Animal models of radiation retinopathy - From teletherapy to brachytherapy.

Radiation retinopathy is a serious vision-impairing complication of radiation therapy used to treat ocular tumors. Characterized by retinal vasculopathy and subsequent retinal damage, the first sign of radiation retinopathy is the preferential loss of vascular endothelial cells. Ensuing ischemia leads to retinal degradation and late stage neovascularization. Despite the established disease progression, the pathophysiology and cellular mechanisms contributing to radiation retinopathy remain unclear. Clinical experience and basic research for other retinal vasculopathies, such as diabetic retinopathy and retinopathy of prematurity, can inform our understanding of radiation retinopathy; however, the literature investigating the fundamental mechanisms in radiation retinopathy is limited. Treatment trials have shown modest success but, ultimately, fail to address the cellular events that initiate radiation retinopathy. Animal models of radiation retinopathy could provide means to identify effective therapies. Here, we review the literature for all animal models of radiation retinopathy, summarize anatomical highlights pertaining to animal models, identify additional physiological factors to consider when investigating radiation retinopathy, and explore the use of clinically relevant tests for studying in vivo models of radiation retinopathy. We encourage further investigation into the mechanistic characterization of radiation retinopathy in the hope of discovering novel treatments.

Incidence of second tumours in high risk prostate cancer patients according to the primary treatment applied. / Incidencia de segundos tumores en pacientes con cáncer de próstata de alto riesgo según el tratamiento primario aplicado.

INTRODUCTION AND OBJECTIVES: The onset of second primary tumours should be considered in high-risk prostate cancer patients in the natural course of the disease. Our aim was to evaluate the influence of primary treatment with curative intent for these patients on the development of second primary tumours. MATERIAL AND METHODS: A retrospective study of 286 patients diagnosed between 1996 and 2008, treated by radical prostatectomy (n=145) or radiotherapy and androgen blockade (n=141). The homogeneity of both series was analysed using the Chi-squared test for the qualitative variables, and the Student's t-test for the quantitative variables. A multivariate Cox regression analysis was performed to assess whether the type of primary treatment influenced the development of second tumours. RESULTS: The median age was 66 years, and the median follow-up was 117.5 months. At the end of follow-up, 60 patients (21%) had developed a second primary tumour. In the prostatectomy group it was located in the pelvis in 13 (9%) cases, and those treated with radiotherapy and hormonotherapy in 8 (5.7%) cases (P=.29). The most common organ sites were: colo-rectal in 17 (28.3%) patients, the lung in 11 (18.3%), and the bladder in 6 (10%) patients. In the multivariable analysis, the risk of a second tumour doubled for those treated with radiotherapy and hormonotherapy (HR=2.41, 95%CI: 1.31-4.34, P=.005) compared to the patients treated by prostatectomy. Age and rescue radiotherapy did not behave as independent predictive factors. CONCLUSIONS: The onset of a second primary tumour was related with the primary treatment given; thus the risk for those treated with radiotherapy and androgen deprivation therapy more than doubled.

The effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial.

AIM: Radiation-induced mucositis is an early effect of head and neck radiotherapy. Mucositis can cause ulcers, and patients may experience pain and dysphasia which need treatment. The aim of this study is to evaluate the effect of pure natural honey on radiation induced mucositis. METHODS AND MATERIALS: In this randomized single blind (examiner blind) clinical trial 40 patients with head and neck cancer requiring radiation to the oropharyngeal mucosa were randomly assigned to two groups. Twenty patients assigned to the study group received honey, while both the study and control groups received standard head and neck radiation therapy based on a standard protocol. In the study group patients were instructed to take 20 ml of honey 15 minutes before radiation therapy, then again at intervals of 15 minutes and six hours after radiation. In the control group patients were instructed to rinse with 20 ml of saline before and after radiation. Patients were evaluated weekly for progression of mucositis using the Oral Mucositis Assessing Scale (OMAS). Data were analyzed using the independent t-test, Mann-Whitney, and Friedman tests. RESULTS: A significant reduction in mucositis among honey-received patients compared with controls (p=0.000) occurred. CONCLUSION: Within the limits of this study the results showed the application of natural honey is effective in managing radiation induced mucositis. CLINICAL SIGNIFICANCE: Natural honey is a product with rich nutritional qualities that could be a pleasant, simple, and economic modality for the management of radiation mucositis.

