Second-Line Chemotherapy for Advanced Non-small Cell Lung Cancer: Past, Present, and Hope for the Future

Keunchil Park 대한암학회 2003 Cancer Research and Treatment Vol.35 No.4

A Multi-Center, Phase II Clinical Trial of Genexol (Paclitaxel) and Cisplatin for Patients with Non-SmallCell Lung Cancer

Se-Hoon Lee,Keunchil Park,Cheolwon Suh,Hoon-Kyo Kim,Jun-Suk Kim,Young-Hyuc Kim,Sang-We Kim,Dae-Seog Heo,Yung-Jue Bang,Noe Kyeong Kim 대한암학회 2003 Cancer Research and Treatment Vol.35 No.1

Purpose: A combination of paclitaxel and cisplatin isan effective and safe regimen for advanced non-small celllung cancer (NSCLC). We conducted a multi-center,phase II trial to evaluate the efficacy and safety ofGenexol (paclitaxel) and cisplatin in patients withNSCLC.Materials and Methods: Chemotherapy-naïve patientshaving histologically confirmed NSCLC were enrolled.Genexol was administered at 175 mg/m2 as a 3-hourintravenous infusion and cisplatin at 75 mg/m2 as anintravenous infusion on day 1 every 3 weeks.Results: Twenty-five of 27 patients that were enteredfrom 5 hospitals between Jan 2001 and Aug 2001 receivedchemotherapy. On an intent-to-treat basis, 9 patients(36%) achieved a partial response, 7 patients (28%) astable disease, and 5 patients (20%) progressed. Theoverall response rate was 36% (95% CI, 17 to 55%). Themedian duration of the response was 7.8 months (95%CI, 6.6 to 9.0 months). The median time to progressionwas 7.4 months (95% CI, 5.3 to 9.5 months), and medianoverall survival was 13.3 months (95% CI, 10.8 to 15.9months) for the intent-to-treat population. The major toxicitywas hematological, with grade 3 and 4 neutropeniain 10% (10/106) of the total cycles. The non-hematologictoxicity was mild, and grade 3 emesis was observed in2 patients (8%). One patient experienced a moderatedegree hypersensitivity reaction.Conclusion: The results suggest that a combination ofGenexol and cisplatin is an effective and well-toleratedregimen for patients with NSCLC. (Cancer Res Treat. 2003;35:30-34)

First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.

Han, Ji-Youn,Park, Keunchil,Kim, Sang-We,Lee, Dae Ho,Kim, Hyae Young,Kim, Heung Tae,Ahn, Myung Ju,Yun, Tak,Ahn, Jin Seok,Suh, Cheolwon,Lee, Jung-Shin,Yoon, Sung Jin,Han, Jong Hee,Lee, Jae Won,Jo, Sook Grune Stratton ; American Society of Clinical Onco 2012 Journal of clinical oncology Vol.30 No.10

<P>Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy.</P>

Preoperative Concurrent Radiochemotherapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer

Kang, Min Kyu,Ahn, Yong Chan,Lim, Do Hoon,Park, Keunchil,Park, Joon Oh,Shim, Young Mog,Kim, Jhingook,Kim, Kwhanmien The Korean Academy of Medical Sciences 2006 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.21 No.2

<P>This is to examine whether aggressive multimodality therapy improves the treatment outcomes in stage IIIA non-small cell lung cancer (NSCLC). Fifty-three consecutive NSCLC patients with N2 disease, confirmed by mediastinoscopic biopsy, received preoperative thoracic radiation therapy (45 Gy/5 weeks) concurrent with two cycles of oral etoposide and intravenous cisplatin and surgery. Postoperative radiation therapy (PORT, 18 Gy/2 weeks) was optionally recommended for those with the risk factors of loco-regional recurrence based on the surgical and pathological findings. Surgical resection was performed in 38 patients (71.7%), and down-staging was achieved in 19 patients (50%). The median survival period was 27 months in 38 patients who underwent resection, and the rates at 3-yr of overall survival, loco-regional control, distant metastasis-free survival, and disease-free survival were 44.3%, 87.9%, 32.9%, and 29.3%. Significantly favorable factor regarding overall survival was achieving p0/I stage by the multivariate analysis. PORT was successful in reducing locoregional recurrences in patients with the risk factors. Current preoperative concurrent radiochemotherapy and surgery by the authors resulted in comparable survival with other reports, however, further refinement of multimodality approach may be warranted for more effective reduction of distant metastasis.</P>

Clinical activity of ASP 8273 in Asian patients with non‐small‐cell lung cancer with EGFR activating and T790M mutations

