Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC.

BACKGROUND: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC. METHODS: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted. RESULTS: We found that NPC was associated with combined common and rare variants in CDKN2A/2B (P = 1.3 × 10-4), BRD2 (P = 1.6 × 10-3), TNFRSF19 (P = 4.0 × 10-3), and CLPTM1L/TERT (P = 5.4 × 10-3). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of CDKN2A/2B, P = 4.6 × 10-4; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU (P = 3.8 × 10-3) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs. CONCLUSIONS: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC. IMPACT: NPC-associated genes, including CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.

Survival without adjuvant chemotherapy for selected patients with stage II and III nasopharyngeal carcinoma after concurrent chemoradiotherapy alone.

BACKGROUND: The role of adjuvant chemotherapy after concurrent chemoradiotherapy (CRT) for nasopharyngeal carcinoma (NPC) is controversial. We report our phase II prospective study of withholding adjuvant chemotherapy in a subgroup of patients with American Joint Committee on Cancer (AJCC) stage II and III NPC with low risk for metastasis. METHODS: Between April 1998 and December 2008, 263 patients with stage II (AJCC 1997 T2aN0, T1-T2aN1; AJCC 2010 T1N1) NPC or stage III (AJCC 1997 T1-T2aN2; AJCC 2010 T1N2) NPC were enrolled. Patients received standard concurrent CRT with cisplatin and 5-fluorouracil (5-FU) but without adjuvant chemotherapy. RESULTS: With a median follow-up of 107 months, the 5-year overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were 92.4%, 84.4%, and 90.7% for all patients; 94.1%, 85.9%, and 92.9% for patients with stage II NPC; and 90.9%, 83.2%, and 88.9% for patients with stage III NPC, respectively. CONCLUSION: It is safe to withhold adjuvant chemotherapy for selected patients with stage II and III NPC.

Is it appropriate to apply the enhanced recovery program to patients undergoing laparoscopic rectal surgery?

BACKGROUND: The laparoscopic approach has played a key role in the successful application of the enhanced recovery program (ERP) in perioperative care for postoperative colon surgery patients. Reports of applying ERP in laparoscopic rectal surgery are rare, and the feasibility of doing so has yet to be solidly evaluated. The goal of this study was to evaluate whether it is appropriate to use ERP on patients who undergo rectal surgery via the laparoscopic approach and to further investigate potential factors that may affect the results of this practice modality. METHODS: Between December 2007 and July 2009, 80 eligible patients (35 women) with a median age of 60 (range, 28-82) years were enrolled. All patients received elective laparoscopic rectal surgery due to malignant or benign rectal lesions. Forty-nine percent of patients received preoperative neoadjuvant chemoradiotherapy (CCRT), because their clinical stage was beyond T3N0 or TanyN(+). The ERP used in this study was modified from a similar protocol used for patients receiving laparoscopic colectomy at the same institution. RESULTS: Sixty-five percent of patients in the study received a sphincter-preserving procedure, whereas 15 other patients underwent abdominoperineal resection (APR). The median operative time was 160 min. The conversion rate of laparoscopic surgery was 7.5%, and the combined intraoperative and postoperative complication rate was 13.8%. Forty-two patients (52.5% of the study pool) received complete postoperative recovery courses as prescribed by ERP. CONCLUSIONS: Our preliminary results of applying ERP to patients receiving laparoscopic rectal surgery showed a success rate of 52.5%. The failure of ERP among these patients was related to low rectal lesion locations (below 7 cm AAV) and surgery-related complications. ERP for laparoscopic rectal surgery is feasible but is not advised for all cases requiring laparoscopic rectal surgery.

Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy?