[Teletherapy ocular complications. A clinical case]. / Complicaciones oculares tras teleterapia. Caso clínico.

CLINICAL CASE: An 82-year-old pseudophakic male patient developed several ocular complications after teletherapy for cavum carcinoma. Three years after receiving the radiotherapy, he presented with a right optic neuritis with some posterior improvement. Five years later he developed an ischemic retinopathy and a severe dry eye syndrome. DISCUSSION: Ocular complications due to radiotherapy used to treat nasopharyngeal carcinomas are not as common as those caused by epiescleral radiotherapy for choroidal melanoma, but must be taken into account due to their special severity. We present a single case of a patient who suffered several subsequent ocular complications after such radiotherapy.

[Treatment of clinically localized prostate cancer. Part III--external beam radiotherapy]. / Leczenie klinicznie zlokalizowanego raka gruczolu krokowego. Czesc III--teleradioterapia.

The optimal management of clinically localized (T1, T2) prostate cancer remains controversial. Patients have possibility of choice between prostatectomy and radiotherapy in two forms: external beam radiotherapy and brachytherapy. Multicentre studies show comparable results of theise two methods. The aim of this paper is to present current knowledge regarding treatment with conformal radiotherapy. Acute and late effects of ionizing radiation are described. Propriety of associate radiotherapy with hormonotherapy was analyzsed.

Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?

PURPOSE: Breast angiosarcomas are rare vascular malignancies that arise secondary to irradiation or de novo as primary tumours. The aim of this study is to know whether c-myc amplification can reliably discriminate these two entities. MATERIEL AND METHODS: Forty-seven patients treated for breast angiosarcomas were studied. Thirty-two patients were diagnosed with postradiation angiosarcomas after breast cancer treatment and 15 patients with primary angiosarcomas. Interphase fluorescence in situ hybridization (FISH) was performed by hybridization of probes covering C-MYC (chromosome 8q24.21) and CEP8 on tissue sections. RESULTS: Amplification (5- to 20-fold) of the c-myc oncogene was found in all breast radiation-induced angiosarcomas (32 tumours) but in none of the 15 primary angiosarcomas except one (7%). CONCLUSION: This study reinforces that there are true pathogenetic differences between the two types of breast angiosarcomas which are morphologically indistinguishable. These data point the pathways preferentially involved in the pathogenesis of post radiation angiosarcomas of the breast and may provide the basis for an additional targeted therapy.

Current issues in the management of advanced Hodgkin's disease.

During the past two decades, the standard drug regimen has been the MOPP program and its variants MVPP or ChlVPP. The search for less toxic chemotherapy in terms of decreased sterility and myelodysplasia-acute non-lymphocytic leukemia prompted the design of ABVD. Recent data from different countries indicate that adriamycin-based combinations as ABVD or MOPP alternating with ABVD appear very useful to improve treatment outcome compared to MOPP alone. The combination of chemotherapy and radiation has been utilized by many institutions in practically all stages of Hodgkin's disease. The intent is to optimize the cure rate and with the theory that less intensive therapy of both modalities may carry a lower risk of iatrogenic complications without compromising treatment outcome. In patients relapsing from curative radiotherapy, combination chemotherapy such as ABVD or MOPP/ABVD is recommended as the most effective salvage regimen, associated to further irradiation if technically feasible. In patients relapsing from primary chemotherapy, clinicians have first to take into consideration whether the duration of first complete remission is longer than 12 months. In this case, retreatment with the same drug regimen remains the treatment of choice. In patients with progressive lymphoma while on primary chemotherapy or showing remission duration lesser than 12 months, non-cross resistant chemotherapy or high dose therapy plus autologous bone marrow transplantation are indicated.

Acute side effects and late complications after radiotherapy of localized carcinoma of the prostate.

