Cutting-Edge Treatment Strategies in Metastatic Pancreatic Cancer: The Clinical Trial Option

Untitled Document

Introduction
Pancreatic cancer is the deadliest of all major cancers in the United States, with a five-year survival rate of just 8%.1 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.2 Pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of cancer-related death around 2020.2 Treatment advances in this disease have been modest with only incremental improvements in survival, and options for patients remain limited. Clinical trials are critical to advancing progress in the field and improving treatment outcomes for individual patients.

Philip Philip MD PhD FRCPInterview
Philip A. Philip, MD, PhD, FRCP, Professor of Oncology and Medicine at Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute and a medical oncologist was interviewed for his perspective on this topic.

Anitra Engebretson (AE): Dr. Philip, when determining a treatment course for a newly diagnosed patient with treatment-naive, metastatic pancreatic cancer, what types of treatment do you consider?

Dr. Philip Philip: Available treatment options and their benefits are both very limited in patients who are diagnosed with metastatic pancreatic cancer; therefore, one would always consider a clinical trial for those patients.

There are two standard-of-care treatment options in the frontline setting for patients with metastatic pancreatic cancer: the chemotherapy combinations of FOLFIRINOX (5-FU/leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel. Gemcitabine and nab-paclitaxel showed a nearly 2 month improvement from 6.7 to 8.5 months in median overall survival versus gemcitabine alone in the Phase III randomized trial,3 that led to its FDA approval in 2013.4 FOLFIRINOX demonstrated a 4.3 month increase in median overall survival from 6.8 to 11.1 months when compared to gemcitabine in a Phase III trial conducted in France and has also been considered a standard option for untreated, metastatic pancreatic cancer patients.5

Here are the facts about clinical trials in the frontline setting. First, not every patient will be eligible for a clinical trial. For example, someone whose performance status [Eastern Cooperative Oncology Group (ECOG) score] is 2 or more will likely not qualify for a clinical trial (Table 1).6 This is important because unfortunately, given the nature of the disease, a fair number of patients we see do not have a good performance status. Additionally, apart from performance status, there are other eligibility considerations such as having adequate organ function within an acceptable range of normality. Also, having a history of other cancers, especially those diagnosed within the preceding few years, may pose a challenge to being accepted in a clinical trial.

Table 1. Eastern Cooperative Oncology Group Performance Status Score

0 Fully active, no restriction in pre-disease performance
1 Restricted in physically strenuous activity but ambulatory and able to carry out light work
2 Ambulatory; capable of all self-care but unable to work; up more than 50% of waking hours
3 Capable of only limited self-care; confined to bed/chair > 50% of waking hours
4 Not capable of self-care; totally confined to bed/chair
5 Dead

There are other criteria that may limit patients going on a clinical trial. For example, investigators will at times put a condition on enrollment requiring that the patient have a specific biochemical marker or genomic alteration. This type of requirement can make enrollment into the trial challenging, as eligible patients tend not to be the majority of patients. Another related potential challenge to clinical trial enrollment would be if the trial requires a new biopsy to determine the genomics. Based on my personal experience, an increasing number of patients are accepting a new “research” biopsy for the purposes of enrollment into a clinical trial.

There are patients who come to me with less favorable performance status [ECOG score] of 3 or even 2 where I know that they will not be eligible for a clinical trial. Unfortunately, in the clinical trials that have been developed thus far, there is very little focus on patients who have unfavorable performance status. You can even add to this group of patients individuals with pancreatic cancer who are older, let’s say over 75. However, increasingly we treat older patients who have good performance status and good organ function in a manner similar to younger patients, including their inclusion in clinical trials.

AE: It sounds like you’re saying that if the patient is eligible for clinical trials, a trial would be your recommended first course of treatment. Is that correct?

Dr. Philip: Undoubtedly, yes.

AE: Besides having good performance status and meeting the eligibility requirements as we’ve discussed, are there any particular types of patients or particular patient characteristics that make someone more likely to benefit from participation in a clinical trial?

Dr. Philip: Before a patient goes on a clinical trial, they ask us, “Am I going to benefit from it?” The answer is that we do not know, for a number of reasons.

Number one, as I mention to them, the patient may not end up getting the experimental agent due to randomization. Number two, even if they get the experimental agent, sometimes we do not know that they got it because it is a placebo-controlled trial. The third factor is that clinical trials have to mature so that we know if the treatment is working well or not. The final analysis of a clinical trial will let us know if the treatment has really helped or not. The endpoint we usually use in clinical trials is prolonging survival (eg, median overall survival), or sometimes prolonging the time until the cancer worsens in the patient (progression-free survival).

