Late Toxicity Data Research Articles

Three-dimensional conformal postoperative radiotherapy in patients with parotid tumors: 10 years' experience at the European Institute of Oncology

Salivary gland malignancies are rare. The aim of our study was to investigate radiotherapy-related toxicity and clinical outcome in patients treated at our division with postoperative radiotherapy (pRT) for parotid tumors. Forty-three consecutive patients (32 with primary parotid tumors, 9 with parotid metastases and 2 with recurrent benign diseases) were retrospectively analyzed. The median follow-up was 28 months. Twenty and 5 patients had a follow-up longer than 2 and 5 years, respectively. Thirty-seven patients were alive and most of them (78%) were free from disease. The local and distant control rates were higher in patients with primary parotid tumors (94% and 87.5%) than in patients with parotid metastases (87.5% and 75%). Grade 3 radiotherapy-related acute toxicity of skin and mucosa was recorded in 20.9% and 28% of patients, respectively. Two patients (4.7%) had grade 4 skin toxicity. Late toxicity data were available for 33 (77%) patients. None of the patients developed severe (grade 3 and 4) late toxicity of soft tissues, skin or temporomandibular joints. Postoperative radiotherapy is a feasible treatment that was found to be effective mainly in patients with primary parotid tumors. Toxicity was acceptable but could probably be further reduced using more advanced radiotherapy techniques. Longer follow-up is required to achieve definitive results.

The Impact of Clinical Factors on the Development of Late Radiation Toxicity: Results from the Medical Research Council RT01 Trial (ISRCTN47772397)

Aims A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. Materials and methods Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. Results On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio = 1.63, 95% confidence interval 1.18, 2.24; P = 0.003) and increased stool frequency (hazard ratio = 1.77, 95% confidence interval 1.27, 2.46; P = 0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio = 0.25, 95% confidence interval 0.09, 0.71; P = 0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio = 1.04 per year of age, 95% confidence interval 1.01, 1.08; P = 0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio = 2.09, 95% confidence interval 1.48, 2.95; P < 0.0005), increased urinary incontinence (hazard ratio = 4.22, 95% confidence interval 2.13, 8.35; P < 0.0005) and decreased stream (hazard ratio = 2.64, 95% confidence interval 1.62, 4.31; P < 0.0005), after treatment and before the most recent follow-up assessment. Conclusions In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed.

Update of the HIPRO study: Late toxicity and outcome at seven years.

81 Background: Dose-escalated radiotherapy for localised prostate cancer improves disease control but at the expense of increased overall treatment time and late toxicity. Given the low alpha-beta ratio for prostate cancer, treatment with hypofractionation should be biologically advantageous. Intensity-modulated radiotherapy (IMRT) allows dose escalation with hypofractionation, while achieving acceptable levels of toxicity. We report our 7 year late toxicity data in patients treated with two such regimens within the Hypofractionated Dose Escalation utilising Intensity-modulated Radiotherapy in Carcinoma of the Prostate (HIPRO) study. Methods: Sixty men, median age 75 years (50-87), with localised adenocarcinoma of prostate (T1-3NOMO) and either Gleason score ≥7 or PSA 20-50ng/L received 57Gy in 19 fractions (n=30) or 60Gy in 20 fractions (n=30) using 5-field inverse-planned IMRT. All patients received neoadjuvant hormone therapy, continuing for up to 6 months after treatment. Late toxicity was assessed at 7 years follow-up using RTOG criteria and LENT/SOMA questionnaire. Results: Forty-four (73%) patients were alive at 7 years. Nine patients (21%) reported RTOG grade 1 bowel or bladder toxicity; there was no grade 2 toxicity or above and no difference between the fractionation schedules. LENT/SOMA questionnaires were returned by 31/44 patients. Mean and median scores were less than one for bowel and urinary symptoms. When compared with pre-treatment, the proportion of patients with significant (maximum LENT/SOMA ≥2) urinary symptoms remained similar (75% vs. 76%), problems with sexual function had decreased (84% vs. 98%) but bowel symptoms increased (62% vs. 25%). At 5 years, overall survival was 83% and 74% and cause-specific survival was 83% and 84% in the 57Gy and 60Gy groups respectively. Conclusions: Dose-escalated hypofractionated IMRT for prostate cancer appears well tolerated with acceptable levels of late toxicity. Studies to assess long term disease control with these regimens are on-going. No significant financial relationships to disclose.

