Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis

Background@#The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathway is involved in the regulation of cellular responses to oxidative stress. Nrf2 acts as a cell protector from inflammation, cellular damage, and tumorigenesis, whereas Keap1 is a negative regulator of Nrf2. Dysregulation of the Nrf2/ Keap1 pathway results in tumorigenesis and the active metabolism of tumor cells, leading to high resistance to radiotherapy. This study aimed to evaluate the predictive role of Nrf2 and Keap1 in the radiosensitivity and prognosis of locally advanced rectal cancer (LARC). @*Methods@#In total, 90 patients with LARC underwent surgery after preoperative chemoradiotherapy (CRT). Endoscopic biopsies from the tumors were obtained before radiation, and the Nrf2 and Keap1 expressions were assessed by immunohistochemistry. The response to therapy was evaluated after surgery following CRT according to the pathologic tumor regression grade. The disease-free survival (DFS) and overall survival rates were also documented. The association between the Nrf2 and Keap1 immunoreactivity and the clinicopathological parameters was analyzed. @*Results@#The overexpression of the nuclear Nrf2 before CRT showed a significant correlation with better DFS. The cytoplasmic Nrf2 expression was associated with more residual tumors after radiotherapy and a more unfavorable DFS, indicating lower radiosensitivity. @*Conclusion@#CRT is an important issue in LARC and is a major aspect of treatment. Thus, the Nrf2/Keap1 expression may be a potential predictor of preoperative therapeutic resistance.The Nrf2-Keap1 modulators that interact with each other may also be effectively applicable to CRT effect in LARC.

Polo-like kinase 4 as a potential predictive biomarker of chemoradioresistance in locally advanced rectal cancer

Background@#Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase located in the centriole of the chromosome during the cell cycle. PLK4 overexpression has been described in a variety of many common human epithelial tumors. Conversely, PLK4 acts as a haploinsufficient tumor suppressor in some situations, highlighting the importance of strict regulation of PLK4 expression, activity, and function. Meanwhile, the importance of chemoradiation resistance in rectal cancer is being emphasized more than ever. We aimed to analyze PLK4 expression and the tumor regression grade (TRG) in patients with rectal cancer, treated with chemoradiotherapy (CRT). @*Methods@#A retrospective study was conducted on 102 patients with rectal cancer who received preoperative CRT. Immunohistochemistry for PLK4 in paraffin-embedded tissue was performed from the biopsy and surgical specimens. @*Results@#We found significant association between high expression of PLK4 and poor response to neoadjuvant CRT (according to both Mandard and The Korean Society of Pathologists TRG systems) in the pre-CRT specimens. Other clinicopathologic parameters did not reveal any correlation with PLK4 expression. @*Conclusions@#This study revealed an association between high expression of PLK4 in the pre-CRT specimens and TRG. Our results indicated that PLK4 could potentially be a new predictor for CRT effect in patients with rectal cancer.

Dose comparison between prescription methods according to anatomical variations in intracavitary brachytherapy for cervical cancer

PURPOSE: We compared how doses delivered via two-dimensional (2D) intracavitary brachytherapy (ICBT) and three-dimensional (3D) ICBT varied anatomically. MATERIALS AND METHODS: A total of 50 patients who received 30 Gy of 3D ICBT after external radiotherapy (RT) were enrolled. We compared the doses of the actual 3D and 2D ICBT plans among patients grouped according to six anatomical variations: differences in a small-bowel V2Gy, small bowel circumference, the direction of bladder distension, bladder volume, sigmoid V3.5Gy, and sigmoid circumference. Seven dose parameters were measured in line with the EMBRACE recommendations. RESULTS: In terms of bladder volume, the bladder and small-bowel D2cc values were lower in the 150–250 mL bladder volume subgroup; and the rectum, sigmoid, and bladder D2mL values were all lower in the >250 mL subgroup, for 3D vs. 2D ICBT. In the sigmoid V3.5Gy >2 mL subgroup, the sigmoid and bladder D2mL values were significantly lower for 3D than 2D ICBT. The bladder D2mL value was also significantly lower for 3D ICBT, as reflected by the sigmoid circumference. In patients with a small bowel V2.0Gy >10 mL or small bowel circumference >15%, most dose parameters were significantly lower for 3D than 2D ICBT. The bladder distension direction did not significantly affect the doses. CONCLUSION: Compared to 2D ICBT, a greater bladder volume can reduce the internal 3D ICBT organ dose without affecting the target dose.