Despite the limitations and challenges associated with clinical trials, overall, we consider getting patients on clinical trials a positive thing for them. Not only is it advantageous because patients may be given a new and possibly a promising drug, but also because patients will have treatment that I would consider top standard-of-care. Generally speaking, clinical trials provide a better experience for patients, and often patients do better than those treated outside of the clinical trial setting.

AE: How does the participation of an individual patient in a clinical trial fit into the broader research community? What impact does an individual patient’s participation make on the field for pancreatic cancer?

Dr. Philip: Well, it is very simple. If you have a patient who goes on a clinical trial, even in the worst case scenario where the clinical trial is negative, the information gained from treating the patient is really very beneficial because it helps us to better build the next treatment strategy for this disease.

There is a lot of information which we gain by treating a patient on a clinical trial ‒ information about the outcome of the patient, how they tolerate the treatment, etc., is all helpful to us. This information is gathered systematically, so it is often top-quality data providing invaluable insight into the disease and its treatment. And, this information will be put together with other clinical trials’ data, or other investigators’ experiences, to really get a better picture on how to improve the treatment of pancreatic cancer and guide future developments.

Sometimes patients tell me that they will be part of the clinical trial because they believe that the information gained and experience learned from their participation is going to help patients who come after them. Apart from the expected potential benefit of the clinical trial, one must also acknowledge the fact that any information generated by being in that study is also very helpful for other patients.

AE: Would you please describe any resources that you are aware of that are available to clinicians to locate trials for specific patients based on factors like the patient’s location, treatment history, and stage of disease? Where would you direct someone to go to look for clinical trials for their patient?

Dr. Philip: Clinical trials are being done throughout the country. There is more availability of clinical trials in the larger academic centers, but also in large community hospitals. Nowadays, many hospitals have cancer centers which not only provide standard-of-care treatments but are also involved with clinical trials. The effort of developing new treatments is very much a collective effort, and studies are often run in a number of institutions. Unfortunately, often doctors may not have the time or resources to find what may be a reasonable clinical trial for a patient in their clinic. This is especially true of doctors in the community where they are really very busy ‒ they are providing excellent care for a large number of patients, but they may not have the time, or more importantly, the resources to easily tap into clinical trial menus that are available for a given patient.

An oncologist who is starting treatment with a patent must always think of clinical trials as an option for the patients and inform the patient as such. Once participation in a clinical trial is expressed as an interest by the patient, there are various ways the oncologist can go about identifying what clinical trials are available.

The simplest way to find a clinical trial(s) that would fit a patient would be to reach out to the nearest academic institution or cancer center and ask them which clinical trials they have available for pancreatic cancer. Unfortunately, when you put a patient on a clinical trial at another center or institution, the patient may have to migrate out of your practice to wherever the clinical trial is being performed due to regulatory restrictions.

Another way of locating clinical trials is to contact the Pancreatic Cancer Action Network. They have a very rich resource to direct patients, caregivers, or doctors to clinical trials. In fact, it is probably the most robust resource that I can think of to get you as many possibilities of clinical trials that are within the radius a patient would be looking.

The Pancreatic Cancer Action Network maintains a unique, up-to-date and comprehensive pancreatic cancer-specific tool for finding clinical trials. Consider using the Pancreatic Cancer Action Network’s Clinical Trial Finder, https://clinicaltrials.pancan.org/.

You can also go to www.ClinicalTrials.gov to do a search of the National Cancer Institute (NCI) database to find a clinical trial that is available within the radius that you are interested in.

But whatever resource you use, the initiating point is to always think first of a clinical trial, then to take a deep breath and work on finding available options. You may want to start treatment immediately, but most of the time waiting a day or two or three or even longer is acceptable. In fact, if the disease gets worse in the next three days, then you know that the type of pancreatic cancer the patient has was not going to be helped by anything.

Patients and caregivers are always very anxious and worried if they are not starting treatment right away. By talking to them, you can explain that it is better to wait and see if they can qualify for a clinical trial. Creating this open channel of communication with the patient is extremely important, not only to ensure their understanding of the benefits of clinical trials, but to foster shared decision-making. By understanding a patient’s goals and values, a health care provider will be better equipped to assess the appropriateness of clinical trial enrollment. Health care providers who treat patients with metastatic pancreatic cancer must incorporate the patient’s voice in treatment decisions and remember to discuss the benefits and clarify misconceptions of clinical trials as a viable option for patients with this disease.

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. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.
  4. FDA approves Abraxane for late-stage pancreatic cancer. FDA News Release. 6 September 2013. Web. Accessed August, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm367442.htm.
  5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
  6. Ma C, Bandukwala S, Burman D, et al. Interconversion of three measures of performance status: an empirical analysis. Eur J Cancer. 2010;45(18):3175-3183

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