Different dose schedules prospectively calculated with the Cumulative Radiation Effect (CRE) form... more Different dose schedules prospectively calculated with the Cumulative Radiation Effect (CRE) formula were used for irradiation of inoperable breast carcinomas. Fractionation with 2 X 260 rad and 2 X 450 rad twice a week, and total doses corresponding to CRE levels 1900 to 2300, were compared. The results showed that prolonged fractionation increased the tolerance of normal skin and the therapeutic ration with respect to early radiation reactions. Late reactions could not be assessed as yet because their development requires several years. With the prolonged course of treatment and 2 X 260 rad per week, no moist desquamation developed despite dose levels between 6800 and 9400 rad. Skin reactions were milder than those in the rapidly treated areas, indicating that the CRE formula cannot exactly predict acute skin reactions for very prolonged treatment schedules. The tumor regressed continuously during the irradiation schedule.
Human papillomavirus (HPV) infections of the genital tract are sexually transmitted and prevalent... more Human papillomavirus (HPV) infections of the genital tract are sexually transmitted and prevalent worldwide. In this study, the role of HPV in 72 patients with anal squamous cell carcinoma was investigated. Polymerase chain reaction (PCR) in combination with in situ hybridization was used to identify HPV-DNA in the patients' biopsies. The HPV typing was conducted by pyrosequencing. Cell cycle and DNA content were analysed by cytometry. Ninety percent of the carcinoma biopsies carried high-risk oncogenic HPV in their malignant cells. Eighty-one percent of these demonstrated a single infection with HPV16, 18 or 33 and 19% were double infected with HPV16 and HPV18. Accumulations of viral genes were seen at the necrotic area of the tumours. The HPV genome in the tumour cell influenced significantly the host cell cycle progression, but not DNA aberrations. Within these patients, HPVstatus in the malignant cells was not found to be associated with patient survival time. High-risk onco...
Purpose: Proton's physical properties offer the maximum radiationdose to the target volume, w... more Purpose: Proton's physical properties offer the maximum radiationdose to the target volume, which is an advantage in the radiotherapy development. The aim of this study is the clinical derivation of the dose‐response relations regarding urinary complications from combined photon and proton prostate radiotherapy.Material and Methods: 189 patients were treated for prostate cancer at Uppsala's Academic Hospital, Sweden from 2002 to 2006. The patients were treated with a proton boost of 20 Gy given in 5 Gy, followed by a X‐ray treatment of 50 Gy in 2 Gy fractions. The dose distribution delivered to the organs of interest and the clinical treatment outcomes (24 months follow‐up time) were available for 72 patients. The delineated regions of interest were the urinary bladder and the region of the lower 3 cm part of the bladder. The photon and protondoses were calculated with the BED (biologically effective dose) concept. Additionally, an RBE of 1.1 was used for protons. The radiobiological parameter acquisition of D 50 and γ was performed for the Poisson, Binomial and Probit models applying the Maximum Likelihood method. Results: Of the 72 patients, 15 (21%) showed urinary complications, whereas 57 (79%) didn't. The best estimated values of the parameters for the whole bladder and bladder 3 cm are D 50=104.0 Gy, γ =0.7 and D 50=88.4 Gy, γ =1.3 for Poisson,D 50=108.0 Gy, γ=0.6 and D 50=88.6 Gy, γ=1.3 for Binomial, whereas for Probit are D 50=97.0 Gy, γ=1.0 and D 50=85.6 Gy, γ=1.8, respectively. The analysis of the mean cumulative DVHs proves that the urinary complications were mainly due to the photontreatment.Conclusions: The dose‐response relations are described well by the estimated parameters of the Poisson, Binomial and Probit models. The results are necessary for a prospective estimation of the clinical effectiveness of radiation therapy using combinations of different radiation modalities.
Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50... more Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50 Gy in daily 2 Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelia...
