• Title/Summary/Keyword: 화학방사선 병용요법

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Preoperative Concurrent Radio-chemotherapy for Rectal Cancer: Report of Early Results (직장암에 대한 수술 전 동시병용 방사선-항암 화학요법: 초기 치료결과 보고)

  • Shin, Seong-Soo;Ahn, Yong-Chan;Chun, Ho-Kyung;Lee, Woo-Yong;Kang, Won-Ki;Park, Young-Suk;Park, Joon-Oh;Song, Sang-Yong;Lim-Do-Hoon;Park, Won;Lee, Jung, Eun;Kang, Min-Kyu;Park, Yung-Je
    • Radiation Oncology Journal
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    • v.21 no.2
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    • pp.125-134
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    • 2003
  • Purpose: To report the early results of preopeartive concurrent radio-chemotherapy (CRCT) for treating rectal cancer. Materials and Methods: From June 1999 to April 2002, 40 rectal cancer patients who either had lesions with a questionable resectability or were candidates for sphincter-sacrificing surgery received preoperative CRCT. Thirty-seven patients completed the planned CRCT course. 45 Gy by 1.8 Gy daily fraction over 5 weeks was delivered to the whole pelvis in the prone position. The chemotherapy regimens were oral UFT plus oral leucovorin (LV) in 12 patients, intravenous bolus 5-FU plus LV in 10 patients, and intravenous 5-FU alone in 15 patients (bolus infusion in 10, continuous infusion in 5). Surgery was planned in 4$\~$6 weeks of the completion of the preoperative CRCT course, and surgery was attempted in 35 patients. Results: The compliance to the current preoperative CRCT protocol was excellent, where 92.5$\%$ (37/40) completed the planned treatment. Among 35 patients, in whom surgery was attempted after excluding two patients with new metastatic lesions in the liver and the lung, sphincter-preservation was achieved in 22 patients (62.9$\%$), while resection was abandoned during laparotomy in two patients (5.7$\%$). Gross complete resection was peformed in 30 patients, gross incomplete resection was peformed in one patient, and no detailed information on the extent of surgery was available in two patients. Based on the surgical and pathological findings, the down-staging rate was 45.5$\%$ (15/33), and the complete resection rate with the negative resection margin 78.8$\%$ (26/33). During the CRCT course, grade 3 $\~$4 neutropenia developed in four patients (10.8$\%$). Local recurrence after surgical resection developed in 12.1$\%$ (4/33), and distant metastases after the preoperative CRCT start developed in 21.6$\%$ (8/37). The overall 3-years survival rate was 87$\%$. Conclusion: Preoperative CRCT in locally advanced rectal cancer is well tolerated and can lead to high resection rate, down-staging rate, sphincter preservation rate, however, longer term follow-up will be necessary to confirm these results.

Results of Radiotherapy in Hypopharyngeal Cancer (하인두암의 방사선치료)

  • Shin Byung Chul;Yum Ha Yong;Moon Chang Woo;Jeong Tae Sik
    • Radiation Oncology Journal
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    • v.20 no.3
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    • pp.206-214
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    • 2002
  • Purpose : The aim of this study was to assess the effectiveness, survival rate and complications of radiation therapy and chemoradiation treatment in hypopharyngeal cancer. Methods and Materials : From January 1984 to December 1999, 56 patients who had hypopharyngeal carcinoma treated with curative radiation therapy were retrospectively studied. Twenty four patients $(42.9\%)$ were treated with radiation therapy alone (Group I) and $32\;(57.1\%)$ treated with a combination of chemotherapy and radiation (Group II). Total radiation dose ranged from 40.5 to 83. 5 Gy (median 67.9 Gy). Radiotherapy was given with conventional technique in 9 patients $(16.4\%)$, with hyperfractionation I ($1.15\~1.2$ Gy/fr., BID) in 26 $(47.2\%)$, hyperfractionation II (1.35 Gy/fr., BID) in 18 $(32.7\%)$, and accelerated fractionation (1.6 Gy/fr., BID) in 2 $(3.6\%)$. In chemotherapy, 5-FU ($1,000\;mg/m^2$ daily for 5 consecutive days) and cisplatin ($100\;mg/m^2$ on day 1) were administered in a cycle of 3 weeks interval, and a total of 1 to 3 cycles (average 2..3 cycles) were given prior to radiation therapy. Follow up duration was $1\~195$ months (median 28 months). Results : Overall 2 and 5 year survival rates were $40.6\%\;and\;27.6\%;\;50.0\%\;and\;30.0\%$ in Group I, and $36.4\%\;and\;26.3\%$ in Group II, respectively. Complete local control rates in Group I and II were $70.0\%\;and\;67.7\%$, respectively. The response to radiotherapy and nodal stage were statistically significant prognostic factors. The complication rate was increased in Group II and was decreased in hyperfractionation. Conclusion : The response to radiotherapy and nodal stage were valid factors to indicate the degree of control over the hypopharyngeal cancer. The induction cisplatin, 5-Fu chemotherapy was not valid in terms of local control rate and survival rate, but did contribute to an increased complication rate. The use of hyperfractionation was valid to reduce the late radiation complications.

