Late Normal Tissue Effects Research Articles

Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: Updated results of a phase III randomized trial

The aim of this study was to compare the toxicity and efficacy of radiation therapy (RT) for localized carcinoma of the prostate, using a hypofractionated (55 Gy/20 fractions/4 weeks) vs. a conventionally fractionated (64 Gy/32 fractions/6.5 weeks) dose schedule. A total of 217 patients were randomized to either the hypofractionated (108 patients) or the conventional (109 patients) dose schedule, with planning with two-dimensional (2D) CT scan planning methodology in the majority of cases. All patients were followed for a median of 48 (6-108) months. Gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated before RT and after its completion using modified late effects of normal tissue-subjective, objective, management, analytic (LENT-SOMA) scales and the European Organization for Research and Treatment of Cancer sexual function questionnaire. Efficacy of RT based on clinical, radiologic, and prostate-specific antigen data were also evaluated at baseline and after RT. Gastrointestinal and GU toxicity persisted 5 years after RT and did not differ between the two dose schedules other than in regard to urgency of defecation. However, 1-month GI toxicity was not only worse in patients with the hypofractionated RT schedule but also adversely affected daily activities. Nadir prostate-specific antigen values occurred at a median of 18.0 (3.0-54.0) months after RT. A total of 76 biochemical relapses, with or without clinical relapses, have occurred since; of these, 37 were in the hypofractionated and 39 in the conventional schedule. The 5-year biochemical +/- clinical relapse-free and overall survival was 55.9% and 85.3% respectively for all patients, and did not differ between the two schedules. Radiation therapy for prostate carcinoma causes persistent GI toxicity that is largely independent of the two dose schedules. The hypofractionated schedule is equivalent in efficacy to the conventional schedule.

Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology

Radiation therapy has curative or palliative potential in roughly half of all incident solid tumours, and offers organ and function preservation in most cases. Unfortunately, early and late toxicity limits the deliverable intensity of radiotherapy, and might affect the long-term health-related quality of life of the patient. Recent progress in molecular pathology and normal-tissue radiobiology has improved the mechanistic understanding of late normal-tissue effects and shifted the focus from initial-damage induction to damage recognition and tissue remodelling. This stimulates research into new pharmacological strategies for preventing or reducing the side effects of radiation therapy.

SU‐DD‐A4‐01: Quantifying Skin Effects After Accelerated Partial Breast Irradiation Using Digital Infrared Imaging (DII): Preliminary Feasibility Data

Purpose: Accelerated partial‐breast irradiation (APBI) is an emerging radiation technique that challenges standard whole breast irradiation. The larger fraction sizes used in these hypofractionated schedules may increase the risk of late normal tissue effects. Identification of the causes of variability in radiation sensitivity and normal tissue reactions could have important implications for breast cancer therapy. For this, a quantitative method of estimating early and late skin effects is needed. DII is recording instantaneous skin temperatures that are directly correlated with the skin blood flow, a parameter known to be an indicator of skin reaction. Material and Methods: An infrared digital camera IRSnapShot® was used to image breast cancer patients treated with APBI to a total dose of 3850 cGy over 10 fractions. The plans consisted of multiple external non‐coplanar photons +/− electron beams. The patients were imaged in a controlled temperature room before and after each fraction. They were also be imaged at regular intervals during their follow‐up. Two sets of orthogonal DII images were taken. The images were then transferred into Matlab where a GUI is being developed for image registration, thresholding and data analysis. Results: Five patients were imaged as described, three treated with photons only, and two with a combination of photons and electrons. The increase in maximum skin temperature from the baseline (pre treatment) to treatment completion is on average 2 to 4 degrees and depends on the techniques used, higher for plans including electrons, as expected due to their way of depositing dose. Conclusions: DII generated skin temperature information is a promising quantitative tool to estimate early and late effects in irradiated breast cancer patients. Our goal is to generate an “Index of Radiosensitivity” based on the early pattern of change in skin temperature that will allow individualization of radiotherapeutic prescription.

