Coverage from the Institute for Value-Based Medicine event with Vanderbilt University Medical Center.
Fighting cancer is a team sport at Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center (VUMC) in Nashville, Tennessee, which uses multidisciplinary teams to make decisions about patient treatment through debates, discussions, and analysis of the latest research. These teams are made up of various oncologists, pathologists, radiologists, and supportive care team members.
Over the course of 3 panel discussions during the Institute for Value-Based Medicine event hosted by The American Journal of Managed Care and Vanderbilt-Ingram Cancer Center at VUMC on August 17, 2023, a group of experts highlighted the way multidisciplinary teams manage head and neck cancer, non–small cell lung cancer (NSCLC), and hepatobiliary cancer.
Head and Neck Cancer
Jennifer Choe, MD, PhD, assistant professor of medicine of head and
neck medical oncology and clinical trials lead at the Division of Hematology and Oncology at VUMC, kicked off the discussion with novel approaches and radiation.
She presented a patient case of locoregionally advanced squamous cell carcinoma of the supraglottic larynx in a 46-year-old man. The patient was an active smoker with 30 pack-years and had dyspnea and difficulty swallowing. Based on a review of the patient and his tumor, Choe’s tumor board had 2 treatment options: laryngectomy plus a bilateral neck dissection or chemoradiation either with or without induction chemotherapy. Ultimately, because the patient was a teacher who needed to talk, they opted for the second treatment option, which would preserve his larynx.
“But I think we can probably do better than this,” Choe said. “Our goal is to improve upon chemoradiation so that we’re going beyond standard of care and improving outcomes for these patients.”
Despite curative-intent management, there is significant local disease recurrence for patients with head and neck cancers, she added. There are efforts to see how immunotherapy can enhance chemoradiation therapy and improve upon standard of care in these cancers.
She highlighted 2 randomized phase 3 trials of chemoradiation therapy with PD-1/PD-L1 inhibitors; however, both studies failed to meet their primary end points. In findings from JAVELIN Head and Neck 100 (NCT02952586),1 chemoradiation vs chemoradiation plus avelumab and 1-year maintenance avelumab failed to meet the progression-free survival end point. Meanwhile, KEYNOTE-412 (NCT03040999)2 evaluated chemoradiation vs chemoradiation plus pembrolizumab and 1-year maintenance pembrolizumab and failed to meet its event-free survival end point.
Although the results were disappointing, Choe noted that the fact that the immunotherapies were given concurrently with the chemoradiation might have had an impact on the outcomes. She said the results may have been due to a sequencing issue.
Choe argued that only part of the issue is being managed in head and neck cancers, because although treatments are inducing immunogenic cell death, radiation causes local immune suppression. As a result, there are lower responses with immunotherapy in head and neck cancers.
At VUMC, there will be a number of trials set to begin, including a trial (NCT04892875; PANTHEoN) comparing chemoradiation with adjuvant PD-1 inhibition and adenosine receptor inhibition that Choe is leading.
There will be 3 cohorts:
“It’s just a highlight on how we’re building out the clinical trial portfolio to try to best serve our patient population [with] head neck cancer,” she said.
Rohde discussed promising results when managing advanced squamous cell carcinoma, Rosenthal discussed how fluorescent imaging could help improve surgery in head and neck cancer, and Topf discussed his research using 3D scanning of surgical specimen.
In Tennessee, providers often see patients who have experienced a lot of sun exposure in their lifetime, which results in advanced skin cancer. These cancers will occur in the head and neck, making treatment more complex, Rohde explained. For years, treatment was the same: surgery with resection and free tissue reconstruction. But now there are more exciting options to offer, she added.
Recent research has shown neoadjuvant cemiplimab may be a possible treatment. Results from a study3 of 79 patients who received neoadjuvant cemiplimab followed by curative-intent surgery found 63% of patients had a complete or partial response. Although they are still undergoing surgery, the addition of cemiplimab means big changes because the surgery might not be as disfiguring anymore.
“Responses to cemiplimab are so promising and especially for our head and neck cancer patients,” Rohde said. “But we still don’t know the correlation to progression-free survival and overall [survival], and that’s what future studies will help us with.”