Treatment Results in Anal Cancer : Non-operative Treatment Versus Operative Treatment (항문암의 치료성적 : 비수술적방법과 수술적방법의 결과 비교)

  • Chie Eui Kyu;Ha Sung Whan;Park Jae-Gahb;Bang Yung-Jue;Heo Dae Seog;Kim Noe Kyeong
    • Radiation Oncology Journal
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    • v.20 no.1
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    • pp.62-67
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    • 2002
  • Purpose : This study was undertaken to analyze the efficacy and sphincter preservation rate of platinum based neoadjuvant chemotherapy Plus radiotherapy versus abdominoperineal resection and Postoperative radiotherapy for anal cancer. Materials and Methods : Data of forty-two patients with anal cancer were retrospectively analyzed. Among thirty-eight patients with epidermoid histology, four patients received radiotherapy, and nineteen patients received abdominoperineal resection and adjuvant radiotherapy with or without chemotherapy $(APR+RT{\pm}CT)$, and fifteen patients received neoadjuvant chemotherapy and radiotherapy (CRT). The CRT regimen was composed of three cycles of 5-fluorouracil $(1,000\;mg/m^2\;bolus\;on\;D1\~5)$ and cisplatin $(60\;mg/m^2\;bolus\;on\;D1)$ followed by 50.4 Gy to the tumor bed and regional lymphatics over 5.5 weeks. Both inguinal lymphatics were treated with an identical dose schedule. Residual disease was treated with an additional three cycles of identical adjuvant chemotherapy. An identical dose schedule was used for post-operative radiotherapy. Median follow-up period was eighty-five months. Results : Overall five-year survival rates were $80.3\%$, 88.9 and $79.4\%$ for entire patients, $APR+RT{\pm}CT$ group, and the CRT group, respectively. No significant difference was found between the two groups (p=0.49). Anus preservation rate for the CRT group was $86.7\%$. Age (0=0.0164) and performance status (p=0.0007) were found to be significant prognostic factors by univariate analysis. Age (p=0.0426), performance status (p=0.0008), and inguinal lymph node metastasis (e=0.0093) were statistically significant prognostic factors by multivariate analysis. No case of RTOG grade 3 complication or higher was reported. Conclusion : This and other recent studies have shown that combined chemotherapy plus radiotherapy for anal cancer results in a high rate of anal sphincter preservation as well as local control and survival. Furthermore, neoadjuvant use of chemotherapy with a cisplatin based regimen rather than a concurrent regimen may lead to a decrease in complications.

Concurrent Chemoradiotherapy with Biweekly Gemcitabine and Cisplatin in Patients with Locally Advanced Non-small Cell Lung Cancer (진행성 비소세포폐암 환자에서 Gemcitabine/Cisplatin을 이용한 동시 화학 방사선 요법)

