	Director, Early Lung & Cardiac Action Program

In CT screening for lung cancer, the regimen of screening is a critical factor in diagnosing lung cancer early while limiting unnecessary tests and invasive procedures. This has been clearly demonstrated by comparing the results of two studies, one with and one without a well-defined regimen of screening. The study that used a regimen of screening had a significantly higher proportion of stage I lung cancer, the tumor size was smaller, and the frequency with which the cancer could be removed surgically was higher.

As a result, the cure rate was also significantly higher. Screening is increasingly being reimbursed by insurance carriers based on the US Preventive Services Task Force (USPSTF) report in 2013, which recommends annual screening for high-risk smokers aged 55 to 80.

 Further, the Centers for Medicare & Medicaid Services recently announced that the agency plans to cover low-dose CT screening

for lung cancer in high-risk Medicare patients. It is increasingly being recognized that to maximize the benefit of screening and minimize potential harms, a regimen of screening must be used, and it requires continuous evaluation and updating to remain state-of-the art, incorporating the latest novel technical innovations and emerging screening data. For this purpose, large databases are needed to provide important information on findings that are identified by screening, particularly in annual rounds of screening where the data have previously been sparse.

Early on in CT screening for lung cancer, data from the Early Lung Cancer Action Project (ELCAP)

 provided guidance that led to the recommendations for workup of nodules identified as a result of the screening. The expanded International Early Lung Cancer Action Program (I-ELCAP), with more than 31,000 participants who had CT screening, provided further information.

Currently, I-ELCAP has more than 66,000 participants and is using this accumulated evidence to develop the updated guidelines for the workup of findings resulting from CT screening for lung cancer.

 It has been previously shown that the frequency of identifying noncalcified nodules—solid and subsolid&mdash;and the frequency of diagnosing lung cancer manifesting in such nodules is very different for the first, baseline round of screening when compared with all subsequent rounds of annual repeat screening.

Using the latest CT scanners, at least one noncalcified nodule is identified in 50% of baseline screenings but much less frequently (about 7%) in annual repeat screenings. Lung cancer is diagnosed much more frequently in the baseline round than in a single round of annual repeat screening. In the baseline round of screening, the probability of diagnosing lung cancer manifesting as a solid nodule is lower than the probability of diagnosing lung cancer manifesting in a sub-solid nodule. But this is reversed in annual repeat rounds where it is more likely to diagnose a cancer manifesting as a new solid nodule than in a new sub-solid nodule. The difference in the relative frequency of different cell-types in baseline and annual rounds of screening has been described.

The relative frequency of adenocarcinoma decreases in annual rounds when compared with the baseline round, while it increases for squamous cell and small-cell carcinomas, reflected in the greater aggressiveness of the latter two cell types.

This difference between the baseline and the subsequent annual repeat rounds becomes important when annual rounds of screening are repeated as often as 24 times, according to the USPSTF recommendations for an individual who starts baseline screening at age 55. Unfortunately, these differences were not so apparent in randomized screening trials, such as the National Lung Screening Trial

 as they had only a few rounds of annual repeat screening, and thus the results are dominated by the baseline round.

In a long-term follow-up of patients in North America who were diagnosed with lung cancer through CT screening and underwent surgical resection of their cancer, 91% had clinical stage I disease and the estimated cure rate was 84% (95% CI, 80%-88%).

 This report also showed that minimally invasive surgery, as well as sublobar resection, has increased significantly since 2006. Thus, the I-ELCAP regimen provided a high cure rate for those diagnosed with lung cancer and the frequency and extent of surgery for nonmalignant disease was minimized.

In summary, adoption of a regimen that is continuously updated based on emerging technology and data results in a high frequency of diagnosis of early stage lung cancer, and when followed by judicious use of surgery, significantly improves cure rates and limits morbidity. These published results reflect the diagnostic workup and treatment of cases over the past 20 years, but as CT scanners, protocol, and clinician knowledge have improved over these past two decades, the results do not fully reflect what can be achieved today. Clearly, the earlier the cancer is detected, the more likely it is cured, and thus the currently published information provides a lower limit of what can be achieved today.

We believe that the essential and well-accepted requirement of screening programs and clinical practice is to inform the participant in a process of shared decision-making and that data provided by these large databases provide the necessary information.

Unfortunately, the rationale for the follow-up is still not completely known to most physicians, and there is an urgent need for development of consensus on management that does not result in unnecessary diagnostics and surgery.

			Yip R, Henschke CI, Yankelevitz DF, et al. The impact of the regimen of screening on lung cancer cure: a comparison of I-ELCAP and NLST [published online vAugust 2, 2014]. Eur J Cancer Prev. doi:10.1097/ CEJ.0000000000000065.

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			International Early Lung Cancer Action Program protocol. www.IELCAP.org. Accessed October 15, 2014.

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Articles

In CT screening for lung cancer, the regimen of screening is a critical factor in diagnosing lung cancer early while limiting unnecessary tests and invasive procedures. 

