NEW RADIOTHERAPY AND CHEMORADIOTHERAPY APPROACHES FOR NON–SMALL-CELL LUNG CANCER Joseph K. Salama and Everett E. Vokes J Clin Oncol 31: R4 신재령

INTRODUCTION Current state of chemoradiotherapy Alternative chemoradiotherapy platforms Induction chemotherapy before chemoradiotherapy Consolidation chemotherapy EGFR-TKI, Cetuximab, Antiangiogenics, other taegeted agents/vaccines Radiation dose escalation

INTRODUCTION Treatment paradigms are shifting to incorporate factors beyond age, performance status(PS), and non–small-cell histology into the decision-making process Molecular tumor characterization Technologic improvements in RT Review the current standards for chemotherapy and RT for patients with NSCLC as well as highlight areas of significant impact that have the potential to alter treatment paradigms

CURRENT STATE OF CHEMORADIOTHERAPY Medically inoperable or technically unresectable stage II-III NSCLC Stage III NSCLC receive CCRTx, median survival rates in recent trials have ranged from 21 to 26 months  Cisplatin/Etopside/RT  Cisplatin/Vinorelbine/RT  Cisplatin/Tegafur/Uracil/RT  Carboplatin/Paclitaxel/RT had the lowest rates of grade 3 to 4 neutropenia, and equal efficacy (median survival 22 months) compared with those receiving Mitomycin/Vindesine/Cisplatin/RT or Irinotecan/Cisplatin/RT Cisplatin-based regimens may lead to improved outcomes over Carboplatin-based regimens ?

ALTERNATIVE CHEMORADIOTHERAPY PLATFORMS Cancer and Leukemia Group B (CALGB) 30407, a phase II randomized study, investigated the utility of pemetrexed 500 mg/m 2, carboplatin (AUC 5), and 70 Gy RT delivered alone or in combination with standard doses of cetuximab  18-month overall survival > 55%  Not significantly different (21.2 v 25 months)  The addition of cetuximab increased toxicity, suggesting that the two-drug regimen without cetuximab should be further investigated in a definitive trial World wide trial was conducted randomly assigning patients with nonsquamous stage III NSCLC either to pemetrexed/cisplatin or to cisplatin/etoposide combined with 66-Gy RT and consolidation chemotherapy

INDUCTION CHEMOTHERAPY BEFORE CHEMORADIOTHERAPY The addition of chemotherapy before standard chemoradiotherapy for NSCLC does not reduce the risk of distant metastases, improve OS, or decrease locoregional progression CALGB 39801, compared weekly carboplatin/paclitaxel/66 Gy alone with two cycles of paclitaxel and carboplatin followed by the same chemoradiotherapy  At a median follow-up of 38 months, there was no significant difference in OS or failure-free survival Induction chemotherapy can potentially benefit otherwise stage III patients with indeterminate metastatic disease not amenable to biopsy or in those with large tumor volumes with a high potential for radiation treatment–related toxicity

CONSOLIDATION CHEMOTHERAPY Phase III Hoosier Oncology Group study found no difference in median survival in patients with stage III NSCLC receiving consolidation docetaxel (21.2months) versus those observed (23.3 months;P=.883) after cisplatin/etopside/RT Phase III study of consolidation cisplatin/vinorelbine  Given the current absence of a strong trial supporting the administration of consolidation after a cisplatin-based regimen Some studies have demonstrated numerically improved survival outcomes for consolidation paclitaxel and carboplatin By testing histology-guided consolidation with pemetrexed for patients with nonsquamous disease (NCT ) Consolidation with vaccine therapy (NCT )

CHEMORADIOTHERAPY FOR POOR PS, WEIGHT LOSS, AND ELDERLY NSCLC Alternative platforms are being investigated for patients with advanced age, poor PS, weight loss greater than 5%, or multiple medical comorbidities Although pathients with advanced age are often grouped with poor- risk patients, demonstrate that CCRTx improved survival – and increased grade 3 to 4 toxicity  Recently reported phase III study in which concurrent carboplatin 30 mg/m 2 given once per week and 66-Gy daily RT was associated with improved median survival (22.4 v 16.5 months) and 3-year OS (34.6%v 14.3%) compared with 66-Gy daily RT alone Fit patients with NSCLC, age alone should not be exclusion criteria for concurrent chemoradiotherapy

CHEMORADIOTHERAPY FOR POOR PS, WEIGHT LOSS, AND ELDERLY NSCLC Attempts to enhance the therapeutic ratio have included the use of biologic modifiers and targeted agents in combination with RT with or without induction or consolidation systemic cytotoxins  The use of cetuximab and RT in primarily elderly and poor PS populations has resulted in promising median (15-20 months) and 2-year (20%-35%) survival  Poor-risk patients treated on CALGB with two carboplatin/paclitaxel cycles followed by gefitinib and 66 Gy RT had promising median survival of 19 months  CALGB 30605, using two cycles of carboplatin/nab-paclitaxel followed by concurrent erlotinib/66 Gy are awaited to further assess the validity of this approach