Late Toxicity and Outcome at 7 Years in Patients Treated within the HIPRO Study

Introduction: Dose-escalated radiotherapy for localised prostate cancer improves disease control but at the expense of increased overall treatment time and late toxicity. The low alpha-beta ratio for prostate cancer suggests treatment with hypofractionation should be biologically advantageous. Intensity modulated radiotherapy (IMRT) allows dose escalation with hypofractionation, while achieving acceptable levels of toxicity. We report our outcome and 7 year late toxicity data in patients treated this way within the HIPRO (Hypofractionated Dose Escalation utilising Intensity Modulated Radiotherapy in Carcinoma of the Prostate) study.

Abstract P4-11-05: Acute and Late Toxicity Results from the SECRAB Trial: The Optimal SEquencing of Adjuvant Chemotherapy (CT) and RAdiotherapy (RT) in Early Breast Cancer (EBC)

Abstract Background: SECRAB is a large multicentre randomised controlled trial designed to determine the optimal sequence of CT and RT for women with EBC. The second objective of this trial was to determine if CT and RT treatment modalities could be given together without increased toxicity or compromising either modality. See abstract no 851519 for details of CT and RT scheduling. Methods: Data on acute skin reaction was collected on completion of RT and graded as mild, moderate or severe. Late toxicity data was collected annually and included lymphoedema, telangiectasia, severe subcutaneous fibrosis, brachial plexopathy, rib fracture, ischaemic heart disease, symptomatic lung fibrosis, and clinical radiation pneumonitis. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Acute toxicity data was collected on 2267 patients who received RT. The distribution of RT schedules was balanced across treatment arms, with the majority of patients (67%) receiving 40Gy/15F (15F). Significantly more patients in the Syn arm experienced a delay of &amp;gt;10 days in CT delivery (11% vs 5%, p &amp;lt; 0.0001). Very few patients experienced a &amp;gt;7 days delay in RT in either arm (Syn n=12 vs Seq n=3). In a sub-set of 880 patients dose intensity of CT was not significantly different between the two arms. Percentage skin toxicities for the Syn and Seq arms respectively were: None 22.9 vs 36.3; Mild 52.4 vs 48.1; Moderate 20.2 vs 13.6; Severe 3.8 vs 1.1. A significantly (p &amp;lt; 0.001) higher proportion of patients on the Syn arm suffered a moderate or severe skin reaction compared to those on the Seq arm. An unplanned exploratory analysis by duration of RT showed that patients receiving &amp;gt;15F (45Gy/20F or 50Gy/25F) had a significantly worse acute skin reaction than those receiving 15F (25% vs 16%, p=&amp;lt;0.001). 5 patients on the Syn arm were admitted to hospital as a result of a severe RT reaction, 3 received &amp;gt;15F. Acute radiation pneumonitis was 0.3% in both arms (n=5 in total). Percentage late toxicities for the Syn and Seq arms respectively were not significantly different for: moderate/severe lymphoedema 6.1 (n=70) vs 5.5 (n=64); severe subcutaneous fibrosis 1.3 (n= 15) vs 0.6 (n=7); brachial plexopathy 0.2 (n=2) vs 0.1 (n=1); rib fracture 0.6 (n=7) vs 0.4 (n=5); ischaemic heart disease 0.4 (n=5) vs 0.4 (n=2); symptomatic lung fibrosis 0.3 (n=15) vs 0.3 (n=7); and late clinical radiation pneumonitis 0.1 (n=1) vs 0.1 (n=1). Howevermoderate/severe telangiectasia was 2.5% vs 1.3% in the Syn and Seq arms respectively (p =0.05). This difference was not seen in patients receiving 15F. Conclusions: The delivery of Syn CT-RT in the adjuvant treatment of EBC is associated with an increase in acute skin toxicity however the percentage of severe reactions is less than 5%. These skin reactions were seen predominantly in patients treated with concurrent RT (&amp;gt;15F). An increase in late skin telangiectasia was also seen in patients receiving &amp;gt;15F. There was no difference in other late toxicities recorded. Syn CT-RT is feasible in the adjuvant treatment of EBC and does not result in a reduction in dose intensity of delivered CT. The optimal schedule is 40Gy/15F which is now the standard regime used in the UK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-05.

Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer

Surgery has been the treatment of choice for patients with rectal cancer. For locally advanced cancer results were poor, with high rates of locoregional recurrences and poor overall survival data. Adding (chemo)radiotherapy upfront improved results mainly in locoregional control. Adding hyperthermia to radiotherapy preoperatively might have an equivalent beneficial effect. To quantify the potential beneficial effect of thermo radiation compared to chemo-radiation with respect to pathological complete responses, overall survival and toxicity in rectal cancer therapy. We identified the relevant phase II and III randomised controlled trials in any language trough electronic searches May 2007 of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2007), the Cochrane Colorectal Cancer Groups Specialised Register, MEDLINE (from 1966), EMBASE (from 1974), CINAHL (from 1982). Furthermore, various trial databases were searched for the identification of recent completed and ongoing trials (metaRegister of Controlled Trials, Cancer Research UK, Cancer.gov, The Eastern Cooperative Oncology Group Trials Database). All studies identified until May 2007 were considered for inclusion in the present study. Only phase II and III randomised controlled clinical trials were included in the analysis. All identified studies were assessed by two independent reviewers. A weighted estimate of the treatment effect was computed for 2, 3, 4 and 5-year survival, for local tumour recurrence, severe acute and late toxicity and complete tumour response (CR). CR was defined either clinically by disappearance of all pretreatment signs of local tumour or pathologically by microscopically free margins. The risk ratio (RR) and hazard ratio (HR) were used. Analyses were performed with the Reference Manager (RevMan). Six RCTs published between 1990 and 2007 were identified. A total number of 520 patients was treated, 258 in the radiotherapy only arm (RT) and 262 in the radiotherapy-hyperthermia arm (RHT). Four studies (424 patients) reported overall survival (OS) rates. After 2 years, OS was significantly better in the RHT group (HR 2.06; 95% CI 1.33-3.17; p=.001), but this difference disappeared after a longer period (3, 4 and 5 year OS). All but one studies reported CR rates. A significant higher CR rate was observed in the RHT group (RR 2.81; 95% CI 1.22-6.45; p=.01). Only 2 studies reported on acute toxicity. In these 2 studies no significant differences were observed between the RT and the RHT group. Late toxicity data were not reported. Further studies are needed to compare chemoradiation versus thermoradiation versus chemoradiation plus hyperthermia in well selected/conducted and quality controlled randomised trials.

Developing a CTCAEs patient questionnaire for late toxicity after head and neck radiotherapy

