Meeting NewsPerspective

Surgical exploration ‘highly recommended’ after induction chemotherapy for locally advanced pancreatic cancer

BARCELONA, Spain — Four months of induction combination chemotherapy followed by surgical exploration made secondary resection feasible for about one-third of patients with nonresectable locally advanced pancreatic cancer, according to results of the randomized phase 2 NEOLAP trial presented at European Society for Medical Oncology Congress.

Conversion surgery appeared associated with a near-doubling of OS.

Approximately 30% of patients with pancreatic cancer present with nonresectable locally advanced tumors.

“Without evidence from prospective randomized studies, multiagent induction chemotherapy is recommended for [these patients], but the optimal regimen and duration is currently unknown,” Volker Kunzmann, MD, managing senior physician at University Hospital Würzburg in Germany, said during his presentation.

Prior prospective multicenter trials reported conversion to resectable tumors at rates ranging from 5% to 15%, typically based on radiographic resectability criteria.

Kunzmann and colleagues conducted the open-label, multicenter NEOLAP trial to compare the efficacy and safety of two induction chemotherapy regimens — nab-paclitaxel (Abraxane, Celgene) and gemcitabine, or FOLFIRINOX — for treatment-naive patients with histologically or cytologically proven nonresectable locally advanced pancreatic cancer.

Nab-paclitaxel and gemcitabine has demonstrated activity in locally advanced pancreatic cancer, and nab-paclitaxel has been shown in preclinical and clinical studies to increase intratumoral concentrations of other cytotoxic drugs by depleting the abundant desmoplastic stroma in pancreatic cancer, Kunzmann said.

“We thought it was reasonable to assess the activity of FOLFIRINOX after nab-paclitaxel pretreatment,” he added.

Researchers recruited 168 patients (age range, 18 to 75 years) with ECOG performance status of 0 or 1. No patients had evidence of distant metastases.

All patients underwent two cycles of nab-paclitaxel and gemcitabine.

Investigators randomly assigned 130 patients who did not have progressive disease or experience unacceptable adverse events to two additional cycles of nab-paclitaxel and gemcitabine (n = 64), or four cycles of sequential unmodified FOLFIRINOX (n = 66). Baseline characteristics were well-balanced between groups with the exception of sex (nab-paclitaxel/gemcitabine, 59% male; FOLFIRINOX, 42% male)

All patients with stable disease after completion of induction chemotherapy underwent exploratory laparotomy to assess secondary resectability.

Conversion rate — or the rate of R0/R1 resection — served as the primary endpoint. This was the first trial to use this endpoint for locally advanced pancreatic cancer, Kunzmann said.

Forty patients (62.5%) in the nab-paclitaxel/gemcitabine group and 42 patients (63.6%) in the FOLFIRINOX group underwent surgical exploration.

The primary endpoint of demonstrating superior conversion rate by sequential FOLFIRINOX compared with nab-paclitaxel/gemcitabine was not met, although there was a trend in favor of the FOLFIRINOX arm.

Researchers reported conversion rates of 30.6% in the nab-paclitaxel/gemcitabine group and 45% in the FOLFIRINOX group (OR = 0.54; 95% CI, 0.26-1.13), with an overall conversion rate in the intention-to-treat population of 27.9%.

OS data were immature at the time of data cutoff. However, after median follow-up of 13.8 months, median OS was 17.2 months among patients assigned nab-paclitaxel/gemcitabine and 22.5 months among those assigned FOLFIRINOX (adjusted HR = 0.73; 95% CI, 0.42-1.28).

In the intention-to-treat population (n = 165), conversion appeared associated with significantly longer median OS (27.4 months vs. 14.2 months; HR = 0.45; 95% CI, 0.26-0.78).

“The survival benefit was essentially mirrored when focusing on the surgical exploration cohort,” Kunzmann said.

Researchers reported no significant differences between group with regard to secondary endpoints, including ORR, disease control rate, PFS, CA 19-9 response, rate of exploratory laparotomy performed, pathological complete response rate and postoperative mortality.

Both induction regimens appeared well-tolerated, with safety profiles consistent with prior studies, Kunzmann said.

