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Neoadjuvant bevacizumab may improve resection of stage III lung cancer
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The addition of bevacizumab to induction chemotherapy appeared associated with high objective response and resectability rates among patients with unresectable stage III lung adenocarcinoma, according to findings from a single-center, single-arm, phase 2 study conducted in China.
Si-Yu Wang, MD, professor in the cancer center of Sun Yat-sen University in Guangzhou, China, and colleagues sought to evaluate whether the addition of bevacizumab (Avastin, Genentech/Roche) to induction chemotherapy with pemetrexed and carboplatin would increase response rates, thus increasing resectability rates and, ultimately, survival among patients with unresectable disease.
Paul A. Bunn Jr., MD
The researchers hypothesized that the 40% resectability rate — or the proportion of patients able to undergo surgery after induction — associated with standard neoadjuvant chemotherapy would increase by 20% if the addition of bevacizumab proved effective.
The resectability rate served as the study’s primary endpoint. Secondary endpoints included induction-related adverse events, perioperative complications, EFS and OS.
The investigators enrolled a small cohort of 42 patients (median age, 56 years; range, 30-65; 61.9% men) with unresectable stage III lung adenocarcinoma between April 2012 and April 2014.
Patients received four cycles of neoadjuvant therapy every 3 weeks, which included bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (area under the receiver operative characteristic curve = 5). Patients underwent surgery 3 to 4 weeks after the last cycle depending on their resectability status.
Median follow-up was 14.3 months (range, 1-30.2).
Overall, 23 patients (54.8%) achieved an objective response, which included one complete response and 22 partial responses. Seventeen patients had stable disease, and two patients had progressive disease.
Of 41 patients evaluable for efficacy after induction, 31 (73.8%) underwent surgical resection. The median time from completion of neoadjuvant therapy to resection was 25 days (range, 22-28).
Twenty-two patients (71%) underwent a complete resection, representing 52.4% of the total study population. Nine patients underwent an incomplete resection, including seven with stable disease and two with progressive disease.
Median EFS in the total study population was 15 months (95% CI, 6.2-24.6), and 56.1% of the population achieved 1-year EFS and 35% achieved 2-year EFS.
Among patients with incomplete resection, median EFS was 9.3 months (95% CI, 5.2-13.4) and the 1-year EFS rate was 33.3%.
Induction-related grade 3 or 4 adverse events included fatigue (n = 5), neutropenia (n = 4), hypertension (n = 1), anemia (n = 1), and thrombocytopenia (n = 1).
The researchers identified several study limitations, including the relatively small sample size and the single-institution design. They also noted the results may have been influenced by careful patient selection, which “is crucial, because some patients who were still unresectable after induction therapy in this trial were not able to receive the standard treatment of concurrent chemoradiotherapy,” the researchers wrote.
“The results of this trial suggest that the addition of bevacizumab to induction chemotherapy … results in a high objective response rate and a high resectability rate,” Wang and colleagues concluded. “[This] treatment modality … followed by surgery should be considered as a feasible and safe treatment option for patients with unresectable stage III lung adenocarcinoma.”
Although the study was well reported and raised important issues, it is essential to consider study limitations and the design, which deviates from the standard of care, Paul A. Bunn Jr., MD, distinguished professor in the division of medical oncology and the James Dudley Chair in lung cancer research at University of Colorado, and colleagues wrote in an accompanying editorial.
Nonstandard approaches used in the study include the use of four cycles of chemotherapy as opposed to two or three, the use of prophylactic growth factors, and the inclusion of patients with N3 and bulky N2 disease, Bunn and colleagues wrote.
Because the follow-up was short and median EFS was only 9 months among those with incomplete resection, “the data do not yet justify the conclusion that such an experimental approach could be used on a routine basis,” Bunn and colleagues wrote.
