Lung Cancer Revie esults of the NSCLC66 Recentl wer ot ere was a highe crapy eithe rapy arm years of 回品 tage nerapy wa study therapy in the IALTstudy and the differences superior in the preoperative setting (90%vs 66%) in overall survival and disease-free survival were no Neoadjuvant chemotherapy was associated with a longer statistically significant.In contrast,the sur nonsignificant trend toward longer disease-free sur 中eo9 vival compared with surgery alone.This study was limited in power and included a high proportion of although many of the adiuvant therapy studies patients with stage I disease,a group in whom the have included patients with stages I,II,and III dis- role of chemotherapy is unproven.These studies ease,among patients with stage I disease.the benefit suggest that neoadjuvant therapy is an efficacious from adjuvant chemotherapy has not been clearly and safe approach for patients with early stage established.In fact,the me -analysis noted a detri NSCLC.The clinical circumstances under which it mental hazard ratio for patients with stage IA dis may be preferred over adjuvant thera treated with othe dard of y defined and ng p tthgeB ng pr studies nodes iciar n to cho efit fo 59 otfcad regimens is unpro the effi therapy ir crapy in patic re fo on cted by the Can- ntegration of rly targeted agents and indi cer and Leukemia Group B(CALGB),despite an vidualization of therapy based on biomarke improvement in disease-free survival,there was no epair cross-complementir g gene 1 (ERCC1)is an mportant mediator of DNA repair and has been noted rative intent of therapy in this setting,the small paunum hem the In a subset analysis of the advantage with cisplatin over carboplatin might be an IALT,tumor specimens of patients were evaluated by important reason to use the former.The optimal num mmunohistochemistr for ERCC1 expression. Patients with high ERCC1 expression did not appear d on the pre sen to derive benefit from cisplatin-based chemother evidence,3 to 4 cvcles of cisplatin-based chem otherapy py h the overall survival for this was m are administered in routin In all of the studiesh ble In the ERCC1-ne evaluat ciated with chemotherapy,deliver of plan n This led 60% to the es that eval te t ERCC1 expression for patie nts with early surgery fo tage NSC lung cancer. To improve the delivery of The EGFR inhibitors have also been investigated therapy in patients with early stage NSCLC,the therapy for patients with early stage neoadjuvant approach has been investigated exten NSCLC.In a recent report,the use of gefitinib was sively.A phase 3 study conducted by the Southwes Oncology Group demonstrated an improvement in tebo in patients with resected early stage NSCLC Notably,there was no benefit noted with gefitinib ver.these differen even in the small percentage of patients(21%)with an ces did not reach statistical significance because the EGER mutation.Pertinent limitations of this study trial was closed early Similar trends were also noted nclude its early closure before full accrual and the in a European study that evaluated preoperative short median duration of gefitinib therapy.Another chemotherapy for patients with early stage study that evaluated erlotinib in the postoperative 96
Recently, the long-term follow-up results of the IALT and the NCI-Canada’s JBR10 study were reported. There was a higher incidence of noncancer deaths in the chemotherapy arm after 5 years of study therapy in the IALT study and the differences in overall survival and disease-free survival were no longer statistically significant.63 In contrast, the survival benefit with chemotherapy was maintained at 9 years of follow-up in the JBR10 study.64 Although many of the adjuvant therapy studies have included patients with stages I, II, and III disease, among patients with stage I disease, the benefit from adjuvant chemotherapy has not been clearly established. In fact, the meta-analysis noted a detrimental hazard ratio for patients with stage IA disease who were treated with adjuvant chemotherapy.62 Among patients with stage IB disease, subset analyses of randomized studies have documented a modest benefit for patients with tumors larger than 4 cm.59 The role of carboplatin-based regimens is unproven as adjuvant therapy in patients with early stage NSCLC. In a phase 3 study conducted by the Cancer and Leukemia Group B (CALGB), despite an improvement in disease-free survival, there was no survival benefit reported with carboplatin and paclitaxel in patients with stage IB disease.59 Given the curative intent of therapy in this setting, the small advantage with cisplatin over carboplatin might be an important reason to use the former. The optimal number of cycles of adjuvant chemotherapy has not been addressed in randomized studies. Based on the