Postoperative radiotherapy appeared to improve the disease free survival rate of patients with extrahepatic bile duct cancer at high risk of loco-regional recurrence

PURPOSE: To investigate the outcomes of postoperative radiotherapy (RT), in patients with extrahepatic bile duct (EHBD) cancer by comparing the survival rate between patients undergoing surgery alone or surgery plus postoperative RT, and to identify the prognostic factors affecting survival. MATERIALS AND METHODS: Between 2000 and 2013, 52 patients with EHBD cancer underwent surgical resection. Of these, 33 patients did not receive postoperative RT (group I), and 19 patients did (group II). R1 resection was significantly more frequent in group II. The median radiation dose was 5,040 cGy. RESULTS: The 3-year overall survival (OS) rate for group I and group II was 38% and 56%, respectively (p = 0.274). The 3-year disease free survival (DFS) rate for group I and group II was 20% and 31%, respectively (p = 0.049), and the 3-year loco-regional recurrence free survival (LRFS) rates were 19% and 58%, respectively (p = 0.002). Multivariate analyses showed that postoperative RT and lymphovascular invasion were independent prognostic factors for DFS and LRFS. Overall, 42 patients (80%) experienced treatment failure. Distant metastasis was the predominant pattern of failure in group II. CONCLUSION: Postoperative RT after surgical resection appeared to improve the loco-regional control and DFS rate. More effort is needed to reduce distant metastasis, the major pattern of failure, in patients who receive postoperative RT.

Concurrent chemoradiotherapy improves survival outcome in muscle-invasive bladder cancer

PURPOSE: To evaluate survival rates and prognostic factors related to treatment outcomes after bladder preserving therapy including transurethral resection of bladder tumor, radiotherapy (RT) with or without concurrent chemotherapy in bladder cancer with a curative intent. MATERIALS AND METHODS: We retrospectively studied 50 bladder cancer patients treated with bladder-preserving therapy at Keimyung University Dongsan Medical Center from January 1999 to December 2010. Age ranged from 46 to 89 years (median, 71.5 years). Bladder cancer was the American Joint Committee on Cancer (AJCC) stage II, III, and IV in 9, 27, and 14 patients, respectively. Thirty patients were treated with concurrent chemoradiotherapy (CCRT) and 20 patients with RT alone. Nine patients received chemotherapy prior to CCRT or RT alone. Radiation was delivered with a four-field box technique (median, 63 Gy; range, 48.6 to 70.2 Gy). The follow-up periods ranged from 2 to 169 months (median, 34 months). RESULTS: Thirty patients (60%) showed complete response and 13 (26%) a partial response. All patients could have their own bladder preserved. Five-year overall survival (OS) rate was 37.2%, and the 5-year disease-free survival (DFS) rate was 30.2%. In multivariate analysis, tumor grade and CCRT were statistically significant in OS. CONCLUSION: Tumor grade was a significant prognostic factor related to OS. CCRT is also considered to improve survival outcomes. Further multi-institutional studies are needed to elucidate the impact of RT in bladder cancer.

Is Prophylactic Irradiation to Para-aortic Lymph Nodes in Locally Advanced Cervical Cancer Necessary? / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement. MATERIALS AND METHODS: A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT. RESULTS: The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group. CONCLUSION: These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings.