Purpose Patient-based reporting of symptoms is increasingly important in providing treatment toxicity information. However, observer-based scoring systems such as the CTCAEs which incorporate the LENT-SOMA scales are not adapted for patient-based reporting. We aim to (1) report the late toxicity in patients following head and neck radiotherapy using a LENT-SOMA patient-based questionnaire, (2) describe how the responses help to improve the questionnaire and (3) adapt the questionnaire for patient reporting using CTCAEs. Methods A 31-item LENT-SOMA patient questionnaire was administered prospectively to 220 patients pre-treatment and at eight time periods post-radical head and neck radiotherapy over 3 years. Exploratory factor analysis was carried out and questionnaire reliability was evaluated using Cronbach’s α coefficient. Results At 3-years follow-up, grade 3/4 toxicity was recorded for xerostomia (44%), hoarseness (14.3%), altered taste (6.1%) and oropharyngeal pain (1.9%). Factor analysis indicated that questionnaire division according to anatomical sub-site was reasonable. Cronbach’s α was 0.851 (95% CI: 0.820–0.883) indicating high reliability. Good compliance was obtained with all questions except for the ‘weight loss’ item. A satisfaction survey showed that the questionnaire was clear and concise. Teeth and mandible sections have been removed. Dietary change due to xerostomia has been incorporated in line with CTCAEs. LENT-SOMA scoring of analgesic needs and dysphagia not described in CTCAEs were found useful and have been retained. Conclusions The questionnaire has enabled reporting of late toxicity and the responses have enabled refinement of the questionnaire. It is reliable, feasible and has been validated for patient-based collection of CTCAEs late toxicity data.

Hypofractionated Intensity-Modulated Radiotherapy for Carcinoma of the Prostate: Analysis of Toxicity

Dose escalation for prostate cancer improves biological control but with a significant increase in late toxicity. Recent estimates of low alpha/beta ratio for prostate cancer suggest that hypofractionation may result in biological advantage. Intensity-modulated radiotherapy (IMRT) should enable dose escalation to the prostate while reducing toxicity to local organs. We report late toxicity data of a hypofractionated IMRT regime. Eligible men had T2-3N0M0 adenocarcinoma prostate, and either Gleason score >or= 7 or prostate-specific antigen 20-50 ng/L. Patients received 57-60 Gy to prostate in 19-20 fractions using five-field IMRT. All received hormonal therapy for 3 months before radiotherapy to a maximum of 6 months. Toxicity was assessed 2 years postradiotherapy using the RTOG criteria, LENT/SOMA, and UCLA prostate index assessment tools. Acute toxicity was favorable with no RTOG Grade 3 or 4 toxicity. At 2 years, there was 4% Grade 2 bowel and 4.25% Grade 2 bladder toxicity. There was no Grade 3 or 4 bowel toxicity; one patient developed Grade 3 bladder toxicity. UCLA data showed a slight improvement in urinary function at 2 years compared with pretreatment. LENT/SOMA assessments demonstrated general worsening of bowel function at 2 years. Patients receiving 60 Gy were more likely to develop problems with bowel function than those receiving 57 Gy. These data demonstrate that hypofractionated radiotherapy using IMRT for prostate cancer is well tolerated with minimal late toxicity at 2 years posttreatment. Ongoing studies are looking at the efficacy of hypofractionated regimes with respect to biological control.

Clinical Outcome for Chemoradiotherapy in Carcinoma of the Cervix

Aims Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone. Materials and methods Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40 mg/m 2 weekly with radiotherapy, (the neoadjuvant dose was 60 mg/m 2 3 weekly). External beam radiotherapy was given to the pelvis (40–45 Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5–32.5 Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15–20 Gy/8–10 fractions). Results The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% ( P = 0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant ( P = 0.14). Conclusion There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.

Fit of a Generalized Lyman Normal-Tissue Complication Probability (NTCP) Model to Grade ≥ 2 Late Rectal Toxicity Data From Patients Treated on Protocol RTOG 94-06

RTOG 94-06 was a multi-institutional dose-escalation trial designed to determine the maximum tolerated dose for 3D conformal radiotherapy (3D-CRT) of prostate cancer. The purpose of the present study was to estimate the parameters of the Lyman NTCP model using censored time-to-toxicity data for the grade ≥ 2 rectal toxicity endpoint among patients treated on RTOG 94-06.

