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Research Rookie – Edition 4

Can We Tell Tumors to Keep Calm So You Can Carry On?

Research Rookies is an ongoing article series designed to help patients and caregivers understand research about pheo para. Articles provide a summary of published pheo para and related research. It’s written in easy-to-understand language focused on making us all better patient and caregiver advocates and providing much-needed hope to those affected. We also provide links to resources where you can find more information about these research topics.

A lay summary of:

Baudin, E., Goichot, B., Berruti, A., Hadoux, J., Moalla, S., Laboureau, S., … & Van Berkel, A. (2024). Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial. The Lancet, 403, 1061-1070.

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Special thanks to Dr. Linda Rose-Krasnor, Chair of the Board of Directors for authoring this edition.

Text in bold is defined in the glossary at the bottom of the page.

The purpose of this study was to assess the effectiveness of the medication Sunitinib for the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs).  In metastatic PPGLs, cancer cells have spread to distant sites in the body beyond the initial tumor, most often to bones, lungs, lymph nodes, and/or liver.

The uncontrolled growth of cancer cells is often fueled by overactive enzymes such as tyrosine kinase. Medications are available that can help stop this tyrosine kinase overactivity and thus, potentially, slow the growth of these cancer cells.  However, there are multiple types of tyrosine kinase enzymes that can support the growth of cancer cells, so a medication that blocks several of these enzymes at once can be more effective than a medication targeting only one enzyme.   Sunitinib is known as a “multi-targeted receptor tyrosine kinase inhibitor” because it blocks the activity of at least three different kinase enzymes.

Why is this study important?

There is currently no FDA-approved medication available for metastatic PPGLs and few “off label” alternatives.  At the time this study was initiated, there was no approved systematic treatment for metastatic PPGLs.

To the researchers’ knowledge, there currently has not been any previous research on the effectiveness of treatment for metastatic PPGLs that has the same rigorous design and sample size of this research.

This study is one of the only double-blind randomized Phase 2 clinical trials for treatment of metastatic PPGLs.  A Phase 2 clinical trial normally involves participants who have the disease that the drug is intended to treat. Completion of a Phase 2 clinical trial is usually a necessary step in government approval of a new treatment. One of the reasons for the lack of Phase 2 research for the treatment of PPGLs is difficulty in obtaining a large enough sample size.  Patients with metastatic PPGLs are rare and it has been very difficult for researchers to find enough participants to conduct rigorous research.  Indeed, the current study required a large multi-institutional team from four countries and an extended recruitment period (seven years) to recruit enough participants to conduct appropriate analyses.

In the authors’ words, “this study provides the highest level of evidence ever reached to support the anti-tumor role of a systematic treatment option in patients with metastatic pheochromocytomas and paragangliomas, and supports sunitinib as a potential candidate for first-line therapy” (p. 1067).

Who was involved in this study?

This study was conducted by over 24 researchers from 14 academic centers in four countries (France, Germany, Italy, and the Netherlands).

Seventy-eight adult patients who had been diagnosed with metastatic PPGLs participated in the study.  Overall, it was a middle-aged patient group (median age 54 years) and slightly over half were male (59% of the sample).  Approximately one-third of the participants had an inherited SDHB mutation and almost all had undergone previous surgery (95%) and/or other prior treatment (69%).  In most of the participants (65%), tumors had spread to their bones.

How was the study conducted?

Participants were randomly assigned to be in either the experimental or placebo treatment group.  Participants in the experimental group received sunitinib, while those in the placebo group received a sham medication that looked like sunitinib but had no effect on the tumors.  Furthermore, this was a “double blind” study, which means that the participants and the health care professionals taking part in the research did not know which patients received the placebo and which received sunitinib.  This procedure makes it unlikely that expectations and biases by the participants, researchers and others involved in the study will distort the results.

The primary measure to assess the effectiveness of sunitinib was “progression free survival rate”.  In this study, progression free survival rate was the percentage of patients in each group whose tumor did not get worse in the 12 months following the start of treatment or placebo.  The researchers predetermined that sunitinib would be considered an effective treatment if the progression free survival rate in the sunitinib group was 20% higher than in the placebo group.

The researchers also included several other measures to assess the effects of sunitinib, including overall survival time, quality of life, and side effects. These measures were gathered at the start of the study and periodically repeated over the next 12 months.

What were the results?

Overall, the findings showed that sunitinib was effective in reducing the number of patients who had tumor growth over the year of the study.  Thirty-six percent of the patients receiving sunitinib showed no tumor growth compared to only 19% of the patients in the comparison placebo group (14 and 7 patients respectively).  Although there was a seeming difference in progression of tumor between groups, this did not reach the 20% difference the authors pre-planned to meet significance. In addition, 17.6% of the sunitinib group’s tumors were still showing no growth after 24 months compared to 8.4% of the placebo group. In summary, sunitinib was effective for treating a subgroup of metastatic PPGLs.

Furthermore, the quality of life in patients receiving sunitinib was maintained while taking the medication.  Although some side effects (e.g., diarrhea, hypertension, nausea) were reported, the participants found these to be manageable.  Sunitinib also was effective for a subgroup of the participants who had an inherited SDHB mutation and across those who had undergone a variety of previous treatments.

Although this research provided reliable evidence that sunitinib was effective in reducing tumor growth, the researchers describe some of the study’s limitations.  The results show that sunitinib was more effective than not receiving any treatment (the placebo group), but it was not compared to alternative treatments (e.g., lutathera) to see if it is more effective. Also, it is not known if the same results for sunitinib would be found across the many differences in tumors, genetic background, and other factors that exist within the metastatic PPGL patient population.  The researchers further caution that it is very important to control pre-existing conditions (e.g., hypertension, bone pain) before starting sunitinib.

Next Steps

The next step in researching sunitinib may be to compare its effectiveness to other treatments for metastatic PPGLs, both alone and in combination with other treatment strategies.  Indeed, a Phase 2 clinical trial such as this study is typically followed by a Phase 3 trial, which involves a much larger number of patients and compares the medication to an alternative treatment or placebo.  Although the current study has some similarity to a Phase 3 trial (i.e., compares sunitinib to a placebo), it lacks the large sample size required by the Phase 3 procedure.  Researchers may attempt to conduct a Phase 3 clinical trial for sunitinib but difficulty in obtaining enough participants may make this unlikely to be successful.

Finally, it is important that information about the results of this study should be made available to health care professionals and patients in order to ensure its appropriate and effective use. As always, please speak with your health care provider to determine which therapies may be appropriate for you.

Glossary

Lymph nodes: A lymph node is a small structure in the body that is part of the immune system.  Lymph nodes are grouped together in nodes that are found throughout the body in places such as the neck, armpits, and groin. The cells in the lymph nodes help destroy harmful bacteria and viruses that may be in the lymph fluid, which is a liquid that flows throughout the body.

Enzyme:  Enzymes are chains of proteins that speed up chemical reactions in the body. They are important for many critical tasks, including digestion, repairing cells, and making new cells.

Off Label:  Regulatory agencies like the FDA (Food and Drug Administration) officially approve specific medications for specific medical conditions.  However, doctors may sometimes find that a medication works well for conditions other than those for which it was originally approved.  In those circumstances, they might prescribe it for “off-label” use.

Hypertension: Hypertension refers to high blood pressure.