In the last two decades, many authors have treated prostatic carcinoma by radiation therapy. Accumulated data have been updated, after 10 and 15 years of follow-up. In stage A and B, the reported survival and local control rates after irradiation (20, 22, 30, 34, 35, 39, 42) are as good as in selected patients treated by radical prostatectomy (9, 18, 23). In stage C, the results after irradiation (20, 22, 30, 42) are better than after radical surgery (23, 43). However, patients are nonrandomly selected and the methods of statistical analysis differ. Therefore, a valid comparison cannot be made. The therapeutic ratio is determined by survival and local control, and also by therapy related complications. It is therefore of interest to find out from radiotherapy series if their incidence is related to the treatment technique. Unfortunately, relatively few studies accurately describe treatment technique and complications. Gastro-intestinal radiation injury becomes significant when the dose at the posterior rectal wall is 65-76 Gy and the length of the treated rectum is at least 10 cm. A hot spot of 80-84 Gy needs to be only 2 to 3 cm to increase the risk of late bowel stenosis. Genito-urinary complications are influenced by local extension of the tumor and by previous surgical manipulations. A dose at the prostatic area exceeding 70 Gy should be avoided, as it does not improve local control (22, 35) and apparently increases the risk of late urethral stricture and penile/scrotal edema (12, 39). The dose at the anterior bladder wall correlates with other types of genito-urinary complications. Therefore, the anterior bladder wall should not receive a dose higher than 65 Gy. Incidence of impaired potency after irradiation is usually 30 to 40%, which is much less than after radical surgery. As many data in the literature dealing with radiation treatment of the prostate are still inadequate a more standardized reporting is recommended to make comparison of effectiveness and side effects possible.

Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.

Delayed radiation-induced bulbar palsy.

We report a man with a slowly progressive bulbar palsy 14 years after radiation therapy for nasopharyngeal carcinoma. Electromyography demonstrated prominent myokymic and neuromyotonic discharges in muscles innervated by the lower cranial nerves. Late effects of radiation therapy can occur in the cranial nerve musculature that are similar to well-recognized syndromes affecting the brachial plexus and spinal cord.

Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkin's disease.

A 27 year old man with Hodgkin's disease experienced three separate episodes of chest pain, each occurring on the sixth day of a cycle of mustargen, oncovin, procarbazine, prednisone (MOPP) combination chermotherapy. The first episode appeared to represent a myocardial infarction, whereas the next two were less serious. Numerous studies were performed including coronary angiography, cardiac catheterization and open pericardial biopsy. It is suggested that the patient represents an example of a previously undescribed syndrome due to chemotherapy administered after cardiac irradiation.

Cylindroma of the nasopharynx: a chronic disease.

From March 1958 to October 1984, 10 patients with cylindroma (cystic adenoid epithelioma) arising in the nasopharynx were treated in our hospital. The presenting symptoms of these patients ranged in duration for 2 weeks to 8 years, with an average of 25 months. Eighty percent of the patients had destruction of the base of skull and 60% had cranial nerve involvement. Of these 10 patients, two had Stage II disease, two had Stage III, and six had Stage IV. Response was seen in this tumor at tissue doses between 5000-8000 rad. Of the seven patients at risk for 5 years, 86% survived, yet 36% of the patients died of tumor between the fifth to tenth year. Fifty percent of the patients lived beyond 10 years. Based on this experience, a dose of more than 8000 rad is advised for the primary lesion. For the neck region, radiation is indicated only when there are lymph node metastases; prophylactic radiation of the neck is not necessary. Local recurrence or single distant metastasis is amenable to radiation therapy. Among the six patients who failed in the course of follow-up, three had local recurrences, two had pulmonary metastases, and one died of cerebral vascular accident.

Cancer of the supraglottic larynx treated by radiotherapy exclusively.