Lung Cancer Screening Needs to Remain State-of-the-Art

		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

Cancers arise from multiple acquired mutations that presumably occur over many years, as shown in a number of models, particularly in colon cancer.

A number of “precancer” phenotypes have already been identified in hematology, such as MGUS, CLUS, and MDS— some of them only evolving to true hematological cancers.

Translocations frequently involved in blood cancers, such as the t(14;18) translocation in B-cell lymphomas, are found in about half of the normal population, illustrating the fact that additional alterations are needed to develop lymphoma.

 The number of copies of t(14;18) varies significantly among individuals and increases with age, carrying a yet to be defined (but likely real) risk of developing the disease. The advent of whole genomics approaches, including whole exome sequencing, have highlighted the dauntingly impressive heterogeneity within a given subtype of cancer (eg, there is an average of 200 nonsilent mutations per genome in large cell lymphoma

) and will likely lead to a redefinition of cancer classification,

Two important papers published last month looked at whole exome sequencing in a large subset of normal individuals. The first series looked at 12,380 normal subjects unselected for cancer or hematologic phenotypes and followed outcomes using Swedish national registries for 2 to 7 years after DNA sampling.

 Somatic mutations consistent with clonal hematopoiesis were observed in 10% of individuals aged >65 years, but in only 1% of those aged <50 years. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (HR = 12.9), and approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling. Analysis of bone marrow in some cases at the time of diagnosis of acute myeloid leukemia revealed that cancers arose from the earlier clones showing abnormalities at the time of “normal individuals” testing.

The second series looked at 17,182 persons focusing on single-nucleotide variants and small insertions or deletions in 160 genes recurrently mutated in hematologic cancers.

 Again, detectable somatic mutations increased with age: rare in those aged <40 years, 9.5% in those aged 70 to 79 years, and 18.4% in those aged ≥90 years. The presence of a somatic mutation was also associated with an increase in risk of hematologic cancer (HR = 11.1), as well as an increase in all-cause mortality, possibly due to an increased risk of cardiovascular disease (though it remains unclear if this was due to confounding variables or a shared consequence of the underlying process of aging).

Overall, both studies showed that somatic mutations that drive clonal expansion of blood cells are a common finding in the elderly and associated with worse outcomes. What is interesting is that the majority of the variants occurred in the same three genes in both series: DNMT3A, TET2, and ASXL1. Though these genes have been implicated in hematologic cancers, they seem to be early initiating events, while known drivers of actually diagnosed hematological entities were typically not found in either series.

Though such mutations theoretically have potential implications for early detection, the absolute risk of conversion from clonal hematopoiesis to hematologic cancer was modest (1.0% per year) and routine screening appears premature at this point.

Once again, the ability to broadly look at the genetic landscape is changing the field in oncology and medicine at large. Hopefully, an improved ability to predict future harm in asymptomatic persons may eventually replace the traditional dichotomy between illness and health.

Future goals would be to identify among a continuum of ascertainable genomic states those that are associated with elevated risk of future illness. Similarly, the next step would be to have the ability to target some of these relevant abnormalities and intervene early. That could become the ultimate genetic counseling answer in individuals who are at risk because of a prior cancer or a known genetic risk factor in their family.

			Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767.

			Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood. 1995;85(9):2528-2536.

			Morin RD, Mungall K, Pleasance E, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood. 2013;122(7):1256-1265.

			Hoadley KA, Yau C, Wolf DM, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin [published online August 7, 2014]. Cell. 2014;158(4):929-944.

			Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence [published online November 26, 2014]. N Engl J Med. doi:10.1056/NEJMoa1409405.

			Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes [published online November 26, 2014]. N Engl J Med. doi:10.1056/NEJMoa1408617.

Clonal Hematopoiesis in Normal Individuals Might Represent a New Way to Approach Blood Cancer Risk and Diagnosis

Surgery remains the most effective curative treatment for esophageal cancer. Yet, many eligible patients do not undergo esophagectomy. An analysis of the NCI's SEER database found that Black and Hispanic patients were significantly less likely to undergo surgery for esophageal cancer compared with whites and that this difference was the underlying cause of disparate survival for esophageal cancer.

Unlike other solid tumors like breast or colon cancer, fewer than half of patients with local or regional disease undergo esophagectomy. Even when surgery is recommended, a significant percentage of patients with esophageal cancer do not undergo surgery.

Patients may be less likely to undergo esophagectomy for a variety of reasons. European studies have found limited benefit for surgery following chemoradiotherapy for esophageal squamous cell carcinoma.

 Compared with other solid tumors, esophagectomy has historically had relatively high morbidity and mortality rates. Even when there are no complications, the procedure has a major impact on quality of life. However, recent advances in surgical care, particularly the advent of minimally invasive esophagectomy (MIE) may ameliorate many of these concerns, potentially allowing more patients to receive curative therapy.

Some European studies, primarily involving squamous cell carcinoma, have failed to demonstrate a survival advantage for esophagectomy after chemoradiation.