BACKGROUND: Neoadjuvant chemoradiation therapy has improved the local control rate and overall survival in locally advanced rectal cancers. The purpose of this retrospective study is to evaluate the correlation between the final pathologic stage and survival in these patients. METHODS: Patients with biopsy-proven rectal carcinoma, pretreatment staging by magnetic resonance imaging such as T3 or T4 tumors, or node-positive disease were treated with preoperative concomitant 5-fluorouracil-based chemotherapy and radiation, followed by radical surgical resection. Clinical outcome with survival, disease-free survival, recurrence rate, and local recurrence rate were compared with each T and N findings using the American Joint Committee on Cancer Tumor-Node-Metastasis (TNM) staging system. RESULTS: A total of 248 patients were enrolled in this study. Overall survival and disease-free survival at 1, 3, and 5 years were 97.1, 92, and 89.9% and 87.5, 71.1, and 69.5%, respectively. Thirty-six patients (14.5%) had a pathologic complete response after neoadjuvant therapy. The recurrence rate was significantly different between the pathologic complete response group and residual group (5.6 vs 31.1%; P = .002). Five-year disease-free survival was significantly better in the complete response group than the residual tumor group (93 vs 66%; P = .0045). There was no statistical difference in survival or locoregional recurrence rate between these two groups. CONCLUSIONS: Posttreatment pathologic TNM stage is correlated to disease-free survival and tumor recurrence rate in locally advanced rectal cancer after preoperative chemoradiation. Also, pathologic complete response to neoadjuvant treatment has its oncologic benefit in both overall recurrence and disease-free survival.

Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma.

PURPOSE: To investigate the clinical benefit of additional radiotherapy to patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE) and the molecular effects of radiation on gene expression in hepatoma cells. EXPERIMENTAL DESIGN: Between August 1996 and August 2003, 276 and 64 patients with American Joint Committee on Cancer stage T3N0M0 hepatocellular carcinoma receiving TACE alone and TACE followed by three-dimensional conformal radiotherapy, respectively, at our institution were studied. Clinical outcome and pattern of failure were analyzed for the association of survival benefit with radiotherapy. The molecular effects of radiotherapy were studied in vitro and in vivo using human hepatoma cells with different p53 mutation and hepatitis B virus infection status. RESULTS: Median follow-up and survival time in the TACE alone and TACE + radiotherapy groups were 39 and 19 months, and 51 and 17 months, respectively. Additional radiotherapy to TACE did not improve overall survival (P = 0.65). However, different failure patterns were noted after TACE and after radiotherapy. Although all irradiated tumors regressed substantially, radiotherapy rapidly enhanced both intrahepatic and extrahepatic tumor progression outside the radiotherapy treatment field in a significant portion of patients, which offset the benefit of radiotherapy on overall survival. In molecular analysis of the radiation effects on human hepatoma cells, radiotherapy rapidly induced p53-independent transcriptional up-regulation of vascular endothelial growth factor (VEGF), increased VEGF secretion in a dose-, time-, and cell type-dependent manner, and promoted hepatoma cell growth in vivo with enhanced intratumor angiogenesis, which correlated well with elevated levels of serum VEGF. CONCLUSIONS: Radiotherapy to eradicate a primary hepatocellular carcinoma might result in the outgrowth of previously dormant microtumors not included in the radiotherapy treatment field. Radiotherapy-induced VEGF could be a paracrine proliferative stimulus. Therapeutic implications of the study justify the combination of three-dimensional conformal radiotherapy with anti-VEGF angiogenic modalities for the treatment of unresectable hepatocellular carcinoma to reduce relapses.

Transanal local wide excision for rectal adenocarcinoma.

BACKGROUND/AIMS: Abdominoperineal resection is associated with high morbidity and mortality, and sphincter preservation is the aim for the patient. Transanal local wide excision of highly selected rectal cancers is an acceptable alternative to radical surgery. METHODOLOGY: This retrospective study of 18 patients with rectal cancer treated with transanal local wide excision at our hospital during a 6-year period (from 1995 to 2001) is discussed. RESULTS: Tumor size ranged from 1 to 6 cm (mean, 2.23 cm). All resection margins were free of tumors. There was no surgical mortality or morbidity. Median follow-up period was 17.9 months. Among 18 patients, 12 patients received radiotherapy and chemoradiotherapy as a postoperative adjuvant treatment. There was one local recurrence with liver metastasis noted within one year after the operation. The 1-yr, 2-yr and 5-yr disease-free survival rate was 92%. CONCLUSIONS: Transanal local wide excision for rectal cancer, when combined with selected chemotherapy or radiotherapy, results in good local-regional control in our series. A Good long-term survival rate was also proven by presented articles. This approach can be safely applied to more advanced tumors (T3 lesion) under accurate pre-op staging, aggressive postoperative adjuvant therapy and careful regular follow-up.