Linear quadratic modeling of increased late normal-tissue effects in special clinical situations

To extend linear quadratic theory to allow changes in normal-tissue radiation tolerance after exposure to cytotoxic chemotherapy, after surgery, and in elderly patients. Examples of these situations are analyzed by use of the biologic effective dose (BED) concept. Changes in tolerance can be allowed for by: estimation of either the contribution of the additional factor as an equivalent BED or the equivalent dose in 2-Gy fractions or by the degree of radiosensitization by a mean dose-modifying factor (x). The estimated x value is 1.063 (95% confidence limits for the mean, 1.056 to 1.070) for subcutaneous fibrosis after cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and radiotherapy in breast cancer. The point estimate of x is 1.18 for the additional risk of gastrointestinal late-radiation effects after abdominal surgery in lymphoma patients (or 10.62 Gy at 2 Gy per fraction). For shoulder fibrosis in patients older than 60 years after breast and nodal irradiation, x is estimated to be 1.033 (95% confidence limits for the mean, 1.028 to 1.0385). The equivalent BED values were CMF chemotherapy (6.48 Gy3), surgery (17.73 Gy3), and age (3.61 Gy3). The LQ model can, in principle, be extended to quantify reduced normal-tissue tolerance in special clinical situations.

Late Toxicity and Early Prostate-Specific Antigen Outcome Following Salvage Prostate Brachytherapy for Select Patients Following Primary Radiation Therapy

Materials/Methods: Between October 2000 and December 2004, 20 men were enrolled on an IRB-approved Phase II salvage prostate brachytherapy (SBT) protocol. Biopsy-proven local recurrence was documented in the setting of a slowly rising PSA (PSA doubling time 9 months) following radiation therapy (RT). PSA failure was defined using the 1997 ASTRO consensus criteria. Late Toxicity was defined according to the 1997 Modified RTOG and Late Effects Normal Tissue Task Force criteria. Cox regression was used to assess whether pre-treatment clinical factors were significantly associated with a complication requiring surgical intervention. Kaplan Meier method was used to estimate freedom from PSA failure and freedom from late Grade 3 or 4 GI and/or GU toxicity.

153 Possible methods to determine dose modification factor in brachytherapy for the estimation of the risk of late effects of normal tissues

153 Possible methods to determine dose modification factor in brachytherapy for the estimation of the risk of late effects of normal tissues

Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy

To determine whether the use of androgen deprivation (AD) increases late morbidity when combined with high-dose three-dimensional conformal radiation therapy (3D-CRT). Between May 1989 and November 1998, 1,204 patients were treated for prostate cancer with 3D-CRT to a median dose of 74 Gy. Patients were evaluated every 3-6 months. No AD was given to 945 patients, whereas 140 and 119 patients, respectively, received short-term AD (STAD; < or =6 months) and long-term AD (LTAD; > 6 months). Radiation morbidity was graded according to the Fox Chase modification of the Late Effects Normal Tissue Task Force late morbidity scale. Covariates in the multivariate analysis (MVA) included age, history of diabetes mellitus, prostate-specific antigen (PSA) level, Gleason score, T category, RT field size, total RT dose, use of rectal shielding, and AD status (no AD vs. STAD vs. LTAD). The only independent predictor for Grade 2 or higher genitourinary (GU) morbidity in the MVA was the use of AD (p = 0.0065). The 5-year risk of Grade 2 or higher GU morbidity was 8% for no AD, 8% for STAD, and 14% for LTAD (p = 0.02). Independent predictors of Grade 2 or higher gastrointestinal (GI) morbidity in the MVA were the use of AD (p = 0.0079), higher total radiation dose (p < 0.0001), the lack of a rectal shield (p = 0.0003), and older age (p = 0.0009). The 5-year actuarial risk of Grade 2 or higher GI morbidity was 17% for no AD vs. 18% for STAD and 26% for LTAD (p = 0.017). The use of LTAD seems to significantly increase the risk of both GU and GI morbidity for patients treated with 3D-CRT.

Rectal wall sparing by dosimetric effect of rectal balloon used during Intensity-Modulated Radiation Therapy (IMRT) for prostate cancer