However, these results should be interpreted with caution and surgery remains the standard of care for most resectable esophageal cancer in the United States. The pathologic complete response rate is much lower for adenocarcinoma, which is the predominant histology of esophageal cancer in the United States. The other main criticism of these studies is the relatively high rate of perioperative mortality, potentially negating the benefits of surgery. Multiple studies have demonstrated improved mortality rates for esophagectomy at high-volume centers. Yet, the majority of esophagectomies in the United States are still performed at low-volume centers. Over the last decade, though, there has been a shift of cases to higher volume centers and an overall decrease in mortality from 8% to 4%.

 This has corresponded with a modest increase in the total number of esophagectomies performed annually.

Beyond volume outcomes, a growing body of literature has found reduced complication rates with minimally invasive esophagectomy compared with open. In the first randomized controlled trial of open versus minimally invasive esophagectomy, the MIE group had one-third the rate of pulmonary complication that the open group had.

 Short-term quality of life was better in the MIE group, as well. Mortality rates were below 4% in both groups. More importantly, MIE does not compromise oncologic outcomes.

Comparisons of long-term survival seem to show no statistically significant difference in overall survival or recurrence rates between open and minimally invasive esophagectomy, which is similar to the experience in other solid tumors.

 In terms of long-term quality of life, results from a study of more than 400 patients after esophagectomy recently presented at the World Congress of the International Society for Diseases of the Esophagus found significant benefits in health-related quality of life persisted even 2 years after surgery for patients undergoing MIE compared to thoracotomy.

 At 24 months, pain scores of patients in the MIE group had returned to baseline, but remained elevated in the open group.

The use of robotic esophagectomy, an adjunct to MIE, has also been increasing. The wristed motion of robotic instrumentation allows greater dexterity compared to standard laparoscopic tools (

		Schematic of roboticassisted minimally invasive esophagectomy mobilization of the thoracic esophagus.

The robotic optical platform also gives surgeons a three-dimensional view and permits use of other wavelengths that have the potential to improve assessment of organ perfusion and tumor location (

). City of Hope was one of the first institutions to report outcomes of robotic esophagectomy.

Since then, we have performed over a hundred robotic esophagectomies and have continued to improve surgical techniques.

 In recent years, we have performed more than 90% of our esophagectomies minimally invasively with laparoscopy and thoracoscopy. The mortality rate has been less than 5%, with an anastomotic leak rate less than 10%. Patients are able to recover better and resume normal activities faster. We have been able to decrease our median length of stay to 7 days, which is less than half the national average of 16 days. These results have come despite almost 90% of our patients receiving neoadjuvant chemoradiation during this time.

		Intraoperative image using near-infrared fluorescence imaging fluorescence angiography during robotic-assisted minimally invasive esophagectomy after administration of indocyanine green.

Esophagectomy continues to be the most effective treatment for esophageal cancer confined to local and regional disease. Improvements in surgical technique, including minimally invasive and robotic esophagectomy, have greatly reduced morbidity and mortality after esophagectomy over the last decade.

However, many eligible patients have not been able to take advantage of these advances, either by undergoing esophagectomy at low-volume centers where these techniques are not offered or by not undergoing esophagectomy at all. Hopefully, greater focus on quality metrics and outcomes will help to centralize surgical care of esophageal cancer at centers of excellence.

			Revels SL, Morris AM, Reddy RM, et al. Racial disparities in esophageal cancer outcomes. Ann Surg Oncol. 2013;20(4):1136-1141.

			Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25(10):1160-1168.

			Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23(10):2310-2317.

			Jafari MD, Halabi WJ, Smith BR, et al. A decade analysis of trends and outcomes of partial versus total esophagectomy in the United States. Ann Surg. 2013;258(3):450-458.

			Biere SS, van Berge Henegouwen MI, Maas KW, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet. 2012;379(9829):1887-1892.

			Dantoc M, Cox MR, Eslick GD. Evidence to support the use of minimally invasive esophagectomy for esophageal cancer: a meta-analysis. Arch Surg. 2012;147(8):768-776.

			McCormack O, Barbour A, Baker P, et al. Long-term health related quality of life outcomes following esophagectomy: a comparison between thoracoscopically assisted and open esophagectomy. Diseases of the Esophagus. 2014; 27(suppl S1):75A.

			Kernstine KH, DeArmond DT, Shamoun DM, et al. The first series of completely robotic esophagectomies with threefield lymphadenectomy: initial experience. Surg Endosc. 2007;21(12):2285-2292.

			Kim J, Lin J, Paz I, et al. Prophylactic pyloric dilation and endoscopic botulinum toxin injection for minimally invasive esophagectomy. Diseases of the Esophagus. 2014; 27(suppl S1):67A-68A.

Surgery remains the most effective curative treatment for esophageal cancer. Yet, many eligible patients do not undergo esophagectomy.

December 2014 | Oncology & Biotech News

Lung Cancer Screening Needs to Remain State-of-the-Art

Clonal Hematopoiesis in Normal Individuals Might Represent a New Way to Approach Blood Cancer Risk and Diagnosis

Minimally Invasive Esophagectomy Improves Outcomes, But Remains Underutilized