TNT Approach to Pancreatic Cancer Tied to Improved Survival

Pam Harrison

April 15, 2019

Chemotherapy followed by chemoradiation (CRT), an approach referred to as total neoadjuvant therapy (TNT), is associated with a dramatic extension of postoperative survival in patients with either borderline or locally advanced pancreatic cancer provided they achieve optimal biochemical and pathologic responses to TNT, new retrospective research shows.

"Traditionally patients with borderline or locally advanced pancreatic cancer have not been offered these types of surgeries because, by definition, their tumors have grown outside of the pancreas and involve a lot of critical blood vessels," Mark Truty, MD, Mayo Clinic College of Medicine, Rochester, Minnesota, explained to Medscape Medical News.

"But we found the more chemotherapy we gave the longer patients lived, although this was predicated on [the fact that] chemotherapy was effective," he added.

"So it's how patients are treated prior to surgery that is different here and we found that PET scans highly correlated with pathologic response, which was the most predictive factor in patient outcome," Truty noted.

The study was published online April 5 in the Annals of Surgery.

Study Details

A total of 194 patients with borderline or locally advanced pancreatic ductal adenocarcinoma (PDAC) were included in the study.

Some 65% of patients had borderline PDAC and 37% had locally advanced cancers, and at least 70% of patients had tumors involving either venous or arterial structures at diagnosis.

At baseline, 6% of patients did not secrete the tumor marker CA19-9, 13% had normal CA19-9 levels, and the remaining 81% had elevated CA19-9 levels.

Most patients received FOLFIRINOX (5-fluorouracil, oxaliplatin [Eloxatin, Pfizer]), irinotecan [Camptosar, Pfizer]) and about one third received gemcitabine (Gemzar, various) plus nab-paclitaxel (GA) (Abraxane, Celgene), as investigators point out.

However, 19% of patients needed to have their chemotherapy switched from one protocol to the other — most often from FOLFIRINOX to GA — because of biochemical or local radiologic progression, no objective response, or toxicity.

Truty noted most oncologists think that if a patient doesn't respond to the first chemotherapy regimen they aren't going to respond to anything else. However, in this series, a lot of patients did not respond to the first regimen but did respond to the second regimen. So patients can be "salvaged" and made ready for the rest of the protocol, he said.

The median number of cycles was 6 but over one third of patients received 8 cycles or more of chemotherapy.

"Following chemotherapy, patients received long-course chemoradiotherapy (CRT) consisting of photon/proton external beam with 50 to 50.4 Gy delivered in 25 to 28 fractions over 5 weeks with 3D-conformal or intensity-modulated techniques," Truty and colleagues elaborate.

Response to preoperative therapy was generally excellent, they add. For example, 92% of patients with normal baseline CA19-9 levels remained within the normal range.

Another 64% of patients with elevated baseline CA19-9 levels also normalized after treatment and 36% of patients with elevated baseline CA19-9 levels remained elevated.

Patients then underwent resection a minimum of 4 weeks after CRT. Resections included pancreatoduodenectomy, subtotal pancreatectomy, and total pancreatectomy with associated lymphadenectomies.

"A negative (RO) margin resection was achieved in...94% [of] patients with a median margin distance of 5 mm," investigators report. CT scans were not found to be effective in predicting major pathologic responses to TNT in the current series.

In contrast, PET scans done after chemotherapy and which showed complete metabolic response (CMR) correlated highly with major pathologic responses with a positive predictive value of 80% and a negative predictive value of 100%.

In the end, 39% of patients achieved a major pathologic response to treatment that was independent of the chemotherapy received or need to switch regimens, as investigators point out.

Oncologic Outcomes

At a median follow-up of 22.4 months after surgery, 38% of patients experienced a recurrence.

On the other hand, 74% of patients were still alive when last contacted and over half, at 52%, had no evidence of recurrence.

Median 1-, 2-, and 3-year recurrence free survival (RFS) rates as well as overall survival (OS) rates were also very impressive, said Truty.  

Oncologic Outcomes: Median RFS and OS rates at 1, 2, and 3 years

Year RFS, mo OS, mo Alive, free of recurrence, % OS, %
1 year 23.5 58.8 65 96
2 years 48 78
3 years 32 62

On sequent analysis, Truty and colleagues identified only three factors that were associated with better patient outcomes.

These factors included optimal post-chemotherapy CA19-9 responses, extended duration of chemotherapy, and major pathologic response.

For example, patients who achieved an optimal CA19-9 response had a 59% longer RFS interlude (P < .001) and a 51% higher OS (P = .01) than those who did not achieve an optimal CA19-9 response, researchers point out.

Those who received 6 cycles or more of chemotherapy had a 51% longer RFS interval (P = .004) and a 55% higher OS rate (P < .001) than those who received fewer than 6 cycles of chemotherapy.

Most significantly, patients who achieved a major pathologic response to upfront therapy had a 74% longer RFS interval (P < .001) and an 84% higher OS rate (P < .001) than those who did not achieve a major pathologic response.

Specific Purpose

"Each component of TNT has a specific purpose," Truty explained.

The purpose of neoadjuvant chemotherapy is to treat any metastatic disease that is likely present at the time of diagnosis.

The radiation component is done to improve the ability of the surgeon to get a negative margin, he added.

"We're not the only place that is doing TNT. Other places are also doing it, but the main problem is they'll give a few months of chemotherapy and wait for the tumor to regress off the blood vessels," Truty observed.

That, however, isn't likely to happen, he said. In their own series, for example, tumors shrank to the point where they no longer involved the blood vessels in only 28% of patients.

"The most critical part [of our protocol] is how these patients are treated prior to surgery," Truty emphasized.

If they are to be offered chemotherapy, "you have to prove that the chemotherapy is effective, and here we've been finding that a PET scan is very useful for this," he added.

If patients do not respond optimally to the up-front protocol, then physicians have a "difficult conversation" ahead of them as there is no point in subjecting a patient to major surgery that is unlikely to make any difference to their outcome.

Widely Accepted, But Great Skill and Support Needed

Asked by Medscape Medical News to comment on the study, Igor Astsaturov, MD, PhD, associate professor of hematology/oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that investigators, following a strategy that is now widely accepted, demonstrated encouraging improvement in survival and identified important prognostic biomarkers of success.

"Remarkably, 94% of patients had resection with negative margins, which would [otherwise] be a very unlikely outcome based on the patient's initial advanced disease status," Astsaturov noted in an email.

Astsaturov cautioned that the type of surgery used in the Mayo Clinic series requires "virtuoso technical skills" along with a range of expert supportive services likely only available in specialized academic and high volume cancer centers.

Nevertheless, he felt that because metastatic recurrence is the main determinant of outcome in pancreatic cancer patients who undergo surgery, the intense chemotherapy used by the Mayo Clinic team likely helped clear the body of occult metastatic deposits.

Patients who achieved a major pathological response to treatment may also have been highly sensitive to the chemotherapy used.

"By projection, such chemosensitivity could potentially explain the improved survival," Astsaturov noted.

"But overall, this study validates the TNT approach in patients with borderline and locally advanced resectable pancreatic cancer," he concluded.

The authors and Astsaturov have reported no relevant financial relationships.

Ann Surg. Published online April 5, 2019. Abstract

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