Editorial

Adjuvant therapy for pancreas cancer: Real progress at last?

It seems that we may finally be seeing a real glimmer of hope for patients with pancreas cancer that has not metastasized clinically.

Although it has long been known that surgical procedures, such as a Whipple’s resection, may achieve cure in apparently localized pancreatic cancer, there are many caveats to that statement, including patient characteristics, influence of the size and local extent of the tumor, absence of nodal involvement, tumor grade, presence of antecedent weight loss, and the rigor of the investigation protocol to ensure true ability to resect completely.

PRODIGE 24 trial

Recently, two interesting studies suggest that we have moved beyond the status quo that has been in place for decades.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

At the ASCO Annual Meeting, Conroy and colleagues reported for the first time the results of the PRODIGE 24/CCTG PA.6 randomized trial comparing a modified regimen of adjuvant FOLFIRINOX — incorporating calcium leucovorin, 5-FU, irinotecan and oxaliplatin — vs. adjuvant gemcitabine, after surgical resection.

From 2012 to 2016, researchers enrolled 493 patients aged 18 to 79 years with R0 and R1 pancreas cancer resections in centers in France and Canada.

At a median follow-up of nearly 3 years, patients treated with adjuvant modified FOLFIRINOX had a median OS of 54.4 months, compared with only 34.8 months for those treated with adjuvant gemcitabine (HR = 0.66; 95% CI, 0.49-0.89).

Similarly, median DFS figures were 21.6 months with modified FOLFIRINOX vs 12.8 months with gemcitabine (HR = 0.59; 95% CI, 0.47-0.74). Nearly 40% of the patients who received modified FOLFIRINOX were disease free at 3 years, compared with 21.4% of the patients receiving adjuvant gemcitabine.

The toxicity pattern for patients receiving FOLFIRINOX was predictably much worse — 75% with grade 3 to grade 4 toxicity — which was not surprising given the extensive published data on this regimen, and included diarrhea, vomiting, mucositis, myelosuppression and peripheral neuropathy. Nearly 60% of patients who received modified FOLFIRINOX required colony stimulating factors, compared with only 3.7% of patients assigned gemcitabine. However, the side effects were manageable, and there were no toxic deaths in the FOLFIRINOX group.

This trial seems to represent really important progress, although it should be noted that a slightly higher proportion of T3-4 cases and R1 resections were allocated to the adjuvant gemcitabine group. That said, the forest plots still showed benefit from the new regimen for these two adverse prognostic groups.

PREOPANC-1 trial

A second potentially important study — PREOPANC-1, also presented at ASCO — described the use of neoadjuvant combination gemcitabine-radiotherapy in an attempt to improve the potential to resect borderline locally advanced pancreas cancers (see related article).

This randomized study conducted in the Netherlands compared the use of the neoadjuvant regimen (n = 119) vs. surgical resection alone (n = 127) among patients accrued between 2013 and July 2017. Neoadjuvant treatment consisted of a cycle of gemcitabine 1000 mg/m2 on days 1, 8 and 15, followed by 15 fractions of 2.4 Gy combined with gemcitabine 1,000 mg/m2 on days 1, 8 and 15, followed by another cycle of gemcitabine.

The combined-modality approach yielded significant improvements in OS (13.5 months vs. 17.5 months; HR = 0.71; P < .05), R0 resection rate (31% vs 65%; P < .001), and distant metastasis-free interval (median, 10.2 months vs. 17.1 months; HR = 0.63; P = .012). For those patients who underwent complete resection, OS was 16.8 months vs. 29.9 months.

The most puzzling aspect of this report was the claim that the patients treated with neoadjuvant therapy had the same level of grade 3 to grade 4 toxicity as those treated by surgery alone, and this might reflect the definition of terms used in reporting or the rigor of toxicity assessment.

Important progress

These two trials cannot be compared directly as they were conducted in different populations with different clinical staging outcomes and occult case selection biases.

However, for those patients not deemed resectable at baseline, this combined chemoradiation approach seems to offer at least the potential for cure, and should be carefully considered in the available armamentarium. Those who read my editorials more than occasionally should be well aware that I am always cautious in interpreting data presented only in abstract form prior to full peer review, and for this reason I am not yet calling “victory!”

Still, these studies do seem to represent important progress in one of the most implacable oncology killers extant today, a disease with a rising incidence, and which killed more than 40,000 men and women in the United States last year. For decades, we have made so little progress in this domain, and I guess that I’m overly sensitive as I have lost so many close friends to this dreadful disease (see “When loss becomes personal: Reflections on one of our own” in the July 25, 2015, issue of HemOnc Today).

Even with the litmus test of cost-effectiveness, in the pricey United States, it seems that six cycles of modified FOLFIRINOX would come in at around $50,000, log-fold less than some of the new regimens trumpeted at the same meeting but with far less potential patient benefit. Hopefully the U.S. prices of this regimen won’t suddenly and magically escalate consequent upon these data.

At last, even this old and cynical agent provocateur believes true progress has been made, and I’m left wondering why the mavens of the ASCO Program Committee, in their wisdom, did not find a place for PRODIGE 24 in their plenary session. I guess pancreatic cancer still doesn’t have enough political clout.

References:

The following were presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago:

Conroy T, et al. Abstract LBA4001.

Van Tienhoven G, et al. Abstract LBA4002.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.

Disclosure: Raghavan reports no relevant financial disclosures.

