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Oncology Times:
doi: 10.1097/01.COT.0000431856.48714.95
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Lung Cancer: European Multidisciplinary Meeting Spotlights Progress in Molecularly Guided Therapy

Goodwin, Peter

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LUGANO, SWITZERLAND—Significant advances in understanding the molecular nature of lung cancer are prompting new approaches to treating the disease. That was the consensus of researchers speaking here last month at the European Multidisciplinary Conference for Thoracic Oncology (EMCTO). Biomarkers, better diagnosis, and tailored radiotherapy were all center stage at the conference, supported by developments in immunology and surgery.

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Centrally Located Tumors: Control vs. Toxicity

A systematic review of stereotactic ablative radiotherapy (SABR) reported approximately 85 percent “durable local control” rates (described as cure) in patients with centrally located, early stage (1 and 2) non-small-cell lung cancer with as little as a nine percent risk of serious damage to normal tissues.

Suresh Senan, MD, of the Department of Radiation Oncology at VU University Medical Center in Amsterdam, said that the technique could be used as safely and effectively in this setting as it is in peripheral tumors. His group found that gentle fractionation schemes—with lower doses spread over more fractions—make SABR “an attractive option for unfit patients who may not be able to come for many visits.”

Patients with large centrally located tumors—who are not candidates for standard surgery or chemoradiation—now have SABR as an option: “We know now that it is safe if you limit the normal tissue doses.” And he added that for aged, unfit patients, “a short course of radiotherapy—five to eight fractions—offers a very high chance of durable control or cure without excessive toxicity.”

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New Drug Targets in Lung Adenocarcinoma

In a session on personalized treatment of patients with advanced lung cancer, Ken O'Byrne, MD, a consultant medical oncology at St. James's Hospital and Trinity College in Dublin, said that following earlier success with drugs targeting angiogenesis for treating adenocarcinoma, new “druggable” targets, including the MEK/k-RAS and B-RAF/MET pathways and heat shock protein—are now giving real hope that cancer doctors could improve outcomes in each of a number of subsets of patients.

He said the discovery of specific biomarkers—which could be treated with tailored drugs—was very promising, and he compared the situation with lung cancer today with that of hematologic malignancies of several decades ago: “As our knowledge of the biology began to expand and our ability to deliver good treatments expanded, those patients became cured. In lung cancer we're going to see the same evolution,” he predicted.

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Emerging Targetable Biomarkers for Squamous Cell Carcinoma

Targetable biomarkers for use in squamous-cell carcinoma treatment were reported by Martin J. Edelman, MD, Professor of Hematology/Oncology and Associate Director for Clinical Research at the University of New Mexico Cancer Center, who listed the mutations DDR2 and FGFR, and antibodies to PD1 and PDL 1 among the molecularly targetable features of this cancer that could soon be treated with individualized therapies.

In a plea to all cancer doctors to collect biopsy samples for molecular analysis, he had strong words of encouragement: “This is the crucial thing that's going to change this landscape: If we're ever going to be able to do anything in the disease we're going to need to be able to target these therapies.”

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Tailored Chemo-Radiotherapy

More opportunities for using chemo--radiotherapy can be found by individualizing treatment according to tissue susceptibility, said Dirk De Ruysscher, MD, PhD, Professor of Radiation Oncology at Maastricht University Medical Centre in the Netherlands. In Stage III non-small-cell lung cancer, targeted dose escalation could bring better outcomes while minimizing toxicity.

“We give a higher dose to parts of the tumors, which show lower susceptibility to radiation, and we remove a bit from those parts that don't need it.”

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PET-CT Guidance for Treating Nodules

Therapeutic guidance from use of positron emission tomography (PET)-computed tomography (CT) to assess suspicious lung nodules was described by Barbara Malene Fischer, MD, of Copenhagen University Hospital as bringing new opportunities to exclude the majority of lesions detected by standard CT which are benign.

“We need a second step test to find out which patients will benefit from biopsy. And that's where PET comes in,” she stated, adding that knowledge provided by PET-CT about the functioning of the individual tumor tissue could be harnessed to refine personalized therapy.

