cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries . the burden of cancer is growing in developing countries as a result of aging populations and increasing cancer - associated lifestyle factors including stress , smoking , physical inactivity , and westernized diets . lung cancer has been the most common type of cancer in the world for several decades . in the year 2008 , there were estimated 1.61 million new cases of lung cancer , representing 12.7% of all new cancers . it was also the most common cause of death from cancer , with 1.38 million deaths ( 18.2% of total cancer - related deaths ) . generally , the prognosis for lung cancer is poor , with a 5-year survival rate of only 15% . non - small - cell lung cancer ( nsclc ) accounts for approximately 85% of all cases of lung cancer   and consists of three major cell types ; adenocarcinomas , squamous cell carcinomas , and largecell carcinomas . the treatment for nsclc involves surgery , radiation therapy , and chemotherapy   and is determined by disease stage . surgery is the mainstay treatment for early - stage and localized disease , and multimodal therapy is the norm for regionallyadvanced disease . for late - stage iiib or iv nsclc patients , hangam - plus(hap ) has been used to treat solid tumors such as lung , pancreatic , colorectal , and stomach cancers at the east west cancer center ( ewcc ) , dunsan oriental hospital ( daejeon , korea ) since its development in 1996 [ 8 - 13 ] . several research findings support its therapeutic role in the immune protective function , antiangiogenesis , inhibition of cancer cell proliferation and metastasis prevention [ 8 - 13 ] . significant prevention of basic fibroblastgrowth- factor ( bfgfs)-induced human umbilical vein endothelial ( huve ) cell proliferation , adhesion , migration , and capillary -like tubular network formation due to the use of hap has been reported . hap has also demonstrated a significant concentration- dependent inhibition of cell motility and invasiveness of nci - h460 nsclc cells . the tight junctions ( tjs ) and matrix metalloproteinases ( mmps ) were the critical targets of hapinduced anti - invasive activity . yoo et al . reported a successful 7-year follow - up case of a squamous - cell lung carcinoma recurrence treated with hap . jeong et al . carried out a prospective study on inoperable nsclc patients treated with hap and proved its synergistic effect with conventional therapy and prolonged survival rate . the goal of this study was to evaluate the efficacy of hap as a third - line treatment for advanced - stage iiib / iv nsclc . in this observational study , six nsclc patients were followed from april 2010 to october 2011 while being treated at the ewcc . the treatment plan was explained in detail , and informed consent was obtained from all patients . the study gained ethical approval from the institutional review board ( irb ) of dunsan oriental hospital of daejeon university on may 24 , 2010 ( irb number : djdsoh-10 - 01 ) . patients eligible for this study included : ( 1 ) patients with cytologically- or histologically - verified nsclc stage iiib or iv who were not candidates for treatment with a curative intent ; ( 2 ) stage iiib / iv nsclc patients who refused first - line chemotherapy or failed at least one cycle of chemotherapy ; ( 3 ) patient with a measurable malignant lesion based on the international standard of response evaluation criteria in solid tumors ( recist ) [ 18 ] , complete / partial response ( cr / pr ) , progression / stable disease ( pd / sd ) ; ( 4 ) eastern cooperative oncology group ( ecog ) [ 19 ] score  2 ; ( 5 ) patients with expected survival of at least three months ; ( 6 ) completion of anticancer drugs and/or radiation treatment three weeks prior to participation ; ( 7 ) recovery from all adverse effects of anticancer drugs and/ or radiation treatment ; ( 8) proper bone marrow function ( peripheral absolute granulocyte count 15010 /l ; platelet count 10010 /l ) ; ( 9 ) proper liver function ( bilirubin  1.5 mg / dl ; serum glutamic pyruvic transaminase or serum glutamic oxaloacetic transaminase 3normal ) and kidney function ( creatinine  1.5 mg / dl ) . demographic and clinical data ( age , gender , histological or cytological tumor type , performance status , disease stage , body height and weight ) , as well as laboratory measures ( hemoglobin , leukocyte and platelet counts , sodium , potassium , calcium , albumin , spartate aminotransferase ( ast ) , alanine aminotransferase ( alt ) , bilirubin , alkaline phosphatase , lactate dehydrogenase and creatinine ) , were recorded . hap is an anti - cancer herbal formula consisting of eight different herbs ( table 1 ) . the manufacture of the hap and the quality control of the herbs in the formula were managed by kim s pharmaceutical company in daejeon , korea . hap is prepared in a capsule form with a dried powder of the extracted herbs inside . hap is generally taken three times a day ( tid ) , 1,000 or 2,000 mg at a time , after meals ( 3,000 or 6,000 mg / day ) . ct scans were taken at the time of initial administration and after 12 weeks of treatment . compared with the initial