Patient-Assessed Late Toxicity Rates and Principal Component Analysis After Image-Guided Radiation Therapy for Prostate Cancer

The aims of this study were to determine the incidence of patient-assessed late toxicity after high-dose, image-guided radiation therapy in a cohort of men with prostate cancer; and to correlate toxicity with conventional dosimetric parameters and rectal and bladder dose-volume histograms (DVH) reduced using principal component analysis. Toxicity questionnaires were sent to 690 men treated for localized prostate cancer to 75.6 Gy or 79.8 Gy using three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) between 1997 and 2003 at the Princess Margaret Hospital. Toxicity was graded according to the modified Radiation Therapy Oncology Group (RTOG)-late effects normal tissue (LENT) scoring system. Late rectal and bladder toxicity scores were dichotomized as < Grade 2 and > or = Grade 2, and correlated with dosimetric parameters and with the first three principal components of rectal and bladder DVHs. In all, 63% of the patients completed the questionnaire. At a median follow-up of 37 months, the incidence of late rectal toxicity RTOG Grades 1, 2, and 3 was 25.2%, 2.5%, and 0.7% respectively. The incidence of late urinary toxicity RTOG Grade 1, 2, and 3 was 16.5%, 8.8%, and 0.9% respectively. Maintenance of erectile function sufficient for intercourse was reported in 68%. No dosimetric parameter analyzed, including principal component analysis reduction of DVHs, correlated with late toxicity. Postal questionnaire was effective for collection of patient-assessed late toxicity data. The incidence of late toxicity was low, with a lack of correlation to dosimetric parameters. We attribute this to the use of conformal techniques and daily image guidance.

Late toxicity after adjuvant radiochemotherapy for gastric adenocarcinoma

14042 Background: There is limited late toxicity data following adjuvant radiochemotherapy for resected gastric cancer. Methods: We reviewed radiation dose volume histograms (DVHs) and toxicity outcomes for gastric cancer patients (stage Ib to IV) who received adjuvant conformal radiochemotherapy between November 2000 and May 2005. Charts were reviewed to determine survival, late clinical toxicity, and biochemical markers of renal or hepatic toxicity (creatinine, bilirubin, ALP, AST, ALT). DVHs for kidneys and liver were correlated with toxicity outcomes. Overall (OS), disease-free (DFS) and event (death or late toxicity) -free (EFS) survival were calculated. Results: 80 of 88 patients’ DVHs were available for review. Mean age was 58 years (range: 22 - 75), with 53 (66%) males and 27 (34%) females. Stage distribution was: IB - 13 (16%), II - 32 (40%), IIIA - 24 (30%), IIIB - 4 (9%) and IV - 7 (9%). 3D conformal radiotherapy (45 Gy/25 fractions) was used. In 69 patients, chemotherapy was standard as per the INT-116 study; 11 study patients received infusional 5FU (200mg/m2/day for 12 weeks) and cisplatin in escalating dose (4 cycles q 2 weeks, 0–30 mg/m2). All treatment was completed in 56 (70%) patients; 9 (11%) did not complete radiotherapy and 22 (27.5%) had chemotherapy dose omissions. Median follow up is 30 months (range 6–62). At 2 years, OS was 84% (95% CI 73%-90%), DFS was 66% (95% CI 53%-75%) and EFS was 61% (95% CI 49–72%). Clinical late toxicity occurred in 6 patients 9 to 53 months following treatment: bowel obstruction/perforation (2) and anastomotic stricture (4), in volumes treated to 45 Gy. No clinical symptoms of renal or hepatic toxicity were reported. Grade 1 (CTCAE v3.0) elevation of creatinine was observed in 8 (10%) patients; at least one liver test was altered in 22 (27.5%) patients, (grade 1–17; 2–4; 3–1). Abnormal bloodwork occurred 9 days to 55 months following treatment and did not correlate with higher kidney and liver doses. Conclusions: In our cohort of patients treated with conformal radiochemotherapy, small bowel and anastomotic toxicity was most common, with no clinical renal or hepatic toxicity observed. Biochemical renal and hepatic changes were not related to clinical toxicity or dose delivered. Further assessment with longer follow-up in a larger sample is planned. No significant financial relationships to disclose.