Postoperative radiotherapy for endometrial cancer

PURPOSE: To investigate the prognostic factors and effectiveness of postoperative radiotherapy alone for endometrial carcinoma. MATERIALS AND METHODS: Sixty four patients with stage I-III endometrial cancer (EC) treated with postoperative radiotherapy alone between January 1989 and December 2008 at the Keimyung University Dongsan Medical Center were chosen for the present study. Typically, total hysterectomy, salpingo-oophorectomy and lymphadenectomy were performed on the patient's pelvis. Total dose from 50.4 Gy to 63 Gy was irradiated at pelvis or extended field. Thirteen patients were treated with Co-60 or Ir-192 intracavitary radiotherapy. Follow-up periods were from 7 to 270 months, with a median of 56 months. RESULTS: Five year overall survival (OS) rate was 58.7%, respectively. Five year disease-free survival (DFS) rate was 59.2%, respectively. In univariate analysis for OS and DFS, stage, menopausal age, type of operation, serosal invasion, and lymph node involvement were found to be statistically significant. Histologic type was marginally significant. In multivariate analysis for OS and DFS, stage, types of operation, histologic type were also found to be statistically significant. Treatment failure occurred in 14 patients. The main pattern of failure was found to be distant metastasis. Time to distant metastasis was from 3 to 86 months (median, 12 months). There were no grade 3 or 4 complications. CONCLUSION: Stage, types of operation, and histologic type could be the predictive prognostic factors in patients. We contemplated postoperative radiation as effective and safe treatment method for EC. Additional treatment would be needed to reduce distant metastasis.

Interval between Surgery and Radiation Therapy Is an Important Prognostic Factor in Treatment of Rectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to evaluate survival and prognostic factors for rectal cancer, including interval between surgery and radiation therapy after surgery, radiation therapy, and chemotherapy. MATERIALS AND METHODS: We conducted a retrospective study of 153 patients with rectal cancer who were treated with surgery, radiotherapy with/without chemotherapy at Keimyung University Dongsan Medical Center from January, 1988 to December, 2005. The study included 89 males and 64 females, with a median age of 56 years (range, 23 to 81 years). Tumor, node and metastasis (TNM) was I in 23 patients, II in 39, and III in 91. Radiation therapy was performed on pelvic fields using a median dose of 54 Gy five days per week, 1.8 Gy once per day. Ninety two patients were treated with radiotherapy, 43 with concurrent chemo-radiation therapy and 18 with sequential therapy after surgery. The median follow-up period was 52 months (range, 4 to 272 months). The interval between surgery and radiation was 1-25 weeks (median, 5 weeks). RESULTS: Two-year and five-year overall survival rate was 64.7% and 46.4%, respectively. Two-year and five-year disease-free-survival (DFS) rate was 58.6% and 43.1%, respectively. Median DFS was 39 months. Loco-regional failure was evident in 10.5% of patients, 8.4% had distant metastasis, and 9.2% had both. In multivariate analysis, TNM stage and interval between surgery and radiation therapy (5 weeks; 95% confidence interval, 1.276 to 2.877; hazard ratio, 1.916; p=0.002) were significant prognostic factors of DFS. CONCLUSION: Survival rates for rectal cancer after surgery, chemotherapy, and radiation therapy were similar to those reported in previous studies. Starting radiation therapy as soon as possible after surgery, especially within the first five weeks after surgery, is suggested.