The use of an air-filled rectal balloon has been shown to decrease prostate motion during prostate radiotherapy. However, the perturbation of radiation dose near the air-tissue interfaces has raised clinical concerns of underdosing the prostate gland. The aim of this study was to investigate the dosimetric effects of an air-filled rectal balloon on the rectal wall/mucosa and prostate gland. Clinical rectal toxicity and dose-volume histogram (DVH) were also assessed to evaluate for any correlation. A film phantom was constructed to simulate the 4-cm diameter air cavity created by a rectal balloon. Kodak XV2 films were utilized to measure and compare dose distribution with and without air cavity. To study the effect in a typical clinical situation, the phantom was computed tomography (CT) scanned on a Siemens DR CT scanner for intensity-modulated radiation therapy (IMRT) treatment planning. A target object was drawn on the phantom CT images to simulate the treatment of prostate cancer. Because patients were treated in prone position, the air cavity was situated superiorly to the target. The treatment used a serial tomotherapy technique with the Multivane Intensity Modulating Collimator (MIMiC) in arc treatment mode. Rectal toxicity was assessed in 116 patients treated with IMRT to a mean dose of 76 Gy over 35 fractions (2.17-Gy fraction size). They were treated in the prone position, immobilized using a Vac-Lok™ bag and carrier-box system. Rectal balloon inflated with 100 cc of air was used for prostate gland immobilization during daily treatment. Rectal toxicity was assessed using modifications of the Radiation Therapy Oncology Group (RTOG) and late effects Normal Tissue Task Force (LENT) scales systems. DVH of the rectum was also evaluated. From film dosimetry, there was a dose reduction at the distal air-tissue interface as much as 60% compared with the same geometry without the air cavity for 15-MV photon beam and 2 × 2-cm field size. The dose beyond the interface recovered quickly and the dose reductions due to air cavity were 50%, 28%, 11%, and 1% at 2, 5, 10, and 15 mm, respectively, from the distal air-tissue interface. Evaluating the dose profiles of the more clinically relevant situation revealed the dose at air-tissue interface was approximately 15% lower in comparison to that without an air cavity. The dose built up rapidly so that at 1 and 2 mm, there was only an 8% and 5% differential, respectively. The dosimetric coverage at the depth of the posterior prostate wall was essentially equal with or without the air cavity. The median follow-up was 31.3 months. Rectal toxicity profile was very favorable: 81% (94/116) patients had no rectal complaint while 10.3% (12/116), 6.9% (8/116), and 1.7% (2/116) had grade 1, 2, and 3 toxicity, respectively. There was no grade 4 rectal toxicity. DVH analysis revealed that none of the patients had more than 25% of the rectum receiving 70 Gy or greater. Rectal balloon has rendered anterior rectal wall sparing by its dosimetric effects. In addition, it has reduced rectal volume, especially posterior and lateral rectal wall receiving high-dose radiation by rectal wall distension. Both factors may have contributed to decreased rectal toxicity achieved by IMRT despite dose escalation and higher than conventional fraction size. The findings have clinical significance for future very high-dose escalation trials whereby radiation proctitis is a major limiting factor.

Comparison of late rectal toxicity from conventional versus three-dimensional conformal radiotherapy for prostate cancer: Analysis of clinical and dosimetric factors

To compare late rectal toxicity (LRT) after definitive radiotherapy (DR) and salvage radiotherapy (SR) in prostate cancer using conventional (CONV) or three-dimensional conformal (3-D) techniques. The outcomes and clinical factors of 212 patients with Stage T1a-T4 prostate cancer were evaluated (separated into DR and SR groups). The median prescribed dose was 66, 74, 66, and 70 Gy, for the CONV-DR, 3-D-DR, CONV-SR, and 3-D-SR groups, respectively. LRT was scored using both Radiation Therapy Oncology Group (RTOG) and modified RTOG and Late Effects Normal Tissue (mRTOG/LENT) scales. The 4-year biochemical relapse-free survival rate was 83% for all patients, with a trend toward improvement in the 3-D groups (78% CONV and 85% 3-D, P = 0.12). One patient (1%) in the CONV group and 24 (24%) in the 3-D group experienced grade 2 or worse LRT by the mRTOG/LENT scale. Patients undergoing DR experienced grade 2 or worse LRT of 1% versus 21% (P = 0.003) for the CONV and 3-D groups, respectively. Patients undergoing SR experienced grade 2 or worse LRT of 0% versus 40% for the CONV and 3-D groups, respectively. The following variables correlated significantly with LRT on both univariate and multivariate analyses: prescribed radiation dose (P <0.0001), percentage of rectal volume receiving 60 Gy (P <0.005), and percentage of rectal volume receiving 70 Gy (P <0.001). The pretreatment clinical factors, when added to the dosimetric data, were not statistically significant on multivariate analysis (P >0.05). The prescribed radiation dose and percentage of rectal volume treated to 60 or 70 Gy had statistically significant correlations with increased LRT. The rate of grade 2 or worse LRT was greater for patients undergoing SR than for those undergoing DR. We believe that continued close attention to dosimetric variables is imperative for future studies of dose escalation.

Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience

To evaluate the efficacy of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC), including the role of dose escalation above 66 Gy level. Between July 2000 and September 2002, 63 newly diagnosed NPC patients were treated with IMRT. The disease was Stage I in 9 (14%), Stage II in 18 (29%), Stage III in 22 (35%), and Stage IV in 14 (22%). The prescribed dose was 66 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the planning target volume (PTV), and 54-60 Gy to the clinically negative neck. All 20 (100%) patients with T1-2a tumors received intracavitary brachytherapy (ICB) boost, and 15/42 (36%) patients with T2b-T4 tumors received conformal boost (8 Gy/4 fractions). Nineteen patients with advanced stage disease also received either neoadjuvant or concurrent chemotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. With a median follow-up of 29 months (range 8-45 months), 4 patients developed local in-field failure, 1 patient developed regional relapse, and 13 patients developed distant metastases. All 4 patients with local failure had either T3 or T4 disease before primary treatment and did not have ICB or conformal boost. The 3-year actuarial LRFS, NRFS, DMFS, and OS were 92%, 98%, 79%, and 90%, respectively. Multivariate analysis showed that dose escalation above 66 Gy was significantly associated with better PFS and DMFS, whereas GTV size was a significant adverse factor for OS. The worst acute mucositis was Grade 1 or 2 in 36 (59%), and Grade 3 in 25 (41%) patients. Acute dysphagia requiring tube feeding occurred in 5 (8%) patients. The proportion of patients with Grade 2-3 xerostomia was 57% at 3 months, and 23% at 2 years after IMRT. Within the subset of patients with a mean parotid dose of <31 Gy, the proportions with Grade 2-3 xerostomia were 30% and 17% at 3 months and 2 years, respectively. Our experience of using IMRT in the primary treatment of NPC showed a very high rate of locoregional control and favorable toxicity profile. Furthermore, we found that dose escalation above 66 Gy of IMRT-based therapy was a significant determinant of progression-free survival and distant metastasis-free survival for advanced T-stage tumors. Distant metastases represent the predominant mode of treatment failure.

Determination of the optimum dose per fraction in fractionated radiotherapy when there is delayed onset of tumour repopulation during treatment.

The choice of fractionation in radiotherapy involves a compromise between a number of competing radiobiological factors. The severity of late normal tissue effects may be highly dependent on fraction size, thus requiring the dose per fraction to be relatively small. This in turn leads to more fractions being used in order to maintain the tumour effect, resulting in a longer overall treatment time. In contrast, tumours possessing short clonogen doubling times ideally require shorter treatment times for improved tumour cell kill in order to reduce the impact of tumour cell repopulation. A mathematical model has been previously developed to investigate ways of optimizing the theoretical treatment outcome by estimating the optimum dose per fraction required for a given set of radiobiological parameters [1, 2]. The earlier model assumed that tumour repopulation proceeds at a constant rate right from the initiation of treatment, i.e. that there is no delay time before the repopulation process begins. However, especially for head and neck tumours, there is evidence for the existence of a lag time before the onset of compensatory re-growth [3, 4]. This report describes a modification to the earlier model and which provides a non-analytical, re-iterative, method for deriving the optimum dose per fraction which produces the maximum biologically effective dose (BED) to the tumour in the presence of a delayed start to repopulation.

Radiothérapie conformationnelle avec modulation d'intensité des cancers des voies aérodigestives supérieures avec irradiation bilatérale du cou : résultats préliminaires