Extended-field radiotherapy and high-dose-rate brachytherapy with concurrent and adjuvant cisplatin-based chemotherapy for locally advanced cervical cancer: a phase I/II study.

OBJECTIVE: The purpose of this prospective study was to investigate the toxicity and efficacy of integrating extended-field para-aortic and pelvic external radiation, high-dose-rate intracavity brachytherapy, and concurrent and adjuvant cisplatin-based chemotherapy for locally advanced cervical cancer. METHOD: A phase I/II study was performed from 1998 to 2003 including sixty-three patients with both clinical FIGO and MRI/CT-based TNM stage IIB-IVA cervical cancer. Patients were treated with extended-field external radiation to the para-aortic and pelvic regions with 45 Gy in 25 fractions, and an additional boost to the gross nodes to 50.4 Gy and the parametrium to 59.4 Gy. Patients also received a high-dose-rate (HDR) intracavity brachytherapy with doses of 22-31 Gy to point A in 4-6 fractions. Concurrently, two cycles of cisplatin (50-80 mg/m(2)) were administered in weeks 1 and 5 during radiotherapy, as well as two cycles of cisplatin (60-80 mg/m(2)) for 1 day and 5-fluorouracil (600-800 mg/m(2)) for 4 days at 1 and 2 months after completion of radiotherapy. The treatment-related acute and late side effects were evaluated using RTOG criteria, and the disease control and survival rate were calculated using the Kaplan-Meier method. The median follow-up interval was 36 months. RESULTS: All sixty-three patients completed the planned extended-field radiotherapy and high-dose-rate brachytherapy with 2 concurrent cycles of cisplatin. Fifty-eight (92%) patients received 2 cycles of the post-radiation adjuvant chemotherapy of cisplatin and 5-fluorouracil. RTOG grade III acute toxicity was gastrointestinal (2%) and hematological (10%). No patient had grade IV acute toxicity. Late grades III-IV morbidity actuarial risk of 6% at 6.5 years primarily involved the injuries to the bowels requiring surgical intervention for intestinal obstruction or fistula formation. Initial sites of recurrence were locoregional failure alone (pelvic and para-aortic regions within the radiation field), 3%; distant metastases only, 8%; and locoregional failure plus distant metastases, 8%. The observed rates at 3-year and 5-year of locoregional control, freedom from distant metastasis, and overall survival were 86% and 86%, 81% and 81%, and 81% and 77%, respectively. CONCLUSION: Incorporating HDR brachytherapy into a regimen including concurrent chemotherapy and extended radiation appears safe and effective.

Interpretation of magnetic resonance imaging for locally advanced rectal carcinoma after preoperative chemoradiation therapy.

PURPOSE: Neoadjuvant concomitant chemoradiotherapy has been used in cases of locally advanced rectal cancer to preserve sphincter function, decrease local recurrence, and improve survival. Preoperative staging is essential for planning and providing optimal therapy. The purpose of this study is to determine the accuracy of staging with magnetic resonance imaging and to define any factors that interfere in interpretation of images obtained after preoperative chemoradiation therapy. METHODS: Thirty-six patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative concomitant 5-fluorouracil-based chemotherapy and radiation, followed six to eight weeks later by radical surgery. Preoperative magnetic resonance images were reinterpreted by one radiologist and the results compared with histopathologic staging. RESULTS: T-level downstaging occurred in 10 of 36 patients (28 percent), and N-level downstaging occurred in 29 of 36 patients (80 percent) after completion of chemoradiation therapy. Pathologic complete remission after chemoradiotherapy occurred in five patients (12 percent). Of the 36 patients, 17 (47 percent) were overstaged and 2 (6 percent) were understaged in T-level, whereas 10 patients (28 percent) were overstaged and 3 patients (8 percent) were understaged in N-level. The accuracy of magnetic resonance imaging for determining depth of wall invasion was 47 percent, with 64 percent accuracy for nodal staging. CONCLUSIONS: Magnetic resonance imaging is commonly used in staging of pelvic malignancies because of its fine resolution, but chemoradiotherapy may decrease its accuracy. Thickening of the rectal wall after radiation by marked fibrosis, and peritumoral infiltration of inflammatory cells and vascular proliferation may contribute to overestimation of stage. By contrast, pathologic residual cancer beneath normal mural structure after chemoradiation therapy may result in understaging of rectal cancer.