  • Oak, Chul-Ho;Kim, Ja-Kyung;Jang, Lee-La;Moon, Dae-Sung;Jang, Tae-Won;Jung, Maan-Hong;Cho, Sung-Whan;Jeung, Tae-Sig
    • Radiation Oncology Journal
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    • v.26 no.3
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    • pp.160-165
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    • 2008
  • Purpose: In cases of locally advanced non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy(CCRT) is the leading therapeutic modality. However, much controversy exists about the chemotherapeutic regimens and radiation methods. Materials and Methods: During concurrent chemoradiotherapy, three or four cycles of gemcitabine ($500\;mg/m^2$) and cisplatin ($30\;mg/m^2$) were administered every two weeks while 50.4 Gy of irradiation was administered in 28 fractions (once/day, 5 treatment days/week) to the tumor site, mediastinum, and the involved lymph node region. In addition, a booster irradiation dose of 18 Gy in 10 fractions was administered to the primary tumor site unless the disease progressed. Two or three cycles of consolidation chemotherapy were performed with gemcitabine ($1,200\;mg/m^2$, $1^{st}$ and 8th day) and cisplatin ($60\;mg/m^2$) every three weeks. Results: A total of 29 patients were evaluable for modality response. Response and treatment toxicities were assessed after concurrent chemoradiotherapy and consolidation chemotherapy, respectively. One patient (4%) achieved a complete response; whereas 20 patients (69%) achieved a partial response after concurrent chemoradiotherapy. Following the consolidation chemotherapy, three patients (10.3%) achieved complete responses and 21 patients (72.4%) achieved partial responses. The median follow-up period was 20 months (range $3{\sim}39$ months) and the median survival time was 16 months (95% CI; $2.4{\sim}39.2$ months). The survival rates in one, two, and three years after the completion of treatment were 62.7%, 43.9%, and 20%, respectively. Complications associated to this treatment modality included grade 3 or 4 esophagitis, which occurred in 15 patients (51.7%). In addition, an incidence of 24% for grade 3 and 14% for grade 4 neutropenia. Lastly, grade 2 radiation pneumonitis occurred in 6 patients (22%). Conclusion: The response rate and survival time of concurrent chemoradiotherapy with biweekly gemcitabine ($500\;mg/m^2$) and cisplatin ($30\;mg/m^2$) were encouraging in patients with locally advanced NSCLC. However, treatment related toxicities were significant, indicating that further modification of therapy seems to be warranted.

Radiotherapy for Oral Cavity Cancer (구강암의 방사선치료)

  • Shim Jae Won;Yoo Seong Yul;Koh Kyoung Hwan;Cho Chul Koo;Yun Hyong Geun;Kim Jae Young
    • Radiation Oncology Journal
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    • v.11 no.2
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    • pp.267-275
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    • 1993
  • Eighty five patients of oral cavity cancer, treated with radiation at the Department of Therapeutic Radiology, Korea Cancer Center Hospital, during the period from March 1985 to September 1990 were analyzed retrospectively. Among 85 patients, 37 patients were treated with radiation only and 48 patients were treated with radiation following surgery. And 70 patients received external irradiation only by $^{60}Co$ with or without electron, the others were 7 patients for external irradiation plus interstitial implantation and 8 patients for external irradiation plus oral cone electron therapy. Primary sites were mobile tongue for 40 patients, mouth floor for 17 patients, palate for 12 patients, gingiva including retromolar trigone for 10 patients, buccal mucosa for 5 patients, and lip for 1 patient. According to pathologic classification, squamous cell carcinoma was the most common (77 patients). According to AJC TNM stage, stage I + II were 28 patients and stage III+IV were 57 patients. Acturial overall survival rate at 3 years was $43.9\%,$ 3 year survival rates were $60.9\%$ for stage I + II, and $23.1\%$ for stage III+IV, respectively. As a prognostic factor, primary T stage was a significant factor (p<0.01). The others, age, location, lymph node metastasis, surgery, radiation dose, and cell differentiation were not statistically significant. Among those factors, radiation plus surgery was more effective than radiation only in T3+T4 or in any N stage although it was not statistically sufficient (p<0.1). From those results, it was conclusive that definitive radiotherapy was more effective than surgery especially In the view of pertainig of anatomical integrity and function in early stage, and radiation plus surgery was considered to be better therapeutic tool in advanced stage.