It seems that we may finally be seeing a real glimmer of hope for patients with pancreas cancer that has not metastasized clinically.

Although it has long been known that surgical procedures, such as a Whipple’s resection, may achieve cure in apparently localized pancreatic cancer, there are many caveats to that statement, including patient characteristics, influence of the size and local extent of the tumor, absence of nodal involvement, tumor grade, presence of antecedent weight loss, and the rigor of the investigation protocol to ensure true ability to resect completely.

PRODIGE 24 trial

Recently, two interesting studies suggest that we have moved beyond the status quo that has been in place for decades.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

At the ASCO Annual Meeting, Conroy and colleagues reported for the first time the results of the PRODIGE 24/CCTG PA.6 randomized trial comparing a modified regimen of adjuvant FOLFIRINOX — incorporating calcium leucovorin, 5-FU, irinotecan and oxaliplatin — vs. adjuvant gemcitabine, after surgical resection.

From 2012 to 2016, researchers enrolled 493 patients aged 18 to 79 years with R0 and R1 pancreas cancer resections in centers in France and Canada.

At a median follow-up of nearly 3 years, patients treated with adjuvant modified FOLFIRINOX had a median OS of 54.4 months, compared with only 34.8 months for those treated with adjuvant gemcitabine (HR = 0.66; 95% CI, 0.49-0.89).

Similarly, median DFS figures were 21.6 months with modified FOLFIRINOX vs 12.8 months with gemcitabine (HR = 0.59; 95% CI, 0.47-0.74). Nearly 40% of the patients who received modified FOLFIRINOX were disease free at 3 years, compared with 21.4% of the patients receiving adjuvant gemcitabine.

The toxicity pattern for patients receiving FOLFIRINOX was predictably much worse — 75% with grade 3 to grade 4 toxicity — which was not surprising given the extensive published data on this regimen, and included diarrhea, vomiting, mucositis, myelosuppression and peripheral neuropathy. Nearly 60% of patients who received modified FOLFIRINOX required colony stimulating factors, compared with only 3.7% of patients assigned gemcitabine. However, the side effects were manageable, and there were no toxic deaths in the FOLFIRINOX group.

This trial seems to represent really important progress, although it should be noted that a slightly higher proportion of T3-4 cases and R1 resections were allocated to the adjuvant gemcitabine group. That said, the forest plots still showed benefit from the new regimen for these two adverse prognostic groups.

PREOPANC-1 trial

A second potentially important study — PREOPANC-1, also presented at ASCO — described the use of neoadjuvant combination gemcitabine-radiotherapy in an attempt to improve the potential to resect borderline locally advanced pancreas cancers (see related article).

PAGE BREAK

This randomized study conducted in the Netherlands compared the use of the neoadjuvant regimen (n = 119) vs. surgical resection alone (n = 127) among patients accrued between 2013 and July 2017. Neoadjuvant treatment consisted of a cycle of gemcitabine 1000 mg/m2 on days 1, 8 and 15, followed by 15 fractions of 2.4 Gy combined with gemcitabine 1,000 mg/m2 on days 1, 8 and 15, followed by another cycle of gemcitabine.

The combined-modality approach yielded significant improvements in OS (13.5 months vs. 17.5 months; HR = 0.71; P < .05), R0 resection rate (31% vs 65%; P < .001), and distant metastasis-free interval (median, 10.2 months vs. 17.1 months; HR = 0.63; P = .012). For those patients who underwent complete resection, OS was 16.8 months vs. 29.9 months.

The most puzzling aspect of this report was the claim that the patients treated with neoadjuvant therapy had the same level of grade 3 to grade 4 toxicity as those treated by surgery alone, and this might reflect the definition of terms used in reporting or the rigor of toxicity assessment.

Important progress

These two trials cannot be compared directly as they were conducted in different populations with different clinical staging outcomes and occult case selection biases.

However, for those patients not deemed resectable at baseline, this combined chemoradiation approach seems to offer at least the potential for cure, and should be carefully considered in the available armamentarium. Those who read my editorials more than occasionally should be well aware that I am always cautious in interpreting data presented only in abstract form prior to full peer review, and for this reason I am not yet calling “victory!”

Still, these studies do seem to represent important progress in one of the most implacable oncology killers extant today, a disease with a rising incidence, and which killed more than 40,000 men and women in the United States last year. For decades, we have made so little progress in this domain, and I guess that I’m overly sensitive as I have lost so many close friends to this dreadful disease (see “When loss becomes personal: Reflections on one of our own” in the July 25, 2015, issue of HemOnc Today).

Even with the litmus test of cost-effectiveness, in the pricey United States, it seems that six cycles of modified FOLFIRINOX would come in at around $50,000, log-fold less than some of the new regimens trumpeted at the same meeting but with far less potential patient benefit. Hopefully the U.S. prices of this regimen won’t suddenly and magically escalate consequent upon these data.

PAGE BREAK

At last, even this old and cynical agent provocateur believes true progress has been made, and I’m left wondering why the mavens of the ASCO Program Committee, in their wisdom, did not find a place for PRODIGE 24 in their plenary session. I guess pancreatic cancer still doesn’t have enough political clout.

References:

The following were presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago:

Conroy T, et al. Abstract LBA4001.

Van Tienhoven G, et al. Abstract LBA4002.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.

Disclosure: Raghavan reports no relevant financial disclosures.