Early-Stage Lung Ca: Better OS with Surgery?

Lobectomy seems to offer better long-term outcomes over radiotherapy, yet the latter is still gaining ground

An ongoing debate in the lung cancer community is whether patients with early-stage disease benefit more from surgery or from stereotactic body radiation therapy (SBRT). Radiation oncologists are certainly on board with SBRT in inoperable patients, and there is some data to back up that assertion, as highlighted in this ASCO Reading Room articlefrom last year.

Meanwhile, thoracic surgeons seem to be moving away from lobectomy, and have stumped for less aggressive surgical approaches, such as wedge resection and segmentectomy.

But any discourse gets that much livelier when there’s someone who is willing to offer a third opinion. Researchers at two University of California branches took on that monkey-wrench role with their study in U.S. veterans that compared lobectomy with SBRT — and decided that surgery was the winner. In an interesting twist, the authors are affiliated with radiation oncology — and not surgery — departments at their respective institutions.

“Our data suggest that the more aggressively we treat early lung cancer, the better the outcome,” noted Alex Bryant, of the University of California, San Diego, in a statement. “This study is one of the best-powered and detailed analyses to date and suggests that lobectomy is still the preferred treatment of this disease for most patients.”

Surgery Scores

Bryant and his colleagues identified early-stage non-small cell lung cancer (NSCLC) patients from the VA Informatics and Computing Infrastructure (VINCI). He described VINCI as “an extremely rich source of health information” from which the authors were able to gather detailed data related to a large, nationwide group of veterans.

The study population ultimately consisted of a little over 4,000 patients (97% male) who were diagnosed with clinical T1 or T2a (<5 cm in greatest dimension), N0 (no regional lymph node metastasis), M0 (no distant metastasis), biopsy-proven NSCLC. The diagnoses took place between Jan. 1, 2006 and Dec. 31, 2015.

Patients were treated definitively with either surgery or radiation. Those with a history of prior malignancy, those with a missing cause of death, those treated more than 6 months after diagnosis, and those with missing covariates were excluded. Covariates derived from VINCI were tumor size, tumor grade, histology, patient age, sex, race, and tobacco history. Having these data makes the registry particularly unique, Bryant noted.

“Factors such as these are often not available and have not been consistently addressed in previous studies, which sets this study apart.”

In terms of the procedures themselves, SBRT was defined as the delivery of one to five daily fractions of radiation directed at the lung (mean biologically equivalent dose of 124 Gy10), while the surgical groups were divided into lobectomy and sublobar resection. The latter included wedge and segmental resection; video-assisted thoracoscopic surgery and open surgeries were combined for this analysis.

The authors compared cancer-specific survival among patients receiving lobectomy, sublobar resection, or SBRT with univariable and multivariable competing risk analyses.

The unadjusted analysis revealed higher immediate post-procedural mortality in the surgery groups versus the SBRT group. While multivariable analysis that looked at long-term survival found higher cancer-specific mortality for SBRT compared with lobectomy (subdistribution hazard ratio 1.45, 95% CI 1.09-1.94, P=0.01), there was no survival difference between SBRT and sublobar resection (subdistribution HR 1.25, 95% CI 0.93-1.68, P=0.15).

“Despite the higher postoperative mortality risk, the lobectomy group had the lowest unadjusted risk of all-cause mortality at 5 years,” the authors wrote. “In the lobectomy group, the unadjusted 5-year overall survival [OS] was 70%, followed by sublobar resection at 56% and SBRT at 44%.”

In addition, the multivariable Cox proportional hazards model showed that SBRT was tied to a 38% increased risk of all-cause mortality versus lobectomy (HR 1.38, 95% CI 1.08-1.78, P=0.01).

There was no significant difference in OS between the SBRT and sublobar groups (HR 1.17, 95% CI 0.90-1.53, P=0.85), and there were no significant differences between groups when evaluating noncancer mortality based on univariable or multivariable analysis. There also was no difference in OS or cancer-specific survival between patients who received wedge versus segmental resection (P>0.09 in all unadjusted and adjusted analyses).

Finally, the authors noted that for every 10 Gy increase in biologically equivalent radiation dose, the risk of cancer-related death decreased by 7% (subdistribution HR 0.93, 95% CI 0.86-1.00, P=0.06).

