Severe Radiation Reactions Research Articles

Ionizing Radiation Protein Biomarkers in Normal Tissue and Their Correlation to Radiosensitivity: A Systematic Review.

Background and objectives: Exposure to ionizing radiation (IR) has increased immensely over the past years, owing to diagnostic and therapeutic reasons. However, certain radiosensitive individuals show toxic enhanced reaction to IR, and it is necessary to specifically protect them from unwanted exposure. Although predicting radiosensitivity is the way forward in the field of personalised medicine, there is limited information on the potential biomarkers. The aim of this systematic review is to identify evidence from a range of literature in order to present the status quo of our knowledge of IR-induced changes in protein expression in normal tissues, which can be correlated to radiosensitivity. Methods: Studies were searched in NCBI Pubmed and in ISI Web of Science databases and field experts were consulted for relevant studies. Primary peer-reviewed studies in English language within the time-frame of 2011 to 2020 were considered. Human non-tumour tissues and human-derived non-tumour model systems that have been exposed to IR were considered if they reported changes in protein levels, which could be correlated to radiosensitivity. At least two reviewers screened the titles, keywords, and abstracts of the studies against the eligibility criteria at the first phase and full texts of potential studies at the second phase. Similarly, at least two reviewers manually extracted the data and accessed the risk of bias (National Toxicology Program/Office for Health Assessment and Translation—NTP/OHAT) for the included studies. Finally, the data were synthesised narratively in accordance to synthesis without meta analyses (SWiM) method. Results: In total, 28 studies were included in this review. Most of the records (16) demonstrated increased residual DNA damage in radiosensitive individuals compared to normo-sensitive individuals based on γH2AX and TP53BP1. Overall, 15 studies included proteins other than DNA repair foci, of which five proteins were selected, Vascular endothelial growth factor (VEGF), Caspase 3, p16INK4A (Cyclin-dependent kinase inhibitor 2A, CDKN2A), Interleukin-6, and Interleukin-1β, that were connected to radiosensitivity in normal tissue and were reported at least in two independent studies. Conclusions and implication of key findings: A majority of studies used repair foci as a tool to predict radiosensitivity. However, its correlation to outcome parameters such as repair deficient cell lines and patients, as well as an association to moderate and severe clinical radiation reactions, still remain contradictory. When IR-induced proteins reported in at least two studies were considered, a protein network was discovered, which provides a direction for further studies to elucidate the mechanisms of radiosensitivity. Although the identification of only a few of the commonly reported proteins might raise a concern, this could be because (i) our eligibility criteria were strict and (ii) radiosensitivity is influenced by multiple factors. Registration: PROSPERO (CRD42020220064).

Abstract A084: Personalized prediction of radiation sensitivity

Abstract Purpose/Objective: Patients of different races with similar cancers are often treated with radiation according to safety criteria largely collected from patients of European origin. However, even among those patients, toxicities are not predictable. Patients of African origin appear to have more severe skin radiation reactions, particularly Black women with breast cancer, than other populations. We have developed a technique using circulating cell-free DNA (cfDNA) that appears to predict toxicity in patients with otherwise similar radiation dosimetry, allowing for early intervention to prevent side effects (marketed as RadToxTM, DiaCarta, Inc.). Methods: Pre-clinical studies were performed in mice with white (BALB/c), brown (C3H/HeJ), or black (C57BL/6) fur. Radiation was delivered to the hind limb, and the skin reaction was evaluated. Blood was collected to evaluate changes in cfDNA as compared to severity of cutaneous toxicity. A phase I/II clinical study (n=54) was also performed to determine if plasma cfDNA measured early in a radiotherapy course can predict the subset of patients who experience grade 2 or higher radiotoxicity. Results: The most severe toxicity was seen in the C57BL/6 mice, and at similar doses the increase in cfDNA was higher than in the other two strains. Fifty-four patients were evaluable for the clinical study. Radiation significantly increased cfDNA on all days following the first radiation session. Acute maximum GI toxicity score, but not acute GU toxicity, was significantly correlated with cfDNA levels obtained on days 1, 2, 3, 4, and 5 of radiotherapy (p<0.005). Conclusions: Plasma cfDNA levels predicted the mouse strain that experienced more severe toxicity, and in a small study detected acute bowel toxicity. A larger study is needed to confirm the results and the value of the test for identifying patients who need special interventions to reduce toxicity. Further testing of this hypothesis is under evaluation in an NCI-funded multi-institutional study. Citation Format: Natalie Lockney, Steven G Swarts, Jennifer Li, Christopher Morris, Randal Henderson, Steven B Zhang, Zhenhuan Zhang, Sadasivan Vidyasagar, Reshu Gupta, Katherine Casey-Sawicki, Robert Zlotecki, Paul Okunieff. Personalized prediction of radiation sensitivity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A084.

