In This Issue

The study compared the outcomes of surgery plus perioperative chemotherapy (PCF: paclitaxel, cisplatin, and 5-fluorouracil) with preoperative chemotherapy alone in 346 patients with resectable squamous cell carcinoma of esophagus. Both arms were randomized to 2 preoperative PCF cycles, with 2 additional postoperative cycles of PCF given to the perioperative arm. The 5-year relapse-free survival and 5-year overall survival were significantly improved in the perioperative-chemotherapy arm versus preoperative-chemotherapy arm (hazard ratio [HR] for relapse, 0.62; P < 0.001; HR for death, 0.79; P < 0.001). Patients undergone resection after chemotherapy achieved a complete response rate of 24.1% (77 of 320). No increase of PCF-related adverse events was observed with the 2 additional postoperative PCF cycles. The authors concluded that perioperative PCF regimen significantly improved survival outcomes of patients with operable esophageal squamous cell carcinoma in comparison to preoperative chemotherapy alone. (p. 1349)

A retrospective study of 1778 surgically resected lung cancer cases was conducted to evaluate bronchial intraepithelial tumor spread in high-grade neuroendocrine carcinoma (HGNEC). Histologically reviewed HGNECs with bronchial intraepithelial tumor spread were examined for neuroendocrine markers, and their clinicopathological parameters. Of the 47 HGNEC cases, 19.1% (n=9) had bronchial intraepithelial tumor spread, in which 8 of them had large cell neuroendocrine carcinoma (LCNEC) or small cell lung carcinoma with an LCNEC component. Four of these with LCNEC component showed continuous tumor spread from the primary tumor to the resected end of the bronchus. Higher recurrence rate was associated with HGNEC showing bronchial intraepithelial tumor spread. The findings suggest that bronchial intraepithelial tumor spread is common in peripherally located HGNEC, particularly those with LCNEC morphology. Surgeons and pathologists are urged to be aware of this phenomenon, which could also indicate HGNEC aggressiveness. (p. 1337)

Single agent, pan-PI3K inhibitor buparlisib (BKM120), was being evaluated in this open-label, two-stage, phase II study BASALT-1 with Stage 1 treating 63 patients harboring PI3K pathway-activated, metastatic, squamous or nonsquamous NSCLC, who relapsed after prior treatments. The squamous and nonsquamous groups achieved a 12-week progression-free survival rate of 23.3% and 20.0%, respectively. Therefore, both groups did not start Stage 2. The analysis of archival tissue samples and circulating tumor DNA (ctDNA) demonstrated that PI3K pathway mutations could be detected in ctDNA but they were more concordant with metastatic tissue than with primary biopsies. In summary, the study did not meet its Stage 1 primary objective. Although PI3K pathway activation was detected using ctDNA, it might not be the main oncogenic driver in NSCLC. The authors suggested that increased efficacy might be observed in combination therapies versus monotherapy. (p. 1319)

This post-hoc analysis included prospectively collected data from tyrosine kinase inhibitor-naïve patients harboring EGFR mutation-positive stage IIIb-IV lung adenocarcinomas treated with afatinib in LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 (N=600). Patients were stratified in the randomized trials by EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs. non-Asian). All uncommon mutations were categorized into group 1 (point mutations or duplications in exons 18–21), group 2 (de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations), and group 3 (exon 20 insertions). Uncommon EGFR mutations were found in 12% patients. Objective responses were observed in 71.1% of group 1, 14.3% of group 2 and 8.7% of group 3. Median progression-free survival (PFS) and overall survival (OS), respectively, were 10.7 months and 19.4 months in group 1, 2.9 months and 14.9 months in group 2, and 2.7 months and 9.2 months in group 3. The analysis of the most frequent uncommon mutations revealed that objective response was achieved in 77.8% patients with Gly719Xaa, 56.3 % with Leu861Gln, and 100% with Ser768Ile. Taken together, afatinib demonstrated efficacy in non-small cell lung cancer harboring certain uncommon EGFR mutations (particularly Gly719Xaa, Leu861Gln, and Ser768Ile). Tumors with de-novo Thr790Met and exon 20 insertion mutations achieved relatively less clinical benefit.

Yang JCH, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. The Lancet Oncology 2015;16:830–838.

