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P.A. Bunn, Jr.



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      DISCUSSION (ID 5657)

      P.A. Bunn, Jr.

      • Abstract
      • Slides

      Abstract not provided

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    G01 - Progress in Lung Cancer: Celebrating 40 Years of IASLC and Research Progress (ID 14)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      G01.4 - Non-Surgical Therapy (ID 3859)

      P.A. Bunn, Jr.

      • Abstract
      • Slides

      Abstract
      Systemic Therapy of Early Stage NSCLC The addition of chemotherapy to surgery before or after surgery was studied because trials in the 1970’s demonstrated that cure rates were lower than in other cancers and because the majority of relapses were in distant sites (1). Initial adjuvant studies showed no survival advantage for single agent chemotherapy. Subsequent trials in the 1980’s and 1990’s established that cisplatin based 2-drug combinations produced a modest (4-5%) improvement in 5 year survival rates but only in stages II and IIIa (2). Adjuvant therapy has not been shown to improve outcomes in Stage I with the possible exception of Stage IB tumors larger than 4 cm (3). Neoadjuvant chemotherapy produces similar improvement compared to adjuvant therapy as demonstrated by randomized trials and metaanalyses (4,5). Post-operative radiotherapy has not shown benefits in stage I and II where it may be harmful and it role in stage IIIa after surgery is under evaluation as there are conflicting data on its role in this setting (6,7).Systemic Therapy of Stage III NSCLC Combinations of radiotherapy with chemotherapy were shown to produce superior survival compared to either alone based on randomized trials conducted in the 1990’s (8). Subsequent studies indicated that concurrent chemo-radiotherapy was superior to sequential therapy (9,10). There are conflicting data on whether two or four cycles of chemotherapy is best (11). There are also conflicting data on whether triple modality therapy is superior to two modalities for Stage IIIA N2 disease (12).Systemic Therapy of Stage IV NSCLC Chemotherapeutic agents and chemotherapy combinations were tested in the 1970’s and early 1980’s but failed to show any survival advantage. Two drug combinations combining cisplatin with vindesine or vinorelbine were shown to prolong survival compared to best supportive care in the 1980’s and 1990’s (13,14). Subsequent studies showed that 2-drug platinum based combinations were superior to a single active drugs (13,15,16). The survival advantage increased median survival times from 4-5 months to 8-12 months. Two-drug combinations with a platinum combined with gemcitabine, paclitaxel, docetaxel or pemetrexed were shown to produce equivalent survival in randomized trials conducted in the 1990’s and in the 2000’s (17,18). An exception to the equivalence was the finding that the pemetrexed/cisplatin combination was superior to gemcitabine/cisplatin in non-squamous cancer but inferior in squamous cancers (19). Three and 4 drug combinations were not superior to 2 drug combinations. These 2 drug combinations were superior in patients with PS 0-1 but benefitted elderly as well as younger patients (20). There is evidence that the paclitaxel/carboplatin combination may benefit PS2 patients (21). Thus, histology and performance status are key factors in therapy selection. Since the 1990’s, docetaxel, erlotinib, and pemetrexed have been shown to prolong survival when used in the 2[nd] line setting (22-24). For pemetrexed this improvement was limited to non-squamous histology (24). Since 2000 the use of targeted therapy began with the studies of inhibitors of VEGFR and EGFR signaling. Angiogenesis inhibitors were widely studied. Bevacizumab, a monoclonal antibody to VEGF, was shown to produce promising results in a randomized phase II trial (25). However, patients with squamous cell carcinoma had excess bleeding on this study and were excluded from all further trials. An ECOG randomized trial (4599) showed that bevacizumab improved survival in non-squamous histologies when combined with platinum doublets (26). However, the survival advantage is small and is less striking in elderly patients. The survival advantage was not observed in a randomized trial from Europe using gemcitabine/cisplatin as the chemotherapy backbone (27). As noted above, the EGFR TKI erlotinib was shown to prolong survival in unselected patients failing 1 or 2 chemotherapy regimens (23). In 2004 an association between mutations in the EGFR and response to EGFR TKIs was established (28,29). Subsequent randomized trials showed that EGFR TKIs were superior to chemotherapy in 1[st] line therapy of EGFR mutant patients but chemotherapy was preferred for those without mutations (30-35). In 2007, it was shown that EML4/ALK fusions could serve as driver molecular changes in up to 5% of NSCLC’s (36). Crizotinib, an ALK TKI was shown to produce high response rates and long PFS