treatment in patients with metastases to the lung or liver consists of resection of the metastasis combined with chemo- and/or hormonotherapy for metastases to the bones treatment consists of radiotherapy + chemotherapy, for metastasis to the brain treatment consists of resection combined with radiotherapy.ZusammenfassungZielDarstellung von Charakteristika, Behandlungsmethoden und Überleben von Patientinnen mit hämatogenen Metastasen des Endometriumkarzinoms ohne lokalen und Fernrezidive.Patienten und MethodenBei 1610 Patientinnen mit Endometriumkarzinom, die mit Operation und postoperativer Strahlentherapie behandelt worden waren, definierten wir hämatogene Metastasen als Ausbreitung bösartiger Tumoren in die Lungen oder andere Regionen über die Blutbahn.ErgebnisseWir beobachteten 110 Endometriumkarzinom-Patientinnen, Stadien I und II, bei denen 134 Metastasenlokalisatione festgestellt wurden: 69 in den Lungen, 32 in der Leber, 23 in den Knochen und 10 im Gehirn. Die am häufigsten eingesetzten Behandlungsregime waren Progestine und Kombinationschemotherapie. Erstbehandlung waren Operationen bei Patientinnen mit einzelnen Lungenmetastasen (30 Fälle), Lebermetastasen (2 Fälle) und Gehirnmetastasen (2 Fälle). Eine Strahlentherapie wurde bei 32 Patienten mit Gehirnmetastasen und mit Knochenmetastasen durchgeführt. Nach 36 Monaten betrug die Überlebensrate 11,6% (8/69) der Patientinnen mit Lungenmetastasen, 6,3% (2/32) der Patientinnen mit Lebermetastasen, 8,7% (2/23) der Patientinnen mit Knochenmetastasen und 20,0% (2/10) der Patientinnen mit Gehirnmetastasen.SchlussfolgerungHormon- und Chemotherapie spielen eine wesentliche Rolle in der palliativen Behandlung von Patientinnen mit hämatogenen Leber-, Lungen- und Knochenmetastasen des Endometriumkarzinoms. Die radikale Behandlung bei Lungen- oder Lebermetastasen umfasst chirurgische Metastasenresektion und adjuvante Chemo- und/oder Hormontherapie, bei Knochenmetastasen Strahlen- plus Chemotherapie und bei Gehirnmetastasen chirurgische Metastasenresektion und adjuvante Strahlentherapie.

Radiotherapy-induced lumbosacral plexopathy in a patient with cervical cancer: a case report and literature review

Radiotherapy-induced lumbosacral plexopathy in cervical cancer treatment is a very rare, but extremely serious complication. The clinical course is associated with severe bilateral lower leg pain, reduced sensation, different degrees of weakness, paresis or paralysis, and sometimes also urinary or fecal incontinence. Patient quality of life becomes significantly deteriorated. Escalating neurological disorders may make self-sufficient functioning impossible. Neurological symptoms, most often irreversible, may develop at different times after irradiation, even after more than 30 years. We present a case of neurological toxicity in a patient successfully treated for cervical cancer with pelvis and para-aortic lymph node irradiation and weekly cisplatin. Neurological symptoms developed a few weeks after completion of external irradiation, were gradually escalating and resulted in complete immobilization of the woman. We underline the significance of long-term, systematic physiotherapy and pharmacological therapy which has resulted in significant improvement of motion efficiency. The literature review concerns the questions of frequency, clinical course and mechanisms of radiation-induced plexopathy.

Prognostic Significance of Pretherapeutic and Therapeutic Factors in Patients with Advanced Cancer of the Uterine Cervix Treated with Radical Radiotherapy Alone

The prognostic importance of various pretherapeutic and therapeutic factors was analysed in a group of 413 cervical cancer patients with stage IIB (183 pts) and IIIB (230 pts) treated with radical radiotherapy, which consisted of external irradiation and intracavitary brachytherapy. Univariate analysis of pretherapeutic factors revealed the prognostic significance of patient age, history of abortion, stage, haemoglobin and hematocrit levels. Five-year overall survival rate in stage IIB patients was 51%, in stage IIIB 40% and the respective rates for local control at each stage were 61%, and 46%. Univariate analysis of therapeutic factors showed that survival and local control rates increased with the dose, but a significant difference was found only in the case of a paracentral (point A) dose. In a multivariate analysis only patient age, abortions, and clinical stage appeared to have a significant and independent impact on survival. Linear regression analysis results indicated that prolongation of treatment time between 33 and 108 days caused a loss of local control of 0.36% per day.