During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, ... more During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, followed by accelerated repopulation to compensate cell loss. However, previous findings in skin with daily 1.1 Gy dose fractions indicate continued and increasing cell depletion. Here we investigated epidermal keratinocyte response with daily 2 Gy fractions as well as accelerated and hypofractionation. Epidermal interfollicular melanocytes were also assessed. Skin-punch biopsies were collected from breast cancer patients before, during and after mastectomy radiotherapy to the thoracic wall with daily 2 Gy fractions for 5 weeks. In addition, 2.4 Gy radiotherapy four times per week and 4 Gy fractions twice per week for 5 weeks, and two times 2 Gy daily for 2.5 weeks, were used. Basal keratinocyte density of the interfollicular epidermis was determined and immunostainings of keratinocytes for DNA double-strand break (DSB) foci, growth arrest, apoptosis and mitosis were quantified. In addit...
Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from ... more Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from clinical data, when there is a wide variation in dose, fraction size, treatment time, etc. This report summarizes estimates of fractionation parameters derived from clinical results. Consistent with the animal data, alpha/beta is higher for acutely responding than for late-responding normal tissues. While many human tumors seem to be characterized by high alpha/beta values, there are exceptions (e.g. melanomas). Repair kinetics may be slower in human than in rodent skin and mucosa, but there are no hard and fast estimates of the repair halftime. Regeneration in head and neck tumors is equivalent to a daily dose of 1 Gy or less, while in the mucosa it is equivalent to approximately 1.8 Gy/day.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2018
High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cance... more High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience. The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2-266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy. The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent G...
Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiat... more Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiation of different organs. Whether parenchymal cell loss is a process well dissociated from vasculoconnective damage, or a consequence of this, is much debated. However, comprehensive radiopathological studies have shown that vasculoconnective tissue is an important common target for late effects in various organs. Scoring of skin telangiectasia was used by us as a clinical assay of late tissue effects after different dose schedules. All studies were done prospectively with standardized skin area, field size and radiation quality. The patients were scored regularly up to 10 years. The number of patients at risk for a prescribed score versus time was calculated with the life-table method. The late effects after 5 X 2.0 Gy/wk, in the dose range 40 to 70 Gy and after 2 X 4.0 Gy/wk, in the dose range 40 to 56 Gy have been established. The skin dose is 90% of the referred dose. Dose-response curves, relating the proportion of patients with a certain score at a fixed time and radiation dose and dose-latency curves, relating the latent period for a fixed proportion of patients with a certain score and radiation dose, were constructed. The analysis shows that: ED10/5 yr and ED50/5 yr for 5 X 2.0 Gy/wk is 50 Gy and 65 Gy, respectively, for distinct telangiectasia; The latent period, concerning both a certain frequency and degree of reaction, varies exponentially with dose level; The latent period for 50% of the patients, to obtain a certain score, LP50, is correlated to that for 10%, LP10, with LP50/LP10 = 2.2 +/- 0.2 (S.D.). This correlation is independent of score, total dose, and fractionation; Isoeffective doses for 5 X 2.0 Gy/wk and 2 X 4.0 Gy/wk, determined from the dose-response curves, resulted in the repair exp N between 0.31 and 0.32 and alpha/beta ratio between 2.9 and 3.1 Gy and determined from the dose-latency curves in exp N between 0.30 and 0.32 and alpha/beta ratio between 3.4 and 2.9 Gy. In conclusion, frequent and careful follow-up with registration of normal tissue reactions, until at least 10% of the patients have obtained the prescribed effect, is predictive for the further progression of the late effects. The fractionation characteristics for telangiectasia agree well with those for animal experimental morphological and functional endpoints for late effects in different organs and support the relevance of telangiectasia as a model for predicting late effects.
The result of a comparison of single and fractionated irradiation at high dose rate with continuo... more The result of a comparison of single and fractionated irradiation at high dose rate with continuous irradiation at low dose rate on pig skin is discussed from a radiobiological point of view. A short review is given of other fractionation and dose-rate investigations. Some dose-rate experiments have resulted in an increased therapeutic gain for continuous irradiation at low dose rate, compared to single acute irradiation. However, there is a lack of data comparing fractionated high dose-rate irradiation with continuous low dose-rate irradiation on normal tissues as well as malignant tumors.