A pilot trial of TAC (paclitaxel, doxorubicin, and carboplatin) chemotherapy with filgastrim (r-metHuG-CSF) support followed by radiotherapy in patients with “high-risk” endometrial cancer

To determine the toxicity, tolerability, and feasibility of delivering combination chemotherapy with subsequent radiation therapy to women with high-risk endometrial cancer and to evaluate the long-term bowel toxicity of this regimen. The trial was approved by the Dana Farber/Partners Cancer Care (DFPCC) Institutional Review Board (IRB). Patients with stage 3 or stage 4 endometrial cancer or patients with high-risk histology and any stage disease were prospectively entered. Complete surgical staging and a normal gated blood pool scan were required prior to entry. Patients were treated with three cycles of paclitaxel (160 mg/m(2) ), doxorubicin (45 mg/m(2)) and carboplatin (AUC 5) (TAC) all on day 1 of a 21-day schedule as an outpatient with G-CSF support. At the conclusion of chemotherapy, patients received radiation therapy (4500 cGy to the whole pelvis) commencing within 35 days of the last cycle of chemotherapy. Paraaortic radiation and/or vaginal brachytherapy were allowed at the discretion of the treating radiation oncologist. Twenty patients were entered onto the trial from November 2000 through February 2003. Eighteen patients successfully completed the trial, and two patients came off trial during chemotherapy (both later completed planned radiation therapy). Patients were initially stage 1 (n = 3), stage 3 (n = 14), and stage 4 (n = 3). Papillary serous was the dominant histology with 13 patients. Chemotherapy was given on average within 32 days of surgery (range 11-63 days) and radiation was initiated on average within 14 weeks of surgery (range 10-18 weeks). Chemotherapy was well tolerated, with 57 total cycles delivered of a planned 60 cycles. Two patients required dose modification in two cycles (two patients in cycle 3 secondary to hematologic toxicity). No grade 3 or grade 4 neurotoxicity was reported. There were six episodes of grade 3 short-term toxicity with radiation therapy reported in a single patient. Late radiotherapy toxicity included bowel obstruction requiring laparotomy in two patients and grade 3 constipation in one patient. Late radiation toxicity data are still being collected as follow-up continues. The TAC chemotherapy regimen is well tolerated and three cycles were delivered successfully with G-CSF support without evidence of the neurotoxicity or cardiac toxicity reported with the cisplatin containing TAP regimen. Standard radiation was deliverable following TAC therapy without excessive toxicity. Further study of this regimen with subsequent radiation therapy is warranted in patients at risk for systemic and regional recurrence of their malignancy.

Dose–volume response analyses of late rectal bleeding after radiotherapy for prostate cancer

Purpose To compare the fits of various normal tissue complication probability (NTCP) models to a common set of late rectal toxicity data, with the aim of identifying the best model for predicting late rectal injury after irradiation. Methods and materials Late toxicity data from 128 prostate cancer patients treated on protocol with three-dimensional conformal radiotherapy at The University of Texas M.D. Anderson Cancer Center (UTMDACC) were analyzed. The dose–volume histogram for total rectal volume, including contents, was obtained for each patient, and the presence or absence of Grade 2 or worse rectal bleeding within 2 years of treatment was scored. Five different NTCP models were fitted to the data using maximum likelihood analysis: the Lyman model, the mean dose model, a parallel architecture model, and models based on either a cutoff dose or a cutoff volume. Results All five of the NTCP models considered provided very similar fits to the UTMDACC rectal bleeding data. In particular, none of the more highly parameterized models (the four-parameter parallel model, three-parameter Lyman model, or three-parameter cutoff dose and volume models) provided a better fit than the simplest of the models, the two-parameter NTCP model describing rectal bleeding as a probit function of mean dose to rectum. Conclusion No dose–volume response model has yet been identified that provides a better description of the UTMDACC rectal toxicity data than the mean dose model. Because this model has relatively low predictive accuracy, the need to identify a better model remains.