Researchers reported comparable rates of grade 3 or higher treatment-emergent adverse events (54.7% vs. 53%) and serious treatment-emergent adverse events (29.7% vs. 34.8%) between the nab-paclitaxel and FOLFIRINOX groups (54.7% vs. 53%).

Investigators did observe a numerical trend to more nonhematologic adverse events in the sequential FOLFIRINOX arm. These included nausea and vomiting, malnutrition, fatigue and peripheral neuropathy, Kunzmann said.

“Consistent with retrospective studies, NEOLAP is the first prospective randomized study to demonstrate a survival benefit for secondary tumor resection, suggesting that surgical exploration is highly recommended for all patients with locally advanced pancreatic cancer after completion of induction chemotherapy without evidence of disease progression,” Kunzmann said. “Central radiographic review concerning resectability status and response rate, as well as translational biomarker analyses, are ongoing and will be presented at future meetings.” – by Mark Leiser

 

Reference: Kunzmann V, et al. Abstract 671O. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

 

Disclosures: Celgene funded this study. Kunzmann reports honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene and Merck KGaA, as well as research funding from AstraZeneca and Celgene. Please see the abstract for all other authors’ relevant financial disclosures.

BARCELONA, Spain — Four months of induction combination chemotherapy followed by surgical exploration made secondary resection feasible for about one-third of patients with nonresectable locally advanced pancreatic cancer, according to results of the randomized phase 2 NEOLAP trial presented at European Society for Medical Oncology Congress.

Conversion surgery appeared associated with a near-doubling of OS.

Approximately 30% of patients with pancreatic cancer present with nonresectable locally advanced tumors.

“Without evidence from prospective randomized studies, multiagent induction chemotherapy is recommended for [these patients], but the optimal regimen and duration is currently unknown,” Volker Kunzmann, MD, managing senior physician at University Hospital Würzburg in Germany, said during his presentation.

Prior prospective multicenter trials reported conversion to resectable tumors at rates ranging from 5% to 15%, typically based on radiographic resectability criteria.

Kunzmann and colleagues conducted the open-label, multicenter NEOLAP trial to compare the efficacy and safety of two induction chemotherapy regimens — nab-paclitaxel (Abraxane, Celgene) and gemcitabine, or FOLFIRINOX — for treatment-naive patients with histologically or cytologically proven nonresectable locally advanced pancreatic cancer.

Nab-paclitaxel and gemcitabine has demonstrated activity in locally advanced pancreatic cancer, and nab-paclitaxel has been shown in preclinical and clinical studies to increase intratumoral concentrations of other cytotoxic drugs by depleting the abundant desmoplastic stroma in pancreatic cancer, Kunzmann said.

“We thought it was reasonable to assess the activity of FOLFIRINOX after nab-paclitaxel pretreatment,” he added.

Researchers recruited 168 patients (age range, 18 to 75 years) with ECOG performance status of 0 or 1. No patients had evidence of distant metastases.

All patients underwent two cycles of nab-paclitaxel and gemcitabine.

Investigators randomly assigned 130 patients who did not have progressive disease or experience unacceptable adverse events to two additional cycles of nab-paclitaxel and gemcitabine (n = 64), or four cycles of sequential unmodified FOLFIRINOX (n = 66). Baseline characteristics were well-balanced between groups with the exception of sex (nab-paclitaxel/gemcitabine, 59% male; FOLFIRINOX, 42% male)

All patients with stable disease after completion of induction chemotherapy underwent exploratory laparotomy to assess secondary resectability.

Conversion rate — or the rate of R0/R1 resection — served as the primary endpoint. This was the first trial to use this endpoint for locally advanced pancreatic cancer, Kunzmann said.

Forty patients (62.5%) in the nab-paclitaxel/gemcitabine group and 42 patients (63.6%) in the FOLFIRINOX group underwent surgical exploration.

The primary endpoint of demonstrating superior conversion rate by sequential FOLFIRINOX compared with nab-paclitaxel/gemcitabine was not met, although there was a trend in favor of the FOLFIRINOX arm.