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Concurrent Docetaxel/Cisplatin and Thoracic Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (국소 진행성 비소세포 폐암에서 Docetaxel Cisplatin을 사용한 화학-방사선 동시치료의 효과)

  • Jang, Tae Won;Park, Jung Pil;Kim, Hee Kyoo;Ok, Chul Ho;Jeung, Tae Sig;Jung, Maan Hong
    • Tuberculosis and Respiratory Diseases
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    • v.57 no.3
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    • pp.257-264
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    • 2004
  • Background : There are many combinations of treatment for locally advanced non-small cell lung cancer (NSCLC). Recent studies have showed the efficacy of concurrent chemoradiotherapy (CCRT) in NSCLC. At present, however, there is no consensus about the optimal dosages and timing of radiation and chemotherapeutic agents. The aims of study were to determine the feasibility, toxicity, response rate, and survival rate in locally advanced NSCLC patients treated with doxetaxel and cisplatin based CCRT. Method : Sixteen patients with unresectable stage III NSCLC were evaluated from May 2000 until September 2001. Induction chemoradiotherapy consisted of 3 cycles of docetaxel (75 $mg/m^2/IV$ on day 1) and cisplatin (60 $mg/m^2/IV$ on day 1) chemotherapy every 3 weeks and concomitant hyperfractionated chest irradiation (1.15 Gy/BID, total dose of 69 Gy) in 6 weeks. Patient who had complete or partial response, and stable disease were applied consolidation chemotherapy of docetaxel and cisplatin. Results : All patients showed response to CCRT. Four patients achieved complete response (25%), partial responses in 12 patients (75%). The major common toxicities were grade III or more of neutropenia (87.3%), grade III esophagitis (68.8%), pneumonia (18.8%) and grade III radiation pneumonitis (12.5%). Thirteen patients were ceased during follow-up period. Median survival time was 19.9 months (95% CI; 4.3-39.7 months). The survival rates in one, two, and three years are 68.7%, 43.7%, and 29.1%, respectively. Local recurrence was found in 11 patients (66.8%), bone metastasis in 2, and brain metastasis in 1 patient. Conclusion : The response rate and survival time of CCRT with docetaxel/cisplatin in locally advanced NSCLC were encouraging, but treatment related toxicities were high. Further modification of therapy seems to be warranted.

Preliminary Results of Concurrent Chemotherapy and Radiation Therapy using High-dose-rate Brachytherapy for Cervical Cancer (자궁경부암에 항암화학요법과 동시 병용요법으로 외부 방사선조사와 고선량률 강내조사의 예비적 치료 결과)

  • Lee, Kyung-Ja;Lee, Ji-Hye;Lee, Re-Na;Suh, Hyun-Suk
    • Radiation Oncology Journal
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    • v.24 no.3
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    • pp.171-178
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    • 2006
  • [ $\underline{Purpose}$ ]: To determine the efficacy and safety of concurrent chemotherapy and radiation therapy with high-dose-rate brachytherapy for cervical cancer. $\underline{Materials\;and\;Methods}$: From January 2001 to December 2002, 30 patients with cervical cancer were treated with concurrent chemotherapy (cisplatin and 5-FU) and definitive radiation therapy. The median age was 58 (range $34{\sim}74$) year old. The pathology of the biopsy sections was squamous cell carcinoma in 29 patients and one was adenocarcinoma. The distribution to FIGO staging system was as follows: stage IB, 7 (23%); IIA, 3 (10%); IIB, 12 (40%); IIIA, 3 (10%); IIIB, 5 (17%). All patients received pelvic external beam irradiation (EBRT) to a total dose of $45{\sim}50.4\;Gy$ (median: 50.4 Gy) over $5{\sim}5.5$ weeks. Ir-192 HDR intracavitary brachytherapy (ICBT) was given after a total dose of 41.4 Gy. HDR-ICBT was performed twice a week, with a fraction point A dose of 4 Gy and median dose to point A was 28 Gy (range: $16{\sim}32\;Gy$) in 7 fractions. The median cumulative biologic effective dose (BED) at point A (EBRT+ICBT) was $88\;Gy_{10}$ (range: $77{\sim}94\;Gy_{10}$). The median cumulative BED at ICRU 38 reference point (EBRT+ICBT) was $131\;Gy_3$ (range: $122{\sim}140\;Gy_3$) at point A, $109\;Gy_3$ (range: $88{\sim}125\;Gy_3$) at the rectum and $111\;Gy_3$ (range: $91{\sim}123\;Gy_3$) at the urinary bladder. Cisplatin ($60\;mg/m^2$) and 5-FU ($1,000\;mg/m^2$) was administered intravenously at 3 weeks interval from the first day of radiation for median 5 (range: $2{\sim}6$) cycles. The assessment was performed at 1 month after completion of radiation therapy by clinical examination and CT scan. The median follow-up time was 36 months (range: $8{\sim}50$ months). $\underline{: The complete response rate after concurrent chemoradiation therapy was 93.3%. The 3-yr actuarial pelvic control rate was 87% and 3-yr actuarial overall survival and disease-free survival rate was 93% and 87%, respectively. The local failure rate was 13% and distant metastatic rate was 3.3%. The crude rate of minor hematologic complications (RTOG grade 1-2) occurred in 3 patients (10%) and one patient had suffered from severe leukopenia (RTOG grade 4) during concurrent treatment. Acute minor enterocolitis (RTOG grade 1-2) occurred in 11 patients (37%) and one patient (3%) was suffered from colon perforation during radiation therapy. Late colitis of RTOG grade 1 occurred in 5 patients (15%). Acute cystitis of RTOG grade 1 occurred in 12 patients (40%) and late cystitis of RTOG grade 2 occurred in one patient (3%). No treatment related death was seen. $\underline{Conclusion}$: The results of this study suggest that the concurrent chemoradiation therapy with HDR brachytherapy could be accepted as an effective and safe treatment for cervical cancer.