Long-term follow-up of patients with Stage III follicular lymphoma treated with primary radiotherapy at Stanford University

Purpose: To report the long-term survival and late toxicity data of Stage III follicular lymphoma patients treated with primary radiotherapy. Methods and Materials: Sixty-six patients with Stage III follicular small cleaved (FSC) or follicular mixed (FM) non-Hodgkin’s lymphoma were treated with total lymphoid irradiation (61 patients) or whole body irradiation (5 patients) as their primary treatment modality from 1963 to 1982 at Stanford University. Adjuvant chemotherapy was given to 13 patients. Results: Median follow-up was 9.5 years with a range of 0.5–24.3 years. Median overall survival, cause-specific survival, freedom from relapse, and event-free survival were 9.5, 18.9, 7.1, and 5.1 years, respectively. Few initial relapses or lymphoma-related deaths were seen beyond the first decade of follow-up. Patient age and number of disease sites were the two strongest predictors of overall survival. The cohort of patients with limited Stage III disease demonstrated an 88% freedom from relapse and a 100% cause-specific survival with up to 23.5 years follow-up. Conclusion: The long-term survival data for Stage III FSC or FM non-Hodgkin’s lymphoma treated with primary radiotherapy are at least comparable and possibly better than results achieved with other therapeutic approaches. Patients with limited Stage III disease do particularly well. Whether these results are superior to an initial approach of deferred therapy until clinically indicated is currently unknown.

Nonstandard fractionation schedules in radiation therapy of head and neck cancer: a review.

The authors present an updated review of the clinical trials on hyperfractionated and accelerated fractionation schedules in radiotherapy of head and neck cancer. The available results in terms of survival and local control, and acute and late toxicity data are summarized in order to show the current status of this research field. The new breed of fractionation schedules that are on study, designed on the ground of new rationales, are presented as well. Finally, an introductory overview of combination therapy including non standard fractionation radiotherapy associated with chemotherapy is reported.

Acute and late toxicity associated with sequential bleomycin-containing chemotherapy regimens and radiation therapy in the treatment of carcinoma of the nasopharynx

Between 1975 and 1984, 33 patients with squamous cell carcinoma of the nasopharynx received adjuvant chemotherapy before and/or after definitive radiotherapy at UT M. D. Anderson Hospital. The favored chemotherapy regimens during this time were BCMF (bleomycin, cyclophosphamide, methotrexate, and 5-FU) and PMB (cisplatinum, methotrexate, and bleomycin). Total radiation doses to the primary site averaged 65 Gy for T1 and T2 lesions and 70 Gy for T3 and T4 lesions. Neck nodes were given boost treatments to a maximum of 70 Gy, depending on the extent of the disease. The outcome of treatment in these patients was compared to that of a stage-matched group of 71 patients treated during the same time period with radiotherapy alone. However, the groups were not matched with regard to histologic subtypes: 45% of the radiation-only group had prognostically unfavorable keratinizing squamous carcinomas (WHO 1) compared with 18% of the combined modality group. Overall disease-free survival at 5 years was 63% in the combined modality group and 44% in the radiation only group ( p = 0.15). Both acute reactions and late treatment complications were much more frequent and severe in patients receiving combined modality treatment. In patients treated with chemotherapy prior to radiation therapy, 10 20 (50%) experienced severe acute toxicity (RTOG Grade 3 or 4) versus 9 71 (13%) in the radiotherapy-only group. Severe late normal tissue injury occurred in 15 33 (45%) of the combined modality group versus 5 71 (7.0%) in the control group. The majority of the late complications in the adjuvant chemotherapy group consisted of severe soft tissue and muscle fibrosis. The average total bleomycin dose in the patients with severe late soft tissue and muscle fibrosis was 336 mg. The actuarial risk of developing a severe late complication by 2 years after treatment was 68% in the combined modality group versus 8% in the radiation-therapy-only group ( p = .001). The probability of remaining both disease-free and complication-free at 5 years was 40% in the radiation-only group and 22% in the combined-modality group ( p = 0.08). Comparison of these results with other published reports emphasizes the importance of late toxicity data in assessing the ultimate value of combined modality therapy.