Chemotherapy is still the standard of care in borderline-resectable adenocarcinoma of the pancreas, but radiation therapy (RT) should be made available for select patients where recurrence or progression leads to poor survival, according to two experts who debated the role of RT in these patients at the 2023 Great Debates & Updates in Gastrointestinal Malignancies.
Pancreatic cancer patients fall along a disease spectrum and present as having a systemic disease with 90 percent of patients being metastatic. The only curative treatment is surgery for localized disease and 10 percent of patients survive 5 years with surgery alone. This doubles with adjuvant chemotherapy.
At the debate, Lisa Kachnic, MD, Chief of the Radiation Oncology Service at NewYork-Presbyterian/Columbia University Irving Medical Center, took the position that there is little role for RT in this patient set.
"The goal of therapy is to get the patient to the point where the disease is resectable. The rationale for neoadjuvant therapy is up for debate," Kachnic said. "The highest response rates available are for chemotherapy, which is about 30 percent with FOLFIRINOX or gemcitabine/nab-paclitaxel. There are no prospective, randomized data that radiation changes this outcome."
After chemotherapy, patients with metastatic disease receive stereotactic body radiation therapy (SBRT), but not many go on to surgical resection. "Conventional chemo-radiation (CRT) does not move the needle. No trials show a significant survival advantage," she said.
Some prospective trials (ESPAC-5F and CONKO-007) show CRT improves the RO resection rate, but this does not translate to higher survival compared to chemotherapy. A meta-analysis of 512 patients with borderline-resectable pancreatic adenocarcinoma from 15 studies showed RT following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but there was no overall survival (OS) benefit with neoadjuvant radiation after modern chemotherapy.
The SMART trial presented at the ASCO 2023 Annual Meeting found a 1-year OS of 65 percent, which "looks improved with low-dose stereotactic body radiation therapy on MRI, but 20 percent of patients had Grade 3 or higher adverse events post-surgery," Kachnic said.
Borderline-resectable disease represents a complex entity requiring a multidisciplinary, individualized approach to management.
"While radiation may help with local control, whether it improves RO resection rates appears to be controversial. Ultimately, it is OS that matters as pancreas cancer is a systemic disease and current evidence does not support a survival benefit with neoadjuvant radiation," Kachnic stated. "Perhaps radiation may still play a role in select patients that have a locally progressive disease phenotype and in these, high-dose adaptive SBRT may improve outcomes. Further clinical trials are warranted."
Maximize Opportunity of RT
In this era of personalized medicine, clinicians need to know which patients can benefit and how to maximize the opportunity of RT, said Joseph Herman, MD, Director of Clinical Research at the Northwell Health Cancer Institute, who took the position in favor of RT.
"We need to set up standards of success for the right patients. We can potentially ablate or eradicate pancreatic cancer, similar to rectal cancer. How do we advance the field to benefit radiation and limit toxicity?" he asked.
To maximize the therapeutic potential benefits of RT, clinicians need to select a regimen based on anatomy, biomarkers, performance status, and patient/family preference; prevent recurrence after surgery or local progression; sensitize the effects of RT with PARP inhibitors or other drugs; and enhance the tumor microenvironment for immunotherapy. Heavy ions, such as protons or carbon, give better radiobiological equivalent dose to tumors with a sharp fall-off of RT dose.
"We need to use imaging, such as CT on rails, PET, or MRI, to better visualize tumors and normal tissues, and also to avoid radiation doses to adjacent normal tissues," Herman said.
Borderline-resectable pancreatic cancer potentially has a higher burden of micro-metastatic disease that may provide a rationale for neoadjuvant systemic therapy, as compared to upfront resection. "The goal of RT in this setting is margin sterilization and local recurrence risk reduction," he noted.
Strides have been made in technology, for example, using 5 days of SBRT versus 5 weeks of standard RT, which has shown outcomes in better-selected patients. SBRT has evolved with image-guided therapy going from high-volume centers to the community, and there are more studies of ablation and combinations with radiosensitizers, he said.
Herman highlighted the results of the Alliance A021501, a prospective, multicenter, randomized Phase II clinical trial that compared treatment with neoadjuvant modified FOLFIRINOX with or without hypofractionated RT with historical data and established standards for therapy in 126 borderline-resectable pancreatic cancer patients. The RT group showed enhanced response rates, even though distant metastases were about twice as common in the RT arm versus the chemotherapy-alone arm.
"Those with higher baseline cancer antigen (CA) 19-9 had worse event-free survival in the RT arm at 6 months. If they had surgery, there was no difference in OS at 18 months between the two groups," Herman said.
He believes certain patients should be offered RT: those with a high risk of margin-positive resection based on anatomy and on multidisciplinary clinic review; Ca 19-9 less than 180; limited response on systemic therapy; and anatomy that allows a dose to support durable control.
"Ideally, patients should be offered a clinical trial. As a field, we need to understand where RT is integrated and put it in context for the right patient," Herman concluded.
Mark L. Fuerst is a contributing writer.