Treatment Outcome of Metastatic Carcinoma of Cervical Lymph Node from an Unknown Primary (원발병소 블명의 경부림프절 전이의 치료결과)

  • Kim Kyubo;Chie EuiKyu;Wu Hong-Gyun;Kim Kwang Hyun;Sung Myung-Whun;Heo Dae Seog;Park Charn Il
    • Radiation Oncology Journal
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    • v.23 no.3
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    • pp.137-142
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    • 2005
  • Purpose: To analyze the outcome of radiation therapy for patients with a metastatic carcinoma of cervical lymph nodes from an unknown primary (MUO), and identify the prognostic factors for these patients. Materials and Methods: Between July 1981 and June 1999, 39 patients with MUO underwent radiation therapy with curative intent. Twelve patients were treated with radiation therapy alone (Group 1), 8 with neoadjuvant chemotherapy followed by radiation therapy (Group 2), and 19 with either an excision or neck dissection and postoperative radiation therapy (Group 3). There were 31 males and 8 females, with a median age of 55 years, ranging from 25 to 77 ears. The median duration of follow-up was 38 months, ranging from 3 to 249 months. Results: The 5-year overall survival rate was $55\%$. According to the treatment modality, the 5-year disease-free survival rates of Groups 1, 2 and 3 were 48, 19 and $75\%$, respectively (p=0.0324). In addition to the treatment modality, the appearance of the primary site was a significant prognostic factor for disease-free survival (p=0.0085). Conclusion: Surgical resection and radiation therapy achieves a superior disease-free survival compared to radiation therapy alone, either with or without chemotherapy Further investigation Is needed to evaluate the role of chemotherapy in the treatment of MUO.

Clinical Factors Predicting the Pathologic Tumor Response after Preoperative Concurrent Chemoradiotherapy for Rectal Cancer (직장암에 수술 전 항암화학방사선 동시 병용요법 후 종양의 병리학적 반응에 영향을 주는 임상적 예측 인자)

  • Lee, Ji-Hae;Lee, Kyung-Ja
    • Radiation Oncology Journal
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    • v.26 no.4
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    • pp.213-221
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    • 2008
  • Purpose: The objective of this retrospective study was to identify predictive factors for the complete pathologic response and tumor downstaging after preoperative concurrent chemoradiotherapy for locally advanced rectal cancer. Materials and Methods: Between the years 2000 and 2008, 39 patients with newly diagnosed rectal cancer without prior evidence of distant metastasis received preoperative concurrent chemoradiotherapy followed by surgery. The median radiation dose was 50.4 Gy (range, $45{\sim}59.4\;Gy$)). Thirty-eight patients received concurrent infusional 5-fluorouracil and leucovorin, while one patient received oral capecitabine twice daily during radiotherapy. Results: A complete pathologic response (CR) was demonstrated in 12 of 39 patients (31%), while T-downstaging was observed in 24 of 39 patients (63%). N-downstaging was observed in 18 of 28 patients (64%), with a positive node in the CT scan or ultrasound. Two patients with clinical negative nodes were observed in surgical specimens. The results from a univariate analysis indicated that the tumor circumferential extent was less than 50% (p=0.031). Moreover, the length of the tumor was less than 5 cm (p=0.004), while the post-treatment carcinoembryonic antigen (CEA) levels were less than or equal to 3.0 ng/mL (p=0.015) and were significantly associated with high pathologic CR rates. The univariate analysis also indicated that the adenocarcinoma (p=0.045) and radiation dose greater than or equal to 50 Gy (p=0.021) were significantly associated with high T-downstaging, while a radiotherapy duration of less than or equal to 42 days (p=0.018) was significantly associated with N-downstaging. The results from the multivariate analysis indicated that the lesser circumferential extent of the tumor (hazard ratio [HR] 0.150; p=0.028) and shorter tumor length (HR, 0.084; p=0.005) independently predicted a higher pathologic CR. The multivariate analysis also indicated that a higher radiation dose was significantly associated with higher T-downstaging (HR, 0.115; p=0.025), while the shorter duration of radiotherapy was significantly associated with higher N-downstaging (HR, 0.028; p=0.010). Conclusion: The circumferential extent of the tumor and its length was a predictor for the pathologic CR, while radiation dose and duration of radiotherapy were predictors for tumor downstaging. Hence, these factors may be used to predict outcomes for patients and to develop further treatment guidelines for high-risk patients.

