Ravin Ratan, MD, MEd, assistant professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the steps that should be taken to diagnose desmoid tumors.

Desmoid tumors are rare, occuring in approximately 900 to 1,500 people in the United States each year. As a result, the diagnosis is not routinely thought of in the community setting when a patient presents with limb swelling, pain, or stiffness, Ratan explains. Often, patients with these symptoms will have self-limiting conditions that do not require immediate imaging or further workup. As such, it can take months to years for patients to be diagnosed. 

Patients may also be diagnosed incidentally after having imaging done for a reason other than to look for a desmoid tumor, Ratan says. Ultimately, given their rarity and vague symptom presentation, clinicians do not have a high degree of suspicion for desmoid tumors when diagnosing a patient. When a patient is diagnosed with a desmoid tumor, it is important that their resected tumor or biopsy be sent to an experienced pathologist, Ratan adds. 

The treatment of patients with desmoid tumors has evolved, but standard sequencing strategies are not established for patients, Ratan says. Moreover, no therapies are FDA approved for use specifically in patients with desmoid tumors, underscoring the need for individualized treatment regimens. 

Although most desmoid tumors are not lethal, the location and symptom burden associated with the tumor, as well as patient preference, can inform how aggressive therapy should be. For example, extensive surgery with reconstruction would be required for patients with intra-abdominal desmoid tumors. However, as the field has shifted away from surgery, that type of aggressive intervention may not be optimal. Even with the limited use of surgery, patients with small desmoid tumors in the thigh, for example, may be best suited for surgery.

Several systemic therapy options with varying efficacy and toxicity can be used for patients with desmoid tumors. For example, TKIs like sorafenib (Nexavar) and pazopanib (Votrient) are used in most patients who require treatment because of symptoms or progressive disease. In patients with desmoid tumors in dangerous locations or that are highly symptomatic, cytotoxic chemotherapy with doxorubicin and dacarbazine can be considered, Ratan says. Incidentally discovered tumors, on the other hand, may be actively monitored or treated with anti-estrogen agents like tamoxifen, Ratan concludes.

Funding from SpringWorks Therapeutics/Content Developed Independently by OncLive

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Ravin Ratan, MD, MEd, discusses the steps that should be taken to diagnose desmoid tumors.  



Dr. Ratan on the Steps of Diagnosing Desmoid Tumors 

Despite their rarity, the management of desmoid tumors has been an area of significant clinical change as the field has shifted away from aggressive surgical interventions to active surveillance and systemic therapies that are less morbid for patients, said a group of experts during interviews with 

®, adding that the field will continue to evolve as treatment-informing tools emerge to guide decisions and improve outcomes.

“We want to turn this into a disease that is amenable with systemic therapies rather than surgery,” stated 

, a professor in the Department of Pathology of the Division of Pathology/Lab Medicine, an academic surgical pathologist, director of the Sarcoma and Melanoma Clinical Genomics Program, and director of the Selective (Soft Tissue) Pathology Fellowship Training Program at The University of Texas MD Anderson Cancer Center in Houston, Texas.

, The David Linn Endowed Chair for Orthopaedic Surgery, professor and chair, Department of Orthopaedic Surgery, University of California (UC) Davis Comprehensive Cancer Center, UC Davis Health

, director, Sarcoma Medical Oncology, deputy associate director, Clinical Research, University of Colorado Medicine in Aurora

, associate professor, assistant director of clinical research, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida

,assistant professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, Texas

The experts highlighted key challenges that remain in the management of desmoid tumors, emerging systemic options that are positioned to transform the paradigm further away from surgical interventions, and the importance of getting second opinions in this space.

What current challenges exist regarding identifying and diagnosing desmoid tumors?

The big challenge with desmoid tumors is that they are rare. Not everybody has a lot of experience with them, so that creates some challenges [in the accuracy and timing of the diagnosis]. The other challenge is that under the microscope, they look a lot like reactive fibrosis or a scar. Unless one is thinking about desmoid tumors and including it in the differential diagnosis, we may not think about it as a diagnosis. We may think it is the reactive part of another [ongoing] process.