Seventy-six cases of squamous cell carcinoma of the supraglottic larynx treated by radiotherapy exclusively and followed for at least 3 years are reported. High doses, close to the maximum tolerable, were used with the shrinking field technique with no attempt at prophylactic whole neck irradiation. T1 and T2 cases represented 40% of the whole group and 40% of the patients presented clinically positive neck disease. This latter group had a significantly lower cure rate (42.8%) than the N0 patients (88.3%). Disease control depended also on the T stage: all 30 T1 and T2 lesions, 18/22 (81.8%) of the T3, and 6/17 (35.3%) of the T4 lesions were controlled. Cord fixation and early cartilage destruction were not a major obstacle for tumor control. Base of tongue involvement and especially the T4 and N3 association were indications of poor prognosis. Adenopathies smaller than 3 cm were controlled in 14/16 cases while nodes greater than or equal to 3 cm were controlled in 5/11 cases. Failures in neck nodes outside the treatment field were encountered in 7% of the cases but as the sole element of failure they represented 5.6%. Absolute survival at 3 years was 69.7% for the whole series while loco-regional control was 74.6%. No patient was salvaged by surgery. Three loco-regional recurrences occurred 3 years after the treatment. Although no lethal complications were encountered severe late reactions were noted in about 20% of the patients with controlled primary lesion, requiring tracheostomy in 4 cases (7%). Treatment guidelines are suggested: T1, T2, & T3 lesions associated with adenopathy smaller than 3 cm should be treated by radiotherapy. Limited extra laryngeal extension especially to cartilage can still be controlled by irradiation. More advanced cases, especially the subcategory of T4 N3 patients, should have a multidisciplinary approach. After high doses of irradiation only limited surgery is permissible.

Experience of telecobalt therapy in operable breast cancer at J. Bordet Institute (1969-1975).

Between 1969 and 1975, postoperative radiotherapy was performed at the J. Bordet Institute on 787 stage I-III operable breast cancer patients. Crude 10 years survival rates are respectively 61% for stage I, 59% for stage II and 30% for stage III. The results have been analysed according to clinical characteristics of significant prognostic value and according to the technical conditions of treatment. The status of the axillary nodes appears to be the most important prognostic factor. Radiotherapy to the thoracic wall and lymph drainage areas has varied little throughout the whole period with the dose to the internal mammary chain being the only parameter which varied significantly. Loco-regional recurrences occurred only in 5, 2% of patients without distant metastases appearing previously or during the following year (2.4 for stage I patients). Severe sequelae were seen in only a very few cases. Survival appears significantly correlated with an adequate dose of irradiation to mammary node chain.

Supraglottic laryngeal carcinoma: an analysis of dose-time-volume factors in 410 patients.

Four hundred and ten patients with supraglottic laryngeal carcinoma treated with moderate dose radical radiotherapy with surgery for salvage (RRSS) were analyzed in detail to determine optimal dose-time-volume parameters to be used in the treatment of each stage of supraglottic carcinoma. In the RRSS group 41% are alive and well at 5 years, 38% died of their tumor and 21% of intercurrent disease. Presence or absence of nodal disease has a major impact on survival. Local control is approximately 70% in T1, T2N0 patients and approximately 50% in T3 and T4N0 patients. Seventeen percent of T1 and T2N0 patients failed in the initially negative neck. Ten major complications (2.4%) have been seen. Local control by irradiation was not influenced by dose or field size. Regional control in the initially negative neck was markedly increased with the use of larger irradiation field sizes. Field sizes of less than 7 X 7 cm resulted in an 18% neck failure rate as compared to 3% with larger field sizes (p = 0.00005). This particularly applied to early stage disease. As a result of the use of larger irradiation field sizes giving reduced neck failure rates, improvement in survival has been seen in early stage supraglottic patients. The results are compared with published results. There is no statistically significant dose response curve in any stage of supraglottic cancer over the dose range 1650-2300 ret. Optimal treatment factors for supraglottic cancer are discussed.

Long-term results of proton beam therapy for carcinoma of the uterine cervix.

PURPOSE: To determine the role of proton therapy in patients with carcinoma of the uterine cervix. METHODS AND MATERIALS: Between 1983 and 1991, 25 patients with squamous cell carcinoma of the uterine cervix (stages IIB-IVA) were treated with a curative intent by external photon irradiation to the pelvis, followed by proton irradiation to the primary tumor, delivering a median total tumor dose of 86 Gy (range 71 Gy/26 Fr-101 Gy/46 Fr), and were followed for a median period of 139 months (range 11-184 months). RESULTS: Ten-year overall survival rates for stages IIB and IIIB/IVA patients were 89% and 40%, respectively. Five-year local control rates for stages IIB and IIIB/IVA patients were 100% and 61%, respectively. Four percent of patients experienced severe (Grade 4 or more) late complications in the intestine or urinary bladder at 5 years. CONCLUSION: External photon and proton therapy is effective for those who are not eligible for intracavitary irradiation, and who otherwise have a poor prognosis. The results show that tumor control, survival, and morbidity are similar to those after conventional therapy.