Different dose schedules prospectively calculated with the Cumulative Radiation Effect (CRE) form... more Different dose schedules prospectively calculated with the Cumulative Radiation Effect (CRE) formula were used for irradiation of inoperable breast carcinomas. Fractionation with 2 X 260 rad and 2 X 450 rad twice a week, and total doses corresponding to CRE levels 1900 to 2300, were compared. The results showed that prolonged fractionation increased the tolerance of normal skin and the therapeutic ration with respect to early radiation reactions. Late reactions could not be assessed as yet because their development requires several years. With the prolonged course of treatment and 2 X 260 rad per week, no moist desquamation developed despite dose levels between 6800 and 9400 rad. Skin reactions were milder than those in the rapidly treated areas, indicating that the CRE formula cannot exactly predict acute skin reactions for very prolonged treatment schedules. The tumor regressed continuously during the irradiation schedule.
Human papillomavirus (HPV) infections of the genital tract are sexually transmitted and prevalent... more Human papillomavirus (HPV) infections of the genital tract are sexually transmitted and prevalent worldwide. In this study, the role of HPV in 72 patients with anal squamous cell carcinoma was investigated. Polymerase chain reaction (PCR) in combination with in situ hybridization was used to identify HPV-DNA in the patients' biopsies. The HPV typing was conducted by pyrosequencing. Cell cycle and DNA content were analysed by cytometry. Ninety percent of the carcinoma biopsies carried high-risk oncogenic HPV in their malignant cells. Eighty-one percent of these demonstrated a single infection with HPV16, 18 or 33 and 19% were double infected with HPV16 and HPV18. Accumulations of viral genes were seen at the necrotic area of the tumours. The HPV genome in the tumour cell influenced significantly the host cell cycle progression, but not DNA aberrations. Within these patients, HPVstatus in the malignant cells was not found to be associated with patient survival time. High-risk onco...
Purpose: Proton's physical properties offer the maximum radiationdose to the target volume, w... more Purpose: Proton's physical properties offer the maximum radiationdose to the target volume, which is an advantage in the radiotherapy development. The aim of this study is the clinical derivation of the dose‐response relations regarding urinary complications from combined photon and proton prostate radiotherapy.Material and Methods: 189 patients were treated for prostate cancer at Uppsala's Academic Hospital, Sweden from 2002 to 2006. The patients were treated with a proton boost of 20 Gy given in 5 Gy, followed by a X‐ray treatment of 50 Gy in 2 Gy fractions. The dose distribution delivered to the organs of interest and the clinical treatment outcomes (24 months follow‐up time) were available for 72 patients. The delineated regions of interest were the urinary bladder and the region of the lower 3 cm part of the bladder. The photon and protondoses were calculated with the BED (biologically effective dose) concept. Additionally, an RBE of 1.1 was used for protons. The radiobiological parameter acquisition of D 50 and γ was performed for the Poisson, Binomial and Probit models applying the Maximum Likelihood method. Results: Of the 72 patients, 15 (21%) showed urinary complications, whereas 57 (79%) didn't. The best estimated values of the parameters for the whole bladder and bladder 3 cm are D 50=104.0 Gy, γ =0.7 and D 50=88.4 Gy, γ =1.3 for Poisson,D 50=108.0 Gy, γ=0.6 and D 50=88.6 Gy, γ=1.3 for Binomial, whereas for Probit are D 50=97.0 Gy, γ=1.0 and D 50=85.6 Gy, γ=1.8, respectively. The analysis of the mean cumulative DVHs proves that the urinary complications were mainly due to the photontreatment.Conclusions: The dose‐response relations are described well by the estimated parameters of the Poisson, Binomial and Probit models. The results are necessary for a prospective estimation of the clinical effectiveness of radiation therapy using combinations of different radiation modalities.
Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50... more Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50 Gy in daily 2 Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelia...