present evidence, 3 to 4 cycles of cisplatin-based chemotherapy are administered in routine practice settings. In all of the studies that evaluated postoperative chemotherapy, delivery of planned courses of chemotherapy was achieved in only 60% to 75% of the patients. This is likely related to comorbid illness and the varying recovery period after surgery for lung cancer. To improve the delivery of systemic therapy in patients with early stage NSCLC, the neoadjuvant approach has been investigated extensively. A phase 3 study conducted by the Southwest Oncology Group demonstrated an improvement in overall survival with chemotherapy followed by surgery versus surgery alone.65 However, these differences did not reach statistical significance because the trial was closed early. Similar trends were also noted in a European study that evaluated preoperative chemotherapy for patients with early stage NSCLC.66 Recently, a phase 3 study compared the administration of chemotherapy either before or after surgery with surgery alone in patients with early stage NSCLC.67 The delivery of chemotherapy was superior in the preoperative setting (90% vs 66%). Neoadjuvant chemotherapy was associated with a nonsignificant trend toward longer disease-free survival compared with surgery alone. This study was limited in power and included a high proportion of patients with stage I disease, a group in whom the role of chemotherapy is unproven. These studies suggest that neoadjuvant therapy is an efficacious and safe approach for patients with early stage NSCLC. The clinical circumstances under which it may be preferred over adjuvant therapy, the current standard of care, have not yet been clearly defined and it is therefore left to the judgment of the treating physician to choose the appropriate setting for systemic therapy in patients with early stage NSCLC. Presently, efforts to improve the efficacy of systemic therapy in patients with early stage NSCLC are focused on the integration of molecularly targeted agents and individualization of therapy based on biomarkers. Excision repair cross-complementing gene 1 (ERCC1) is an important mediator of DNA repair and has been noted in several studies to be a determinant of sensitivity to platinum-based therapy.68,69 In a subset analysis of the IALT, tumor specimens of patients were evaluated by immunohistochemistry for ERCC1 expression.70 Patients with high ERCC1 expression did not appear to derive benefit from cisplatin-based chemotherapy, although the overall survival for this group was more favorable. In the ERCC1-negative group, adjuvant chemotherapy was associated with a robust survival advantage over observation. This observation has led to prospective studies that evaluate treatment selection based on ERCC1 expression for patients with early stage NSCLC. The EGFR inhibitors have also been investigated as adjuvant therapy for patients with early stage NSCLC. In a recent report, the use of gefitinib was associated with inferior results compared with placebo in patients with resected early stage NSCLC.71 Notably, there was no benefit noted with gefitinib, even in the small percentage of patients (21%) with an EGFR mutation. Pertinent limitations of this study include its early closure before full accrual and the short median duration of gefitinib therapy. Another study that evaluated erlotinib in the postoperative Lung Cancer Review 96 CA: A Cancer Journal for Clinicians
CA CANCER J CLIN 2011:61:91-112 setting has completed accrual and the results ar of many studies.The current standard of 60 to 66 awaited.Other strategies currently under evaluation for grays (Gy)was established by a randomized study ombination of be ducted in the 1970s.7s With the availability ith chemothe apy genomic approac he mp ved radiothe it has be for risk stratification ible higher do radiotherap city.Se Surgically Unresectable Stage Ill Disease than 70 Gy and noted promis sed on this,a randomized study is currently Locally advanced disease that is not amenable to sur- inderway to compare 74 Gy of radiotherapy with gical resection is treated with combined modality the standard 60-Gy dose for patients with locally approaches involving systemic therapy and radio advanced NSCLO The use of hyperfractionated therapy.Typically,tumors that directly invade the radiotherapy has also been associated with favorable mediastinum.maior blood vessels.heart.or the ver results over standard once-daily fractionation in tebral body are considered surgically unresectable.In randomized studies,although this approach has been addition ratients with multistation n2 disease are also considered candidates for definitive combined modality treatment approaches. ve the benefit of sys mic therapy The addition of sy mic chemother to radio the inte tion of t