The phase III study evaluated the treatments with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in 1093 treatment-naïve patients with stage IV squamous non-small cell lung cancer (NSCLC). The necitumumab arm demonstrated significantly improved median overall survival (OS) versus the control arm (11.5 months vs. 9.9 months; hazard ratio [HR] 0?84; ?=0?01). Median progression-free survival was 5.7 months versus 5.5 months (HR 0.85; P=0.02), objective response rates were 31% versus 29%, and disease control rates were 82% versus 77%. The overall safety profile of the necitumumab regimen was acceptable with no new adverse events. The necitumumab arm showed more frequent grade ≥3 adverse events (72% vs. 62%), including hypomagnesemia and rash, and higher incidence of serious adverse events (48% vs. 38%). Treatment termination was mostly due to neutropenia and thrombocytopenia. The investigators concluded that the addition of necitumumab to gemcitabine and cisplatin improved OS in the study patient population, indicating a new first-line therapeutic strategy for the disease.

Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. The Lancet Oncology 2015;16:763–774.

This study aimed to estimate the proportion of lung cancer cases in Quebec that were “more likely than not” caused by cigarette smoking among the patients for a class action suit against the tobacco industry. The authors measured smoking in terms of pack-years to evaluate the dose-response relationship between smoking and lung cancer, and the distribution of pack-years of smoking among cases. The analysis estimated that 3 – 11 pack-years satisfy the “more likely than not” criterion. More than 90% of lung cancer cases in Quebec were found to be legally attributable to smoking. The novel methodology used in this study would facilitate class action suits against the tobacco industry.

Siemiatycki J, Karp I, Sylvestre MP, Pintos J. Estimating the proportion of cases of lung cancer legally attributable to smoking: a novel approach for class actions against the tobacco industry. American J Pub Health 2014;104:e60-e66.

The authors assessed data from an internet survey involving 4219 U.S. adults (aged ≥18 years) in order to determine attitudes toward increasing the minimum tobacco age of sale to 21 years among U.S. adults. Participants were asked if they favor or oppose increasing the legal minimum age to purchase all tobacco products from 18 to 21. The analysis showed that 50.4% strongly and 24.6% somewhat favored increasing the age to 21 years, in which 77.5% were never smokers, 74.6% were former smokers, and 69.9% were current smokers. In this group of people who favored, the adjusted odds were higher among adults aged 25–44 (odds ratio [OR]=1.8), 45–64 (OR=2.3), and ≥65 (OR=3.1) years, and were lower among former and current smokers (both OR=0.7). In summary, adults in favor of increasing the minimum tobacco age of sale to 21 years accounted for three quarters of the study participants, of which 7 in 10 were smokers. Incorporating the increase in minimum age of sale into proven tobacco control strategies could help curb youth tobacco use.

King BA, Jama AO, Marynak KL, Promoff GR. Attitudes Toward Raising the Minimum Age of Sale for Tobacco Among U.S. Adults. American Journal of Preventive Medicine, doi:http://dx.doi.org/10.1016/j.amepre.2015.05.012.

The Medicine and Healthcare products Regulatory Agency in the UK has granted approval to Bristol-Myers Squibb's immunotherapy Opdivo for Early Access to Medicines Scheme (EAMS) for the treatment of patients with locally advanced or metastatic squamous non-small cell lung cancer, treated with prior chemotherapy. This EAMS status would accelerate patient access to the treatment in advance of an official green light for its use. The approval was based on findings from the Phase III CheckMate-017 trial, demonstrating that patients treated with Opdivo had a one-year overall survival (OS) rate of 42% and median OS of 9.2 months compared with 24% and 6.0 months, respectively, in the current standard care, docetaxel, arm. Opdivo was the first PD-1 inhibitor approved in Europe for treating skin cancer.