5 Rak endometrium – wstępna ocena tolerancji pooperacyjnej pulsacyjnej brachyterapii

Cel Ocena tolerancji dopochwowego leczenia PDR (pulsed dose-rate) chorych operowanych z powodu raka trzonu macicy. Material i Metoda U 110 chorych operowanych z powodu raka trzonu macicy przeprowadzono po raz pierwszy w Polsce w okresie od 1.10.1998 do 31.12.1999 roku uzupelniające dopochwowe leczenie techniką PDR. Chore leczone byly cylindrycznym aplikatorem dopochwowym, otrzymywaly 21 Gy w ciągu 21 godzin leczenia (dawka 1 Gy/h, czas trwania pulsu od 10 do 30 minut w związku ze spadkiem aktywności źrodla irydowego). Dawke obliczano 0,5 cm od powierzchni aplikatora oraz 1cm od szczytu pochwy. U kazdej chorej indywidualnie obliczono rozklad dawki w terenie miednicy przy uzyciu IBU oraz systemu Plato. U 43 chorych (39%) PDR byl jedyną formą uzupelniającej radioterapii, u 67 chorych (61%) zastosowano dodatkowo napromienianie od zewnątrz. Odczyny popromienne oceniono w oparciu o klasyfikacje EORTC/RTOG. Wyniki Średni czas obserwacji chorych wynosil 15 miesiecy – od 6 do 32 miesiecy. Tolerancja leczenia byla dobra. Wszystkie chore otrzymaly napromienianie zgodnie z planem. Wczesny odczyn popromienny w pochwie w stopniu G1 wystąpil u 8 chorych (7,3%). U 10 chorych (9%) poza obszarem leczenia, w okolicy podcewkowej wystąpila odlezyna o powierzchni do 1,5 cm 2 , podobnie jak u chorych leczonych cylindrycznym aplikatorem Selektronowym, wynikająca z rozmiaru aplikatora i jego ucisku. Wczesne odczyny popromienne w pecherzu i w odbytnicy o lekkim przebiegu wystąpily odpowiednio u 5 i 4 chorych. Poźna reakcja popromienna w pochwie w stopniu G2 wystąpila u jednej chorej. Poźna reakcja popromienna w pecherzu i w odbytnicy w stopniu G1 wystąpila odpowiednio u 2 i 4 chorych. U jednej chorej wystąpil odczyn popromienny w odbytnicy w stopniu G4. W okresie obserwacji loko-regionalne niepowodzenie wystąpilo u 3 chorych (2,7%). Wnioski Brachyterapia dopochwowa PDR wydaje sie byc obiecującą, bezpieczną i dobrze tolerowaną metodą uzupelniającego leczenia chorych operowanych z powodu raka trzonu macicy.

Classical prognostic factors in patients with non-advanced endometrial cancer treated with postoperative radiotherapy

Summary Aim Analysis of classical prognostic factors in patients with non-advanced endometrial cancer treated with postoperative radiotherapy. Materials/Methods In the years 1985–1999, 705 patients underwent postoperative radiotherapy due to endometrial cancer: 529 patients with FIGO stage I and 176 with FIGO stage II cancer. Mean age was 58 years. In 96% of patients endometrioid adenocarcinoma was found. In 49.9% the cancer had a high, in 27.9% a medium, and in 22.2% a low degree of differentiation. Results 82% of patients had 5-year disease-free survival. In univariate analysis a significantly higher rate of disease-free survival was observed in: patients younger than 60, with moderately and well differentiated cancers, with stage I endometrioid adenocarcinoma with less than 50% myometrial invasion. In multivariate analysis degree of cancer differentiation was the only independent prognostic factor. Conclusions In a group of patients with non-advanced endometrial cancer treated with postoperative radiotherapy, degree of cancer differentiation is the primary prognostic factor.

74 Ocena skuteczności leczenia przerzutów odległych u chorych na miejscowo wyleczonego raka szyjki macicy

Cel pracy Ocena skuteczności leczenia przerzutow odleglych u chorych na miejscowo wyleczonego raka szyjki macicy. Metodyka Retrospektywna analiza materialu obejmującego 113 chorych na miejscowo wyleczonego RSM, u ktorych wystąpily przerzuty odlegle. Wszystkie chore badanej grupy byly leczone w Krakowskim Oddziale Centrum Onkologii (COOK) w latach 1986–1992. Oceniono wplyw leczenia chirurgicznego na przezycie chorych oraz efekt paliatywny tego leczenia. Wyniki Najczestszą lokalizacją pierwszego lub pierwszych przerzutow byly pluca (37 chorych), kości (26 chorych) i wątroba (20 chorych); ponadto stwierdzono przerzuty do mozgu (11 chorych), obwodowych wezlow chlonnych (11 chorych) i skory (8 chorych). U 3 4 chorych stwierdzono przerzuty pojedyncze, u 1/4 mnogie. W ciągu pierwszego roku po leczeniu miejscowym, przerzuty odlegle wystąpily u 42,5% chorych, w ciągu 3 lat u ponad 3 4 chorych; średni czas wystąpienia przerzutow wynosil 23 miesiące. Spośrod 113 chorych badanej grupy, leczenie przyczynowe przerzutow odleglych podjeto jedynie u 48 tzn. 42,5% pacjentek; u 3 chorych zastosowano leczenie operacyjne (metastazektomia pojedynczych przerzutow do pluc), u 20 wylącznie teleradioterapie, u kolejnych 20 wylącznie chemioterapie, u 5 skojarzenie chemioradioterapii. Od momentu wystąpienia przerzutow odlegfych,odleglych, 12 miesiecy przezylo jedynie 15% chorych badanej grupy, a 24 miesiące 4% chorych. Wnioski 1. Zarowno telaradioterapia jak i chemioterapia oparta na cysplatynie z 5-fluorouracylem lub karboplatynie, nie mialy statystycznie znamiennego wplywu na przezycia chorych badanej grupy. 2. Telaradioterapia jest skuteczną metodą lagodzenia dolegliwości u chorych z przerzutami RSM do kości, obwodowych wezlow chlonnych i skory.