EGFR-TKI PLUS CHEMORADIOTHERAPY

Avoid maintenance EGFR-TKI after Chemoradiotherapy and consolidation chemotherapy in unselected patients  Continuous EGFR-TKI exposure results in cell-cycle arrest at G1, predominantly in wild-type EGFR, reducing the cell-cycle phase-dependent activity of chemotherapy  Nonsynchronous administration of weekly carboplatin/paclitaxel 1 day of the week and 150mg erlotinib for the remaining 6 days of the week with 63-Gy daily RT, a median survival of 26 months EGFR mutations detected by either FISH or mutational analysis have improved outcomes when treated with combined modality regimens, including EGFR inhibition, delivered with either cetuximab or TKIs

CETUXIMAB PLUS CHEMORADIOTHERAPY

ANTIANGIOGENICS IN COMBINATION WITH RT/CHEMORADIOTHERAPY The monoclonal antibody to the vascular endothelial growth factor receptor (bevacizumab) into chemoradiotherapy platforms have been associated with high-grade toxicities  OS and progression-free survival in completed studies were not improved over chemoradiotherapy alone AE-941, a shark cartilage extract inhibiting endothelial proliferation and matrix metalloproteinases or placebo with two cycles of induction and concurrent chemotherapy (carboplatin/paclitaxel or cisplatin/vinorelbine) and 60 Gy RT  No benefit, median survival 14.4 vs 15.6 months Eastern Cooperative Oncology Group (ECOG) study 3598 randomly assigned patients to two cycles of carboplatin and paclitaxel followed by 60 Gy RT or concurrent once weekly carboplatin/paclitaxel with or without escalating doses of thalidomide (200-1,000 mg per patient tolerance)  Not improved OS (16.0 vs 15.3 months), PFS (7.8 vs 7.4 months)

OTHER TARGETED AGENTS/VACCINES WITH RT WITH OR WITHOUT CHEMOTHERAPY Efaproxiral, a synthetic allosteric modifier of hemoglobin facilitating the release of oxygen as a means to overcome tumor hypoxia  Combining this with RT after two cycles of paclitaxel/carboplatin/64 Gy resulted in a median survival of 20.6 months The administration of L-BLP25, a vaccine to MUC-1, glycoprotein antigen widely expressed on many cancer, in patients with nonmetastatic stage IIIB NSCLC without effusions resulted in a median survival of 30.6 months versus 13.3 months without in a randomized phase II study Phase II study administering GV 1001, a telomerase peptide vaccine, after chemoradiotherapy demonstrated a doubling of progression-free survival and significantly improved OS (19 v 3.5months; P<.001) in immune responders

PET AND RADIOTHERAPY RADIATION DOSE ESCALATION Technologic advances in RT  appropriate tumor targeting, and enhance radiation delivery to tumors while minimizing exposure of surrounding normal tissues Standard radiation dose for locoregionally advanced NSCLC concurrently with chemotherapy remains Gy, 2-Gy doses of radiation delivered daily Hyperfractionated radiation - small radiation doses delivered multiple times per day, typically with higher cumulative doses Accelerated radiation - dosing schemes greater than 10 Gy per week HART (hyperfractionated accelerated RT) Hypofractionated radiation - delivery of fewer, larger (>2 Gy) doses of radiation

RADIATION DOSE ESCALATION The recently reported results of RTOG 0617, which randomly assigned patients to 60 versus 74 Gy concurrently with carboplatin and paclitaxel, failed to show any benefit to higher radiation dose  Not shown a survival benefit to hyperfractionated radiation with concurrent chemotherapy delivered either continuously or as a split course compared with standard chemoradiotherapy

RADIATION DOSE ESCALATION Continuous HART, delivering 54 Gy in Gy fractions during 12 days, resulted in improved survival compared with conventional radiation alone, particularly in patients who had squamous carcinomas ECOG 2597 demonstrated that patients randomly assigned to HART(1.5 Gy three times per day for 2.5 weeks) after two cycles of carboplatin/paclitaxel had numerically improved median survival (20.3 v 14.9 months; P=.28) and 3-yearOS (24%v 14%) compared with patients treated with the same chemotherapy and standard RT (2-Gy doses of radiation delivered daily to a total of dose of 64 Gy)

RADIATION DOSE ESCALATION Moderately hypofractionated RT ( Gy/fraction) has shown promise in cooperative group studies for early-stage and locoregionally advanced NSCLC  locoregional control, 93%; median survival, 38.5months Hypofractionated image-guided RT (HIGRT),Stereotactic body RT  Three to four radiation treatments are used to deliver a total dose of 48 to 60 Gy  84% to 100% local control, and 43% to 57% 3-year survival

PROTON THERAPY Protons have become more widely studied alone or with CTx for patients with NSCLC  Smaller entry dose and dramatic dose fall-off beyond the target, resulting in low exit dose  High cost of constructing and operating a proton center has restricted access and investigation Phase II studies using protons in conjunction with concurrent CTx for stage III NSCLC have resulted in promising survival within the expected range (median, 29 months), local control (79.5%), and limited toxicity—better than when protons are delivered alone without chemotherapy

TREATMENT OF OLIGOMETASTATIC PATIENTS WITH NSCLC The use of Hypofractionated image-guided RT(HIGRT) for patients with limited volume metastatic NSCLC has resulted in a surprising 23- month median survival and longterm disease control for 17% of patients Recent analysis suggest that microRNA 200c may contribute to the oligometastatic phenotype, possibly aiding in the selection of patients who may benefit from treatment of limited metastatic disease