A Resolution?

In spite of the perioperative mortality risks linked with surgery, lobectomy improved survival compared with SBRT in the long term, the researchers concluded. So did the group make the ultimate mic drop in favor of lobectomy? Not quite.

As one MedPage Today reader commented, SBRT is generally reserved for patients who are poor candidates for surgery. But a number of trials designed to compare SBRT with surgery in early-stage disease — STARS, ROSEL, RTOG 1021 — were shuttered early because of poor accrual.

“The probable reason that earlier prospective randomized trials failed to accrue was because surgeons who had operable stage I patients would not consider SBRT, and patients who were not surgical candidates didn’t qualify for randomization in the failed studies,” the reader pointed out.

That leaves the lung cancer community anticipating results from two recently launched trials — VALOR and STABLE-MATES.

The JoLT-Ca Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) for Lung Cancer (STABLE-MATES) trial aims to recruit 258 patients at more than 30 institutions, and has an estimated primary completion date of December 2021.

STABLE-MATES’ principal investigator, Robert Timmerman, MD, of UT Southwestern Medical Center in Dallas, explained in a statement that the “two therapies [surgery and SABR] are both fiercely competitive, like thoroughbreds in a race. Yet when not competing on the track, they reside together in a stable enjoying each other’s company — ready and eager to be called on for the next challenge.”

Meanwhile, the currently recruiting Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR) trial will compare the two modalities in 670 patients at 16 VA centers. The estimated primary completion date is September 2027.

VALOR co-principal investigator Drew Moghanaki, MD, MPH, of the VCU Massey Cancer Center in Richmond, VA, noted in a statement: “There is a lot of research that suggests stereotactic radiotherapy might be just as effective as surgery for lung cancer, or even better. Currently, more than 90% of lung cancers that are caught at an early stage can be controlled with this non-surgical treatment. We know it is often safer than surgery and, for this reason, cancer researchers now question whether surgery is still the optimal treatment for lung cancer.”

He added, however, that while this new treatment approach is promising, there has as yet been no successful comparison of stereotactic radiotherapy with surgery in a head-to-head trial to know how well it works in the long-term: “There are many oncologists who believe stereotactic radiotherapy might be the best way to treat lung cancer. But, until a study like the VALOR trial is completed we will not know what is the best treatment for all of our lung cancer patients.”

More on Surgery

Other recent research has also evaluated ways to refine lung cancer surgery:

  • Two investigators at Houston Methodist Hospital reported on the “five on a dice” port placement and technique to allow for minimal assistance during lobectomy
  • An Italian team explained why the technique for video-assisted thoracoscopic surgery (VATS) lymphadenectomy was the same as that of thoracotomy in early-stage lung cancer
  • Another group of Italian researchers found that VATS lobectomy for locally advanced-stage NSCLC was safe and effective in appropriately selected patients, ensuring perioperative results similar to those obtained in early-stage tumors
  • Japanese researchers reported on two patients in whom salvage VATS lobectomy was feasible after SBRT

The study by Bryant’s group was supported by the National Institutes of Health. Bryant disclosed no relevant relationships with industry; one co-author disclosed support from EMD Serano.

The VALOR trial is funded by the Veterans Affairs Cooperative Studies Program.

Central-Airway Necrosis after Stereotactic Body-Radiation Therapy.

Stereotactic body-radiation therapy ( delivers large doses of radiation with millimeter accuracy.1 With SBRT, control rates for stage I non–small-cell lung cancer are 90% or greater, and this effectiveness has led to its worldwide adoption in treating patients with inoperable disease.1,2 Despite technological advances that permit the precision required for SBRT, normal tissues near the tumor receive higher biologic doses of radiation than with standard treatment. Consequently, patients with tumors adjacent to radiation-sensitive structures, such as the large airways, great vessels, heart, phrenic nerves, and spinal cord, may be at an increased risk for severe radiation injury.3 Documenting the extent of the toxic effects on these central structures represents a challenge given the competing risk of death in patients with lung cancer and the extended time required for toxicity to develop.