reted ager ther nt in and the devel Alth EGFR kinase inhib rand The initial adiothe the ng strateg ves th nb n a pha and neck cancer,the addi ton of tuximab to radi tial approach. Although the con current approach is associated with higher toxicity,there is a modest the overall survival. Based on this,cetuximab improvement in overall survival as well.Therefore,for now being tested in combination with chemoradic patients with a good performance status.concurrent therapy for the treatment of patients with locally chemoradiotherapy has become the standard of care advanced nsClC in a phase 3 study (Radiation Two different chemotherapy oaches are com Therapy Oncology Group [RTOG]0617).A monly used for locally advanced NSCLC.One e randomized study that evaluated gefitinib as mainte- men involves the use of full doses of cisplatin and nance therapy after combined modality therapy etoposide with radiotherapy.76 The other demonstrated inferior survival compared with pla cebo.4 The use of antiangiogenic ag ents has under reekly schedule at "radio itiz II dis cvcles of full-dose the conducted in oted th approaches haveen y in the al fistula in pat rren che reated ith acizun etopos e regin ith higher to servation a the of t ha he pote l eding,the dey opment of b therapy stat an Conversely n patients with lod the weekly regime of carboplatin and paclitaxel has o be pursued furthe a more favorable tolerability profile and can be com- The use of induction or consolidation chemother bined with higher doses of radiotherapy.These 2 apy has not been associated with improvement in strategies have not been directly compared in randomized clinical trials. Recently,pemetrexed has been com- The optimal dose of radiotherapy for patients bined with cisplatin or carboplatin in full systemic with locally advanced NSCLC has been the subject doses with concurrent radiotherapy.Promising results 97
setting has completed accrual and the results are awaited. Other strategies currently under evaluation for early stage NSCLC include the combination of bevacizumab with chemotherapy and genomic approaches for risk stratification. Surgically Unresectable Stage III Disease Locally advanced disease that is not amenable to surgical resection is treated with combined modality approaches involving systemic therapy and radiotherapy. Typically, tumors that directly invade the mediastinum, major blood vessels, heart, or the vertebral body are considered surgically unresectable. In addition, patients with multistation N2 disease are also considered candidates for definitive combined modality treatment approaches. The addition of systemic chemotherapy to radiotherapy was associated with improvement in overall survival compared with radiotherapy alone in randomized studies.72,73 The initial trials used a sequential approach involving the 2 modalities. Subsequently, a number of studies have compared the concurrent use of chemoradiotherapy with the sequential approach.74,75 Although the concurrent approach is associated with higher toxicity, there is a modest improvement in overall survival as well. Therefore, for patients with a good performance status, concurrent chemoradiotherapy has become the standard of care. Two different chemotherapy approaches are commonly used for locally advanced NSCLC. One regimen involves the use of full doses of cisplatin and etoposide with radiotherapy.76 The other approach involves the use of carboplatin and paclitaxel on a weekly schedule at ‘‘radiosensitizing’’ doses, followed by 2 cycles of full-dose therapy.77 Both of these approaches have demonstrated efficacy in the concurrent chemoradiotherapy setting. The cisplatin and etoposide regimen is associated with higher toxicity, but has the potential to eradicate micrometastatic disease at an earlier time point. Conversely, the weekly regimen of carboplatin and paclitaxel has a more favorable tolerability profile and can be combined with higher doses of radiotherapy. These 2 strategies have not been directly compared in randomized clinical trials. The optimal dose of radiotherapy for patients with locally advanced NSCLC has been the subject of many studies. The current standard of 60 to 66 grays (Gy) was established by a randomized study conducted in the 1970s.78 With the availability of improved radiotherapy technology, it has become possible to deliver even higher doses of radiotherapy without a substantial increase in toxicity. Several phase 2 studies have evaluated radiotherapy doses higher than 70 Gy and noted promising results.79,80 Based on this, a randomized study is currently underway to compare 74 Gy of radiotherapy with the standard 60-Gy dose for patients with locally advanced NSCLC. The use of hyperfractionated radiotherapy has also been associated with favorable results over