“These patients have disease that is potentially curable using concurrent chemoradiation, with a median survival in the range of 2 years in large cooperative group studies,” they added. “Similar operability results with higher rates of lymph node response can be obtained using preoperative chemoradiation therapy. The results may justify further study with a larger randomized trial focusing on a single question, such as the role of bevacizumab. However, considerable thought should be given to whether such a trial is warranted, and, if such a trial were instituted, then the eligibility criteria should be well-defined.” – by Anthony SanFilippo
Disclosure: The researchers report no relevant financial disclosures. Bunn reports a consultant/advisory role with Genentech/Roche.
Perspective
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Brendon M. Stiles, MD
In the study by Ou and colleagues, the researchers describe the results of a phase 2 trial of neoadjuvant therapy in patients with “unresectable” stage IIIA/IIIB lung adenocarcinoma.
The researchers hypothesized that adding bevacizumab (Avastin, Genentech/Roche) to standard chemotherapy (pemetrexed and carboplatin) would increase response rates, improve resectability and potentially prolong survival in this patient cohort.
Despite obvious limitations, I found the study to be quite compelling.
The enrollment criteria, preoperative workup and delivery of neoadjuvant therapy are not what many centers would consider standard. The definition of “unresectable” was not given, although presumably it related to TNM staging. Patients with bulky N2 disease, those with T4N2 disease and those with N3 disease were all included. A PET scan was not obtained in 83% of patients, and a brain MRI was omitted in 14%.
These patients undoubtedly had very advanced disease, some potentially having metastatic disease at presentation. Preoperative radiation therapy, often included in neoadjuvant protocols, was omitted given the lack of safety data with bevacizumab. Further, patients received four cycles of induction chemotherapy rather than the two or three cycles more commonly given.
In the context of those distinctions, the results are nevertheless quite compelling.
Neoadjuvant therapy with bevacizumab was well tolerated with infrequent grade 3 to grade 4 adverse events, limited to fatigue and neutropenia. The objective response rate was a robust 55%, and the percentage of patients who made it to surgery (74%), was similar to modern trials with chemoradiation. For instance in RTOG 0229, 66% of patients underwent surgical resection of their tumors.
The rate of R0 resection was also similar between the current trial and RTOG 0229 (71% vs. 76%), as were rates of N2/N3 downstaging (61.3% vs. 63% mediastinal nodal clearance in RTOG 0229).
Finally, the EFS/PFS rates were similar between the trials, with a reported EFS of 15.4 months in the Ou study vs. a PFS of 12.9 months in RTOG 0229. OS in the Ou study, although not reported, looks to be competitive when compared with the 2-year rates of 54% reported in RTOG 0229 and with the rates reported for various subgroups in RTOG 0617, a trial of definitive chemoradiation for stage III patients with non–small cell lung cancer.
This comes with a note of caution, however, as follow-up was limited to 14.3 months in the Ou study.
So where does this leave us? The most interesting argument to be made is for more trials evaluating novel therapeutics with neoadjuvant chemotherapy for patients with lung cancer and stage III disease.
This is a compelling cohort who, despite being high risk for disease progression, are potentially curable. Many biologic drugs, including targeted therapies and immune checkpoint inhibitors, have been primarily used in the setting of stage IV disease without radiation therapy. As such, toxicity with neoadjuvant chemoradiation trials is a concern.
However, Ou and colleagues have shown — albeit in a small trial — that a biologic can be used in place of radiation therapy and that such patients can safely undergo surgery for local control.
In some instances, such drugs could prove to be competitive financially to radiation therapy and may actually have less toxicity when combined with chemotherapy.
Ou and colleagues demonstrate equivalent rates of downstaging, resection and disease control compared with induction chemoradiation, even in their population that was likely understaged from the beginning.
By “saving” it, radiation therapy could then be used in a directed fashion in the adjuvant setting when appropriate for R1 resections or close margins. Such a strategy may allow for optimization of upfront systemic therapy, as well as for the inclusion of novel therapeutics, potentially increasing cure rates in this challenging cohort of patients.
References:
Bradley JD, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(14)71207-0.
Suntharalingam M, et al. Int J Radiat Oncol Biol Phys. 2012;doi:10.1016/j.ijrobp.2010.07.284.
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