Effects of Adjuvant Radiation Therapy and Chemotherapy Following Curative Surgery in Locally Advanced Rectal Cancer (국소 진행된 직장암에서 근치적 절제술 후 방사선치료와 항암화학요법과의 병용치료에 대한 효과)

  • Kang, Ki-Mun;Choi, Ihl-Bohng;Kim, In-Ah;Jang, Jee-Young;Shin, Kyung-Sub;Jang, Suck-Kyun;Lee, Jae-Hak;Kim, Young-Ha;Won, Chong-Man;Choi, Dong-Hwan;Kim, Jin-Seung;Park, Shinn-Hee
    • Radiation Oncology Journal
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    • v.15 no.2
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    • pp.121-128
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    • 1997
  • Purpose : To evaluate the effect of postoperative adjuvant radiation therapy and chemotherapy on the survival, pattern of failure and complication for locally advanced rectal carcinoma Materials and Methods : From October 1992 to September 1995, twenty eight patients with rectal carcinoma were treated by postoperative adjuvant radiation therapy and chemotherapy Radiation therapy was delivered with 6MV and 15MV linear accelerator, 180c0y fractions 5 day per week. Total radiation doses were 5040cGy in $B_{2+3}$ and 5580cGy in $C_{2+3}$. Within 4 weeks after radical surgery. 5-FU$(400mg/m^2/day)\;and\;Leucovorin(20mg/m^2/day)$ were administered by intravenous injection for 4 days during the first and fifth week of radiation therapy. The median follow up was 19 months with a range 2 to 47 months. Results : The 2 year overall survival and disease free survival rates were $78.6\%\;and\;70.8\%$, respectively. The 2 year overall survival was $93.0\%\;in\;B_{2+3}$ and $76.2\%\;in\;C_{2+3}$(p=0.11) The 2 year disease free survival was $79.4\%\;in\;B_{2+3}\;and\;69.2\%\;in\;C_{2+3}(p=0.13)$. The overall failure rate was $21.42\%$(6/28) including $10.72\%$(3/28) locoregional recurrence, $3.62\%$(1/28) distant metastasis and $7.12\%$(2/28) locoregional recurrence with distant metastasis. The overall locoregional recurrence rate was $17.92\%$(5/28). The 2 year locoregional recurrence rates were $13.32\%(2/15)\;and\;23.12\%$(3/13) for respectively for $B_{2+3}\;and\;C_{2+3}$ The difference between the locoregional recurrence of $B_{2+3}\;and\;C_{2+3}$ patients was not significant(p=0.07). Complications developed in 13 patients$(46.42\%)$, including 8 dermatitis, 7 loose stool, 6 leukopenia, 4 tenesmus, 2 diarrhea. In Univariate analysis, there was no statistically significant factor except for tumor grade in locoregional recurrence, disease free survival and overall survival rate(p=0.04, 0.05, 0.04). Conclusion : This study sugges1s that postoperative adjuvant radiation therapy and chemotherapy is effective in patients with locally advanced rectal cancer. Therefore these results need to be confirmed with a long term follow-up and larger number of patients with the further clinical trials including prospective controlled studies.

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