tumor size , disappearance of all target lesions was confirmed as cr , at least a 30% decrease in the sum of the diameters of the target lesions was confirmed as pr , at least a 20% increase in the sum of the diameters of the target lesions was confirmed as pd , and neither sufficient shrinkage to qualify for pr nor sufficient increase to qualify for pd was confirmed as sd . endpoints included the following : ( 1 ) survival rate , including overall survival ( from initial administration of hap to death or to last follow - up ) and progression - free survival ( from randomization to the first of either recurrence or relapse , second cancer , or death ) [ 20 ] , ( 2 ) response rate , measured by using the international standard provided by recist as cr , pr , pd , and sd [ 18 ] , ( 3 ) adverse effects during hap treatment , reported based on common terminology criteria for adverse events ( ctcae ) version 3.0 [ 21 ] . correlations between the " tumor response " , " treatment period " and " survival time " were investigated using fisher 's exact tests . estimates of the median os and the median pfs were calculated using kaplan - meier analyses based on all six patients . estimates for each " sd - pd " and " before - after " group were calculated using the same method . the comparisons of group survival functions were conducted using log rank tests based on the os and the pfs . in this observational study , six nsclc patients were followed from april 2010 to october 2011 while being treated at the ewcc . the treatment plan was explained in detail , and informed consent was obtained from all patients . the study gained ethical approval from the institutional review board ( irb ) of dunsan oriental hospital of daejeon university on may 24 , 2010 ( irb number : djdsoh-10 - 01 ) . patients eligible for this study included : ( 1 ) patients with cytologically- or histologically - verified nsclc stage iiib or iv who were not candidates for treatment with a curative intent ; ( 2 ) stage iiib / iv nsclc patients who refused first - line chemotherapy or failed at least one cycle of chemotherapy ; ( 3 ) patient with a measurable malignant lesion based on the international standard of response evaluation criteria in solid tumors ( recist ) [ 18 ] , complete / partial response ( cr / pr ) , progression / stable disease ( pd / sd ) ; ( 4 ) eastern cooperative oncology group ( ecog ) [ 19 ] score  2 ; ( 5 ) patients with expected survival of at least three months ; ( 6 ) completion of anticancer drugs and/or radiation treatment three weeks prior to participation ; ( 7 ) recovery from all adverse effects of anticancer drugs and/ or radiation treatment ; ( 8) proper bone marrow function ( peripheral absolute granulocyte count 15010 /l ; platelet count 10010 /l ) ; ( 9 ) proper liver function ( bilirubin  1.5 mg / dl ; serum glutamic pyruvic transaminase or serum glutamic oxaloacetic transaminase 3normal ) and kidney function ( creatinine  1.5 mg / dl ) . demographic and clinical data ( age , gender , histological or cytological tumor type , performance status , disease stage , body height and weight ) , as well as laboratory measures ( hemoglobin , leukocyte and platelet counts , sodium , potassium , calcium , albumin , spartate aminotransferase ( ast ) , alanine aminotransferase ( alt ) , bilirubin , alkaline phosphatase , lactate dehydrogenase and creatinine ) , were recorded . hap is an anti - cancer herbal formula consisting of eight different herbs ( table 1 ) . the manufacture of the hap and the quality control of the herbs in the formula were managed by kim s pharmaceutical company in daejeon , korea . hap is prepared in a capsule form with a dried powder of the extracted herbs inside . hap is generally taken three times a day ( tid ) , 1,000 or 2,000 mg at a time , after meals ( 3,000 or 6,000 mg / day ) . ct scans were taken at the time of initial administration and after 12 weeks of treatment . compared with the initial tumor size , disappearance of all target lesions was confirmed as cr , at least a 30% decrease in the sum of the diameters of the target lesions was confirmed as pr , at least a 20% increase in the sum of the diameters of the target lesions was confirmed as pd , and neither sufficient shrinkage to qualify for pr nor sufficient increase to qualify for pd was confirmed as sd . endpoints included the following : ( 1 ) survival rate , including overall survival ( from initial administration of hap to death or to last follow - up ) and progression - free survival ( from randomization to the first of either recurrence or relapse , second cancer , or death ) [ 20 ] , ( 2 ) response rate , measured by using the international standard provided by recist as cr , pr , pd , and sd [ 18 ] , ( 3 ) adverse effects during hap treatment , reported based on common terminology criteria for adverse events ( ctcae ) version 3.0 [ 21 ] . correlations between the " tumor response " , " treatment period " and " survival time " were investigated using fisher 's exact tests . estimates of the median os and the median pfs were calculated using kaplan - meier analyses based on all six patients . estimates for each " sd - pd " and " before - after " group were calculated using the same method . the comparisons of group survival functions were conducted using log rank tests based on the os and the pfs . subjects in the study consisted of two males ( 33.3% ) and four females ( 66.7% ) . one patient had stage iiib ( 16.7% ) and 5 patients had stage iv ( 83.3% ) nsclc . two patients were treated for less than 100 days ( 33.3% ) , and four patients were treated for more than 100 days ( 66.7% ) . the median duration of hap treatment was 5.3 months . in the 12-week - interval chest ct assessment , three patients showed sd , and the other three patients showed pd ( table 2 and 3 ) . * ecog : eastern cooperative oncology group ecog : eastern cooperative oncology group ( 0 = fully active ; 1 = restricted in physically strenuous activity ; 2 = up and about more than 50% of waking hours ; 3 = limited self - care , confined to bed or chair more than 50% of waking hours ; 4 = totally confined to bed or chair ; 5 = dead ) ; recist = response evaluation criteria in solid tumors : complete response ( cr ) = disappearance of all target lesions . partial response ( pr ) = at least a 30% decrease in the sum of the diameters of the target lesions , taking as a reference the baseline sum diameters . progressive disease ( pd ) = at least a 20% increase in the sum of the diameters of the target lesions , taking as a reference the smallest sum under study ( this includes the baseline sum if that is the smallest under study ) . in addition to the relative increase of 20% , the sum must also demonstrate an absolute increase of at least 5 mm . stable disease ( sd ) = neither sufficient shrinkage to qualify for pr nor sufficient increase to qualify for pd , taking as a reference the smallest sum of the diameters under study ; pfs = progression free survival ; os = overall survival . of the six patients , three patients expired during the study , and the remaining three patients were still living as of october 31 , 2011 . the os ranged from 234 to 512 days , with a median survival of 397 days and a 66.7% one - year survival rate . two of the three sd patients and one of the three pd patients survived ( fig . one of the two patients who received less than 100 days of hap treatment survived , and two of the four patients who received more than 100 days of hap treatment survived . pfs is defined as the time from randomization to the first of either recurrence or relapse , second cancer , or death . the pfs of the patients ranged from 88 to 512 days , with a median pfs of 96 days . one of the two patients who received less than 100 days of hap treatment had progressive disease . three of the four patients who received more than 100 days of hap treatment had progressive disease . no hap - related hematologic / non - hematologic toxicity , hepatotoxicity or nephrotoxicity were observed . however , transient abdominal discomfort was reported in two patients ( patients no . 1 and 5 ) during treatment , but no treatment was required and symptoms disappeared soon after . 2 was a 74-year - old male patient diagnosed with stage iv nsclc ( t4n3m1a ) in september 2009 . he received three cycles of chemotherapy ( paclitaxel - cisplatin ) from september 2009 to november 2009 . due to his old age and adverse effects , he discontinued conventional treatment and received hap , instead as a complementary and alternative medicine ( cam ) treatment , from may 7 , 2010 , to august 26 , 2010 . his performance status was ecog 2 at the time of initial administration . according to the chest ct scans taken on may 31 , 2010 , and september 1 , 2010 , his disease was stable , and the cancer growth has been halted for at least 12 weeks ( 3 months ) since the initial hap administration . as of october 31 , 2011 patient no.3 was a 74-year - old female patient diagnosed on may 2010 with stage iv nsclc with spinal metastasis in t11 . as she refused all conventional therapy and wished to be treated with cam only , she received hap from june 16 , 2010 to august 2 , 2011 . follow - up chest ct scans were taken on june 16 , 2010 , and september 17 , 2010 , and showed sd but aggravation of the spine ( t11 ) metastasis was revealed by magnetic resonance imaging ( mri ) on september 29 , 2010 . she was then treated for the spine metastasis by using radiation therapy from november 16 , 2010 , to november 22 , 2010 . as of october 31 , 2011 4 was a 47-year - old female patient diagnosed with stage iv nsclc on august 31 , 2009 . she received her first - line of chemotherapy ( gemzar - cisplatin ) from september 2009 to november 2010 and her second - line of chemotherapy ( tarceva ) from november , 2009 to february , 2010 . she received hap as the third - line treatment from april 6 , 2010 , to december 8 , 2010 . chest ct scans taken on june 16 , 2010 , and september 15 , 2010 , showed sd , and cancer growth has been halted for at least 12 weeks ( 3 months ) since the initial hap administration . as of october 31 , 2011 , she was still alive without any evidence of progression . subjects in the study consisted of two males ( 33.3% ) and four females ( 66.7% ) . one patient had stage iiib ( 16.7% ) and 