Prognostic significance of parapharyngeal space venous plexus and marrow involvement: potential landmarks of dissemination for stage I-III nasopharyngeal carcinoma.

PURPOSE: To determine whether the parapharyngeal space venous plexus and marrow of the skull base bones are anatomic landmarks of the potential routes for the spread of disease for Stage I-III (American Joint Commission on Cancer 1997 staging system) nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: A total of 364 patients with NPC were enrolled in this study. The selection criteria were Stage I-III disease and primary radiotherapy at our hospital between 1990 and 2001. All patients had undergone MRI to evaluate the head-and-neck tumors. Patients who had undergone inadequate radiotherapy at a dose of <60 Gy and/or preradiotherapy chemotherapy before the imaging evaluation were excluded from the study. RESULTS: Of the 364 patients treated between 1990 and 2001, 163 (44.8%) had low-risk Stage I-III NPC (without parapharyngeal space extension or T3 disease). The 5-year distant metastasis-free survival rate, with and without adjuvant chemotherapy, was 97% and 96%, respectively. The remaining 201 patients had Stage II-III with parapharyngeal space extension or T3 disease. Their 5-year recurrence-free survival rate, with and without adjuvant chemotherapy, was 76.8% and 53.2% (p = 0.01), respectively. CONCLUSION: Our findings suggest that the risk of distant metastasis in Stage I-III NPC patients without parapharyngeal space extension or T3 disease is extremely low. Invasion into the parapharyngeal space venous plexus and marrow of the skull base bones is associated with distant metastasis, and involvement of these anatomic sites is considered a potential route for hematogenous disease spread in patients with Stage I-III NPC.

Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.

PURPOSE: To identify the factors associated with radiation-induced liver disease (RILD) and to describe the difference in normal tissue complication probability (NTCP) between subgroups of hepatocellular carcinoma patients undergoing three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 89 hepatocellular carcinoma patients who completed 3D-CRT for local hepatic tumors were included. The average isocenter dose was 49.9 +/- 6.2 Gy. Logistic regression analysis was used for the association between statistically significant factors and RILD (defined as Grade 3 or 4 hepatic toxicity of elevated transaminases or alkaline phosphatase within 4 months of completing 3D-CRT) in multivariate analysis. Maximal likelihood analysis was conducted to obtain the best estimates of the NTCP model parameters. RESULTS: Of the 89 patients, 17 developed RILD. In univariate analysis, hepatitis B virus (HBV)-positive status and the mean radiation dose to the liver were the two factors significantly associated with the development of RILD. Of the 65 patients who were HBV carriers, 16 had RILD compared with 1 of 24 non-carrier patients (p = 0.03). The mean radiation dose to liver was significantly greater in patients with RILD (22.9 vs. 19.0 Gy, p = 0.05). On multivariate analysis, HBV carrier status (odds ratio, 9.26; p = 0.04) and Child-Pugh B cirrhosis of the liver (odds ratio, 3.65; p = 0.04) remained statistically significant. The best estimates of the NTCP parameters were n = 0.35, m = 0.39, and TD(50)(1) = 49.4 Gy. The n, m, TD(50)(1) specifically estimated from the HBV carriers was 0.26, 0.40, and 50.0 Gy, respectively, compared with 0.86, 0.31, and 46.1 Gy, respectively, for non-carrier patients. CONCLUSION: Hepatocellular carcinoma patients who were HBV carriers or had Child-Pugh B cirrhosis presented with a statistically significantly greater susceptibility to RILD after 3D-CRT.

