In the JournalsPerspective

GTX effective neoadjuvant treatment in locally advanced pancreatic cancer

Patients with locally advanced, unresectable pancreatic adenocarcinoma experienced favorable survival when they received neoadjuvant gemcitabine, docetaxel and capecitabine, according to study results.

Researchers observed the benefit among patients who subsequently underwent treatment with gemcitabine and capecitabine plus radiotherapy, as well as patients who did not undergo that subsequent treatment.

“In our hands, gemcitabine, docetaxel and capecitabine is the most active regimen in pancreatic cancer causing documented regression in the metastatic setting in more than 50% of the patients,” William H. Sherman, MD, of the department of medicine at Columbia University, told HemOnc Today. “As there was no known effective neoadjuvant regimen for the 30% of patients with locally advanced disease, especially those with arterial involvement, we elected to study this treatment.”

Sherman and colleagues evaluated data from 45 patients with locally advanced pancreatic adenocarcinoma (mean age, 64 years; range, 44-83 years). All patients had unresectable disease. Thirty-four were deemed unresectable due to arterial involvement and 11 were deemed unresectable due to extensive venous involvement.

All patients received six cycles of treatment with gemcitabine, docetaxel and capecitabine (GTX). Patients with arterial involvement then were treated with gemcitabine and capecitabine (GX) plus radiation therapy.

Researchers attempted surgical resection of the residual tumor in patients with venous involvement 3 weeks after chemotherapy, and patients with arterial involvement underwent resection 4 to 5 weeks after radiation therapy. 

Twenty-nine patients with arterial involvement underwent resection, 20 (69%) of whom achieved R0 resections. Twenty-four patients (71%) in this cohort survived for at least 1 year, and the median OS among these patients was 29 months (95% CI, 21-38).

Thirteen patients (38%) in the arterial arm had not relapsed at the time of the analysis (follow-up range, 5 to 49+ months).

All patients with venous involvement underwent resection. Eight of these patients achieved R0 resection and 3 achieved complete pathological responses.

At 42+ months, median survival had not yet been reached in the venous-involvement arm. Six patients (55%) in this cohort had not experienced recurrence (range, 6.2-42+ months).

Patients with venous-only involvement demonstrated significantly prolonged survival compared with patients with arterial involvement (P˂.03).

“GTX with or without radiation therapy effectively decreased the size of the cancer in at least 85% of the patients so that surgical resection became possible,” Sherman said. “For those with arterial involvement, 60% of the patients achieved complete resections with greater than 2 mm margins and about 40% of these patients have not relapsed in over 3 years.”

Adverse events associated with GTX and GX plus radiation therapy were as expected, researchers said. No patients experienced bowel perforations, pancreatitis or delayed strictures.

These data pave the way for future research, Sherman said.

“There are many more questions to be answered,” Sherman said. “Amongst them are:  What molecular markers predict response/relapse?  Would more cycles of chemotherapy benefit those who seem to be slow responders or have larger tumors?  Would some chemotherapy post-surgery add to the benefit? Are there other agents that can be added to GTX to further improve the response rate?” – by Alexandra Todak

Disclosure: The researchers report no relevant financial disclosures.

William H. Sherman, MD, can be reached at Department of Medicine, Columbia University, 88 Central Park West, New York, NY 10023; email: whs@williamhshermanmd.com.

Patients with locally advanced, unresectable pancreatic adenocarcinoma experienced favorable survival when they received neoadjuvant gemcitabine, docetaxel and capecitabine, according to study results.

Researchers observed the benefit among patients who subsequently underwent treatment with gemcitabine and capecitabine plus radiotherapy, as well as patients who did not undergo that subsequent treatment.

“In our hands, gemcitabine, docetaxel and capecitabine is the most active regimen in pancreatic cancer causing documented regression in the metastatic setting in more than 50% of the patients,” William H. Sherman, MD, of the department of medicine at Columbia University, told HemOnc Today. “As there was no known effective neoadjuvant regimen for the 30% of patients with locally advanced disease, especially those with arterial involvement, we elected to study this treatment.”

