Ching-Yeh Hsiung

Oral glutamine to alleviate radiation-induced oral mucositis: a pilot randomized trial

PURPOSE To evaluate the influence of oral glutamine on radiation-induced oral mucositis in the radiotherapy of head and neck cancer. METHODS AND MATERIALS From July 1997 through June 1998, 17 patients with head and neck cancer receiving primary or adjuvant irradiation were randomized to either glutamine suspension (16 g in 240 ml normal saline) (n = 8) or placebo (normal saline) (n = 9) arm. Patients were instructed to swish the test solutions (30 ml) four times per day. All patients received half-mouth irradiation at least. Patients were treated 1.8 Gy per fraction daily, 5 days a week. We evaluated the grading of oral mucositis daily fraction at each day of treatment until 45 Gy/25 fractions. World Health Organization (WHO) step analgesic medication and body weight change were compared between the two arms. RESULTS The duration of objective oral mucositis > or = Grade 1 (p = 0.0097), Grade 2 (p = 0.0232), and Grade 3 (p = 0.0168) was shorter in the glutamine arm. Mean maximum grade of objective oral mucositis was less severe in the glutamine arm (1.6 vs. 2.6) (p = 0.0058). Glutamine did not reduce the duration and severity of subjective oral mucositis except for duration > or = Grade 3 (p = 0.0386). In the analysis of mean maximum WHO step of analgesic medication, there was no statistical difference (p = 0.5374) between the two arms. Mean body weight change was also not significantly different (p = 0.8070). CONCLUSIONS Oral glutamine may significantly reduce the duration and severity of objective oral mucositis during radiotherapy. It may shorten the duration of > or = Grade 3 subjective mucositis.

The degree and time-course assessment of radiation-induced trismus occurring after radiotherapy for nasopharyngeal cancer.

Objectives/Hypothesis: The objectives were to measure the degree of trismus induced after radiation therapy for nasopharyngeal cancer and assess its progress over time.

INTENSITY-MODULATED RADIOTHERAPY VERSUS CONVENTIONAL THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR BOOST OR SALVAGE TREATMENT OF NASOPHARYNGEAL CARCINOMA

PURPOSE To compare intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy (3D-CRT) for the boost treatment of new-onset nasopharyngeal carcinoma (NPC) or the salvage treatment of locally recurrent NPC. METHODS AND MATERIALS Between January 14 and February 23, 2000, 5-field 3D-CRT treatment plans were generated for 14 consecutive NPC patients using the ADAC Pinnacle planning system in Chang Gung Memorial Hospital, Kaohsiung, Taiwan. The planning data of these patients were later transferred to Memorial Sloan-Kettering Cancer Center, where new IMRT plans, also using 5-7 radiation fields were created for each patient using an inverse treatment planning system. The IMRT and 3D-CRT plans were compared for all 14 patients. The relationship between the anatomic shapes and locations of targets and the results of different plans were studied. RESULTS Target doses were more homogeneous in IMRT plans. The average maximal brainstem dose (D(05), the dose received by 5% of the brainstem volume) decreased from 30.9% of the prescription dose with 3D-CRT to 15.3% and 14.7% with 5- and 7-field IMRT, respectively (p = 0.004 and 0.003, respectively, compared with 3D-CRT, paired Students t test). Five anatomic factors were found that predicted greater benefits with IMRT. These factors were (1) vertical length of target >7 cm, (2) minimal distance between target and brainstem <0.1 cm, (3) maximal AP overlap of target and brainstem >0.6 cm, (4) maximal AP overlap of target and spinal cord >1 cm, and (5) vertical overlap of target and eyes >0 cm. For the 7 patients with at least 1 of these 5 anatomic factors, the benefits achieved by IMRT planning would have been greater than the benefits for the other 7 patients (p = 0.005, Fishers exact test). CONCLUSION For boost or salvage treatment of NPC, lower normal tissue doses and more homogeneous target doses were achieved with IMRT plans. For NPC patients with at least 1 of the 5 anatomic factors, IMRT is highly recommended.