How aggressive should we be in patients with stage IV colorectal cancer?

PURPOSE: The prognosis for metastatic colorectal cancer is grave. Whether to perform surgical resection or palliative treatment remains controversial for this advanced disease. In this retrospective study, we collected data from patients with Stage IV colorectal cancer to identify prognostic factors for predicting selection criteria for surgical treatment in patients with metastatic disease. METHODS: A retrospective chart review was performed for patients treated from 1992 to 1999 from the Koo Foundation Sun Yat-Sen Cancer Center Tumor Registry. Seventy-four patients were identified as having Stage IV disease at the time of diagnosis. Data concerning the patients' demographics, laboratory results, operative procedure, mortality, morbidity, and survival were collected. Independent variables and survival time were analyzed by the independent t-test method. The difference was considered statistically significant at P < 0.05. RESULTS: Overall survival time for the patients with Stage IV colorectal cancer was 16.1 months. Survival in the curative resection group was significantly longer than that in the noncurative group (31.9 vs. 12.7; P < 0.016). The operative mortality and morbidity rates were 5.6 percent (4 of 71) and 21.1 percent (15 of 71), respectively. The two most common complications were leakage at the site of anastomosis and urinary tract infection. Based on these results, we conclude that patients older than 65 years, with metastases at multiple sites, intestinal obstruction, preoperative carcinoembryonic antigen level > or =500 ng/ml, lactate dehydrogenase > or =350 units/liter, hemoglobin <10 mg/dl, or hepatic parenchymal replacement by tumor >25 percent have poor prognosis for surgical intervention. CONCLUSION: Whether to perform primary tumor resection in patients with asymptomatic Stage IV colorectal cancer remains controversial; however, the more aggressively we perform radical resection and metastasectomy to selected patients, the more survival benefits the patients obtain.

Unique role of proximal rectal dose in late rectal complications for patients with cervical cancer undergoing high-dose-rate intracavitary brachytherapy.

PURPOSE: To investigate the correlation of the radiation dose to the upper rectum, proximal to the International Commission of Radiation Units and Measurements (ICRU) rectal point, with late rectal complications in patients treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary brachytherapy (ICRT) for carcinoma of the uterine cervix. METHODS AND MATERIALS: Between June 1997 and February 2001, 75 patients with cervical carcinoma completed definitive or preoperative RT and were retrospectively reviewed. Of the 75 patients, 62 with complete dosimetric data and a minimal follow-up of at least 1 year were included in this analysis. Of the 62 patients, 36 (58%) also received concurrent chemotherapy, mainly with cisplatin during EBRT. EBRT consisted of a mean of 50.1 +/- 1.3 Gy of 18-MV photons to the pelvis. A parametrial boost was given to 55 patients. Central shielding was used after 40-45 Gy of pelvic RT. HDR ICRT followed EBRT, with a median dose of 5 Gy/fraction given twice weekly for a median of four fractions. The mean dose to point A from HDR ICRT was 23.9 +/- 3.0 Gy. In addition to the placement of a rectal tube with a lead wire during ICRT, 30-40 mL of contrast medium was instilled into the rectum to demonstrate the anterior rectal wall up to the rectosigmoid junction. Late rectal complications were recorded according to the Radiation Therapy Oncology Group grading system. The maximal rectal dose taken along the rectum from the anal verge to the rectosigmoid junction and the ICRU rectal dose were calculated. Statistical tests were used for the correlation of Grade 2 or greater rectal complications with patient-related variables and dosimetric factors. Correlations among the point A dose, ICRU rectal dose, and maximal proximal rectal dose were analyzed. RESULTS: Fourteen patients (23%) developed Grade 2 or greater rectal complications. Patient-related factors, definitive or preoperative RT, and the use of concurrent chemotherapy were not associated with the occurrence of rectal complications. The maximal rectal dose during ICRT was at the proximal rectum rather than at the ICRU rectal point in 55 (89%) of 62 patients. Patients with Grade 2 or greater rectal complications had received a significantly greater total maximal proximal rectal dose from ICRT (25.6 Gy vs. 19.2 Gy, p = 0.019) and had a greater maximal proximal rectal dose/point A dose ratio (1.025 vs. 0.813, p = 0.024). In contrast, patients with and without rectal complications had a similar dose at point A (25.0 Gy vs.23.6 Gy, p = 0.107). The differences in the ICRU rectal dose (17.8 Gy vs.15.4 Gy, p = 0.065) and the ICRU rectal dose/point A dose ratio (0.71 vs. 0.66, p = 0.210) did not reach statistical significance. Patients with >62 Gy of a direct dose sum from EBRT and ICRT to the proximal rectum (12 of 29 vs. 2 of 33, p = 0.001) and >110 Gy of a total maximal proximal rectal biologic effective dose (13 of 40 vs. 1 of 22, p = 0.012) presented with a significantly increased frequency of Grade 2 or greater rectal complications. The correlations between the maximal proximal rectal dose and the ICRU rectal dose were less satisfactory (Pearson coefficient 0.375). Moreover, 11 of the 14 patients with rectal complications had colonoscopic findings of radiation colitis at the proximal rectum, the area with the maximal rectal dose. CONCLUSION: Eighty-nine percent of our patients had a maximal rectal dose from ICRT at the proximal rectum instead of the ICRU rectal point. The difference between patients with and without late rectal complications was more prominent for the proximal rectal dose than for the ICRU rectal dose. It is important and useful to contrast the whole rectal wall up to the rectosigmoid junction and to calculate the dose at the proximal rectum for patients undergoing HDR ICRT.

Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease.

PURPOSE: This study compares the difference in dose-volume data between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for patients with hepatocellular carcinoma (HCC) and previously documented radiation-induced liver disease (RILD) after 3D-CRT. MATERIALS AND METHODS: Between November 1993 and December 1999, 68 patients with HCC were treated with 3D-CRT at our institution. Twelve of them were diagnosed with RILD within 4 months of completion of 3D-CRT. RILD was defined as either anicteric elevation of alkaline phosphatase level of at least twofold and nonmalignant ascites, or elevated transaminases of at least fivefold the upper limit of normal or of pretreatment levels. Three-dimensional treatment planning using dose-volume histograms of normal liver was used to obtain the dose-volume data. These 12 patients with RILD were replanned with an IMRT planning system using the five-field (gantry angles 0 degrees, 72 degrees, 144 degrees, 216 degrees, and 288 degrees ) step-and-shoot technique to compare the dosimetric difference in targets and organs at risk between 3D-CRT and IMRT. Mean dose and normal tissue complication probability with literature-cited volume effect parameter of 0.32, curve steepness parameter of 0.15, and TD(50)(1) of 40 Gy, were used for the liver, whereas volume fraction at a given dose level was used for other critical structures. Paired Student t-test with 2-tailed p < 0.05 was used to assess the statistical difference between the two techniques. RESULTS: With comparable target coverage between 3D-CRT and five-field step-and-shoot IMRT, IMRT was able to obtain a large dose reduction in the spinal cord (5.7% vs. 33.2%, p = 0.007), and achieved at least similar organ sparing for kidneys and stomach. IMRT had diverse dosimetric effect on liver, with significant reduction in normal tissue complication probability (23.7% vs. 36.6%, p = 0.009), but significant increase in mean dose (2924 cGy vs. 2504 cGy, p = 0.009), as compared with 3D-CRT. CONCLUSIONS: IMRT is capable of preserving acceptable target coverage and improving or at least maintaining the nonhepatic organ sparing for patients with HCC and previously diagnosed RILD after 3D-CRT. The true impact of this technique on the liver remains unsettled and may depend on the exact volume effect of this organ.

Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication.