5 patients had stage iv ( 83.3% ) nsclc . two patients were treated for less than 100 days ( 33.3% ) , and four patients were treated for more than 100 days ( 66.7% ) . the median duration of hap treatment was 5.3 months . in the 12-week - interval chest ct assessment , three patients showed sd , and the other three patients showed pd ( table 2 and 3 ) . * ecog : eastern cooperative oncology group ecog : eastern cooperative oncology group ( 0 = fully active ; 1 = restricted in physically strenuous activity ; 2 = up and about more than 50% of waking hours ; 3 = limited self - care , confined to bed or chair more than 50% of waking hours ; 4 = totally confined to bed or chair ; 5 = dead ) ; recist = response evaluation criteria in solid tumors : complete response ( cr ) = disappearance of all target lesions . partial response ( pr ) = at least a 30% decrease in the sum of the diameters of the target lesions , taking as a reference the baseline sum diameters . progressive disease ( pd ) = at least a 20% increase in the sum of the diameters of the target lesions , taking as a reference the smallest sum under study ( this includes the baseline sum if that is the smallest under study ) . in addition to the relative increase of 20% , the sum must also demonstrate an absolute increase of at least 5 mm . stable disease ( sd ) = neither sufficient shrinkage to qualify for pr nor sufficient increase to qualify for pd , taking as a reference the smallest sum of the diameters under study ; pfs = progression free survival ; os = overall survival . of the six patients , three patients expired during the study , and the remaining three patients were still living as of october 31 , 2011 . the os ranged from 234 to 512 days , with a median survival of 397 days and a 66.7% one - year survival rate . two of the three sd patients and one of the three pd patients survived ( fig . one of the two patients who received less than 100 days of hap treatment survived , and two of the four patients who received more than 100 days of hap treatment survived . pfs is defined as the time from randomization to the first of either recurrence or relapse , second cancer , or death . the pfs of the patients ranged from 88 to 512 days , with a median pfs of 96 days . one of the two patients who received less than 100 days of hap treatment had progressive disease . three of the four patients who received more than 100 days of hap treatment had progressive disease . no hap - related hematologic / non - hematologic toxicity , hepatotoxicity or nephrotoxicity were observed . however , transient abdominal discomfort was reported in two patients ( patients no . 1 and 5 ) during treatment , but no treatment was required and symptoms disappeared soon after . 2 was a 74-year - old male patient diagnosed with stage iv nsclc ( t4n3m1a ) in september 2009 . he received three cycles of chemotherapy ( paclitaxel - cisplatin ) from september 2009 to november 2009 . he failed his first - line chemotherapy and experienced significant adverse effects . due to his old age and adverse effects , he discontinued conventional treatment and received hap , instead as a complementary and alternative medicine ( cam ) treatment , from may 7 , 2010 , to august 26 , 2010 . his performance status was ecog 2 at the time of initial administration . according to the chest ct scans taken on may 31 , 2010 , and september 1 , 2010 , his disease was stable , and the cancer growth has been halted for at least 12 weeks ( 3 months ) since the initial hap administration . as of october 31 , 2011 patient no.3 was a 74-year - old female patient diagnosed on may 2010 with stage iv nsclc with spinal metastasis in t11 . as she refused all conventional therapy and wished to be treated with cam only , she received hap from june 16 , 2010 to august 2 , 2011 . follow - up chest ct scans were taken on june 16 , 2010 , and september 17 , 2010 , and showed sd but aggravation of the spine ( t11 ) metastasis was revealed by magnetic resonance imaging ( mri ) on september 29 , 2010 . she was then treated for the spine metastasis by using radiation therapy from november 16 , 2010 , to november 22 , 2010 . as of october 31 , 2011 , she was still alive without any evidence of progression . 4 was a 47-year - old female patient diagnosed with stage iv nsclc on august 31 , 2009 . she received her first - line of chemotherapy ( gemzar - cisplatin ) from september 2009 to november 2010 and her second - line of chemotherapy ( tarceva ) from november , 2009 to february , 2010 . she received hap as the third - line treatment from april 6 , 2010 , to december 8 , 2010 . chest ct scans taken on june 16 , 2010 , and september 15 , 2010 , showed sd , and cancer growth has been halted for at least 12 weeks ( 3 months ) since the initial hap administration . as of october 31 , 2011 , she was still alive without any evidence of progression . in advanced cancer trials , the time - honored standard for demonstrating efficacy of new adjuvant therapies is an improvement in the os . however , the os requires extended followups , which may prevent the timely dissemination of results and a consequent delay in the