Honing in on Subtypes to Guide More Individualized Treatment of Soft Tissue Sarcoma

Oncology (Williston Park). 33(6):212-4, 216.

Margaret von Mehren, MD

Soft tissue sarcoma can be challenging to diagnose and treat due to the vast number of different subtypes that comprise the disease. ONCOLOGY recently spoke with Margaret von Mehren, MD, regarding the diagnosis and treatment of soft tissue sarcoma. She reviewed the latest research in this area, including the results of several trials that showed that combining pazopanib with gastric acid–suppressive agents decreased survival in patients-as well as strategies that may aid in alleviating this issue.

Q: First, what is the biology of soft tissue sarcoma, and are there different subtypes of these tumors?

DR. VON MEHREN: The first thing I always like to point out about sarcomas is that we think of them as distinct from carcinomas. They arise from different cell types. While sarcomas come from fat, muscle, bone cartilage, or blood vessels, carcinomas usually come from epithelial structures or the tissue of glands. Like all malignancies, sarcomas have the ability to grow and metastasize, and truly malignant tumors can be biologically aggressive and fatal.

There are at least 50, if not more, different subtypes of sarcomas. This is one of the elements that makes caring for sarcoma patients so challenging. While some tumors are derived from fat or liposarcoma, others are from smooth muscle from vascular-type structures. Once we classify the sarcoma, we treat patients accordingly in terms of what type of testing we conduct and which specific treatments we select.

Q:Are specific genetic abnormalities associated with any of the various subtypes of soft tissue sarcoma?

DR. VON MEHREN: Certainly, classical genetic abnormalities define some tumors. Such abnormalities are much more common in pediatric patients than adult patients, but we do see them in some young adults and older patients as well. Many soft tissue sarcomas, such as synovial sarcoma and myxoid liposarcoma, have very specific chromosomal translocations that can aid in establishing the diagnosis. Other tumors have specific gene mutations that can help in identifying the tumor type, as well as which therapy makes the most sense. For example, two genes represent about 80% to 85% of gastrointestinal stromal tumors that have mutations. Those genetic abnormalities help to define how to take care of it.

Q: What are the main types of therapy for patients diagnosed with soft tissue sarcoma?

DR. VON MEHREN: There are three major modalities used to treat soft tissue sarcoma: surgery, radiation, and chemotherapy. A probable fourth modality that remains an active area of research is immunotherapy, but we are still in the process of developing immunotherapies for soft tissue sarcoma and understanding which patients will benefit.

Surgery is a mainstay for patients with primary disease that has not spread to other organ sites. However, we also consider adding radiation therapy before or after surgery to help with local control in certain patients, particularly those with tumors that are in the extremity; this approach allows us to avoid amputations. In specific situations, we also discuss the use of chemotherapy to prevent recurrence of the sarcoma. Whether the recurrence is at a local site or elsewhere, we analyze whether the disease can be easily removed surgically or is located in many areas. When the latter situation exists, this usually requires systemic therapy. Essentially, each patient requires highly individualized care.

Of note, we consider surgery to manage metastatic disease more frequently for sarcomas than we do for many other carcinomas. For carcinomas, we often use systemic therapies such as chemotherapy as well as radiation. However, in the treatment of sarcomas, I think we’ve demonstrated a real value in removing tumors by surgery in the appropriate circumstances to help with disease control.

Q:The European Organisation for Research and Treatment of Cancer (EORTC) conducted a single-arm phase II trial and a placebo-controlled phase III trial evaluating pazopanib, which is approved for the treatment of advanced soft tissue sarcoma that has been pretreated with doxorubicin-based regimens. Can you discuss the rationale for and findings of these studies?

DR. VON MEHREN: The EORTC evaluated single-agent pazopanib for the treatment of soft tissue sarcoma in a nonrandomized phase II trial,[1] as well as a phase III randomized placebo-controlled trial,[2] and then retrospectively studied the effect of gastric acid– suppressive agents on therapy. The authors demonstrated that patients who were taking medications such as ranitidine or omeprazole, particularly those who took them consistently for 80% or more of the time they were on pazopanib therapy, had decreased time to disease progression and survival compared with patients who were not taking these agents. Why would that happen? Pazopanib needs to be in an acidic environment in order for it to be absorbed. Gastric acid–suppressive agents such as ranitidine and omeprazole work to decrease the acidity in the stomach, meaning that pazopanib will not be absorbed as well in patients who are taking these medications.

These data are very important because many patients are on some form of this therapy. We must educate them about this effect, as well as evaluate what we can do if patients require treatment with both pazopanib for sarcoma as well as gastric acid–suppressive agents for reflux disease or other conditions. Some research has focused on this dilemma, in patients taking pazopanib specifically, as well as other drugs that affect the acidity of the stomach. For example, if we test the level of pazopanib in the blood and determine that it is not being absorbed well, we can titrate the dosage. The US Food and Drug Administration–approved dose of pazopanib is 800 mg daily, but we may need to consider increasing the dose in patients taking antacids to reach the level in the blood that will be most effective, much like we do in patients taking digoxin. I would say this method is not likely to become routine, but it may be one way of overcoming this issue.

Another method that has been tested, although not extensively, is spacing out the timing of when the pazopanib and gastric acid–lowering therapy are taken. Spreading them out as much as possible seems to be best, such as taking the pazopanib 10 or more hours after the gastric acid–lowering therapy. Other research has focused on whether the acidity in the stomach can temporarily be increased. One study is evaluating whether taking pazopanib with soda will improve the absorption of pazopanib in patients on acid-lowering agents. I think these studies are all intriguing in terms of what we can do to potentially overcome this issue.