When surgery takes place, being precise with removing cancer can be challenging because during a procedure the surgeon cannot actually see the cancer, which makes it difficult to determine margins, Rosenthal explained. When presented with a patient, how much tissue should the surgeon remove? How aggressive should they be about taking the lymph nodes? If they don’t remove enough, the cancer comes back and the patient has a poor outcome.
“If you could see cancer better, you could potentially remove the cancer more precisely,” he said.
Vanderbilt is conducting trials looking at an optical dye labeled to the antibody therapy panitumumab, which binds to EGFR. This antibody binds specifically to the cancer and not the surrounding tissue. They’re using it in 2 ways:
The fluorescence can identify the hotspot, which is the closest margin and the area that the pathologist needs to cut.
“I think this is the future of what surgery will look like in multiple disease types,” Rosenthal said.
When tissue specimen is taken from a patient, there is a pathology report, which can be incredibly difficult to interpret even for individuals who see them regularly, Topf said. In addition, as part of the pathology analysis, the specimen is destroyed, which can lead to difficult conversations weeks later between the surgeon and the pathologist.
Topf has been working on creating a working 3D map of specimen, which provides a good visual representation that can be annotated and marked up and leads to more meaningful conversations. The technology is starting to move into other tumors, with 3D scanning of musculoskeletal and breast cancers.
He envisions a future where pathology reports are not just written text and instead are “screenshots of our 3D specimen maps clearly pointing out the different margins and the distances.”
In addition to more meaningful conversations, the technology has major cost implications. A lot of surgeons will take their specimens to the pathology laboratory, which is time away from the patient who is under general anesthesia. Reducing or eliminating that time can save a hospital a lot of money quickly.
There are limitations, though. There is a cost to the scanner equipment, which takes up approximately 5 feet of space in the laboratory, and the personnel will need to be trained, which can take approximately a week.
“We need to show a way to demonstrate that this [3D scanning] shows value,” Topf said. “I think we all agree this is an improvement upon the current standard of care.”
The current landscape still has a lot of questions regarding neoadjuvant and adjuvant management of NSCLC. In the second panel of the night, 3 speakers explained the latest in treatment at VUMC for this disease state.
In lung cancer, the outcomes are poor, with survival at 5 years being nowhere near where providers and patients want it to be, Erin A. Gillaspie, MD, MPH, said. Gillaspie is assistant professor of thoracic surgery and head of thoracic surgery robotics at VUMC and provided an overview of the latest in early-stage lung cancer. She reviewed 3 specific studies: IMpower010 (NCT02486718),4 ADAURA (NCT02511106),5 and CheckMate 816 (NCT02998528).6
In IMpower010, patients received chemotherapy before being randomly assigned to immunotherapy (atezolizumab) or best supportive care. Disease-free survival (DFS) was the major surrogate end point, and there was a statistically significant benefit for patients receiving the intervention. However, there was less of a benefit for overall survival (OS), which did not achieve statistical significance.4
The results present a challenge because it’s a newly approved therapy in patients with stage II and stage IIIA NSCLC with PD-L1–positive disease, but these patients did receive a survival benefit, Gillaspie said. Digging into the subanalysis, the patients who will benefit the most are those with larger tumors.
The ADAURA trial included patients with completely resected stage IB, II, and IIIA NSCLC and treated patients with either placebo or osimertinib. The final results of the trial recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting5 showed that osimertinib substantially improved OS over placebo.
There was such a difference between the 2 arms that the study was stopped and patients were allowed to cross over. The final results published in the New England Journal of Medicine showed that the 5-year OS was 88% for patients on osimertinib.5
“We never talk about [survival] numbers like that for patients with lung cancer,” Gillaspie said. “So [we’re] really, really excited.”
New treatments with better outcomes mean changing the way the multidisciplinary team works. With immunotherapies and molecular therapies available, team members have to start working with patients early to ensure they are getting the tests needed to give them the opportunities to receive these therapies, she explained.
On the surgery side, physicians are finding they can remove smaller portions for similar outcomes. The 15-year CALGB 140503 trial (NCT00499330) analyzed the survival outcomes for patients undergoing lobectomy, in which an entire lobe of the lung is removed, vs segment or wedge resection, which removes a smaller, wedge-shaped section of the lung around a tumor.
