Expert Insight into the 2016 ASCO Updates for Metastatic Pancreatic Cancer

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Introduction
Pancreatic cancer is the deadliest of all major cancers in the United States, with a five-year survival rate of just 8%. In 2016, an estimated 53,070 Americans will be diagnosed with the disease, and 41,780 will die from it.1 Additionally, the number of deaths from pancreatic cancer will surpass those from breast cancer, making it the third leading cause of cancer-related death in the United States. Pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of cancer-related death around 2020.2

The American Society of Clinical Oncology (ASCO) recently published three clinical practice guidelines that address the treatment and care of patients with pancreatic ductal adenocarcinoma.3 The guidelines were developed by a panel of experts and are based on a systematic review of the literature with the goal of providing evidence-based recommendations to clinicians. The pancreatic cancer clinical practice guidelines are written based on stage of disease and include potentially curable, locally advanced, and metastatic pancreatic cancer.


Interview
Alok Khorana, MD, Sondra and Stephen Hardis Chair in Oncology Research, and Director of the Gastrointestinal Malignancies Program at Taussig Cancer Institute, Cleveland Clinic, medical oncologist and guideline co-author, was interviewed and asked to provide an overview of several important topics within the guidelines.

Anitra Engebretson (AE): Please describe initial treatment options for patients with potentially curable pancreatic cancer according to the ASCO Clinical Practice Guidelines.

Dr. Alok Khorana: The ASCO guideline on potentially curable pancreatic cancer4 addresses all aspects of staging and selection of appropriate treatment. In terms of staging, the guidelines strongly recommend a multi-phase CT scan or MRI of the abdomen to assess anatomic relationships of the cancer. The guideline also emphasizes that treatment decisions should not be made in isolation by a single physician but by a multidisciplinary team of providers, which should include physicians with surgical expertise as well as physicians with medical oncology and radiation oncology expertise. It is also preferred that treatment be conducted in the setting of a high-volume institution where a multidisciplinary team or tumor board will be involved in the interpretation of images and treatment decisions.

The guidelines go on to emphasize that decisions should not be based on just the disease in isolation, but also should take into account the patient’s performance status, goals of care, and comorbidity profile.

Upfront surgical resection is recommended for patients in whom there is no distant metastatic disease, that have a decent performance status, and no major comorbidities that would increase the risks associated with surgical resection. However, the panel also recognized that there are often patients for whom it is unclear whether they should proceed straight to upfront resection. In the past, terms like borderline resectable have been used to describe these patients. The panel suggested moving away from those descriptions because there is not a clear consensus on what is resectable versus borderline resectable. Rather, the panel acknowledged that there are some patients in whom there is a high risk of margin positive or incomplete resection if they were to be offered upfront surgery, and in those patients, preoperative treatment is recommended. That preoperative treatment can take the form of either preoperative chemoradiation or chemotherapy.

All patients who get a resection should be offered six months of adjuvant chemotherapy, or six months total of treatment. If they did not get preoperative treatment, then all of the six months will be postoperative. If they got some amount of chemotherapy before the surgery, then these months are included in the six months of total adjuvant chemotherapy.

At the time the panel met and wrote the guidelines, there was not a clear consensus on what the postoperative adjuvant treatment should be, due to equal amounts of data for single-agent 5-fluorouracil or single-agent gemcitabine. Since the guideline was published, there has been one randomized trial of the doublet regimen of gemcitabine and capecitabine, which was tested versus gemcitabine alone. In preliminary results presented in abstract form, the combination appears to be successful. It is possible that the guideline might be revised later this year to include these new data, but as the guideline is written, it recommends single-agent gemcitabine or 5-fluorouracil as adjuvant treatment.

Patients who did not receive preoperative therapy and who continue to have positive margins and/or node-positive disease after four to six months of adjuvant chemotherapy may be offered adjuvant chemoradiation.4

Finally, the guideline touches on surveillance options after completion of adjuvant treatment for several months, up to five years.

AE: Now let’s look at locally advanced unresectable pancreatic cancer patients. Would you please explain the initial treatment options for those patients, according to the ASCO guideline?

Dr. Khorana: In this guideline,5 locally advanced pancreatic cancer is defined as that which is not resectable. It is important to clarify this point because there is an intentional alignment on the definitions between the potentially curable guideline and the locally advanced guideline. The locally advanced guideline does not include patients that, under some terminology, are considered as borderline resectable. So, if there is hope of resection, if the disease is potentially resectable and potentially curable, then those patients should be treated according to the potentially curable guideline. Locally advanced, in this framework, refers to patients who are clearly unresectable but do not have metastatic disease. This does make up a substantial proportion of patients with pancreatic cancer.

In this population, the panel had several recommendations. One emphasis from the guideline is to make sure that a palliative care referral occurs at the first visit. This is especially important in patients with pancreatic cancer because they suffer not just from the disease itself, but also from a high symptom burden ‒ higher than in other cancers. And in particular, pain can be a big issue in patients with pancreatic cancer. To make sure that patients are treated for their whole symptom burden and not just based on their illness, it is important to include palliative care as early as possible in institutions where palliative care partnerships exist.

With regard to treatment, initial systemic chemotherapy is recommended for most patients. In terms of the selection of regimen, the panel stated that there is no clear evidence to support one regimen over another. Much of the data in terms of recommendation of systemic chemotherapy is extrapolated from metastatic setting clinical trials as, unfortunately, many of the clinical trials of metastatic patients did not include locally advanced patients. There are several combination regimens that could be considered, including gemcitabine and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, the so-called FOLFIRINOX regimen. Again, the data are primarily from the metastatic setting, but in the absence of large randomized trials in the locally advanced setting, it is appropriate to extrapolate from the metastatic studies.

