recent phase iii trials have demonstrated the benefits of maintenance therapy with pemetrexed for metastatic non - small cell lung cancer ( nsclc ) [ 1 , 2 ] .
pemetrexed maintenance therapy improved progression - free survival and overall survival by both continuation and switch maintenance strategies . with the support of emerging evidence ,
oncologists have become accustomed to prolonging the administration of cytotoxic pemetrexed for advanced nsclc , similar to the use of molecular targeting agents for anaplastic lymphoma kinase ( alk)-positive or epidermal growth factor receptor ( egfr)-mutant nsclc . however , disease progression during maintenance pemetrexed is almost inevitable after a median progression - free survival of 46 months .
local ablative therapies for oligoprogressive disease ( opd ) , including surgery , radiofrequency ablation , and stereotactic ablative radiotherapy ( sabr ) have been reported to extend survival with continued tyrosine kinase inhibitors ( tki ) for alk - positive or egfr - mutant lung cancer [ 4 , 5 ] . a preliminary report from a phase ii trial demonstrated prolonged progression - free survival in oligo - metastatic nsclc patients receiving local consolidative therapy for non - progressive disease , compared to systemic therapy alone .
however , there have been no previous investigations on local ablative therapy for opd in patients receiving maintenance pemetrexed . here ,
we present our preliminary results of sabr eradicating progressive lesions with the continued use of pemetrexed .
patients diagnosed with advanced lung adenocarcinoma were treated with pemetrexed in combination with cisplatin / carboplatin as the first - line treatment , or as the salvage regimen , after systemic progression under tki .
maintenance pemetrexed ( 500 mg / m ) in a 21-day cycle was given after four to six cycles of the initial pemetrexed / platinum if there was no disease progression .
response evaluation criteria in solid tumors ( recist ) version 1.1 for imaging studies was adopted to evaluate treatment responses .
patients with oligoprogression ( 5 discrete progressing lesions ) that continued to derive systemic benets from pemetrexed were prospectively enrolled to receive sabr for locoregional disease .
meanwhile , pemetrexed was continued until further systemic progression not suitable for local therapy developed .
treatment - related toxicities were scored according to common terminology criteria for adverse events ( ctcae ) version 4.0 . here , we present three consecutively enrolled cases receiving sabr for thoracic oligoprogression under pemetrexed with > 18 months of clinical and imaging follow - up .
case 1 involves a 55-year - old woman with stage iv egfr - mutant ( del19/l858r ) nsclc , presenting with multiple lung tumors and pleural nodular seeding .
she initially responded to gefitinib , but 5 months later developed enlarged left upper - lung tumors and increased pleural nodularity .
six cycles of pemetrexed / cisplatin achieved partial remission , and maintenance pemetrexed was given after the induction treatment .
after six cycles of maintenance pemetrexed , slight enlargement of the left lung tumors and pleural lesions were noted by computed tomography ( ct ) of the chest , without other systemic progressions .
she underwent sabr via cyberknife targeting on oligoprogressive tumors ( five lesions in total ) , each with 2022 gy in a single fraction on 5 separate days .
repeat chest imaging 2 and 4 months later demonstrated stationary thoracic disease with grade 1 radiation pneumonitis ( fig .
maintenance pemetrexed was continued for an additional 10 cycles until new nodular lesions in the left lung developed 7 months after sabr .
she later developed t790 m mutations and spine metastases with subsequent failure of erlotinib and gemcitabine , while her chest disease remained relatively stable 2 years after the sabr .
case 2 is a 71-year - old man with metastatic egfr - mutated adenocarcinoma of the lung .
he received first - line afatinib and palliative radiotherapy for a metastatic lesion at t8 of the spine .
the primary tumor in his left upper lung initially regressed but demonstrated apparent enlargement 7 months later .
pemetrexed / cisplatin were given for salvage treatment , and the tumor showed partial regression .
he remained on tri - weekly pemetrexed for 2 years with good locoregional and systemic disease control .
only mild toxicities , such as grade 1 fever , grade 1 anemia / eosinophilia , and grade 1 gastrointestinal discomfort occurred during the maintenance treatment .
follow - up chest ct revealed enlargement of the primary tumor , with no evidence of extra - thoracic progression .
sabr targeted the tumor in his left upper lung with 44 gy in four fractions .
the tumor regressed after sabr treatment and has been unchanged for 2 years with postradiation fibrotic changes ( fig .
currently , the patient has remained on maintenance pemetrexed for more than 48 months with no evidence of disease recurrence .
case 3 demonstrates a 63-year - old man diagnosed with stage iia ( t1bn1m0 ) nsclc in september 2006 .
the patient underwent salvage radiotherapy with 60 gy in 25 fractions to the recurrent mediastinal lymphadenopathies .