and was superior to chemotherapy in the second line setting (37-39). Patients with ALK fusions nearly always have adenocarcinoma histology, more often are younger and female sex and are light or never smokers (40) but clinical features should not be used to determine who should be tested (41). These and other molecular drivers may be present in more than 50% of lung adenocarcinomas (42). Molecular analyses of squamous and small cell cancers have recently been described (43-46). Checkpoint inhibitors such as PD1 and PDL1 were shown to be therapeutic targets since 2010. Antibodies to PD1 and PDL1 have produced responses in about 20% of patients who had failed multiple lines of chemotherapy and many of these were durable (46,47). PDL1 expression is being evaluated as a biomarker and many trials are in progress. Maintenance therapy with continuation of the original platinum doublet was shown in many trials to be associated with an increase in the PFS, an increase in toxicity but no increase in survival and therefore this approach was not adopted (48) . In 2009, Fidias et al reported that maintenance docetaxel could increase survival as well as PFS (49). This trial was followed by a trial showing that erlotinib could improve PFS and survival as maintenance after a platinum doublet (50). PFS and survival were improved in all histologies but the improvement in PFS and OS was most striking in patients with EGFR mutations. Pemetrexed was shown to improve PFS and survival as switch maintenance after a platinum doublet that did not contain pemetrexed (51). A subsequent trial showed that pemetrexed continuation maintenance also improved PFS and OS after induction therapy with a pemetrexed/platinum doublet induction (52). An unpublished trial, (POINTBREAK), comparing pemetrexed/carboplatin/bevacizumab with pemetrexed/bevacizumab maintenance compared to paclitaxel/carboplatin/bevacizumab followed by bevacizumab, showed no difference in survival. Thus, there is no evidence at presence that maintenance should contain two drugs although the ECOG is comparing pemetrexed with bevacizumab or the combination after induction therapy with paclitaxel/carboplatin/bevacizumab.Systemic Therapy of Early Stage SCLC Patients with Stage I and IIA SCLC, although infrequent, benefit from resection and adjuvant chemotherapy and the IASLC TNM classification is more accurate than the old VA classification (53). SCLC patients with stage IIB and III (limited stage SCLC) were shown to have prolonged survival when treated with chemotherapy and radiotherapy compared to either alone (54,55). An ECOG randomized trial showed that chest RT with BID radiation to 45 Gy was superior to once daily chest RT to the same dose when combined with etoposide/cisplatin (56). However, similar results were obtained with higher total doses of once daily RT and both once daily and twice daily are in routine practice. Concurrent chemoradiotherapy is superior to sequential therapy but results with radiotherapy starting at either cycle 1 or cycle 3 are similar. The combination of etoposide/cisplatin is the most frequent chemotherapy regimen because of reduced toxicities compared to Adriamycin or other combinations. Prophylactic cranial irradiation in good responders reduces brain relapse and prolongs survival (57). 25 Gy is the preferred dose (58).Systemic Therapy for Stage IV SCLC Both cisplatin and etoposide were first tested and shown to be active in the 1970’s. Studies in the 1980’s showed that the combination of etoposide and cisplatin produced high response rates (80%) with some complete responses (10-15% (59, 60). These results lead to randomized trials comparing etoposide/cisplatin to CAV, CAE or alternating combinations. Etoposide/cisplatin (EP) produced equivalent efficacy with less toxicity (60,61) and thus became the standard combination in the 1990’s. Pemetrexed/carboplatin was compared to etoposide/carboplatin and was inferior (62). Several trials have shown that irinotecan combined with cisplatin or carboplatin is equivalent to etoposide with cisplatin or carboplatin (63, 64). Thus EP remains the standard today. Topotecan is approved for used in the second line setting albeit at a dose and schedule rarely used due to toxicity (65,66). Both oral and intravenous topotecan produce similar results. Topotecan improved PFS as maintenance but did not improve survival and increased toxicity (67). Thus, use in the maintenance setting was not widely adopted. Retreatment with EP for those with late relapse has been the most successful retreatment approach and is standard in this setting (68). After 2000, randomized trials showed that PCI after induction response could prolong survival in extensive stage as well as limited stage SCLC and as now used routinely in this setting (69). There has been little change in chemotherapy options for SCLC over the past 20 years but there is some hope that the immune checkpoint inhibitors could improve outcomes (70).

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