To report preliminary results of a prospective study of intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinoma (HNC) with bilateral irradiation of the neck. At the Alexis Vautrin Cancer Center, 23 patients have been treated with IMRT for HNC since January 2002-August 2003. The first 10 patients with a minimum follow-up of 3 months were analyzed. All tumors were oropharyngeal. There were four females and six males, with a mean age of 50 years (range 39-66). Stages were I-II in eight and III-IV in two. CTV1 was microscopic disease and N0 neck (prescribed dose : 50 Gy) and CTV2 was macroscopic disease and the volume at risk (prescribed dose: 66-70 Gy). PTV were CTV + 5 mm. Patient's immobilization consisted of a five-point head neck shoulder thermoplastic mask. Set-up verifications were done by semi-automatically matching portal images and digitized reconstructed radiographs. IMRT used dynamic multileaf collimation. Five patients (group A) received 50 Gy IMRT (two post-operative and three with a brachytherapy boost with a mean dose: 27.5 Gy), and five patients (group B) received 66-70 Gy IMRT (four post-operative). Acute and late normal tissue effects were graded according to the RTOG-EORTC radiation morbidity scoring criteria. With a median follow-up of 7.4 months (range 3-18.5), no patient died or had loco-regional relapse. The displacements were <4 mm in 98% cases. CTV1 and 2 received 95% of the prescribed dose in 100% of the volume. On average the mean dose to the contralateral parotid was 25.5 Gy for group A vs. 31 Gy for group B (P = 0.09). Mean doses <26 Gy were obtained in three of five patients in group A vs. zero of five patients in group B (P = 0.04). Acute skin toxicities were grade 1 in five patients, grade 2 in four and grade 3 in one. Acute mucositis cases were grade 1 in three patients, grade 2 in five and localized grade 3 in two. At 3 months, 50% of the patients had a grade 0-1 late xerostomia. The 26 Gy dose limit constraint to the contralateral parotid was easier to satisfy when IMRT was prescribed at a maximum dose of 50 Gy. Acute toxicity is low. The displacements in the mask indicate that it is possible to define the PTV as CTV + 4 mm. This reduction should decrease the mean dose to the parotids. At 3 months, a 50% rate of grade 0-1 late xerostomia encourages the hope of a very low rate at 2 years.

Barium paste: useful for primary tumour localization in oral cancer.

The role of external beam radiotherapy (RT) in the management of squamous cell carcinoma (SCC) of the oral cavity is well established. The local control for early tumours (T1 and T2 lesions), when managed with RT is comparable with surgery although a direct comparison in a randomized setting is lacking. Multimodality treatment using surgical resection, RT and chemotherapy are usually required for more advanced lesions. However, with recent refinement and advancement in reconstructive techniques, surgery has gained popularity in many centres, as functional impairment from modern free flap techniques is considerably less than older surgical techniques. Nevertheless, for small volume oral cavity tumours, radiotherapy still offers excellent local control and functional results. Some patients are often too frail or unwilling to undergo radical surgery. Therefore, radiotherapy remains an effective alternative to surgery. One of the potential disadvantages of RT for oral cavity cancer is osteoradionecrosis (ORN) of the mandible. This late effect of RT may contribute to continuing morbidity in patients that are otherwise cured of their cancers and should be prevented where possible. Numerous clinical and physical factors have been reported [1] to be associated with ORN; these factors are summarized in Table 1. However, the underlying cause of ORN is often speculative as most studies are retrospective and heterogeneous. The effect of radiotherapy field size or irradiated volume, as a treatment-related factor for ORN is not comprehensively established in the literature. We previously reported the relationship between normal tissue late effects and RT treatment volume in a cohort of 333 patients with SCC of the oral cavity treated with radical radiotherapy [2]. There was no grade 3 or 4 late morbidity seen at radiation doses of 50 Gy and 52.5 Gy in 3 weeks for volumes less than 700 cm 3 and 300 cm 3 , respectively.

Assessment of morbidity in carcinoma of the cervix: a comparison of the LENT SOMA scales and the Franco-Italian glossary

Background and purpose: To assess the correlation between the LENT (late effects on normal tissue) SOMA (subjective objective management analytic) system and the Franco-Italian glossary scores of late morbidity in cervical cancer patients treated with radiation, and to compare the ability of the scoring systems to detect differences between radiation treatment groups. Materials and methods: The study was retrospective. Patients, invited to take part in the study, had radiotherapy for cervical cancer and had a minimum of 3 years follow-up with no evidence of recurrence. One hundred patients agreed to take part. LENT subjective data were obtained using a patient questionnaire approach in order to complete the scales as published. The LENT objective, management and Franco-Italian glossary scores were obtained by a physician. Correlations between scores and differences between treatment groups were examined using non-parametric tests. Results: The average LENT SOMA scores had a greater resolution than the maximum scores, and using the maximum score alone underestimated treatment morbidity. The Franco-Italian glossary scores correlated strongly with the LENT objective scores ( ρ=0.61, P<0.0005), and less strongly with the LENT subjective scores ( ρ=0.45, P<0.0005). Significant differences in morbidity between the radiation treatment groups were measured using both the LENT SOMA system and the Franco-Italian glossary. Conclusions: The maximum and average LENT scores should be reported for each subsite. The LENT objective scores correlated well with the scores obtained using the established Franco-Italian glossary, but the LENT system provided additional information on subjective treatment effects. Both systems were able to measure significant differences in morbidity between radiation treatment groups. In conclusion, the LENT SOMA system is a valid and comprehensive approach for scoring the late normal tissue effects of radiotherapy.