The Trans-Pacific Partnership Agreement (TPPA) has been summarised in previous columns (most recently June 2015) as a new type of international trade agreement that is still under negotiation, has a number of interested or committed parties and that has the potential to affect domestic policy development for the countries that are party to it, chiefly via ISDS (investor-state dispute settlement) provisions. These provisions allow companies to take legal actions against governments, ostensibly to protect them against poor decisions. However such provisions in other treaties have been used by Big Tobacco to oppose domestic tobacco control policy such as the Philip Morris action against Australia's plain packing legislation. Malaysia which is part of the TPPA has asked other countries to endorse a tobacco carve out so tobacco would not be part of any trade deals. The Obama Administration hit the TPPA headlines recently with a struggle in the US Senate. On the 12^th of May, a group of Senate Democrats voted to block the Trade Promotion Authority bill (the TPA bill not the TPPA). This was a “fast-track” bill that would give the President authority to negotiate trade agreements, which are taking place in secret, much to the frustration of a variety of interest groups in the US and around the world. Concerns about TPPA secrecy have been published by experienced and senior trade negotiators highlighting potential problems with domestic labour, the environment, investor-state disputes, intellectual property and state-owned enterprises. The text is secret, which may explain why it is late to garner interest (initial discussions started in 2005 with the “P4” Trans Pacific Strategic Economic Partnership between Chile, New Zealand, Singapore and Brunei). In late June, the Senate (Republican controlled) supported the TPA bill 60–38; Congress will as a result be able to accept or reject the TPPA (secret until final draft) but not amend it or subject it to filibuster. As far as tobacco control goes, there are major concerns about the impact of the TPPA, particularly via ISDS provisions. The UK, which recently passed plain packaging legislation is facing its own lawsuit from Philip Morris International, filed on the 22^nd of May using similar trade agreement arguments as those used against Australia. An interesting and perhaps startling perspective for the tobacco control community comes from criticism of TPP protestors in a short article in The Australian Financial Review from July that describes the FCTC as “very patchy and unenforceable UN convention to regulate tobacco. In legal terms this is little more than a code of practice”. After all, we base the modern approach to global tobacco control on the elements of the FCTC. We do well to remember the contempt in which certain powerful interest groups hold the FCTC and all tobacco control efforts. The next and potentially last TPPA negotiating session will take place 28–31 July 2015 in Hawaii.

Singapore is setting a standard in bans of tobacco and related products, including any products that contain nicotine. In a report from Today, the Singapore government will introduce from December 2015 a ban on emerging smokeless tobacco products not already in the market such as smokeless cigarettes and cigars as well as topical, implant or injectable products containing tobacco or nicotine and e-cigarettes. From August 1 2016, the ban will also include emerging tobacco products already in the market including various forms of snuff and chewable tobacco. Products registered under the Medicines Act are excluded from the ban. E-cigarette news is always puzzling to report on. Over the last month alone we have a multitude of conflicting commentaries, attitudes and policies presented in the media. From Wales, The Week reports on planned legislation to ban the use of e-cigarettes in public places, supported by Public Health Wales and the British Medical Association, but opposed by respected organisations such as ASH Wales (an anti-smoking group) and Cancer Research UK. In the United States, The Hill carries the headline “Spending bill exempts e-cigs from FDA review”. This slightly confusing article does a stunning turn in serial negatives in its first sentence – an amendment is blocked … a provision is removed… . to make exempt and so on (… . till the house that Jack built …). What the article actually says, I think, by the end is that a bill to fund the FDA to regulate e-cigarettes (among other things) was threatened by a provision that would have made e-cigarettes exempt from the FDA pre-market review process. An amendment was proffered by a Democrat representative and was blocked by Republicans. This means that a handbrake on the introduction of e-cigarettes to the market may not come into being. But it is a little hard to be sure. And not even the BBC, that perennial voice of reason and reassurance, can tell us whether e-cigarettes are good or bad. BBC News reports that e-cigarettes are used by far greater numbers of people now than even a short time ago (tripled since 2010). The largest group by number is the current smoker group, where e-cigarettes are used along with tobacco cigarettes; the next group is the ex-smoker group and the smallest group (about 1%) is the non-smoker group. This may mean, drawing upon quotes from anti-smoking executives and study leaders, that e-cigarettes are not normalising smoking and that they are associated with reductions in tobacco cigarette consumption. However the director of a smoker support group welcomed the presence of e-cigarettes as an extension of choice for smokers. For the tobacco control community, e-cigarettes promise many more studies, reports and discussions on whether they are good or whether they are bad. At the moment, the jury is clearly still out.