Concurrent Chemoradiotherapy in Locally Advanced Esophageal Cancer / 대한방사선종양학회지

PURPOSE: This study was designed to evaluate the results of local control, survival rate, prognostic factors, and failure pattern in locally advanced esophageal cancer. MATERIALS AND METHODS: We retrospectively studied 50 patients with locally advanced esophageal cancer treated with concurrent chemoradiotherapy at Keimyung University Dongsan Medical Center from June of 1999 to August of 2008. Seven patients with inappropriate data were excluded, and 43 patients were analyzed. There were 39 males and four female patients ranging in age from 43 to 78 years (median, 63 years). There were seven patients with stage IIA and 36 with stage III. Irradiation from 46 Gy to 63 Gy (median, 54 Gy) was carried out 5 days per week, 1.8 Gy once a day. There were eight patients with neo-adjuvant chemotherapy, and we mostly used 5-fluorouracil, cisplatin with 3 cycles for concurrent chemotherapy. The range of follow up periods was from 2 to 82 months (median, 15.5). RESULTS: There were nine patients that exhibited a complete response, 23 that exhibited a partial response, 9 that exhibited no response, and 2 that exhibited disease progression. The median survival time was 15 months. Two-year and 5-year survival rates were 36.5% and 17.3%, respectively. Two-year and 5-year disease-free survival rates were 32.4% and 16%, respectively. Treatment failure occurred in 22 patients (51.2%). Patterns of failure were categorized as local failure in 18 patients and distant metastasis in four patients. In a univariate analysis for prognostic factors related to overall survival and disease-free survival, the hemoglobin levels during chemoradiotherapy (> or =12 vs. <12, p=0.02/p=0.1) and the response to the treatments (CR/PR vs. NR/PD, p=0.002/p<0.0001) were statistically significant. In a multivariate analysis, only response to the treatments was revealed to be statistically significant. There was no statistical significance associated with patient age, gender, disease stage, T-stage, smoking history, tumor location, or neo-adjuvant chemotherapy. CONCLUSION: Our survival rate was similar to those of other institutions. Local recurrence was the main reason for failure. It is suggested that further prospective studies should be performed to improve local control.

Radiation Therapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis / 대한방사선종양학회지

PURPOSE: To evaluate the effectiveness of radiation therapy (RT) for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) and to analyze the prognostic factors. MATERIALS AND METHODS: From December 2004 to April 2009, 70 patients who had HCC with PVTT were treated with RT at Keimyung University Dongsan Medical Center. Nineteen patients whose total dose was below 30 Gy and one patient who underwent liver transplantation were excluded. The remaining 50 patients (45 males, 5 females; median age 55 years) were analyzed. According to the LCSGJ TNM stage, there were 27 patients (54.0%) with stage III and 23 (46.0%) with stage IV. Total dose of 30~54 Gy was administered (median 45). Thirty patients (60.0%) were treated with concurrent chemoradiation therapy (CCRT). The median follow-up duration was from 13.5 months (range, 3 to 70 months). RESULTS: The median survival time from the start of RT was 9 months. One-year and 2-year overall survival rates were 24.9% and 11.2%, respectively. At the follow-up time, three patients (6.0%) displayed no evidence of disease. Seven patients (14.0%) were alive with disease, and 40 (80.0%) patients had expired due to disease progression. CCRT was associated with worse survival than RT alone (p=0.034). Response to RT (p=0.037), CLIP stage (p=0.017), and TNM stage (p=0.041) were statistically significant prognostic factors. There was no radiation-induced liver disease. CONCLUSION: RT is an effective and safe modality for HCC with PVTT. Further studies such as prospective randomized trials are needed to confirm the role of RT for HCC with PVTT.