External radiation therapy of stage I cancer of the endometrium: a need for reappraisal of this adjunctive modality.

One hundred and eighty-five patients with Stage I cancer of the endometrium were irradiated preoperatively. All were irradiated to the whole pelvis by external beam only using supermegavoltage apparati. The total mid-pelvis dose ranged from 4500 cGy/5 weeks to 5500 cGy/6 1/2 weeks. Surgery followed usually in 6 weeks. Complications were minimal. Disease-free survival at Stage IA was 92.4% 5-year, 87.7% 10-year; Stage IB was 83.5% 5-year, 74.6% 10-year. Prognosis was related to stage, grade, depth of myometrial penetration, the presence of "residual" tumor at hysterectomy. External beam preoperative irradiation is recommended for all Stage I patients; Stage IB with higher grade pathology should have intracavitary irradiation supplemental to the external irradiation.

High-dose-rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications.

PURPOSE: This retrospective analysis aims to report results of patients with cervix cancer treated by external beam radiotherapy (EBR) and high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: From September 1992 to December 1996, 138 patients with FIGO Stages II and III and mean age of 56 years were treated. Median EBR to the whole pelvis was 45 Gy in 25 fractions. Parametrial boost was performed in 93% of patients, with a median dose of 14.4 Gy. Brachytherapy with HDR was performed during EBR or following its completion with a dose of 24 Gy in four weekly fractions of 6 Gy to point A. Median overall treatment time was of 60 days. Patient age, tumor stage, and overall treatment time were variables analyzed for survival and local control. Cumulative biologic effective dose (BED) at rectal and bladder reference points were correlated with late complications in these organs and dose of EBR at parametrium was correlated with small bowel complications. RESULTS: Median follow-up time was 38 months. Overall survival, disease-free survival, and local control at 5 years was 53.7%, 52.7%, and 62%, respectively. By multivariate and univariate analysis, overall treatment time up to 50 days was the only statistically significant adverse variable for overall survival (p = 0.003) and actuarial local control (p = 0.008). The 5-year actuarial incidence of rectal, bladder, and small bowel late complications was 16%, 11%, and 14%, respectively. Patients treated with cumulative BED at rectum points above 110 Gy(3) and at bladder point above 125 Gy(3) had a higher but not statistically significant 5-year actuarial rate of complications at these organs (18% vs. 12%, p = 0.49 and 17% vs. 9%, p = 0.20, respectively). Patients who received parametrial doses larger than 59 Gy had a higher 5-year actuarial rate of complications in the small bowel; however, this was not statistically significant (19% vs. 10%, p = 0.260). CONCLUSION: This series suggests that 45 Gy to the whole pelvis combined with four fractions of 6 Gy to point A with HDR brachytherapy is an effective and safe fractionation schedule in the treatment of Stages II and III cervix cancer if realized up to 50 days. To decrease the small bowel complications, we decreased the superior border of the parametrial fields to the S2-S3 level and the total dose to 54 Gy.

Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems.

PURPOSE: To test the correlation of LENT/SOMA and RTOG/EORTC late-effect scales for rectum and bladder, 116 cases with gynecologic malignancies that were treated with radiotherapy were assessed with both scales. METHODS AND MATERIALS: All cases had been treated at least 6 months before the date of assessment with external beam radiotherapy (50--54 Gy to midline) and 1--2 fractions of HDR brachytherapy (2 x 8.5 Gy to point-A for 32 inoperable cases; 1 x 9.25 Gy to 5--9 mm from the ovoid surface for 84 postoperative cases). The patients were questioned with both scales, and the correlation between the two scales was analyzed by Spearman's rho (rank correlation) test. RESULTS: There were 64 cases with uterine cervix carcinoma and 52 cases with endometrium carcinoma, The overall (external + brachy) doses to ICRU points were 57.8 +/- 3.8 Gy for rectum and 59.3 +/- 4.9 Gy for bladder. The statistical analysis of LENT/SOMA and RTOG/EORTC scales revealed a very good correlation for rectum (r = 0.81; p < 0.01) and a good correlation for bladder (r = 0.72; p < 0.01). CONCLUSION: The LENT/SOMA system is a further step on the reporting of late radiation effects. Some modifications will improve its precision, and multicentric randomized studies are needed to test its validity.