During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, ... more During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, followed by accelerated repopulation to compensate cell loss. However, previous findings in skin with daily 1.1 Gy dose fractions indicate continued and increasing cell depletion. Here we investigated epidermal keratinocyte response with daily 2 Gy fractions as well as accelerated and hypofractionation. Epidermal interfollicular melanocytes were also assessed. Skin-punch biopsies were collected from breast cancer patients before, during and after mastectomy radiotherapy to the thoracic wall with daily 2 Gy fractions for 5 weeks. In addition, 2.4 Gy radiotherapy four times per week and 4 Gy fractions twice per week for 5 weeks, and two times 2 Gy daily for 2.5 weeks, were used. Basal keratinocyte density of the interfollicular epidermis was determined and immunostainings of keratinocytes for DNA double-strand break (DSB) foci, growth arrest, apoptosis and mitosis were quantified. In addit...
Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from ... more Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from clinical data, when there is a wide variation in dose, fraction size, treatment time, etc. This report summarizes estimates of fractionation parameters derived from clinical results. Consistent with the animal data, alpha/beta is higher for acutely responding than for late-responding normal tissues. While many human tumors seem to be characterized by high alpha/beta values, there are exceptions (e.g. melanomas). Repair kinetics may be slower in human than in rodent skin and mucosa, but there are no hard and fast estimates of the repair halftime. Regeneration in head and neck tumors is equivalent to a daily dose of 1 Gy or less, while in the mucosa it is equivalent to approximately 1.8 Gy/day.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2018
High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cance... more High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience. The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2-266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy. The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent G...
Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiat... more Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiation of different organs. Whether parenchymal cell loss is a process well dissociated from vasculoconnective damage, or a consequence of this, is much debated. However, comprehensive radiopathological studies have shown that vasculoconnective tissue is an important common target for late effects in various organs. Scoring of skin telangiectasia was used by us as a clinical assay of late tissue effects after different dose schedules. All studies were done prospectively with standardized skin area, field size and radiation quality. The patients were scored regularly up to 10 years. The number of patients at risk for a prescribed score versus time was calculated with the life-table method. The late effects after 5 X 2.0 Gy/wk, in the dose range 40 to 70 Gy and after 2 X 4.0 Gy/wk, in the dose range 40 to 56 Gy have been established. The skin dose is 90% of the referred dose. Dose-response curves, relating the proportion of patients with a certain score at a fixed time and radiation dose and dose-latency curves, relating the latent period for a fixed proportion of patients with a certain score and radiation dose, were constructed. The analysis shows that: ED10/5 yr and ED50/5 yr for 5 X 2.0 Gy/wk is 50 Gy and 65 Gy, respectively, for distinct telangiectasia; The latent period, concerning both a certain frequency and degree of reaction, varies exponentially with dose level; The latent period for 50% of the patients, to obtain a certain score, LP50, is correlated to that for 10%, LP10, with LP50/LP10 = 2.2 +/- 0.2 (S.D.). This correlation is independent of score, total dose, and fractionation; Isoeffective doses for 5 X 2.0 Gy/wk and 2 X 4.0 Gy/wk, determined from the dose-response curves, resulted in the repair exp N between 0.31 and 0.32 and alpha/beta ratio between 2.9 and 3.1 Gy and determined from the dose-latency curves in exp N between 0.30 and 0.32 and alpha/beta ratio between 3.4 and 2.9 Gy. In conclusion, frequent and careful follow-up with registration of normal tissue reactions, until at least 10% of the patients have obtained the prescribed effect, is predictive for the further progression of the late effects. The fractionation characteristics for telangiectasia agree well with those for animal experimental morphological and functional endpoints for late effects in different organs and support the relevance of telangiectasia as a model for predicting late effects.
The result of a comparison of single and fractionated irradiation at high dose rate with continuo... more The result of a comparison of single and fractionated irradiation at high dose rate with continuous irradiation at low dose rate on pig skin is discussed from a radiobiological point of view. A short review is given of other fractionation and dose-rate investigations. Some dose-rate experiments have resulted in an increased therapeutic gain for continuous irradiation at low dose rate, compared to single acute irradiation. However, there is a lack of data comparing fractionated high dose-rate irradiation with continuous low dose-rate irradiation on normal tissues as well as malignant tumors.
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