Evaluation of concave dose distributions created using an inverse planning system

PURPOSE To evaluate and develop optimum inverse treatment planning strategies for the treatment of concave targets adjacent to normal tissue structures. METHODS AND MATERIALS Optimized dose distributions were designed using an idealized geometry consisting of a cylindrical phantom with a concave kidney-shaped target (PTV) and cylindrical normal tissues (NT) placed 5-13 mm from the target. Targets with radii of curvature from 1 to 2.75 cm were paired with normal tissues with radii between 0.5 and 2.25 cm. The target was constrained to a prescription dose of 100% and minimum and maximum doses of 95% and 105% with relative penalties of 25. Maximum dose constraint parameters for the NT varied from 10% to 70% with penalties from 10 to 1000. Plans were evaluated using the PTV uniformity index (PTV D(max)/PTV D(95)) and maximum normal tissue doses (NT D(max)/PTV D(95)). RESULTS In nearly all situations, the achievable PTV uniformity index and the maximum NT dose exceeded the corresponding constraints. This was particularly true for small PTV-NT separations (5-8 mm) or strict NT dose constraints (10%-30%), where the achievable doses differed from the requested by 30% or more. The same constraint parameters applied to different PTV-NT separations yielded different dose distributions. For most geometries, a range of constraints could be identified that would lead to acceptable plans. The optimization results were fairly independent of beam energy and radius of curvature, but improved as the number of beams increased, particularly for small PTV-NT separations or strict dose constraints. CONCLUSION Optimized dose distributions are strongly affected by both the constraint parameters and target-normal tissue geometry. Standard site-specific constraint templates can serve as a starting point for optimization, but the final constraints must be determined iteratively for individual patients. A strategy whereby NT constraints and penalties are modified until the highest acceptable PTV uniformity index is achieved is discussed. This strategy can be used, in simple patient geometries, to ensure the lowest possible normal tissue dose. Strategies for setting the optimum dose constraints and penalties may vary for different optimization algorithms and objective functions. Increasing the number of beams can significantly improve normal tissue dose and target uniformity in situations where the PTV-NT separation is small or the normal tissue dose limits are severe. Setting unrealistically severe constraints in such situations often results in dose distributions that are inferior to plans achieved with more lenient constraints.

Changing Quality of Life in Patients with Advanced Head and Neck Cancer after Primary Radiotherapy or Chemoradiation

Objective: The purpose of this study was to investigate the longitudinal changes in quality of life (QoL) for patients with advanced stage (stage III or IV) head and neck squamous cell carcinoma (HNSCC) following primary radiotherapy (RT) or concomitant chemoradiotherapy. Methods: From January 2001 to January 2003, 149 patients with advanced HNSCC were enrolled. The data pertaining to their QoL were collected using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and the EORTC Head and Neck Module (QLQ-H&N35) before and 1 year after RT. Results: Sixty-eight (46%) patients dropped out during the study period. Thirty-nine (57%) of them died of cancer. Those who were older, stage IV, treated by RT alone, or had worse pretreatment EORTC QoL scales were significantly more likely to drop out. For those completing the study, only the problems of swallowing, dry mouth, and sticky saliva were found to become more serious with both statistical (p < 0.05) and clinical (difference >10 points) significance 1 year after RT. Those subjects with cancer at the hypopharynx/larynx had a 3.3-fold higher probability to report an improvement in global QoL (95% confidence interval, CI: 1.11–6.82) than those with cancer at the oral cavity/oropharynx. Those alive without cancer 1 year after RT had a 3.6-fold higher probability to report an improvement in global QoL (95% CI: 1.32–7.13) than those alive with cancer. Conclusion: The study showed a high dropout rate in this longitudinal QoL study for patients with advanced HNSCC. Pretreatment cancer sites and living with cancer or not after treatment significantly affected the change in global QoL 1 year after RT.

Intensity-modulated radiotherapy for nasopharyngeal carcinoma: the reduction of radiation-induced trismus

The purpose of this study was to evaluate the degree of radiation-induced trismus after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). From 2003 to 2004, 17 non-metastatic NPC patients treated with parotid-sparing IMRT were enrolled. The maximal interincisal distance (MID) was measured to represent the maximum mouth opening. All 17 patients had both pre- and post-IMRT measurements taken, and the normalized MID (post-IMRT MID/pre-IMRT MID) was analysed to evaluate the percentage decrease in MID after IMRT. The median follow-up time was 20.5 months. One patient had nodal failure and was successfully salvaged with radiotherapy. All 17 patients were alive without cancer at the last follow-up. The average MID before IMRT was 46.2 mm (standard deviation (SD), 8.6 mm). The average MID at 12 months post-IMRT was 45.4 mm (SD, 8.9 mm). The averages of normalized MID were 94% (SD, 3.9%) at 5 months post-IMRT and 98.1% (SD, 4.2%) at 12 months post-IMRT. Based on the satisfactory preservation of normalized MID (average of 98.1% at 12 months post-IMRT), we demonstrate that IMRT reduces radiation-induced trismus in NPC patients. The recovery of normalized MID exists in the period from 5-12 months post-IMRT.