Evaluation of the LENT-SOMA scales for the prospective assessment of treatment morbidity in cervical carcinoma

Purpose To examine the Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) scales prospectively in carcinoma of the cervix treated curatively with radiotherapy (RT) using interviews and postal questionnaires and to test the sensitivity of the scales in assessing the radiation effects. Methods and materials A consecutive series of 100 patients completed questionnaires to score the subjective part of the published LENT-SOMA scales. Assessments were made before RT and at approximately 21, 70, 200, 400, 600, and 800 days after the start of treatment. The acceptability and feasibility of using the scales was examined using compliance in completion of the questionnaires. The scales were validated by evaluating the concordance of data obtained by two independent scorers and by examining the ability of the scales to measure radiation-related symptoms. Results Questionnaires were completed for 89 patients before RT. The level of noncompliance was 11%. The concordance between scores when two people completed the questionnaires independently was excellent. Subjective subsite scores were highest 21 days after treatment but generally fell by 70 days. The average baseline overall LENT-SOMA subjective scores increased with advancing stage ( p = 0.008) and were higher for patients treated with RT alone ( p = 0.044). Conclusion In cervical carcinoma, the LENT-SOMA scales were acceptable and feasible to administer in the clinic and appropriate in the measurement of early subjective morbidity from RT.

Evidence for efficacy without increased toxicity of hypofractionated radiotherapy for prostate carcinoma: early results of a Phase III randomized trial

Purpose: We performed a randomized trial to compare the GI and urogenital toxicity of radiotherapy (RT) for localized (confined to the organ), early-stage (T1-T2N0M0, TNM classification) carcinoma of the prostate, using a conventional (64 Gy in 32 fractions within 6.5 weeks) vs. a hypofractionated (55 Gy in 20 fractions within 4 weeks) schedule and to determine the efficacy of the respective treatment schedules. Methods and Materials: This report is based on an interim analysis of the first 120 consecutive patients in this Phase III trial after a median follow-up of 43.5 months (range 23–62). RT planning was based on two-dimensional CT data, and the treatment was delivered using a three- or four-field 6–23-MV photon technique. GI and urogenital toxicity (symptom questionnaires incorporating the subjective elements of the late effects of normal tissues—subjective, objective, management, analytic classification of late effects and the European Organization for Research and Treatment of Cancer sexual function questionnaire) were evaluated before RT and 1 month, 1 year, and 2 years after RT completion. The efficacy of RT was assessed clinically (digital rectal examination and radiologic imaging) and biochemically (prostate-specific antigen assay) at baseline, and every 3 months for 2 years after RT and every 6 months subsequently. Results: RT, whether conventional or hypofractionated, resulted in an increase in all six symptom categories used to characterize GI toxicity and in four of five symptom categories used to document urinary morbidity 1 month after therapy completion. Sexual dysfunction (based on limited data), which existed in more than one-third of patients before RT, also increased to just more than one-half of patients 1 month after RT. The increase in urinary toxicity after RT was not sustained (diurnal urinary frequency had decreased significantly at 2 years). In contrast, all six symptom categories of GI toxicity remained increased 1 year after RT. Four of the six GI symptom categories (rectal pain, mucous discharge, urgency of defecation, and rectal bleeding) were still increased at 2 years compared with baseline. Except for a slightly greater percentage of patients experiencing mild rectal bleeding at 2 years among those who received hypofractionated RT, no differences were noted in toxicity between the conventional and hypofractionated RT schedule. The mean prostate-specific antigen level was 14.0 ± 1.0 ng/mL at baseline and declined to a nadir of 1.3 ± 0.2 ng/mL at a median of 16.8 months (range 0.8–28.3) after RT completion. However, it then rose in 17 patients (8 in the hypofractionated and 9 in the conventional treatment group). Only 8 of these 17 patients were found to have signs of clinical relapse (5 local, 1 regional lymph node, and 2 systemic [bony metastases]) after histopathologic and radiologic reassessment). The remaining 9 patients had biochemical relapse only (defined as three consecutive rises in prostate-specific antigen after nadir). The 4-year biochemical relapse-free survival rate was 85.8% for all patients and did not differ significantly between the two radiation dose schedules (86.2% for the hypofractionated and 85.5% for the conventional fractionation group). Conclusion: RT for prostate carcinoma, using a three- or four-field 6–23-MV photon technique without posterior shielding of the lateral fields, is an underestimated cause of persistent GI morbidity. The incidence of clinically significant GI and urogenital toxicity after conventional and hypofractionated RT appears to be similar. Hypofractionated RT for carcinoma of the prostate seems just as effective as conventional RT after a median follow-up approaching 4 years.