Hyperbaric oxygenation for tumour sensitisation to radiotherapy.

Hyperbaric oxygenation for tumour sensitisation to radiotherapy.

Роль брахитерапии в лечении капиллярных гемангиом сетчатки

Purpose: to evaluate the efficiency of brachytherapy treatment in capillary retinal hemangioma and the emerging complications. Material and methods. Between 2005 and 2014, 18 patients with capillary hemangioma of the retina (11 females and 7 males, mean age 29 ± 13.9 years) were treated, 8 patients had monocular and 10 patients had binocular lesion. In 12 cases, capillary hemangioma of the retina was associated with Hippel - Lindau disease, in 6 cases a sporadic tumor appeared. 90Sr and 106Ru ophthalmic applicators were used. In 7 eyes, brachytherapy was preceded by laser coagulation. After local irradiation, the patients were followed up for 1 month to 3 years. Results. The pathological process was stabilized in 13 eyes. 5 eyes, no later than 3 months after the procedure, developed a severe radiation reaction, total retinal detachment, and recurrent hemophthalmos, which later, after 6 months or more, led to the development of neovascular glaucoma. In one case, the eye had to be enucleated due to terminal painful glaucoma. In 3 eyes despite tumor regression, retinal detachment persisted over the follow-up period, although the macular area remained unaffected. Complicated cataract (12 eyes), neuroretinopathy (2 eyes), appearance of new capillary hemangiomas (1 eye), increased epiretinal fibrosis (4 eyes), and secondary central chorioretinal dystrophy (2 eyes) were observed over the period of up to 2 years. Conclusion. In most cases, brachytherapy of retinal capillary brings about a satisfactory anatomical result. However, in order to reduce postoperative complications and improve the functional result, a thorough preoperative selection of patients is needed, which should take into account the initial retinal status. For citation: Neroev V.V., Saakyan S.V., Ilyukhin P.A., Valskiy V.V., Ryabina M.V., Novikova A.Yu. The role of brachytherapy in the treatment of retinal capillary hemangiomas. Russian ophthalmological journal. 2018; 11 (3): 5-10 (In Russian). doi: 10.21516/2072-0076-2018-11-3-5-10

RTtxGap: An android radiobiological tool for compensation of radiotherapy treatment interruption

Treatment interruption is not uncommon in radiotherapy. Common reasons for treatment interruption include machine breakdown, holidays and patient severe radiation reactions. Here RTtxGap, an Android application to assist calculations of compensation for treatment gap, is reported. It uses linear quadratic (LQ) model to calculate the biological effective dose (BED) that is used to solve for treatment gap compensations. Solutions are calculated using BED equation, with consideration for tissue proliferation. The accuracy of results has been verified using LQL Equiv software to be accurate within 1%. Five treatment interruption examples were used to illustrate the capability of the software to calculate the treatment compensation schedules. Solving these examples also illustrates the general consensus regarding compensating for unscheduled treatment interruptions, which ultimately involves balancing the BEDs of tumour and organ at risk. In addition to compensation for treatment gap, RTtxGap can also be used to calculate equivalent total dose in 2-Gy fraction (EQD2), to modify treatment schedule and to calculate alternative dose prescriptions having the same isoeffect.

Brachytherapy in thetreatment of the oral and oropharyngeal cancer

Background. One of the methods of radiotherapy of malignant tumors of oral cavity and oropharyngeal region today is interstitial radiation therapy – brachytherapy, allowing you to create the optimum dose of irradiation to the tumor, necessary for its destruction, without severe radiation reactions in the surrounding tissues unchanged. Brachytherapy has the following advantages: high precision – the ability of the local summarization of high single doses in a limited volume of tissue; good tolerability; a short time of treatment. At this time, brachytherapy is the method of choice used as palliative therapy and as a component of radical treatment. Objective: The purpose of this article is a literature review about the latest achievements of interstitial brachytherapy in malignant tumors of the oral cavity and oropharynx.

Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia

Background:Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213).Methods:A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The ATM gene was sequenced and ATM mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed.Results:Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense ATM mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity.Conclusion:Patient A-T213 has a milder form of A-T with biallelic ATM mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.

Radiotherapy for Glottic T1N0 Carcinoma with Slight Hypofractionation and Standard Overall Treatment Time: Importance of Overall Treatment Time

We retrospectively investigated treatment outcomes in patients with glottic T1 carcinoma treated with 65 Gy in 26 fractions four times a week and discuss the importance of the overall treatment time. Two hundred one patients with glottic T1 carcinoma were evaluated. Sixty-five Gray in 26 fractions were delivered for 200 patients, whereas 1 patient received 62.5 Gy in 25 fractions. We delivered radiotherapy once daily four times a week in this period, for a weekly dose of 10 Gy. Weekdays except Wednesday were treatment days. The overall survival rate was 96.8 ± 1.3% (standard error) at 3 years and 90.8 ± 2.2% at 5 years. The local control rate was 91.9 ± 2.0% at 3 years and 89.8 ± 2.3% at 5 years. In patients with an overall treatment time equal to or longer than 47 days, the local control rate was 82.6 ± 6.0% at both 3 and 5 years. In the patients with overall treatment time equal to or less than 46 days, the local control rate was 94.6 ± 1.9% at 3 years and 91.8 ± 2.4% at 5 years. There was a significant difference between these two groups (P = 0.0349). A severe late radiation reaction occurred in one patient. He experienced severe laryngeal edema that required tracheotomy at 6 months after the completion of radiotherapy. The tracheotomy was closed at 14 months after completion of radiotherapy. Overall treatment time seems to be an important factor for a good local control rate for glottic T1N0 carcinoma even when treated with slight hypofractionation.

Unexpectedly Severe Acute Radiotherapy Side Effects Are Associated With Single Nucleotide Polymorphisms of the Melanocortin-1 Receptor

The melanocortin-1 receptor (MC1R) regulates melanin biogenesis. Deoxyribonucleic acid sequence variants in the form of single nucleotide polymorphisms (SNPs) of MC1R affect melanin expression and are linked to skin phenotype. We aimed to determine whether SNPs of MC1R were associated with unexpectedly severe ionizing radiation reactions. The MC1R genotype of a cohort of Australians with unexpectedly severe acute and/or late reactions (Common Terminology Criteria Version 3 (CTCv3) Grade 3 or 4) to radiotherapy (RT) for cancer (n = 30) was analyzed. The findings were compared with control data from our previous study of MC1R representative of the general Australian population (n = 1,787). The difference in frequency of alleles encoding a "red hair color" phenotype in the cohort of patients with unexpectedly severe acute radiation reactions (n = 12) was significantly increased compared with the control population (p = 0.003). Acute radiosensitivity was especially associated with the R160W variant allele (odds ratio, 3.64 [95% confidence interval, 1.3-10.27]). The corresponding comparison of MC1R controls with unexpectedly severe late radiation reactions (n = 18) was not significant. It was also found that R160W as a part of the genotype in the patients with unexpectedly severe acute RT side effects as compared with the control group was also significant (p = 0.043). In this small cohort of cancer patients, deoxyribonucleic acid sequence variants of the MC1R gene, especially the R160W variant, have been associated with unexpectedly severe acute reactions to RT. This result needs to be verified in a larger cohort of patients.