PURPOSE: To analyze the correlation of radiation-induced liver disease (RILD) with patient-related and treatment-related dose-volume factors and to describe the probability of RILD by a normal tissue complication probability (NTCP) model for patients with hepatocellular carcinoma (HCC) treated with three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: Between November 1993 and December 1999, 93 patients with intrahepatic malignancies were treated with 3D-CRT at our institution. Sixty-eight patients who were diagnosed with HCC and had complete 3D dose-volume data were included in this study. Of the 68 patients, 50 had chronic viral hepatitis before treatment, either type B or type C. According to the Child-Pugh classification for liver cirrhosis, 53 patients were in class A and 15 in class B. Fifty-two patients underwent transcatheter arterial chemoembolization with an interval of at least 1 month between transcatheter arterial chemoembolization and 3D-CRT to allow adequate recovery of hepatic function. The mean dose of radiation to the isocenter was 50.2 +/- 5.9 Gy, in daily fractions of 1.8-2Gy. No patient received whole liver irradiation. RILD was defined as Grade 3 or 4 hepatic toxicity according to the Common Toxicity Criteria of the National Cancer Institute. All patients were evaluated for RILD within 4 months of RT completion. Three-dimensional treatment planning with dose-volume histogram analysis of the normal liver was used to compare the dosimetric difference between patients with and without RILD. Maximal likelihood analysis was conducted to obtain the best estimates of parameters of the Lyman NTCP model. Confidence intervals of the fitted parameters were estimated by the profile likelihood method. RESULTS: Twelve of the 68 patients developed RILD after 3D-CRT. None of the patient-related variables were significantly associated with RILD. No difference was found in tumor volume (780 cm(3) vs. 737 cm(3), p = 0.86), normal liver volume (1210 cm(3) vs. 1153 cm(3), p = 0.64), percentage of normal liver volume with radiation dose >30 Gy (V(30 Gy); 42% vs. 33%, p = 0.05), and percentage of normal liver volume with >50% of the isocenter dose (V(50%); 45% vs. 36%, p = 0.06) between patients with and without RILD. The mean hepatic dose was significantly higher in patients with RILD (2504 cGy vs. 1965 cGy, p = 0.02). The probability of RILD in patients could be expressed as follows: probability = 1/[1 + exp(-(0.12 x mean dose - 4.29))], with coefficients significantly different from 0. The best estimates of the parameters in the Lyman NTCP model were the volume effect parameter of 0.40, curve steepness parameter of 0.26, and 50% tolerance dose for uniform irradiation of whole liver [TD(50)(1)] of 43 Gy. Patients with RILD had a significantly higher NTCP than did those with no RILD (26.2% vs. 15.8%; p = 0.006), using the best-estimated parameters. CONCLUSION: Dose-volume histogram analysis can be effectively used to quantify the tolerance of the liver to RT. Patients with RILD had received a significantly higher mean dose to the liver and a significantly higher NTCP. The fitted volume effect parameter of the Lyman NTCP model was close to that from the literature, but much lower in our patients with HCC and prevalent chronic viral hepatitis than that reported in other series with patients with normal liver function. Additional efforts should be made to test other models to describe the radiation tolerance of the liver for Asian patients with HCC and preexisting compromised hepatic reserve.

Improvement of local control of T3 and T4 nasopharyngeal carcinoma by hyperfractionated radiotherapy and concomitant chemotherapy.