Murakami, Haruyasu,Nokihara, Hiroshi,Hayashi, Hidetoshi,Seto, Takashi,Park, Keunchil,Azuma, Koichi,Tsai, Chun‐,Ming,Yang, James Chih‐,Hsin,Nishio, Makoto,Kim, Sang‐,We,Kiura, Katsuyu John Wiley and Sons Inc. 2018 CANCER SCIENCE Vol.109 No.9

<P>Epidermal growth factor receptor (EGFR)‐activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non‐small‐cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once‐daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose‐escalation/dose‐expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25‐600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M‐positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two‐stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9‐54.0). Median duration of progression‐free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment‐related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR‐activating and T790M mutations.</P>

The Outcomes of Hypertransfusion in Major ABO Incompatible Allogeneic Stem Cell Transplantation

Lee Se Hoon,Park Joon Oh,Jung Chul Won,Park Keunchil,Lee Kyoo Hyung,Lee Mark Hong,Lee Kyung Eun,Park Jinny,Kim Kihyun,Kim Won Seog,Im Young Hyuk,Kang Won Ki,Kim Seon Woo,Lee Je Hwan,Park Se Hoon 대한의학회 2004 Journal of Korean medical science Vol.19 No.1

Original Article:The Continuation of Erlotinib Treatment in Non-Small Cell Lung Cancer Patients Whose Brain Lesion Is the Only Site of Progression: Prospective Pilot Study

안명주,정기선,김성태,이지은,임성희,이민영,권희진,김인영,선종무,안진석,Keunchil Park,김혜수,유쾌한 한양대학교 의과대학 2015 Hanyang Medical Reviews Vol.35 No.3

There have been conflicting reports on the continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with newly developed or progressive brain metastasis of non-small cell lung cancer (NSCLC). Patients with newly developed or progressive intracranial lesions, but who maintained well-controlled extracranial disease during erlotinib treatment, were enrolled in this study. The proposed therapy included stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and/or surgical resection for intracranial lesions. Erlotinib treatment was continued simultaneously unless extracranial disease progressed. The evaluation of both extra- and intra-cranial lesions was performed every 3 months. From October 2009 to June 2012, 14 patients were enrolled in this pilot study. For intracranial disease, 4 patients received SRS alone, 7 patients received both SRS and WBRT, 2 patients received SRS, WBRT and surgical resection, and 1 patient received no local therapy due to the presence of asymptomatic lesions. Of the patients with extracranial disease who were placed on continued erlotinib therapy, 6 patients (42.9%) showed partial response (PR), while 7 patients (50.0%) remained in stable disease (SD). The progression-free survival (PFS) of extracranial and intracranial disease was 11.1 (range 1.6-34.6) and 10.2 (range 1.5-34.6) months, respectively. In 5 cases, brain lesions relapsed before the progression of extracranial disease. Overall survival (OS) was 22.6 (range 2.1-50.4) months. For NSCLC patients with progression of only intracranial disease during erlotinib treatment, the continuation of erlotinib in combination with local therapy to brain metastases can be an effective treatment option.

N2 병기 비소세포 폐암의 수술 전 동시화학방사선요법

이규찬(Kyu Chan Lee),안용찬(Yong Chan Ahn),박근칠(Keunchil Park),김관민(Kwhan Mien Kim),김진국(Jhin Gook Kim),심영목(Young Mog Shim),임도훈(Do Hoon Lim),김문경(Moon Kyung Kim),신경환(Kyung Hwan Shin),김대용(Dae Yong Kim),허승재(Seung 대한방사선종양학회 1999 Radiation Oncology Journal Vol.17 No.2