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Researchers reported conversion rates of 30.6% in the nab-paclitaxel/gemcitabine group and 45% in the FOLFIRINOX group (OR = 0.54; 95% CI, 0.26-1.13), with an overall conversion rate in the intention-to-treat population of 27.9%.

OS data were immature at the time of data cutoff. However, after median follow-up of 13.8 months, median OS was 17.2 months among patients assigned nab-paclitaxel/gemcitabine and 22.5 months among those assigned FOLFIRINOX (adjusted HR = 0.73; 95% CI, 0.42-1.28).

In the intention-to-treat population (n = 165), conversion appeared associated with significantly longer median OS (27.4 months vs. 14.2 months; HR = 0.45; 95% CI, 0.26-0.78).

“The survival benefit was essentially mirrored when focusing on the surgical exploration cohort,” Kunzmann said.

Researchers reported no significant differences between group with regard to secondary endpoints, including ORR, disease control rate, PFS, CA 19-9 response, rate of exploratory laparotomy performed, pathological complete response rate and postoperative mortality.

Both induction regimens appeared well-tolerated, with safety profiles consistent with prior studies, Kunzmann said.

Researchers reported comparable rates of grade 3 or higher treatment-emergent adverse events (54.7% vs. 53%) and serious treatment-emergent adverse events (29.7% vs. 34.8%) between the nab-paclitaxel and FOLFIRINOX groups (54.7% vs. 53%).

Investigators did observe a numerical trend to more nonhematologic adverse events in the sequential FOLFIRINOX arm. These included nausea and vomiting, malnutrition, fatigue and peripheral neuropathy, Kunzmann said.

“Consistent with retrospective studies, NEOLAP is the first prospective randomized study to demonstrate a survival benefit for secondary tumor resection, suggesting that surgical exploration is highly recommended for all patients with locally advanced pancreatic cancer after completion of induction chemotherapy without evidence of disease progression,” Kunzmann said. “Central radiographic review concerning resectability status and response rate, as well as translational biomarker analyses, are ongoing and will be presented at future meetings.” – by Mark Leiser

 

Reference: Kunzmann V, et al. Abstract 671O. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

 

Disclosures: Celgene funded this study. Kunzmann reports honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene and Merck KGaA, as well as research funding from AstraZeneca and Celgene. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective

    The treatment of choice for locally advanced pancreatic cancer is combination chemotherapy. There have been randomized studies in this setting but NEOLAP is the first randomized study to use nab-paclitaxel/gemcitabine or FOLFIRINOX.

    The resection rates were higher than expected. They aimed to increase the resection rate from 20% to 40%, but actually it was increased from 30% to 45%. Among treated patients, there was no significant difference in OS in terms of sequential FOLFIRINOX but, of course, we would like to see some longer follow-up.

    So why did they use sequential or alternating therapy? This was based on the old Goldie and Coldman hypothesis that predicted that maximum tumor killing can be achieved when alternating noncross-resistant agents are used. In addition, alternating administration of different drugs may avoid or limit the cumulative toxicity observed with the concomitant administration of the same drug-drug combination.

    I reviewed the literature from the last 20 or 30 years to look into the benefit of alternating treatment instead of using a fixed regimen. I found a very old study of patients with small cell lung cancer that showed a very small benefit, but none of the other trials show any evidence that it was a good choice to offer patients alternating therapies.

    I am not in favor of randomized trials with three arms, but an arm in which patients received all FOLFIRINOX might have [provided] important information. I look forward to seeing all data on radiological evaluation.

    I agree that, until proven otherwise, all patients who undergo conversion therapy and do not have disease progression should undergo laparotomy to evaluate resectability.

    It also is critical to discriminate between locally advanced pancreatic cancer and borderline resectable disease, and the exact stage must be reported. Patient participation in clinical trials — preferably randomized trials — also is extremely important.


    • Per Pfeiffer, MD, PhD
    • Odense University Hospital

    Disclosures: Pfeiffer reports consultant or speakers’ roles with, as well as research funding from, Amgen, Celgene, Eli Lilly, Isofol Medical, Merck, Merck Serono, Nordic Drugs, PledPharma, Roche and Servier.

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