Historically, lobectomies have been performed for lung cancer regardless of the size of the tumor, despite finding smaller and smaller nodules. Results from the trial found that wedge resection was noninferior for both DFS and OS compared with lobectomy. In addition to outcomes being equivalent, so were the recurrence rates. Both arms had an approximately 30% recurrence rate, which they didn’t expect to see.
“I think that really underscores the biology of lung cancer. We need to know more,” Gillaspie said. “We need to keep thinking about moving these other drug therapies into earlier and earlier settings.”
Wade Iams, MD, MSCI, assistant professor of medicine and director of thoracic clinical trials at VUMC, discussed trials being conducted to address 3 major questions:
For perioperative immunotherapy, there is an FDA-approved neoadjuvant chemoimmunotherapy based on findings from the CheckMate 816 trial.6 In addition, there is the FDA approval of adjuvant atezolizumab, a PD-L1 inhibitor, and pembrolizumab, a PD-1 inhibitor, but neither of these use neoadjuvant immunotherapy. However, this has left uncertainty about whether it’s better to treat in the neoadjuvant or adjuvant setting.
Findings from trials recently presented at the ASCO Annual Meeting and the American Association for Cancer Research Annual Meeting showed success with using immunotherapies in both the neoadjuvant and adjuvant settings. KEYNOTE 671 (NCT03425643) evaluated pembrolizumab,7 and AEGEAN (NCT03800134) evaluated durvalumab.8
“I don’t think [it’s] too presumptive to say I think both those regimens are going to get approved, and I think they’re going to be the standard of care because the current landscape is very unclear what patients should do in the neoadjuvant, adjuvant setting,” Iams said.
Beyond PD-1 and PD-L1 inhibitors, there is a trial recruiting patients (NCT05061550; NeoCOAST-2) that will evaluate neoadjuvant chemotherapy and PD-L1 plus a CD73 inhibitor (oleclumab) or NKG2A inhibitor (monalizumab) or a PD-1/CTLA4 bispecific antibody (volrustimog). Iams called the treatment being evaluated in the NeoCOAST-2 trial “the next evolution in thoracic oncology.”
For consolidative radiation, there is the SiCARIO trial (NCT05501665), which allows up to 10 sites of disease, and all these sites are managed with radiation during induction cycles of immunotherapy either with or without chemotherapy. Medical oncologists like the design of the trial because it’s good standard of care, and patients like it because all disease sites are being managed, he noted.
For the interventional novel immunotherapy trial, he highlighted the study (NCT04495153) of CAN-2409 (aglatimagene besadenovec) plus prodrug (oral valacyclovir), a novel investigational viral immunotherapy. There are 15 patients enrolled, and they will receive 2 injections approximately 5 weeks apart and continue on immunotherapy.
According to Iams, the disease control rate has been approximately 90%, with a response rate of approximately 15% to 20%. Overall, he called the results an “intriguing signal.”
Ryan Whitaker, MD, PhD, assistant professor of radiation oncology at VUMC, followed to discuss radiation therapy in oligometastatic disease. There is a thought that patients with limited metastatic disease can be treated with radiation or surgery. There have been findings from trials to show that stereotactic body radiation therapy (SBRT) can be used when there remains a disease site resistant to management that is otherwise effective. The use of SBRT allows the patient to continue on the systemic therapy.
The driver behind successful use of SBRT is the adaptive radiotherapy platform and its software, which scans the patient and allows them to generate a new radiation plan depending on changes seen in the anatomy and improve target coverage.
One of the trials he discussed that is recruiting patients would add a novel radiation approach to standard-of-care chemotherapy plus atezolizumab to manage extensive-stage small cell lung cancer. The trial will give a low-dose, immune-modulatory priming total-body irradiation followed by a hypofractionated dose of radiation for up to 10 sites of disease. The hope is to enhance systemic antitumor immunity, he explained.