목 적:N2 병기 비소세포폐암에서 수술 전 동시화학방사선요법과 수술을 적용하여 급성 부작용, 수술절제가능성 및 수술 후 병기 강하율을 보고하고자 한다. 대상 및 방법:1997년 5월부터 1998년 6월까지 삼성서울병원에서 N2 병기 비소세포폐암으로 진단 받은 15명의 환자들을 대상으로 하였다. 환자들 연령의 중앙값은 61세(45∼67세), 남녀 성비는 12:3 이었으며 세포 조직형은 편평상피암종이 11명, 선암종이 4명이었다. 치료 전 임상적 T병기는 T1, T2, 및 T3가 각각 2명, 12명, 및 1명씩이었으며 모든 환자들이 N2 병기로서 이중 10명은 종격동내시경을 통한 조직생검을 통하여 종격동 림프절 전이를 확인하였고 나머지 5명은 흉부 CT 영상 상 종격동 림프절 전이가 강력히 의심된 경우였다. 수술 전 방사선치료는 흉부 CT 영상을 기준으로 하여 원발 병소, 동측 폐문부 및 종격동 림프절에 대하여 10MV X-선을 이용하여 45Gy를 5주간에 걸쳐서 조사하도록 계획하였다(일회 선량 1.8Gy, 일일 1회, 주 5회). 수술 전 복합화학요법은 cis-Platin(100mg/m2) 을 제 1일에 급속 정주하고 Etoposide(50mg/m2/day)를 제 1일부터 제 14일까지 경구로 2회에 분복하도록 하였으며, 첫 번째 화학요법은 방사선치료의 시작일에, 두 번째 화학요법은 4주 후에 시행하도록 계획하였다. 수술은 방사선-복합화학요법의 완료 3주째에 흉부 CT 영상을 얻어 병변의 진행이나 원격전이의 소견이 없음을 확인한 후 시행하였다. 결 과:방사선치료는 15명 모두에서 계획된 목표 선량 45Gy를 조사하였으며, 복합 화학요법은 11명의 환자에서는 계획대로 2회를, 나머지 4명에서는 1회만 시행하였다. 본 연구의 치료 방법과 관련하여 1명의 환자가 수술 15일만에 급성 호흡부전으로 사망하였으며 입원치료를 요하는 정도의 급성 부작용의 발현은 방사선폐렴과 호중구 감소로 인한 발열이 각각 1명, 2명이었다. 급성 식도염은 RTOG grade 1이 9명, grade 2가 3명으로 대체로 경미한 편이었다. 총 26회의 복합 화학요법과 관련된 급성 부작용으로 grade 3 이상의 백혈구 감소증, 혈소판 감소증, 및 빈혈이 각각 26.9%, 7.7%, 3.8%에서 나타났다. 수술을 시행한 환자는 13명으로 이 중 12명에서 근치적 절제술이 가능하여 수술절제율은 92.3%(12/13) 이었다. 한 명에서는 수술 시 늑막 전이가 확인되어 절제 수술을 시행하지 못하였다. 다른 2명은 수술을 거부하였다. 수술 후 병리학적 T병기는 T0, T1, 및 T2가 각각 3명, 6명, 및 3명이었으며 N병기는 N0, N1, 및 N2가 각각 8명, 1명, 및 3명이었다. 병리학적 완전 관해는 모두 3명의 환자에서(27.3%) 확인되었으며, 수술 전 임상적 병기와 비교하여 볼 때 병기 강하, 불변, 상승이 각각 8명(61.5%), 4명(30.8%), 1명(7.7%) 이었다. 결 론:N2 병기 비소세포폐암에 대한 동시화학방사선요법은 대체로 만족할 만한 결과를 얻을 수 있었으나 보다 많은 환자들을 대상으로 하는 장기간의 추적 관찰을 요한다. Purpose:This is to evaluate the acute complication, resection rate, and tumor down-staging after pre-operative concurrent chemoradiotherapy for stage IIIA (N2) non-small cell lung cancer. Materials and Methods:Fifteen patients with non-small cell lung cancer were enrolled in this study from May 1997 to June 1998 in Samsung Medical Center. The median age of the patients was 61 (range, 45∼67) years and male to female ratio was 12:3. Pathologic types were squamous cell carcinoma (11) and adenocarcinoma (4). Pre-operative clinical tumor stages were cT1 in 2 patients, cT2 in 12, and cT3 in 1 and all were N2. Ten patients were proved to be N2 with mediastinoscopic biopsy and five had clinically evident mediastinal lymph node metastases on the chest CT scans. Pre-operative radiation therapy field included the primary tumor, the ipsilateral hilum, and the mediastinum. Total radiation dose was 45 Gy over 5 weeks with daily dose of 1.8 Gy. Pre-operative concurrent chemotherapy consisted of two cycles of intravenous cis-Platin (100 mg/m2) on day 1 and oral Etoposide (50 mg/m2/day) on days 1 through 14 with 4 weeks' interval. Surgery was followed after the pre-operative re-evaluation including chest CT scan in 3 weeks of the completion of the concurrent chemoradiotherapy if there was no evidence of disease progression. Results:Full dose radiation therapy was administered to all the 15 patients. Planned two cycles of chemotherapy was completed in 11 patients and one cycle was given to four. One treatment related death of acute respiratory distress syndrome occurred in 15 days of surgery. Hospital admission was required in three patients including one with radiation pneumonitis and two with neutropenic fever. Hematologic complications and other acute complications including esophagitis were tolerable. Resection rate was 92.3% (12/13) in 13 patients excluding two patients who refused surgery. Pleural seeding was found in one patient after thoracotomy and tumor resection was not feasible. Post-operative tumor stagings were pT0 in 3 patients, pT1 in 6, and pT2 in 3. Lymph node status findings were pN0 in 8 patients, pN1 in 1, and pN2 in 3. Pathologic tumor down-staging was 61.5% (8/13) including complete response in three patients (23.7%). Tumor stage was unchanged in four patients (30.8%) and progression was in one (7.7%). Conclusion:Pre-operative concurrent chemoradiotherapy for Stage IIIA (N2) non-small cell lung cancer emonstrated satisfactory results with no increased severe acute complications. This treatment scheme deserves more patient accrual with long-term follow-up.