One unique feature of locally advanced pancreatic cancer is that radiation therapy can sometimes be used. The panel recommended that radiation not be used upfront unless there is an urgent need for palliation of pain and other options for treatment of pain have been exhausted. However, in patients who have only local progression after several months of chemotherapy but no distant metastases or, alternatively, in patients in whom there is no progression that have completed six months of systemic therapy and there is no metastatic disease, one could utilize radiation therapy, including the option of stereotactic body radiation therapy (SBRT); early emerging data suggests that this technique offers evidence of sustained local control.

AE: What are the initial treatment options for patients diagnosed with metastatic pancreatic cancer?

Dr. Khorana: Unfortunately the bulk of patients with pancreatic cancer are diagnosed with metastatic disease. For patients with metastatic pancreatic cancer,6 again, the panel emphasized the need for a palliative care referral that should occur at the first visit, due to the acknowledgement of the substantial symptom burden that is carried by patients with pancreatic cancer, particularly pain.

The panel reviewed the data and there is not a clear consensus on one standard of care. The panel made recommendations, categorizing patients primarily by performance status and comorbidity profile. The panel recommended either FOLFIRINOX, which is a combination of leucovorin, 5-fluorouracil, oxaliplatin, and irinotecan, or gemcitabine with nab-paclitaxel, in patients who have a very good comorbidity profile and a good performance status. These two combination regimens are competing standards of care for the first-line setting in these patients.

For patients who have a poor performance status [Eastern Cooperative Oncology Group score] of 2 or higher, or in patients in whom the comorbidity profile precludes other regimens, one could consider gemcitabine alone. One could also offer an addition of capecitabine or erlotinib, although the data and the expected benefit from those two combinations are relatively minimal. For patients with a really poor performance status [ECOG score] of 3 or higher, or with poorly controlled comorbidities, the panel suggested that there would be individualization of decision-making that include the patients’ goals of care. These patients should be informed of the risk/benefit ratio of systemic therapy and only offered cancer-directed therapy on a case-by-case basis.

The guidelines panel for metastatic pancreatic cancer also touched on second-line treatment, which largely depends on the first-line treatment. In patients who have been offered FOLFIRINOX upfront, clinicians should then consider gemcitabine and nab-paclitaxel for second-line treatment, or the other way around. There is very little data on third-line or higher-line treatment, and the panel emphasized the need for clinical trials across all of these different settings ─ first-line, second-line, and higher ─ but especially in the third-line setting, where there is very little data to support ongoing chemotherapy.

AE: Are there any other components of the entire set of guidelines, for all three stages of disease, that you would like to highlight or that you find particularly important?

Dr. Khorana: Yes. I think the reason ASCO has emphasized these three guidelines is that pancreatic cancer is an illness that is rising in prevalence and rising in the mortality chart across the United States, even though the incidence is not as high as some of the other, more common solid tumors. It continues to be a "relatively low incidence" cancer, but the public health burden of pancreatic cancer on mortality is high and is expected to have even more impact by the end of this decade. So, these guidelines really draw attention to what is known about pancreatic cancer and where the knowledge gaps are.

I have discussed some of those knowledge gaps, one being in the locally advanced setting where we do not have a lot of randomized trials and where we do not fully understand the role of radiation therapy. In the potentially curable setting, we do not fully understand the role of preoperative versus postoperative treatment, as well as the role of preoperative radiation therapy.

These knowledge gaps are best addressed by clinical trials, and each of these panels emphasized the need to enroll patients on available clinical trials across all the different settings. I think one big thrust for these guidelines is to say that this is an important illness. It has not received the attention it should have; it is rising in mortality rankings, and we need to address important knowledge gaps and find new therapeutics based on the context of clinical research, whether we partner with the National Institutes of Health (NIH), industry, advocacy organizations, or all of the above.

All three guidelines recommend that information about available clinical trials be offered to all patients. A comprehensive and unique pancreatic cancer-specific resource to locate information about relevant clinical trials is the Clinical Trial Finder offered by the Pancreatic Cancer Action Network at clinicaltrials.pancan.org.

A second big thrust across all of these guidelines is on the importance of multidisciplinary care. Pancreatic cancer is a difficult illness to treat. It requires ample input from multiple physician disciplines, including surgery, radiation oncology, palliative medicine, medical oncology, gastroenterology, and so on. And so, it is really important, especially in the curative intent setting, that we involve all of these different disciplines.

Also, across the board, all patients with pancreatic cancer should have access to palliative care, because if we cannot affect the outcome of the cancer itself that much, then we should at least be able to minimize the symptom burden by using all the tricks that we know. That is really best done in the context of an early palliative care partnership ─ not waiting until patients are terminally ill, but involving palliative care early on so that we co-manage the symptom burden as early as possible and emphasize patients’ quality of life.



References

  1. Cancer Facts & Figures (2016). Accessed August 2016. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf
  2. Pancreatic Cancer Action Network Pancreatic Cancer Facts 2016. Accessed August 2016. https://www.pancan.org/wp-content/uploads/2016/02/2016-GAA-PC-Facts.pdf
  3. ASCO Website. Gastrointestinal Cancer reference. Accessed August 2016. https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/gastrointestinal-cancer
  4. Khorana AA, Mangu PB, Berlin J, et al. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(21):2541-2556.
  5. Balaban EP, Mangu PB, Khorana AA, et al. Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(22):2654-2668.
  6. Sohal DP, Mangu PB, Khorana AA, et al. Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(23):2785-2796.

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