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Video, Robots, and Specialist Expertise to Treat Thymoma

Surgery for thymoma needs to be conducted only in centers of special expertise, said Walter Klepetko, MD, Professor and Head of the Department of Thoracic Surgery at Medical University of Vienna, whose hospital sees about 30 of these rare tumors annually, he noted.

Personalized surgery, including the use of video-assisted thoracic surgery (VATS) and robotic surgery, can help to resect thymoma optimally and will improve outcomes, he said. “These tumors have to be seen by a really specialized team; it's not a routine resection, and you have to set up a real thymoma interest group at your institution to deal with a disease like that.”

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Immune Therapies Restore Tissue Immunity

Martin Reck, MD, PhD, of the Department of Thoracic Oncology at Grosshansdorf Hospital in Germany pointed to several molecules that have good therapeutic potential in squamous cell carcinoma. In particular he highlighted those involved with “checkpoint inhibition”—including the CDL A4 receptor, the PD 1 receptor and the PDL 1 ligand, for all of which there are now specific therapeutic antibodies to inhibit their structures and, it is hoped, kick-start immune function in surrounding tissues.

Encouraging results with ipilimumab—initially in melanoma and now in lung cancer—suggest that there is a capacity to reactivate anti-cancer immune processes. But to prove new immune-therapies work needs randomized investigation: so Reck called for clinicians to participate in trials:

“We will only get the valid knowledge about the efficacy of the drug if we really are able to run these trials in patients with advanced cancers,” he said.

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'Marginally Operable”?

The advent of two cancer management approaches—SABR and surgery techniques including VATS have increased the chances of curing stage T1b non-small cell lung cancer, but questions remain about when to use one or the other of these modalities.

Paul van Schil, MD, of University Hospital Antwerp in Belgium, said it is beneficial to use surgery when the patient is in good shape and has fewer comorbidities. “The main message is: when a patient is functionally operable—when he's in good general condition—then the preference is still to do a lobectomy if possible.”

In marginally operable patients, however, he said there is still need for research to establish the optimal surgical strategy. And, stereotactic radiotherapy is an option.

Radiotherapist Kevin Franks, MD, a consultant clinical oncologist at St. James Institute of Oncology in Leeds, UK, said SABR could deliver potentially curative therapy to marginally operable patients in less good shape. “For patients who are clearly not operable, stereotactic radiotherapy offers a big advantage,” he said, also acknowledging, though, that for patients in the “marginal zone” there are still research questions to be answered about whether radiotherapy can eliminate some of the risks of surgery.

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Mesothelioma Treatment Improvements

Hopes for better treatment for patients with mesothelioma have emerged from improved understanding of how molecular structures—such as the NF2 molecule, cyclin-dependent kinase inhibition, and the BRCA-associated protein BAP1—can modulate this disease, and thus be targeted, said Emanuela Felley-Bosco, PhD, of University Hospital in Zurich.

She warned, though, that merely targeting cells that are cycling—as is done with chemotherapy—could be ineffective: “In mesothelioma the median proliferating index—cells cycling at any time—is about 10 percent, so with classical chemotherapy we will destroy just a small part—about 10 percent—of the tumor,” she said.

Chairing the session on mesothelioma, Paul Baas, MD, PhD, of the Netherlands Cancer Institute, pointed out that an unmet need is to identify—perhaps with the help of biomarkers—patients who are not fit so they can be spared the rigors of “curative” therapy that could potentially reduce survival.

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Next-Gen Sequencing to Monitor Response

And finally, Antonio Marchetti, MD, Professor of Pathology at the University of Chieti in Italy, explained how next-generation sequencing has given access to thousands of molecular signatures—each one present in only a small number of patients, but which—in those cases—can make a big difference as specific drugs are produced. He said he thought there is a role for this new technology in optimizing existing treatments.

“Detection of mutations in blood can make it possible in the near future to monitor patients during treatment,” he said.

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iPad Exclusive!

Special Edition ofAudio Journal of Oncology

Listen on the iPad edition of this issue to hear interviews from the meeting in a special edition of the Audio Journal of Oncology with OT, produced with the help of ecancertv. Ken O'Byrne, Martin Edelman, Suresh Senan, Dirk De Ruysscher, Barbara Malene Fischer, and Martin Reck discuss their research with Peter Goodwin and Sarah Maxwell.

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