The Relation between Histopathologic Findings on Surgical Specimen and Outcomes in Patients with N2 Positive Stage IIIA Non-Small Cell Lung Cancer Receiving Preoperative Concurrent ..

Bo Kyong Kim,임도훈,Won Park,Joungho Han,Keunchil Park,Kwan Min Kim,김진국,Young Mog Shim,Yong Chan Ahn,Kyoung Ju Kim 대한암학회 2003 Cancer Research and Treatment Vol.35 No.6

Purpose: To evaluate the prognostic implication of histopathologic findings on the surgical specimens of N2 positive stage IIIA non-small cell lung cancer (NSCLC) patients who were treated with preoperative concurrent radiochemotherapy (CRCT) and surgery.Materials and Methods: From May 1997 to April 2000, 48 patients with N2 positive stage IIIA NSCLC were treated with preoperative CRCT and surgery. Retrospective analyses were performed on 33 patients who underwent surgical resection. The thoracic radiation therapy (TRT) dose was 45 Gy over 5 weeks with a 1.8 Gy daily fraction using 10 MV X-rays. Chemotherapy consisted of two cycles of intravenous cisplatin (100 mg/m2, on days 1 and 29) and oral etoposide (50 mg/m2/day, on days 1?? 14 and 29??42), concurrently delivered with TRT. Surgery was performed around 4 weeks of the completion of CRCT. The median follow up was 18 months. The histopathologic findings, including the proportions of viable tumor cells, fibrosis, and necrosis, as well as the tumor and nodal statuses on the surgical specimens following the preoperative CRCT, were analyzed.Results: The 3-year overall survival, disease-free survival, and local control rates were 46.1%, 49.5%, and 85.5%, respectively. Post-surgical stages decreased in 18 patients (54.5%), including 3 pathologic complete responses, were unchanged in 13 (39.4%), and increased in two (6.1%). On univariate analyses, the low proportion of the viable tumor cells was the only factor favorably affecting the overall survival rate (p=0.0386), and the histologic type of squamous cell carcinoma was a favorable factor affecting disease free survival rate (p=0.0452). On multivariate analyses, however, no factor affected the overall survival, disease free survival, or local control rates.Conclusion: The histopathologic findings of the proportion of viable tumor cells, fibrosis, and necrosis on the surgical specimens following preoperative CRCT had few prognostic implications on uni-and multi-variate analyses.Furthermore, the primary tumor and nodal responses to preoperative CRCT did not influence the outcomes. Longer- term follow-up with a larger number of patients, however, is awaited. (Cancer Research and Treatment 2003; 35:497-501)

국한성 소세포 폐암에서 항암 화학 및 흉부 방사선치료의 병합요법 적응

김문경,안용찬,박근칠,임도훈,허승재,김대용,신경환,이규찬,권오정,Kim Moon Kyung,Ahn Yong Chan,Park Keunchil,Lim Do Hoon,Huh Seung Jae,Kim Dae Yong,Shin Kyung Hwan,Lee Kyu Chan,Kwon O Jung 대한방사선종양학회 1999 Radiation Oncology Journal Vol.17 No.1