Treatment outcome and prognostic variables for local control and survival in patients receiving radical radiotherapy for urinary bladder cancer

The aim of this retrospective study was to analyze the outcome of radical radiotherapy in 292 patients with bladder cancer and to identify prognostic factors for local control and survival. Median age was 72.3 years (range 45–83 years). Median follow up was 66 months (range 18–121 months). All patients were treated by use of a standard 3-field technique with 60 Gy in 30 fractions to the tumor and the bladder. The elective lymph nodes were treated with doses in the range from 46 Gy to 60 Gy. Complete response was obtained in 52% of the patients at 3-month control. However, 41% of all patients with an initial CR developed recurrence during follow-up. The 3-year and 5-year overall survival rate was 31% and 21%, respectively. Performance status, T-stage, macroscopic complete TURB, hydronephrosis, and serum creatinine were independent prognostic factors for overall survival and, thus, important for the selection of patients for curative intended radiotherapy. During radiotherapy acute transient side effects were recorded in 78% of the patients; severe bowel complications were recorded in 9 patients (3%). Following radiotherapy, 10 patients (3%) developed intestinal reactions requiring surgery. Three patients (1%) were cystectomized because of severe radiation reactions in the bladder. At 5-year follow-up, the actuarial risk of complications requiring surgery was 15%. Treatment-related mortality was 2%.

Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients

Purpose: Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion— hHR21. Methods and Materials: Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. Results: The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine → arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. Conclusions: We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

Indikationen und ergebnisse der HDR-afterloading-therapie bei erkrankungen der haut und schleimhaut mit standardisierten oberflächenapplikatoren (Leipzig-Applikator)

In our department we have developed a standardized applicator for HDR brachytherapy of surface lesions, the so called Leipzig-applicator. We have used this method since September 1987, initially with a Decatron remote afterloading machine, but more recently from November 1990 with a microSelectron-HDR. We report about our experience of 10 years. Since 1987 we treated 520 patients in 3,026 fractions with this method. In most of the cases we irradiated tumors of the skin of the face, but we also treated tumors of the mouth, of the tongue, of the perianal region and the external genitalia. The histological types were in most of the cases squamous cell carcinomas and basal cell carcinomas, but we also treated tumors like Kaposi-sarcomas, melanomas and skin manifestations of lymphomas and solid organ tumors. We also irradiated benign lesions like keloids after excision. We use single doses between 5 and 10 Gy once to twice a week. The isodose distribution was depending of the tissue infiltration of the tumor. The total dose was 30 to 40 Gy. In 91% of the cases we obtained a complete remission of the tumor, in 6% a partial remission. Recurrences appeared in 8% of the patients. In most cases the reason of the recurrence was a lower brachytherapy dose because of a prior radiotherapy. We didn't observe any severe late radiation reaction. We consider that our series of patients treated with HDR brachytherapy and a range of standardized applicators demonstrates that this is a successful method of treating surface lesions.

Chromosomal in-vitro radiosensitivity of lymphocytes in radiotherapy patients and AT-homozygotes.