PURPOSE: When the primary tumor of nasopharyngeal carcinoma (NPC) is treated at the base of skull and intracranium with conventional radiotherapy, the result is generally poor. In this report, we investigated whether hyperfractionated radiotherapy (HFRT) and concomitant chemotherapy (CCT) could achieve better local control and survival in NPC patients with T3 and T4 lesions. PATIENTS AND METHODS: Forty-eight patients (11 T3 and 37 T4 NPC) were treated with HFRT and CCT. HFRT was administered at 1.2 Gy per fraction, two fractions per day, Monday-Friday for 62 fractions for a total dose of 74.4 Gy. Concomitant chemotherapy consisting of cis-diamino-dichloroplatinum (CDDP) alone or CDDP and 5-fluorouracil was delivered simultaneously with radiotherapy during Weeks 1 and 6. Adjuvant chemotherapy consisted of CDDP and 5-fluorouracil for 2 to 3 cycles and was given monthly beginning 1 month after completion of radiation. RESULTS: With a median follow-up of 57 months (range: 28-94 months), the 3-year locoregional control rate was 93%, the disease-free survival rate was 71%, and the overall survival rate was 72%. For T4 patients, the 3-year locoregional control rate was 91%, disease-free survival was 62%, and overall survival was 63%. The major acute toxicity was Grade 3 mucositis in 73% and Grade 2 weight loss in 31% of patients. Fifty percent of patients were tube fed. Most patients tolerated the combined modality treatments relatively well; 88% of patients completed their radiation treatment within 8 weeks. CONCLUSION: HFRT and CCT for T3 and T4 NPC were associated with excellent local control and improved survival. The treatment-related toxicity was acceptable and reversible. We would recommend using HFRT with CCT for advanced T-stage NPC if the three-dimensional conformal radiation planning shows a significant portion of the brainstem to be inside the treatment field.

Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy.

PURPOSE: To analyze the incidence and risk factors for locoregional recurrence (LRR) in patients with breast cancer who had T1 or T2 primary tumor and 1-3 histologically involved axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy (RT). MATERIALS AND METHODS: Between April 1991 and December 1998, 125 patients with invasive breast cancer were treated with modified radical mastectomy and were found to have 1-3 positive axillary nodes. The median number of nodes examined was 17 (range 7-33). Of the 125 patients, 110, who had no adjuvant RT and had a minimum follow-up of 25 months, were included in this study. Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. Patient-related characteristics (age, menopausal status, medial/lateral quadrant of tumor location, T stage, tumor size, estrogen/progesterone receptor protein status, nuclear grade, extracapsular extension, lymphovascular invasion, and number of involved axillary nodes) and treatment-related factors (chemotherapy and hormonal therapy) were analyzed for their impact on LRR. The median follow-up was 54 months. RESULTS: Of 110 patients without RT, 17 had LRR during follow-up. The 4-year LRR rate was 16.1% (95% confidence interval [CI] 9.1-23.1%). All but one LRR were isolated LRR without preceding or simultaneous distant metastasis. According to univariate analysis, age <40 years (p = 0.006), T2 classification (p = 0.04), tumor size >==3 cm (p = 0.002), negative estrogen receptor protein status (p = 0.02), presence of lymphovascular invasion (p = 0.02), and no tamoxifen therapy (p = 0.0006) were associated with a significantly higher rate of LRR. Tumor size (p = 0.006) was the only risk factor for LRR with statistical significance in the multivariate analysis. On the basis of the 4 patient-related factors (age <40 years, tumor >==3 cm, negative estrogen receptor protein, and lymphovascular invasion), the high-risk group (with 3 or 4 factors) had a 4-year LRR rate of 66.7% (95% CI 42.8-90.5%) compared with 7.8% (95% CI 2.2-13.3%) for the low-risk group (with 0-2 factors; p = 0.0001). For the 110 patients who received no adjuvant RT, LRR was associated with a 4-year distant metastasis rate of 49.0% (9 of 17, 95% CI 24.6-73.4%). For patients without LRR, it was 13.3% (15 of 93, 95% CI 6.3-20.3%; p = 0.0001). The 4-year survival rate for patients with and without LRR was 75.1% (95% CI 53.8-96.4%) and 88.7% (95% CI 82.1-95.4%; p = 0.049), respectively. LRR was independently associated with a higher risk of distant metastasis and worse survival in multivariate analysis. CONCLUSION: LRR after mastectomy is not only a substantial clinical problem, but has a significant impact on the outcome of patients with T1 or T2 primary tumor and 1-3 positive axillary nodes. Patients with risk factors for LRR may need adjuvant RT. Randomized trials are warranted to determine the potential benefit of postmastectomy RT on the survival of patients with a T1 or T2 primary tumor and 1-3 positive nodes.