, he developed a right hilar mass and a new nodular lesion in the left upper lobe , without other systemic relapse .
salvage pemetrexed / carboplatin were given and maintenance pemetrexed was started after six cycles of induction treatment .
he had good response of thoracic disease in serial follow - up imaging studies , until an oligoprogressive tumor at the left upper lobe showed enlargement after 14 cycles of maintenance pemetrexed .
he received sabr to the left upper lung tumor with 45 gy in 3 fractions in december 2013 .
the patient has remained on maintenance pemetrexed for non - progressive disease at this time with grade 1 fatigue and radiation fibrosis ( fig .
survival benefits for patients with advanced nsclc carried out by maintenance pemetrexed have been clearly demonstrated by a series of clinical trials [ 1 , 2 , 3 ] .
pemetrexed , as a multi - targeted folate antimetabolite , is well tolerated during long - term use . in the paramount trial , more than one third of patients allocated to the maintenance arm received more than six cycles of pemetrexed without worsening quality of life .
though numerous questions were left unanswered regarding optimal patient selection , multi - agent regimens , and administration duration of maintenance pemetrexed . for non - progressive advanced non - squamous nsclc , oncologists have recently tended to prescribe maintenance pemetrexed in a similar way as for tki , which is uninterruptedly until disease progression .
opd arises from subclone expansion resistant to ongoing treatment , and is an early state of disease progression .
before the dissemination of resistant subclones becomes the predominant burden of the patient , opd with a limited number of isolated regions amenable to local ablative therapy offers a chance to delay the start of overwhelming progression . local ablative therapy for opd prevents the early termination of the ongoing treatment , while there is still effective systemic disease suppression by the current regimen .
gomez et al .   recently reported local therapy prolonged progression - free survival in advanced nsclc with non - progressive disease after initial systemic treatment , demonstrating the value of aggressive local treatment on consolidating disease control .
by contrast , in this case series , we showed that sabr targeting opd prolonged the treatment with pemetrexed , maintaining clinical benefits ( table 1 ) .
sabr is an effective tool at controlling local disease in opd under tki [ 4 , 5 , 8 ] or oligometastases . in this report ,
all patients had sustained local control of thoracic oligoprogression after the sabr , while there was only mild radiation - related pneumonitis / fibrosis . with only one case having her second progression during follow - up , all of them had longer time - to - further - progression than their initial progression - free time under maintenance pemetrexed , reflecting apparent benefits from sabr . in the paramount trial
, superior survival outcomes were observed in patients receiving longer exposure to pemetrexed . in this series ,
two patients with long progression - free intervals before sabr also continued additional pemetrexed treatment ( 12 cycles in average ) without a second progression . the extended use of maintenance pemetrexed could be attributed to not only early elimination of drug - resistant subclones by sabr , but also the interactions between the pemetrexed response and driver oncogene mutations .
reported that for patients with alk - positive nsclc , the time - to - progression under pemetrexed was significantly longer compared to that of patients with egfr mutations and alk - negative / egfr wild - type control groups .
although the underlying molecular basis behind the different responses to pemetrexed remains unclear , berge et al .   have demonstrated that pemetrexed exposure in crizotinib - nave patients did not affect subsequent crizotinib outcomes after pemetrexed failed .
recently , a cost - effectiveness analysis on molecular testing of alk - gene rearrangement and rst - line therapy with crizotinib for patients with advanced nsclc showed that early detection with alk - targeted inhibition in alk - positive cases is not cost - effective . in the present report
, we demonstrated that for opd during maintenance pemetrexed , sabr successfully extended the time of effective systemic disease suppression by pemetrexed , thus reserving the high expenses of tests for alk - driver mutation and possible crizotinib use for definite systemic failure .
this combined - modality strategy should be considered first , especially in low - income or developing countries , where resources for second - line treatment after pemetrexed failure are much more limited . to our knowledge , this is the first report indicating that sabr targeting oligoprogression with continued maintenance pemetrexed is an effective approach for patients with advanced non - squamous nsclc .
although the true benefits from sabr during maintenance pemetrexed warrants a clear demonstration by a randomized trial , this consecutive case series shows that a subset of patients receiving sabr during maintenance pemetrexed for opd can experience long - term disease control without severe treatment - related toxicities , in a similar way to those with driver mutations receiving targeted therapy .
 maintenance pemetrexed offers survival benefit with well - tolerated toxicities for advanced non - squamous non - small cell lung cancer ( nsclc ) . 
 we present 3 consecutively enrolled patients with advanced non - squamous nsclc , receiving stereotactic ablative radiotherapy ( sabr ) for oligoprogressive disease during maintenance pemetrexed . 
 all of them had sustained local control of thoracic oligoprogression after the sabr , while maintenance pemetrexed were kept for additionally long progression - free interval . 
 sabr targeting oligoprogression with continued pemetrexed is an effective and safe approach to extend exposure of maintenance pemetrexed , thus maximizing the benefit from it . 
Introduction
Patients and Methods
Case Report
Discussion
Statement of Ethics
Disclosure Statement