standard once-daily fractionation in randomized studies, although this approach has been limited by the logistical challenges in delivering multiple fractions of treatment on a daily basis.81,82 Efforts to improve the benefit of systemic therapy have focused on the integration of targeted agents and the development of newer chemotherapeutic agents. Although EGFR tyrosine kinase inhibitors can be safely administered with chemoradiotherapy, the most promising strategy involves the use of cetuximab. In a phase 3 study of patients with head and neck cancer, the addition of cetuximab to radiotherapy resulted in nearly a 2-fold improvement in the overall survival.83 Based on this, cetuximab is now being tested in combination with chemoradiotherapy for the treatment of patients with locally advanced NSCLC in a phase 3 study (Radiation Therapy Oncology Group [RTOG] 0617). A randomized study that evaluated gefitinib as maintenance therapy after combined modality therapy demonstrated inferior survival compared with placebo.84 The use of antiangiogenic agents has undergone limited evaluation for stage III disease. Two studies conducted in patients with SCLC noted the development of tracheoesophageal fistula in patients treated with bevacizumab after radiotherapy.85 Because of this observation and the higher risk of bleeding, the development of bevacizumab therapy in patients with locally advanced NSCLC is unlikely to be pursued further. The use of induction or consolidation chemotherapy has not been associated with improvement in overall survival in patients with locally advanced NSCLC.86,87 Recently, pemetrexed has been combined with cisplatin or carboplatin in full systemic doses with concurrent radiotherapy. Promising results CA CANCER J CLIN 2011;61:91–112 VOLUME 61 _ NUMBER 2 _ MARCH/APRIL 2011 97
noted in a randomized phase 2 study by the ands,both CALGB that of NSCLC I n extens y st gene boplati lity profl the cisplatin and pemetrexed regimen with the cispla- over cisplatin-based regimens. Despite the margin tin and etoposide regimen in combination with radic ally higher response rate noted with cisplatin-based therapy for patients with locally advanced NSCLC regimens,considering the palliative intent of therapy, Multimodality approaches result in cure for carboplatin-based regimens have found wide applic approximately 20%of the patients with locally ability in routine care.However.recent improvements advanced NSCLC.Both improvements in svstemi in antiemetic therapy have rendered the use of therapy and local therapy have contributed to the cisplatin-based regimens more tolerable. more favorable patient outcome noted in recent A pumber of randomized clinical trials have estab vears Another factor that warrants mention is the ishcdhtcsupciotiyofaplhatinum-containing role of positron emission tomography,which has drug combination over single-agent therapy. improved the accuracy of stagi The response rate,progre -free rvival,and As esult,stage m igration of lung cancer. rall survival all a o be 6 mpr to the ments in outcom pat nts tage fits xicity.Pa eta Advanced Stage NSCLC ine. om to as the"thi eration"cytotoxic agents ng cance have advanced stage disease at the time of diagnosis with a platinum with Even patients without any cancer-related symptoms advanced NSCLC A large randomized at diagnosis will manifest symptoms as their disease clinical trial conducted by the Eastern Cooperative progresses.Therefore,the overall goals of treatment Oncology Group (ECOG)compared the efficacy of are to improve symptoms,preserve or improve qual 4 commonly used combination regimens in the ity of life.and prolong survival.The performance treatment of patients with advanced NSCLC.97 The status of the patient remains an important determi- ombinations of cisplatin and docetaxel.cisplatir nant of overall ore nosis and is a nrime considera and gemcitabine,and carboplatin and paclitaxel were tion in treatment selection.Recently,gender has also all associated with efficacy become recognized as an important prognostic fac- tor,with females exp periencing ival thar avel remi en.These obser vations rted b nales on the database for the nev of other taging able stablished acy plateau"had rath met to the of patients with oxicity without ar evide nce of an improvement i me dise sease to Mla and M1b efficacy across clinical trials Platinum-Based Chemotherapy available platinum-based 2-drug regimens,the me Systemic therapy remains the mainstay of treatment dian survival and one-vear survival rate are 8 months of advanced stage nsclc.Combination chemo therapy with a platinum-based regimen has emerged non分nn as standard therapy for patients with advanced st disease.Improvements in overall survival and qualit Role of Histology of life have been demonstrated with platinum-based Until ll histolocal suypes of NSCLC regimens over supportive care alone in randomized were treated alike because a diffe ntial sensitivity 8