Finally, he covered new strategies to manage brain metastases with stereotactic radiosurgery, which spares patients cognitive adverse effects. Historically, radiation of the whole brain was the standard of care for patients who had just 1 brain metastasis. In comparison, stereotactic radiosurgery is a precise form of radiation that can locate small targets. Whitaker noted that he’s managed as many as 33 lesions in a single patient who was in surgery for approximately an hour.
Having the entire multidisciplinary team all under 1 roof is a luxury at VUMC, Kamran Idrees, MD, MSCI, MMHC, FACS, explained. Idrees is
chief of the Division of Surgical Oncology & Endocrine Surgery and director of pancreatic and gastrointestinal surgical oncology at VUMC. Time to treatment from diagnosis is key, and patients lose time when they have to go to different locations for diagnosis, chemotherapy, surgery, and radiation.
Although Gillaspie had earlier discussed the research about doing a lobectomy vs a wedge resection for a small tumor, that isn’t a concern in hepatobiliary cancer.
“We just take the liver out,” Martin Montenovo, MD, FACS, joked to laughter from the audience. Montenovo is chief of the Division of Hepatobiliary Surgery & Liver Transplantation and surgical director of the Adult Liver Transplant Program at VUMC. In the 1990s, the thought was that removing the liver would cure the cancer, but it doesn’t work that way based on tumor biology.
He provided an overview of the transplant criteria for patients with hilar cholangiocarcinoma because liver transplant is not for everyone. The protocol for transplants is very selective for patients based on who can achieve the best long-term outcomes. There are very specific diagnosis and tumor characteristic criteria for the patient to be eligible for transplant. For instance, the tumor must be above the cystic duct and be less than 3 cm in diameter locally.
There also cannot be any evidence of extrahepatic disease. In addition, any patient who received radiation therapy for the cancer or underwent prior attempts of resection is not eligible. “That’s the reason why it’s so important to educate…that when you find one of these patients, you really need to transfer this patient to an oncology center that [has] transplant capabilities,” Montenovo said. “Otherwise, you are burning a bridge…[and] liver transplant is not an option anymore.”
Patients eligible for transplant must then receive adjuvant chemotherapy radiation with capecitabine for 2 to 3 weeks followed by maintenance gemcitabine plus capecitabine. They undergo imaging and laboratory tests every 3 months and a CT scan at least 4 weeks prior to the transplant.
Results from a study9 across 10 centers in 2018 found that the 3- and 5-year survival for patients who underwent transplant was superior compared with those who underwent resection. The basic conclusion is that patients who meet the criteria for transplantation but instead receive resection have a decreased survival compared with those who undergo transplantation.
“In a very selective group of patients, transplantation seems to be the way to go,” Montenovo said.
As a result of the strict transplantation criteria, the role of interventional endoscopy is limited in these patients, Patrick Yachimski, MD, director of pancreatobiliary endoscopy and associate professor of medicine of VUMC, said. An endoscopic ultrasound would only be used in patients potentially eligible for transplant to sample nodes to document the metastatic disease.
In addition, he noted that data have shown that preoperative endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically resectable clinical carcinoma is independently associated with mortality. For these patients, the next step should be a consultation with a surgeon and not ERCP.
ERCP should be used for diagnostic tissue sampling to lower bilirubin levels for the patient to receive systemic chemotherapy (if the bilirubin levels would have prevented that treatment) and for the management of symptoms such as pruritus and cholangitis.
“If I give a patient pancreatitis from ERCP that they didn’t need, then they’re not getting surgery [and] they’re not getting chemotherapy anytime soon,” Yachimski said.
Although liver transplant is also the best option for patients with a new diagnosis of hepatocellular carcinoma (HCC), surgical resection may be an option for patients who are ineligible and have a noncirrhotic liver or limited cirrhosis with preserved liver function, Idrees said. In addition, they should have a single lesion, preserved liver function, sufficient liver volume, and no comorbidities that would prevent anesthesia and surgery.
The liver, he noted, is a fascinating organ. For a normal, healthy liver, 80% could be removed and the remaining 20% would increase in size to compensate. For patients with fatty liver disease or cirrhosis, the remaining liver should be greater than 30% without evidence of cirrhosis.