We investigated the in-vitro radiosensitivity of peripheral blood lymphocytes with a special FISH/CISS-technique. From October 1993 through April 1996, a total number of 52 cancer patients was enrolled in the study. The tumor sites in these patients were: breast (n = 41), lung (n = 4), head and neck (n = 3) as well as prostate, bladder, rectal cancer and Hodgkin's disease (each n = 1). Twenty-six of them were examined prior to planned radiotherapy (prospective group) and 26 after radiotherapy (retrospective group). Three additional individuals (without cancer or radiotherapy) with proven ataxia telangiectasia (Louis-Bar syndrome, AT-homozygotes) were also investigated and their blood samples served as positive control for radiosensitivity. The clinical radiation response of normal tissue in radiotherapy patients was scored according to the WHO grading system for acute and according to the RTOG grading system for late effects. For to estimate the intrinsic radiosensitivity, blood samples were taken and irradiated in vitro with 0 (control) or 0.7 or 2 Gy with a 6 MV-linear accelerator, standard 48-hour lymphocyte cultures were prepared, chromosomes #1, #2 and #4 were simultaneously labeled with a FISH/CISS-technique and 200 to 1,000 metaphase spreads were scored for chromosomal aberrations. The radiation sensitivity of lymphocytes was expressed as the number of radiation-induced chromosomal breaks per mitosis after 0.7 Gy or 2 Gy corrected for the 0-Gy control value. The frequency of chromosomal breaks/mitosis in the unirradiated control lymphocytes was 0.020 +/- 0.015 in prospective patients who had not yet received radiotherapy. It was significantly higher in retrospective patients (0.264 +/- 0.164 breaks/mitosis) as a result of the previous radiation exposure. The 3 AT-homozygotes showed also an increased number of spontaneous chromosomal breaks (0.084 +/- 0.016 breaks/mitosis), probably resulting from the chromosomal instability in this disease. This figure, however, was significantly lower than in retrospective patients. The number of radiation-induced breaks after in-vitro irradiation was comparable in lymphocytes of patients who showed no normal tissue reaction (n = 11) as compared to those with mild to moderate radiation reaction (n = 32, acute reactions Grade 1 to 2, late reactions Grade 0 to 2). In 9 patients with unexpected severe plus late Grade 3 to 4 reactions, however, a significantly higher number of radiation-induced chromosomal breaks was measured; the highest number was observed in a patient with a radiation myelitis. The 3 AT-homozygotes showed, as expected, an extreme radiosensitivity of their lymphocytes. The number of breaks/mitosis after 0.7 Gy in vitro irradiation of lymphocytes was 0.103 +/- 0.059 in patients with no normal tissue radiation reaction (n = 11), 0.122 +/- 0.146 in the group with mild to moderate radiation reactions Grade 1 to 2 (n = 32), 0.359 + 0.226 in patients with unexpected Grade 3 to 4 normal tissue reactions (n = 9) and 0.550 +/- 0.243 in the 3 AT-homozygotes (p < 0.01, t-test). The difference in lymphocyte radiosensitivity between these 4 groups was also detected after in-vitro irradiation with 2 Gy (0.484 +/- 0.132 vs. 0.535 +/- 0.228 vs. 0.926 +/- 0.349 vs. 1.423 +/- 0.072). We found a significantly higher number of chromosomal breaks in lymphocytes of patients with severe or extreme radiation reaction of normal tissues as compared to patients with no or only mild to moderate radiation reactions. The radiosensitivity of lymphocytes in these radiosensitive patients was in the range between normal radiosensitivity and the radiosensitivity of AT-homozygotes. Detection of patients with severely enhanced intrinsic radiosensitivity might be possible with this method.

Absence of ATM truncations in patients with severe acute radiation reactions

Purpose: Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia–telangiectasia (A-T). Methods and Materials: Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM. Results: LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested. Conclusions: All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.

Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations

Background and purpose: The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy. Materials and methods: A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size. Results: Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21–77 years) and 42 years (range 23–83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan–Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years. Conclusions: Despite their younger age at presentation, breast cancer patients harboring BRCA1 or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

Treatment of Late Recurrent Vaginal Malignancy after Initial Radiotherapy for Carcinoma of the Cervix: An Analysis of 73 Cases

Purpose.To evaluate the reirradiation therapy in late recurrent vaginal malignancy after initial radiotherapy for carcinoma of the cervix.Methods.From July 1972 to July 1992, 73 cases of late recurrent (over 5 years) vaginal malignancy after initial radiotherapy for cervical cancer were treated in our hospital. Both the original and recurrent cancers were biopsy-proven squamous cell carcinoma. All of these patients received reirradiation therapy; chemotherapy or operation was combined when necessary. The reirradiation was planned according to the site and volume of the recurrent tumor, previous radiation dose, and radiation side effects. Brachytherapy was mainly used. Before 1981, radium therapy was delivered at 30–40 Gy in 3–5 fractions to tumor base within 3–4 weeks. High-dose-rate (100 cGy/min) cobalt-60 afterloading therapy (Ralstron therapy) has been used instead of radium since 1981; the dose to the tumor base was 20–35 Gy/3–5 fractions/3–4 weeks. Then, vaginal mold was supplemented with a dose to a point 0.5 cm below the surface of the vaginal mucosa at 20–30 Gy/4–6 fractions/2–3 weeks. When the vulva or groin was involved, cobalt-60 or high-energy electron beam radiation was added with a dose at 30–40 Gy. Among these, 61 patients received irradiation therapy alone. Eleven patients received irradiation combined with chemotherapy. One patient received hysterectomy after reirradiation.Results.The 2-, 3-, and 5-year survival rates in this series were 54.7% (40/73), 46.6% (28/60), and 40.3% (21/52), respectively. The 5-year survival rates for upper, upper–middle, and upper–lower vaginal tumor were 81.8% (9/11), 33.3% (5/15), and 25.0% (3/12), respectively. The effect for upper vaginal recurrent malignancy was remarkably better than that for the upper–lower rate (P< 0.05). The local control rates for tumor >4 and <4 cm were 26.6% (4/15) and 86.5% (32/37), respectively (P< 0.01). The side effects of reirradiation in this series were serious: both moderate and severe radiation reactions were rectum 13.6% (10/73), hematuria 12.3% (9/73), vesicovaginal fistula 1.4% (1/73), and rectum–vaginal fistula 11.0% (8/73).Conclusions.We conclude that reirradiation for late recurrence in the vagina after previous radiotherapy for cervical cancer is valuable. Early detection and treatment could achieve better results. The smaller the recurrent tumor volume, the better the treatment effects. Reirradiation therapy should be carefully managed in order to reduce the complications as much as possible.