Sherman and colleagues evaluated data from 45 patients with locally advanced pancreatic adenocarcinoma (mean age, 64 years; range, 44-83 years). All patients had unresectable disease. Thirty-four were deemed unresectable due to arterial involvement and 11 were deemed unresectable due to extensive venous involvement.

All patients received six cycles of treatment with gemcitabine, docetaxel and capecitabine (GTX). Patients with arterial involvement then were treated with gemcitabine and capecitabine (GX) plus radiation therapy.

Researchers attempted surgical resection of the residual tumor in patients with venous involvement 3 weeks after chemotherapy, and patients with arterial involvement underwent resection 4 to 5 weeks after radiation therapy. 

Twenty-nine patients with arterial involvement underwent resection, 20 (69%) of whom achieved R0 resections. Twenty-four patients (71%) in this cohort survived for at least 1 year, and the median OS among these patients was 29 months (95% CI, 21-38).

Thirteen patients (38%) in the arterial arm had not relapsed at the time of the analysis (follow-up range, 5 to 49+ months).

All patients with venous involvement underwent resection. Eight of these patients achieved R0 resection and 3 achieved complete pathological responses.

At 42+ months, median survival had not yet been reached in the venous-involvement arm. Six patients (55%) in this cohort had not experienced recurrence (range, 6.2-42+ months).

Patients with venous-only involvement demonstrated significantly prolonged survival compared with patients with arterial involvement (P˂.03).

“GTX with or without radiation therapy effectively decreased the size of the cancer in at least 85% of the patients so that surgical resection became possible,” Sherman said. “For those with arterial involvement, 60% of the patients achieved complete resections with greater than 2 mm margins and about 40% of these patients have not relapsed in over 3 years.”

Adverse events associated with GTX and GX plus radiation therapy were as expected, researchers said. No patients experienced bowel perforations, pancreatitis or delayed strictures.

These data pave the way for future research, Sherman said.

“There are many more questions to be answered,” Sherman said. “Amongst them are:  What molecular markers predict response/relapse?  Would more cycles of chemotherapy benefit those who seem to be slow responders or have larger tumors?  Would some chemotherapy post-surgery add to the benefit? Are there other agents that can be added to GTX to further improve the response rate?” – by Alexandra Todak

Disclosure: The researchers report no relevant financial disclosures.

William H. Sherman, MD, can be reached at Department of Medicine, Columbia University, 88 Central Park West, New York, NY 10023; email: whs@williamhshermanmd.com.

    Perspective
    Andrew H. Ko

    Andrew H. Ko

    This single-institution experience highlights both the promise — and, at the same, time many of the uncertainties — associated with the treatment of patients with locally advanced pancreatic cancer. One might argue that even the title of the article is somewhat misleading: this patient cohort would more aptly be described as having borderline resectable tumors, which is increasingly recognized as a separate and unique entity distinct from truly locally advanced, unresectable disease (the latter representing patients who have no realistic possibility of undergoing an R0 resection, even with aggressive preoperative multimodality therapy). Designing studies for patients with borderline resectable pancreatic cancer is tricky, starting with coming up with precise and standardized definitions of who is eligible, and deciding which endpoints should be measured (ranging from R0 resection rate to pathologic responses to OS). The Alliance for Clinical Trials in Oncology cooperative group recently completed a pilot study specifically for this disease indication (Intergroup trial A021101), and further efforts are underway to answer many of the questions that still abound in this borderline resectable context: What is the most effective chemotherapy regimen to use, and for how long? The GTX regimen was used in the Sherman study, but although it has gained fairly widespread adoption, it is important to note that this combination has never been formally evaluated in a phase 3 study in the advanced/metastatic setting. How do contemporary regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel compare? Moreover, how important is radiation as a modality in this context — and should it be administered as standard fractionation, or using newer techniques such as stereotactic body radiation? Larger, multicenter and randomized studies are needed to address these and other issues relative to this stage of disease, especially as it reflects a group of patients who — in the very best scenario — may have the potential for long-term DFS or even be considered curable.

    • Andrew H. Ko
    • HemOnc Today Editorial Board member UCSF Comprehensive Cancer Center

    Disclosures: Ko reports no relevant financial disclosures.