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

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

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

Purpose: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.Methods and Materials: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.Results: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm3 of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).Conclusion: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.

Curative radiotherapy for primary orbital lymphoma

Purpose : To review our institutional experience with primary orbital lymphoma and determine the prognostic factors for survival, local control, and distant metastases. In addition, we also analyzed the risk factors for complications in the radiotherapeutic management of this tumor. Methods and Materials : Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32–89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000–4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000–5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6–232). Results : The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival. Seven patients (15%) developed distant recurrence (brain 2, extremity 2, mediastinum 1, liver 1, and retroperitoneum 1). One patient (2%) developed cervical node metastasis. The 5- and 10-year cataract-free survival rate was 56.7% and 32.9%, respectively. Of the 12 lens complications, 8 were LENT Grade 1 and 4 were Grade 3 toxicity. Only male gender predicted for an increased risk of cataract formation. Radiotherapy dose and technique did not predict for cataract formation; however, none of the patients who underwent the lens-sparing technique developed Grade 3 lens toxicity or required surgical correction. Of the nine corneal events, two were Grade 1, four Grade 2, and three were Grade 3 toxicity. Ten dry eyes were recorded; all were mild, and no patient had severe dry eye syndrome. Neovascular glaucoma was seen in 1 patient. No injury to the retina or optic nerve was reported. Conclusion : Radiotherapy alone is a highly effective modality in the curative management of primary orbital lymphoma. Most complications were minimal and did not require medical or surgical intervention. Although the use of the lens-sparing technique did not influence the incidence of cataractogenesis, we continue to recommend this approach whenever possible, because our experience indicates a higher grade of toxicity occurs and a higher incidence of corrective surgery is needed in patients treated without lens protection.

Acute ocular toxicity and long-term visual outcome of primary and adjuvant hyperfractionated/accelerated radiation therapy of advanced paranasal sinus cancer employing proton irradiation

Materials/Methods: Between 1991 and 2001, HART (4 MeV photons and 160 MeV protons) was used to treat 35 pts with advanced stage primary (n 32) or recurrent (n 3) malignant tumors of the paranasal sinuses for whom full neuroophtalmologic follow-up was obtained. Median age was 52 years (range, 18.5-74.4). Ten (29%) unresectable patients were treated with primary and 25 (71%) with adjuvant radiation therapy, respectively. Chemotherapy (CT) was administered to 13 (37%) patients, however, none received concurrent CT. Prospectively specified neuro-ophtalmologic follow-up consisted of pupillary examination, exophtalmometry, color vision and ocular pressure measurements, motility testing, as well as dilated fundus exam and Goldmann visual field. The median dose to the macroscopic gross tumor volume (GTV) was 69.6 CGE (range, 60-76.6 CGE, CGE proton Gy 1.1 RBE). Optical apparatus dose constraint was 2 CGE/day and 56 CGE total dose, respectively. If clinically indicated, the treating physician had the option to relax the optical dose constraints. Median GTV and clinical tumor volume were 90 cc (range, 5.4-318) and 251 cc (range, 40.9-636), respectively. Lens and retinal late complications were graded according to objective portion of the SOMA scale of the Late Effects of Normal Tissue (LENT) Scoring system. Other late ocular/visual symptoms were classified according to the NCI Common Toxicity Criteria (CTC) grading system. Disease-free Survival (DFS) and visual complication free survival (CFS) rate were calculated using KaplanMeier method. The studied risk factors for late visual complications included dose, gender, age, acute ocular toxicity, GTV volume, adjuvant chemotherapy and follow-up length. Statistical analysis was performed on SAS 8.1 software, using adequate methods including Student T-test and Log rank analysis. The median follow-up was 37.6 months (range, 4.4-122.8).