In a seminal study, patients with centralized tumors treated with a full-dose regimen of 60 to 66 Gy of radiation administered in three fractions, the risk of severe toxicity was 11 times as high as the risk of the development of peripheral tumors.3 Consequently, an SBRT “danger zone” was defined and subsequent multi-institutional trials have excluded patients with tumors in this area. A more protracted and presumably safer fractionation scheme (in which 50 Gy of radiation were administered in five fractions) has been widely adopted for the treatment of centrally located tumors and is the starting point for a dose-determination trial.4,5 Below we describe the clinicopathological features of central-airway necrosis in a patient who had received SBRT, with 50 Gy administered in five fractions, 8 months earlier.


A 61-year-old woman with a smoking history of 52 pack-years presented with two primary non–small-cell lung cancers: a central tumor measuring 1.4 cm in diameter (Figure 1AFigure 1

Initial Tumors and Post-SBRT Necrotic Tissue in a Patient with Non–Small-Cell Lung Cancer.) and a peripheral

tumor measuring 2.4 cm in diameter (Figure 1B). Biopsies of the tumors confirmed that both were adenocarcinomas. Staging studies revealed no metastatic disease. Poor pulmonary function precluded the performance of surgery.


The patient was treated with SBRT in accordance with a protocol for a registration study that allows for long-term surveillance of adverse events; the protocol was approved by an institutional review board. Dose, fractionation, technique, and constraints were established and applied in accordance with published standards.5 Acute toxicity was not observed, and the patient had an excellent radiographic response.


A surveillance scan obtained with the use of positron-emission tomography–computed tomography 8 months after treatment showed new mediastinal metastases, both of which were confirmed on the examination of biopsy specimens as recurrent adenocarcinomas. Incidental findings included an extensive area of necrosis in the proximal right airway (Figure 1C, 1D, and 1E) in the tissue within the radiated area. (A three-dimensional video reconstruction of the larynx, trachea, and proximal main bronchi that shows of the area of necrosis is available with the full text of this letter at NEJM.org.)


The patient received one cycle of treatment with pemetrexed and cisplatin before plans for salvage chemoradiotherapy were abandoned. Several weeks later hemoptysis developed, necessitating intubation. Bronchoscopy confirmed that the bleeding originated from the right proximal airway. With the consent of the family, care was transitioned to comfort-only measures, and the patient died 11 months after her original presentation.


This report of fatal central-airway necrosis in a patient treated with SBRT underscores the importance of long-term follow-up of patients with central tumors and the necessity of protocol-based treatment. Furthermore, it may be prudent to consider post-treatment bronchoscopic surveillance of patients with central tumors to determine the true frequency of tracheobronchial injury.


SBRT is an effective treatment for patients with peripheral stage I non–small-cell lung cancer that is inoperable. However, the long-term effects of this treatment, especially on central lesions, should be carefully documented and reported.

Source: NEJM

New radiation therapy aimed at lung cancer

A relatively new type of radiation therapy — stereotactic body radiation therapy — appears to rid patients with early-stage lung cancer cells better than conventional radiotherapy.may also increase a lung cancer patient’s life expectancy. Those were the findings of a nationwide study published last year in the Journal of the American Medical Association.

Most patients think surgery is their only choice for treat ment of cancer, but based on the findings of this and earlier studies, they now may have another choice.

The University of Kentucky’s Markey Cancer Center is one of a handful of centers nationwide participating in several clinical trials of this emerging form of treatment.

These research trials are for patients with small, localized lung cancers — cancer that has not spread. They should also be either basically healthy besides having cancer and therefore a good candidate for surgery or have health issues that place them at a high risk for surgery.

Markey is also the only center in the country study ing the use of this therapy on patients who have the most common stage of lung cancer and most advanced stage of cancer — Stage III.

These patients first undergo the standard five to six weeks of radiation treatment. They then get two intense rounds of stereotactic body radiation therapy.

The stereotactic body radiation therapy treatments vary but generally are given daily over one to five days.

What we are learning is helping us fine-tune treatment based on the excellent results we have already seen.

Side effects from this non-invasive treatment with radiation vary depending on the size and location of the cancer, but patients have very few problems generally.

Clinical research into effective new treatments such as stereotactic body radiation therapy is important as we work to help patients live longer and with a high quality of life after being diagnosed with lung cancer.