were noted in a randomized phase 2 study by the CALGB that evaluated carboplatin and pemetrexed with concurrent radiotherapy.88 These favorable results have prompted an ongoing phase 3 study to compare the cisplatin and pemetrexed regimen with the cisplatin and etoposide regimen in combination with radiotherapy for patients with locally advanced NSCLC.89 Multimodality approaches result in cure for approximately 20% of the patients with locally advanced NSCLC. Both improvements in systemic therapy and local therapy have contributed to the more favorable patient outcome noted in recent years. Another factor that warrants mention is the role of positron emission tomography, which has improved the accuracy of staging of lung cancer.90 As a result, stage migration could also have contributed to the recent improvements in outcome for patients with stage III disease. Advanced Stage NSCLC Approximately 50% of the patients with lung cancer have advanced stage disease at the time of diagnosis. Even patients without any cancer-related symptoms at diagnosis will manifest symptoms as their disease progresses. Therefore, the overall goals of treatment are to improve symptoms, preserve or improve quality of life, and prolong survival. The performance status of the patient remains an important determinant of overall prognosis and is a prime consideration in treatment selection. Recently, gender has also become recognized as an important prognostic factor, with females experiencing a better survival than males.91-94 In addition, the database for the new staging system demonstrated a more favorable outcome for patients without extrathoracic disease, with a median survival of 14 months compared with only 6 months in those with distant metastasis. This led to the additional subclassification of patients with metastatic disease to M1a and M1b. Platinum-Based Chemotherapy Systemic therapy remains the mainstay of treatment of advanced stage NSCLC. Combination chemotherapy with a platinum-based regimen has emerged as standard therapy for patients with advanced stage disease.95 Improvements in overall survival and quality of life have been demonstrated with platinum-based regimens over supportive care alone in randomized clinical trials.96 Among the platinum compounds, both cisplatin and carboplatin have been extensively studied for the treatment of NSCLC. In general, carboplatinbased regimens have a favorable tolerability profile over cisplatin-based regimens.97,98 Despite the marginally higher response rate noted with cisplatin-based regimens, considering the palliative intent of therapy, carboplatin-based regimens have found wide applicability in routine care. However, recent improvements in antiemetic therapy have rendered the use of cisplatin-based regimens more tolerable. A number of randomized clinical trials have established the superiority of a platinum-containing, 2- drug combination over single-agent therapy.99-101 The response rate, progression-free survival, and overall survival all appear to be improved with combination regimens in patients with advanced NSCLC, although the benefits come with higher toxicity. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and pemetrexed, commonly referred to as the ‘‘third-generation’’ cytotoxic agents, have all demonstrated efficacy when given in combination with a platinum compound in patients with advanced NSCLC.97,99,102-105 A large randomized clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) compared the efficacy of 4 commonly used combination regimens in the treatment of patients with advanced NSCLC.97 The combinations of cisplatin and docetaxel, cisplatin and gemcitabine, and carboplatin and paclitaxel were all associated with efficacy parameters comparable to those of the control arm of the cisplatin and paclitaxel regimen. These observations, supported by the findings of other contemporaneous clinical trials, established the notion that an ‘‘efficacy plateau’’ had been reached with 2-drug combinations in patients with advanced stage NSCLC. The use of 3-drug cytotoxic combinations has generally resulted in higher toxicity without clear evidence of an improvement in efficacy across clinical trials and has therefore not been pursued subsequently.106 With the currently available platinum-based 2-drug regimens, the median survival and one-year survival rate are 8 months to 11 months and 30% to 40%, respectively, in patients with a good performance status.107 Role of Histology Until recently, all histological subtypes of NSCLC were treated alike because a differential sensitivity Lung Cancer Review 98 CA: A Cancer Journal for Clinicians