목적 : 국한성 병기의 소세포 폐암에 대하여 항암 화학 및 흉부 방사선치료의 병합요법을 적용하여 국소 반응율, 급성 부작용의 빈도, 단기 임상 추적 관찰 결과 등을 보고하고자 한다. 대상 및 방법 : 1994년 10월부터 1998년 4월까지 국한성 병기의 소세포 폐암으로 진단되어 VIP 요법(etoposide, ifosfamide, cis-platin) 또는 EP 요법(etoposide, cis-platin)의 복합 항암 화학 및 흉부 방사선치료의 동시 병합요법을 시행받은46명의 환자를 대상으로 하였다. 항암 화학요법은 3주 간격으로 모두 6회의 시행을 목표로 하였고, 흉부 방사선치료는 10MV X-ray를 사용하여 일일선량 2Gy씩 44Gy를 4.5주간에 첫번째 화학요법과 동시에 시행하고자 하였다. 관해율은 예정된 치료가 모두 종료된지 4주만에 판정하였으며, 완전 관해를 얻었던 경우에는 10회에 걸쳐 25Gy의 예방적 전뇌 방사선치료를 예정하였다. 급성 부작용의 빈도와 정도는 SWOG 부작용 판정 등급체계를 적용하였으며, 단기 추적 관찰 결과로서 1년 및 2년 생존율, 무병 생존율 등은 Kaplan-Meter법을 사용하였다. 결과 : 전체 환자에 대한 추적 기간의 중앙값은 16개월이었다(범위 2개월$\~$41개월). 완전 관해는 30명(65$\%$)에서 있었으며, 이 중 22명에서 예방적 전뇌 방사선치료를 시행하였다. 동시 병합요법의 3도 이상의 혈액학적 부작용의 빈도는 각각 백혈구감소증 23명(50$\%$), 적혈구감소증 17명(37$\%$), 혈소판감소증 9명(20$\%$)이었고, 비혈액학적 부작용은 탈모 9명(20$\%$), 오심 및 구토 5명(11$\%$), 그리고 말초신경염 1명(2$\%$)이었으며, 이로 인한 화학요법의 지연은 한명에서, 화학요법제의 용량 감소는 전체 246회의 화학요법 중 58회에서 있었다. 3도 이상의 방사선 식도염은 없었으나 화학요법의 부작용으로 인한 흉부 방사선치료의 일시 중단은 21명에서 평균 8.3일간 필요하였다. 국소 재발은 완전 관해 환자에서 8명, 국소 진행은 부분관해 및 불변 환자에서 6명이 확인되었고, 원격 전이는 17명에서 확인되었으며, 이 중 4명에서 국소 재발과 원격 전이가 함께 확인되었다. 원격 전이의 주요 장기로는 뇌가 10명으로 가장 많았고, 간이 4명으로 다음을 차지하였다. 전체 환자들의 생존기간의 중앙값은 23개월이었으며, 1년, 2년 생존율 및 무재발 생존율은 각각 79%$\%$ 45$\%$ 및 55$\%$, 32$\%$였다. 결론 : 국한성 소세포 폐암환자에서 항암 화학 및 방사선치료의 병합요법을 적용하여 만족할 만한 관해율 및 1년, 2년 생존율을 얻었으며, 대체적인 환자들의 치료 방침에 대한 순응도는 양호한 편으로 판단된다. Purpose : This is a retrospective study to evaluate the response rate, acute toxicity, and survival rate of a combined chemotherapy and radiation therapy in limited disease small cell lung cancer, Materials and Methods : Firty-six patients with limited disease small-cell lung cancer who underwent combined chemotherapy and radiation therapy between October 1994 and April 1998 were evaluated. Six cycles of chemotherapy were planned either using a VIP regimen etoposide, ifosfamide, and cis-platin) or a EP regimen (etoposide and cis-platin). Thoracic radiation therapy was planned to deli- ver 44 Gy using 1 OMV X-ray, starting concurrently with chemotherapy. Response was evaluated 4 weeks after the completion of the planned chemotherapy and radiation therapy, and the prophylaetic cranial irradiation was planned only for the patients with complete responses. Acute toxicity was evaluated using the SWOG toxicity criteria, and the overall survival and disease-free survival were calculated using the Kaplan-Meier Method. Results : The median follow-up period was 16 months (range:2 to 41 months). Complete response was achieved En 30 (65$\%$) patients, of which 22 patients received prophylactic cranial irradiations. Acute toxicities over grade III were granulocytopenia in 23 (50$\%$), anemia in 17 (37$\%$), thrombo- cytopenia in nine (20$\%$), alopecia in nine (20$\%$), nausea/vomiting in five (11$\%$), and peripheral neuropathy in one (2$\%$). Chemotherapy was delayed in one patient, and the chemotherapy doses were reduced in 58 (24$\%$) out of the total 246 cycles. No radiation esophagitis over grade 111 was observed, while interruption during radiation therapy for a mean of 8.3 days occurred in 21 patients. The local recurrences were observed in 8 patients and local progressions were in 6 patients, and the distant metastases in 17 patients. Among these, four patients had both the local relapse and the distant metastasis. Brain was the most common metastatic site (10 patients), followed by the liver as the next common site (4 patients). The overall and progression-free survival rates were 79$\%$ and 55$\%$ in 1 year, and 45'/) and 32% in 2 years, respectively, and the median survival was 23 months. Conclusion : Relatively satisfactory local control and suwival rates were achieved after the combined chemotherapy and radiation therapy with mild to moderate acute morbidities in limited disease small cell lung cancer.