Concomitant boost radiation therapy for inoperable non–small-cell lung cancer: preliminary report of a prospective randomized study

PURPOSE The radiation therapy results for patients with inoperable non-small-cell lung cancer (NSCLC) have been disappointing. Tumor dose escalation using concomitant boost technique (CBT) has been shown to improve local control in a few prospective studies. This trial was carried out to prospectively assess the radiation response and acute toxicity of CBT in comparison to the conventional treatment technique (CTT). METHODS AND MATERIALS Ninety-seven consecutive eligible patients were entered in this prospective clinical trial between November 1994 and February 1998. Patients were randomized to receive either CBT (43 patients) or CTT (54 patients) radiation therapy. These patients either refused chemotherapy or were judged as unsuitable for chemotherapy. Patients in the CBT group received 46.8 Gy in 26 fractions using large fields that encompassed the gross and occult disease. A concomitant boost of 18.2 Gy (0.7 Gy per fraction) was delivered to the gross disease using small fields with 1.5-cm margins. The small fields were treated concurrently with the large fields and the total dose to the tumor area was 65 Gy in 26 fractions. Patients in the CTT group received 70.8 Gy in 38 fractions. The acute toxicity between each group was compared. The response rate was analyzed and compared by treatment group, gender, age, stage, histology, initial Karnofsky performance score (KPS), severity of acute toxicity, and maximum body weight loss (MBWL) during treatment course. RESULTS The demographic parameters such as sex, age, and stage were evenly distributed in each treatment group. The majority of these patients had Stage IIIA and IIIB disease. Overall median treatment times were 39 days for the CBT group of patients and 62 days for the CTT group. No treatment-related mortality was found. There were 2 patients in the CTT group with acute RTOG Grade 3 lung toxicity, and no Grade 3 lung or esophageal toxicity was observed in CBT group. The response rates, assessed by radiographic images, were 69.8% and 48.1% for the CBT and CTT patients, respectively. Univariate and multivariate analysis revealed that patients in the CBT group, patients with better KPS, and patients with more severe acute toxicity had a higher response rate. CONCLUSION This study demonstrates that concomitant boost radiation therapy is tolerable, and produces a superior response rate than conventional radiation therapy for patients with inoperable NSCLC. The length of treatment was reduced from 38 to 26 treatment days, almost a 30% reduction.

Prognostic Factors and Results of Radiotherapy for Brain Stem Gliomas

Purpose:To analyze the prognostic factors and treatment results in patients with brainstem gliomas following radiotherapy. Materials and Methods:Between 1986 and 2000, 44 patients with brain stem gliomas were evaluated retrospectively. Included were 27 males and 17 females ranging in age from 3 to 74 years (median, 26.5 years). Out of 19 patients with histologically proven glioma, 13 had a partial tumor resection. These patients were treated with various combinations of surgery and radiotherapy. A median total tumor dose of 55.9 Gy was given in daily fractions of 1.8-2.0 Gy. The median follow up time of survivors was 3years. Results: Neurological improvement was achieved in 16/44 patients. Reduction of tumor size was reported in 4/44, in 28 patients the lesion was unchanged, and 12 patients progressed radiologically. Median time to progression was 13.2 months, and median overall survival time was 17.9 months with an actuarial survival of 53% at 1 year, 37% at 2 years and 27% at 5 years. For patients who had Karnofsky performance score≧70%, their median overall survival was 31.6 months compared to 7.9 months for those who had Karnofsky performance score ＜ 70% (p = 0.037). None of the other potential prognostic factors evaluated (including patient age, gender, tumor grade, tumor location, subtotal resection, presence or absence of cranial nerve palsies, total dose, 3D conformal radiotherapy, duration of symptoms, or radiological response) were associated with patient overall survival in multivariate analysis. Conclusions:Karnofsky performance score is the most important prognostic factor in this study. The result of radiotherapy for brain stem glioma is still disappointed. It is necessary to continue to search for more effective treatment methods.