The role of the gamma knife in the treatment of malignant primary and metastatic brain tumors.

Gamma knife treatment is a clinically effective, safe, and cost-effective adjunctive therapy for primary malignant brain tumors. For most brain metastases, radiosurgery is the treatment of choice and will result in effective tumor control in more than 90% of treated tumors.

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

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. 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. 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. 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.

Analysis of prognostic factors and patterns of failure in dogs with malignant oral tumors treated with megavoltage irradiation

Objective To determine quality and duration of progression-free survival (PFS) time in dogs with malignant oral tumors after definitive megavoltage irradiation, to analyze prognostic factors for PFS time and patterns of failure, and to analyze the influence of tumor recurrence and development of metastasis on survival. Design Prospective clinical trial. Animals 105 dogs with squamous cell carcinoma, fibrosarcoma, or malignant melanoma of the oral cavity without evidence of metastasis. Procedure Dogs were treated with 48 Gy over 4 weeks on an alternate-day schedule of 4 Gy/fraction. Multivariate analysis was done by use of Cox's regression model to determine significant prognostic factors and by use of a competing risk model to determine the differential effects of prognostic factors on type of, and time to, failure. In 8% of the dogs, severe acute radiation reactions in the final week of treatment resulted in treatment discontinuation. In 7.6% of the dogs, chronic radiation reactions, including bone necrosis and fistula formation, developed. Results Prognostic factors that independently affected PFS time were histologic type and tumor T stage. Histologic type significantly influenced pattern of failure, but not time to failure, whereas clinical stage significantly influenced time to failure, but not type of failure. Clinical Implications Irradiation was a safe and effective treatment of malignant oral tumors. Because the local efficacy of radiation was influenced only by tumor size, early treatment of oral tumors should improve the prognosis. In dogs without tumor recurrence, systemic metastases, rather than regional metastases, limited long-term survival after radiation therapy. (J Am Vet Med Assoc 1997;210:778–784

Analysis of prognostic factors and patterns of failure in dogs with periodontal tumors treated with megavoltage irradiation

Objective To determine quality and duration of progression-free survival (PFS) time in dogs with periodontal tumors after definitive megavoltage irradiation and to analyze prognostic factors for PFS time and patterns of treatment failure. Design Prospective clinical trial. Animals 47 dogs with acanthomatous, fibromatous, or ossifying epulis. Procedure Dogs were treated with 48 Gy over 4 weeks on an alternate-day schedule of 4 Gy/fraction. Multivariate analysis was done by use of Cox's proportional hazards regression model to determine prognostic factors for PFS time. Results The only independent prognostic factor for PFS time was tumor T stage. Pattern of local tumor recurrence (marginal vs infield regrowth) was independent of clinical stage, tumor location, and site. In 4% of the dogs, severe acute radiation reactions in the final week of treatment resulted in treatment discontinuation. In 6.4% of the dogs, chronic radiation reactions included bone necrosis. Clinical Implications Irradiation was a safe and effective treatment of small (T1 and T2 stage) periodontal tumors. The usefulness of the radiation protocol in this study is limited in dogs with large (T3) tumors, particularly those located in the caudal half of the oral cavity, because of poor results and high risk of acute radiation toxicoses. (J Am Vet Med Assoc 1997;210:785–788