Long Term Results of Radiation Therapy in Early Glottic Cancer / 대한방사선종양학회지

PURPOSE: This study was designed to evaluate long-term results in terms of failure, survival and voice preservation after radiation therapy for early glottic cancer. MATERIALS AND METHODS: From February 1988 to December 2003, 70 patients with early glottic cancer were treated with radiation therapy at Keimyung University Dongsan Medical Center. Patient age distribution was from 39 to 79 years, with a median age of 62 years. All patients had squamous cell carcinoma. According to the TNM stage, 58 patients had stage I disease, 12 patients had stage II disease; 67 patients were male. The laryngeal area was irradiated with the use of bilateral opposing fields with/without a wedge filter with 6 MV photons at a total dose of 54~70.2 Gy in 1.8~2.2 Gy fractions over 6~8 weeks. We delivered a median radiation dose of 60 Gy for stage I patients and a median radiation dose of 66 Gy for stage II patients. Salvage surgery was performed in patients with local recurrence. The voice preservation rate was analyzed after all treatments including salvage surgery. Follow-up periods were from 13 to 180 months, with a median follow-up period of 77.5 months. The survival rate was analyzed by the use of the Kaplan Meier method and log rank test. A comparison of two groups was performed with the use of the chi-squared test. RESULTS: The local control rate was 98.5% (69/70). The five-year-overall survival rate was 93.9%. The five-year disease free survival rate (5YDFS) was 84.1% and the 5YDFS after radiation and salvage surgery was 92.8%. According to stage, the 5YDFS was 93.1% and 91.7% for stage I and stage II respectively. Thirteen patients (18.5%) had local failure with 24 months of median time to local failure and nine patients received salvage surgery; however, four patients were lost to follow-up after a diagnosis of recurrence. Only two patients died due to a distant metastasis at 33 months and 71 months after radiation therapy, respectively. Nine patients died due to other diseases with a median time of 73 months. There were no severe acute or chronic complications after radiation therapy. Voice preservation was ultimately achieved in 88.5% (62/70) of patients. CONCLUSION: We considered that radiation therapy was effective and we achieved excellent survival and voice preservation in early laryngeal cancer. The use of radiation therapy should be the first choice for the treatment of early glottic cancer.

Long-term Results of Breast-conserving Surgery and Radiation Therapy in Early Breast Cancer / 대한방사선종양학회지

PURPOSE: To evaluate the long-term results after breast-conserving surgery and radiation therapy in early breast cancer in terms of failure, survival, and cosmesis. MATERIALS AND METHODS: One hundred fifty-four patients with stage I and II breast cancer were treated with conservative surgery plus radiotherapy between January 1992 and December 2002 at the Keimyung University Dongsan Medical Center. According to TNM stage, 93 patients were stage I, 50 were IIa, and 11 were IIb. The affected breasts were irradiated with 6 MV photons to 50.4 Gy in 28 fractions over 5.5 weeks with a boost irradiation dose of 10~16 Gy to the excision site. Chemotherapy was administered in 75 patients and hormonal therapy in 92 patients with tamoxifen. Follow-up periods were 13~179 months, with a median of 92.5 months. RESULTS: The 5- and 10-year overall survival rates were 97.3% and 94.5%, respectively. The 5- and 10-year disease-free survival (5YDFS and 10YDFS, respectively) rates were 92.5% and 88.9%, respectively; the ultimate 5YDFS and 10YDFS rates after salvage treatment were 93.9% and 90.2%, respectively. Based on multivariate analysis, only the interval between surgery and radiation therapy (6 weeks, p=0.017) was a statistically significant prognostic factor for DFS. The major type of treatment failure was distant failure (78.5%) and the most common distant metastatic site was the lungs. The cosmetic results were good-to-excellent in 96 patients (80.7%). CONCLUSION: Conservative surgery and radiation for early stage invasive breast cancer yielded excellent survival and cosmetic results. Radiation therapy should be started as soon as possible after breast-conserving surgery in patients with early breast cancer, ideally within 6 weeks.

A Case Report of Intraocular Metastasis Treated with Radiotherapy / 대한방사선종양학회지

Intraocular metastasis is the most common malignancy of the eye. The frequency of intraocular metastasis in all the patients dying of cancer is about 12% and ocular metastases will be detected more frequently in the future because the patients with malignant tumor are now living longer. Intraocular metastasis can cause a serious clinical problem such as blindness. The early recognition and treatment of intraocular metastasis are very important clinical oncologic issues to maintain vision and to maximize the quality of life. However, significance of intraocular metastasis is still under-evaluated for practicing oncologists. External beam radiotherapy is a safe, effective palliative treatment in terms of preserving both the vision and the eye globe.