implementation of an effective treatment regimen , so the pfs is sometimes suggested as an alternative endpoint to the os . the weakness of the pfs lies in its overlooking the long - term effects of the treatment , such as endorgan toxicities or secondary malignancies , that may adversely impact survival . in this study , both the os and the pfs were used as endpoints to measure the efficacy of hap to make up for the short follow - up time and the small population of the study . chemotherapy is the primary first - line treatment for 70 to 80% of patients who present with locally advanced ( stage iiib ) or metastatic ( stage iv ) disease . in advanced nsclc , the objectives of chemotherapy are prolonged survival , improved quality of life and enhanced symptom control . although first - line chemotherapy has contributed to the survival of patients with advanced nsclc , the overall and the one - year survival rates ( 8- 11 months and 27 - 47% , respectively ) still remain poor [ 26 - 27 ] . in stage iiib / iv patients , response to first - line therapy is generally short lived , and progression is often witnessed on an average of 4 - 6 months after discontinuation of the treatment . for patients who fail to respond to first - line chemotherapy , second - line chemotherapy is recommended . docetaxel or pemetrexed is used as a second - line chemo agent for locally advanced or metastatic nsclc patients who have progressed on first - line therapy . in a current review , objective response rate of second - line chemotherapeutic agents was found to be lower than that of the first - line setting in advanced nsclc cases . considering the incurable nature of advanced nsclc and the modest survival seen in second - line settings , patient convenience and preference must be taken into account when selecting the third - line treatment agent . the impact of second - line chemotherapy has been studied in a large cohort of 4,318 patients in 19 phase iii trials . docetaxel ( 75 mg / m every 3 weeks ) significantly prolonged median survival , one - year survival and median pfs in comarison with best supportive care ( median survival : 7.5 versus 4.6 months ; median pfs : 2.1 versus 1.6 months ; one year survival : 37 versus 12% ) . in our study , median survival was 13.2 months ( 397 days ) , median pfs was 3.2 months ( 96 days ) and the one - year survival rate was 66.7% . the results of this study showed that hap treatment yielded an os and pfs longer than three of the best supportive care group and the docetaxel - treated group with no significant adverse events . the limitations of this observational study include ( 1 ) the small numbers of patients , ( 2 ) the short and variable hap treatment period , ( 3 ) the different treatment histories of the individual patients and ( 4 ) limitations on regular and continuous followups . in conclusion , hap is worth investigating as a third - line regimen for stage iiib / iv nsclc patients who fail chemotherapy , but its effect has not yet been confirmed . in the future , additional controlled clinical trials with larger samples from multi - centers are warranted to further evaluate the efficacy and the safety of hap .
background and objectives : non - small - cell lung cancer ( nsclc ) represents approximately 80% of all lung cancers . 
 unfortunately , at their time of diagnosis , most patients have advanced to unresectable disease with a very poor prognosis . 
 the oriental herbal medicine hangam - plus(hap ) has been developed for antitumor purposes , and several previous studies have reported its therapeutic effects . in this study , 
 the efficacy of hap was evaluated as a third - line treatment for advanced - stage iiib / iv nsclc.methods:the study involved six patients treated at the east- west cancer center ( ewcc ) from april 2010 to october 2011 . 
 inoperable advanced - stage iiib / iv nsclc patients received 3,000 or 6,000 mg of hap on a daily basis over a 12-week period . computed tomography ( ct ) 
 scans were obtained from the patients at the time of the initial administration and after 12 weeks of treatment . 
 we observed and analyzed the patients overall survival ( os ) and progression - free survival ( pfs).results : of the six patients , three expired during the study , and the three remaining patients were alive as of october 31 , 2011 . 
 the os ranged from 234 to 512 days , with a median survival of 397 days and a one - year survival rate of 66.7% . in the 12-week - interval chest ct assessment , three patients showed stable disease ( sd ) , and the other three showed progressive disease ( pd ) . 
 the pfs of patients ranged from 88 to 512 days , the median pfs being 96 days . 
 longer os and pfs were correlated with sd . 
 although not directly comparable , the os and the pfs of this study were greater than those of the docetaxel or the best supportive care group in other studies.conclusion:hap may prolong the os and the pfs of inoperable stage iiib / iv nsclc patients without significant adverse effects . in the future , more controlled clinical trials with larger samples from multi - centers should be conducted to evaluate the efficacy and the safety of hap .