Three Dimensional Conformal Radiation Therapy to Portal Vein Thrombosis Area as the Initial Treatment for Hepatocellular Carcinoma With Portal Vein Thrombosis: Prognostic Factors and Outcome for Patie

Background and Purpose: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) indicated poor prognosis and is the contraindication for transcatheter hepatic arterial embolization (TAE). Although the conventional method of external irradiation to HCC has been proven not effective, three-dimensional conformal radiation therapy (3D-CRT) may be an alternative choice. In this study, the prognostic factors and results of 3D-CRT to PVT area as the initial treatment for HCC with PVT patients who could not receive other treatments was investigated. Materials and Methods : From September 1997 to August 1999, 42 patients who were initially diagnosed as HCC with PVT without any previous treatment and Eastern Cooperative Oncology Group (ECOG) performance status superior to Grade II were enrolled into the study. Radiation therapy (RT) was given via 3D-CRT technique to PVT area with 50 Gy to 61.3 Gy in daily fraction of 1.8 Gy to 2.5 Gy by individual condition. Age, sex, ECOG performance status, Child-Pugh classification, tumor location, tumor type, invaded PVT area, radiation treatment volume, alpha-fetoprotein (AFP), upper gastrointestinal (UGI) bleeding history, viral hepatitis markers for B and C, and pre-treatment liver function, on-treatment liver function, post-treatment liver function, including Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Total Bilirubin (Bil-T), were recorded for analysis. Results: Twenty-four patients (57%) completed the RT course and others withdrew from RT due to worsened ECOG performance status. Seven complete RT patients were lost to follow-up. Nine of 17 followed patients (53%) had positive response to RT. Seven patients (41%) underwent further TAE after RT. In the patients who could complete RT, overall survival for 3 months and 6 months were 63% and 34%. Survival rate for incomplete RT patients was 24% and 8% for 3 months and 6 months respectively. There was statistically significant difference (p = 0.022) in survival between patients who completed RT and their counterpart. There were no significant difference in pre-treatment, on-treatment and post-treatment AST, ALT and Bil-T level. Only 6 patients (35%) were reported to have suspicious gastric complications. Bil-T was the only significant factor for predicting whether RT could be completed or not (p = 0.028). Conclusions : Less than half of the patients completed the planned RT and were adequately followed, indicating the poor prognosis and selection of patients in this study. Further prospective control studies with appropriate patient enrollment, such as low bilirubin level, is required to verify the feasibility, patterns of failure, and the possible benefit of 3D-CRT as the initial treatment of HCC with PVT.

Preoperative Radiotherapy in Patients with Lower Rectal Cancer: Results of Sphincter-Preservation, Treatment Outcome and Morbidities

Purpose: To study the impact of preoperative irradiation on enhancing sphincter preservation and to evaluate the treatment outcome in patients with lower rectal cancer. The results were analyzed for the endpoints of sphincter preservation, sphincter function, pelvic control, disease-free survival, overall survival and treatment-related morbidities. Materials and Methods: From 1992 to 1996, 43 patients with clinically resectable rectal cancer received preoperative radiotherapy at our department. All of these patients had undergone a prospective clinical assessment by their surgeons and were declared to require an abdominoperineal resection due to the proximity of the tumor to the anal sphincter. The whole pelvis received 37.5 Gy in daily fraction of 2.5 Gy with parallel opposed anterior-posterior portals. Results: Thirty of the forty-three patients (70%) were able to undergo low anterior resection. The majority (88%) of patients had good sphincter function after sphincter-preserving surgery. The pathologic stage was T2 in 11 patients and T3 in 32 patients. The 3- year overall survival rate, disease-tree survival rate, and local control rate of the 43 patients were 60%, 62%, and 89%, respectively. In univariate analysis, pathologic stage and the presence of regional lymphadenopathy were noted as significant prognostic factors for both overall survival and disease-free survival. With regard to local control, only the presence of regional lymphadenopathy showed prognostic significance for local control. No difference in survival rate and local control rate was observed between patients undergoing low anterior resection and those undergoing abdominoperineal resection. In multivariate analysis, pathologic stage was noted as the only independent prognostic factor for disease-free survival; likewise, only the presence of lymphadenopathy was demonstrated as an independent predictor for local control. No clinical and pathologic parameters were proved to be independent prognostic factors for overall survival. Acute intestinal toxicity included grade 1 in 10 (23%) patients, grade 2 in 18 (42%) patients, and grade 3 in 2 patients (5%). No patients had acute urological toxicity. Conclusion: With the help of preoperative radiotherapy, a significant proportion of patients would have a chance to receive sphincter-preserving surgery. Furthermore, the preserved sphincter functioned well in most of the patients. Further efforts should be made to reduce the treatment-related morbidities.