Finally, when patients are deemed unresectable, they have to be treated with a therapy they can tolerate. Natalie Lockney, MD, assistant professor of medicine in the Department of Radiation Oncology and residency program director at VUMC, discussed the radiation options available.
The liver, she explained, is a very radiosensitive organ and requires more advanced technology that has recently been gained. It was only a few years ago that the American Society for Radiation Oncology published consensus criteria for external beam radiotherapy (EBRT) indications for HCC.
Patients who are not candidates for surgery, transplant, or thermal ablation may be treated with radiation if their disease is confined to the liver. In addition, it may be used as a neoadjuvant treatment for patients with portal vein thrombosis whose disease is potentially resectable.
Findings from studies have shown that EBRT can reestablish portal vein flow in 15% to 30% of patients.10 Findings from the NRG/RTOG-1112 trial (NCT01730937), just released this year at the ASCO Annual Meeting, also established SBRT as the standard treatment option for patients with locally advanced HCC with macrovascular invasion.11
Finally, Anthony Borgmann, MD, assistant professor of clinical, clinical radiology, and radiological sciences at VUMC, reviewed interventional radiology treatment options for HCC.
Based on liver function and performance status, there are 3 main therapies to choose from: transarterial chemoembolization (TACE), transarterial radioembolization (TARE) with yttrium-90 (Y90), or percutaneous ablation.
In findings from 2 trials12,13 comparing Y90 with TACE, patients had a longer time to progression on Y90. Guidelines from the National Comprehensive Cancer Network have incorporated some of these data, but it is not clear when patients should receive locoregional or systemic therapy. According to Borgmann, the level and amount of portal vein tumor thrombosis will influence this decision, and systemic therapy is usually preferred. However, that may not always be true. In findings from 3 trials14-16 analyzing TARE vs sorafenib, all failed to show a survival benefit of Y90 over the systemic therapy. However, although they found TARE was noninferior to sorafenib, Y90 may offer a better safety profile.
“So fewer complications and better quality of life,” Borgmann said. “So it is something that we can consider in these patients who have limited portal vein tumor thrombosis.”
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2. Merck provides update on phase 3 KEYNOTE-412 trial in unresected locally advanced head and neck squamous cell carcinoma. News release. Merck. July 20, 2022. Accessed September 19, 2023. https://bit.ly/3B1f2yN
3. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568. doi:10.1056/NEJMoa2209813
4. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023;34(10):P907-919. doi:10.1016/j.annonc.2023.07.001
5. McNulty R. Osimertinib shows significant OS benefit in patients with resected, EGFRm NSCLC. The American Journal of Managed Care. June 4, 2023. Accessed September 27, 2023. https://www.ajmc.com/view/osimertinib-shows-significant-os-benefit-in-patients-with-resected-egfrm-nsclc
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8. Heymach JV, Harpole D, Mitsudomi T, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Abstract presented at: American Association for Cancer Research Annual Meeting 2023; April 14-19, 2023; Orlando, FL. Abstract CT005.
9. Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018;267(5):797-805. doi:10.1097/SLA.0000000000002574
10. Yang JF, Lo CH, Lee MS, et al. Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis. Radiat Oncol. 2019;14(1):180. doi:10.1186/s13014-019-1382-1
11. Dawson LA, Winter KA, Knox JJ, et al. NRG/RTOG 1112: randomized phase III study of sorafenib vs stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). J Clin Oncol. 2023;41(suppl 4):489. doi:10.1200/JCO.2023.41.3_suppl.489
12. Salem R, Gordon AC, Mouli S, et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2016;151(6):1155-1163.e2. doi:10.1053/j.gastro.2016.08.029
13. Dhondt E, Lambert B, Hermie L, et al. 90Y radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phase II randomized controlled trial. Radiology. 2022;303(3):699-710. doi:10.1148/radiol.211806
14. Ricke J, Bulla K, Kolligs F, et al; SORAMIC study group. Safety and toxicity of radioembolization plus sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35(2):620-626. doi:10.1111/liv.12622
15. Vilgrain V, Pereira H, Assenat E, et al; SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi:10.1016/S1470-2045(17)30683-6
16. Chow PKH, Gandhi M, Tan SB, et al; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi:10.1200/JCO.2017.76.0892