Q: Beyond the effect of gastric acid– lowering agents on therapy, are there any other contraindications or considerations for pazopanib that clinicians should consider?

DR. VON MEHREN: Patients need to take their medication on an empty stomach, which can be a challenge. There are some medications that need to be avoided since they may change how the drug is metabolized and lead to higher or lower drug levels; higher levels may lead to more side effects, and lower levels to less effi cacy. These interactions can occur with some foods as well, such as grapefruit.

Q:Lastly, can you talk about some of the broader hurdles that exist in terms of establishing a diagnosis of soft tissue sarcoma, and in selecting the best therapy for patients with these tumors?

DR. VON MEHREN: I think the biggest hurdle for soft tissue sarcomas is that they are very biologically diverse, and the large number of subtypes makes the diagnosis challenging. Depending on where a patient is cared for, the pathologist’s familiarity with all of the different subtypes may be limited. Certainly, it can help to obtain a second pathology opinion or to have the patient go to a center that has a dedicated sarcoma team, including a sarcoma pathologist, in place. We are increasingly understanding that these tumors are different, and that certain molecular drivers are responsible for them, so directing and selecting therapy based on the specific subtype is important. Twenty years ago, most of our studies collected or treated all patients with soft tissue sarcoma on one study. Increasingly, however, the studies have become more specific to histology. For example, studies might now focus on just liposarcoma, leiomyosarcoma, or disease sites that are even more rare to evaluate whether very specific molecularly targeted therapies are effective. One current study (ClinicalTrials.gov identifier: NCT03148275) is looking at epithelioid hemangioendothelioma with a very specific drug based on the molecular profile of that tumor. So, I think that familiarity with these different subtypes is paramount in patients getting the best care. We need to ensure that patients are being well served by having a good pathology review, as well as access to physicians who have a good understanding of the subtleties of these unique and often rare subtypes.

Financial Disclosure:Dr. von Mehren receives research funding from Novartis (previously GlaxoSmithKline) that is provided to her institution for the conduction of a National Comprehensive Cancer Network– funded trial focusing on pazopanib for the treatment of angiosarcoma.

PERSPECTIVE

Pros and Cons of Oral Cancer Therapy and Necessary Teaching Points for Patients and Providers

Jill Kestel, PharmD, BCOP

The development of numerous oral chemotherapy agents has led to a new paradigm in cancer treatment. While traditionally most cancer patients have been treated with intravenous cytotoxic drugs, several oral drugs are now being utilized routinely for cancer therapy. Oral cancer therapy makes treatment more convenient for patients by reducing administration time, eliminating infusion center visits, and avoiding complications from having a central line. Moreover, pharmacokinetic considerations may also favor oral delivery of drugs by providing exposure to lower concentrations of cytotoxic drugs and may offer higher antitumor efficacy.

However, a major disadvantage of oral delivery of chemotherapy agents is the risk of subtherapeutic drug concentrations. A number of drugs have reduced or unreliable bioavailability in oral form. Food and concomitant medications can significantly affect the pharmacokinetic profile of orally administered drugs. Food may lead to decreased drug absorption due to drug instability in gastric fluids or binding with food. On the other hand, food may actually increase the absorption of other drugs.

In this interview, Dr. von Mehren provides an articulate summary of soft tissue sarcomas, including the results from a new soft tissue sarcoma trial showing decreased overall and progression-free survival with the concurrent use of pazopanib and gastric acid–suppressive agents. With the increased use of oral administration as the route of various molecularly targeted therapies, drug-drug interactions have become apparent. Many tyrosine kinase inhibitors have shown pH-dependent solubility. This solubility might be decreased by the coadministration of gastric acid–suppressing agents. Pazopanib is most effectively absorbed in an acidic environment, with very little absorption at a pH greater than 4. In patients taking proton pump inhibitors (PPIs), the pH of the stomach readily rises to over 4, leading to limited absorption of this drug.

The sarcoma studies discussed in this interview emphasize the importance of obtaining an accurate and complete medication history, including over-the-counter medications, from every cancer patient.[1,2] Frequently, cancer patients experience gastric upset or acid reflux while undergoing anticancer treatments. Since many PPIs and H2 blockers are available without a prescription, cancer patients may be taking these agents, but may not report them as part of their medication history to their oncologist or healthcare providers. Based on the study findings and the interview with Dr. von Mehren, it is very clear that educating cancer patients as well as cancer care providers about this drug-drug interaction is as important, if not more important, than making treatment decisions and choosing anticancer treatments. In an era of targeted and personalized cancer care with more and more anticancer drugs becoming available in oral formulations, educating cancer patients and caregivers on proper medication administration and adherence to established pharmacologic guidelines, as well as clinically significant drug-drug interactions, is critical to ensure our patients are receiving the best possible cancer care.

Financial Disclosure:Dr. Kestel has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

REFERENCES

1. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). J Clin Oncol. 2009;27:3126–32.

2. van der Graaf WTA, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–86.

Dr. Kestel is an Oncology Pharmacist and Senior Analyst at Nebraska Medicine, Omaha, Nebraska.

References:

1. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27:3126-32.
2. van der Graaf WT, Blay JY, Chawla SP, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879-86.