: Desmoid tumors are very rare, in the range of a couple hundred cases a year in the United States. In practical terms, that means that most doctors a patient interacts with don’t see these often or might not know they exist. If a patient in the community is noticing swelling in an arm or leg, pain, stiffness, or any of the myriad of symptoms desmoid tumors can present with, it is likely that the doctor caring for them is not going to jump to a desmoid tumor [diagnosis]. The reality is that they probably shouldn't because most of those aches and pains are going to be conditions that are self-limited and don’t require immediate work-up. However, patients often have to persist and raise these symptoms over and over again before they are taken to a place for imaging or further work-up that results in the diagnosis of a desmoid tumor.

The other pathway we see to diagnosis is a patient had imaging done for some other reason, which incidentally finds a mass diagnosed as desmoid tumors. That is one issue. There isn’t a high index of suspicion ever for desmoid tumors because symptoms are often vague.

The second issue is once a mass is diagnosed and removed or biopsied, making sure that specimen gets put in front of a pathologist who has some expertise in the diagnosis of soft tissue tumors or desmoid is important. That doesn’t happen uniformly. By the time someone makes it to me at a specialty center, they usually come with a diagnosis, but that diagnosis can take months or longer.

: If a patient has a known desmoid tumor, the first bridge to cross is whether they have an 

 mutation and whether they are at risk for Gardner syndrome or multiple desmoid fibromatosis and polyps. That is hurdle No. 1. We know that patients with Gardner syndrome [can] have multiple relapses…because they [can] have multiple desmoids. Those patients need to be watched more aggressively than patients who do not have the mutation. Genetic counseling for patients with a solitary desmoid tumor, especially if they have a history of colon cancer in the family, is strongly recommended.

What challenges exist in terms of managing patients with these tumors?

: The first inclination most people have when they are told they have a desmoid tumor is to cut it out. The problem is that doing surgery on desmoid tumors can trigger recurrences in a fair number of patients, as many as up to 50% of tumors can recur after surgery. It’s important not to necessarily jump into surgery and to, instead, learn about different [treatment] options. Some desmoid tumors can regress on their own. [Approximately] 20% of desmoid tumors will simply go away by doing nothing. The biggest [things for patients] are to find an expert [on soft-tissue sarcoma], have their individual case analyzed [by a multidisciplinary team], and learn about the whole spectrum of options before jumping into a surgery or other procedure.

: The challenge right now in the field is determining at what point and in which cases do we decide to go with aggressive treatment and which we continue watchful waiting. We are hoping that some of the new oral or intravenous systemic therapies can make a real difference for these patients in absence of surgical management, which can sometimes be mutilating.

How often do you see patients with a misdiagnosed desmoid tumor? What are some best practices for avoiding that?

: There can sometimes be misclassification, but probably more importantly, we have seen a delay in diagnosis because it takes people awhile to come up with the idea [of desmoid tumors] or to [transfer the case] to someone who has more experience with this disease. Because we have a lot more tools to differentiate different types of spindle-cell neoplasms, the number of misdiagnoses has probably gone down over time. However, there is still some delay in diagnosis because of challenges in recognizing this disease as a definitive tumor as opposed to a reactive process.

: If a patient is told that they have a very rare tumor, [such as] a desmoid tumor, the first thing they need to do is have their tissue rereviewed at a [center specialized in soft-tissue sarcomas]. That means sometimes asking for a second opinion or asking whoever did their biopsy to send it to an expert center. I have had patients with desmoid tumors who were told they have a full-blown sarcoma and needed chemoradiation. I’ve also had patients who were told they had benign disease when they did have a full-blown sarcoma that required additional therapies. This goes for any diagnosis of a cancer, precancer, or benign tumor––second-opinion review by an expert center for rare diseases is critical to ensure the diagnosis is accurate.

What is your current treatment approach for these patients? Has it changed with recent advancements in available therapies?

: Old school thinking was surgery. Now we have specific guidelines that were put together by the Desmoid Tumor Research Foundation. Sarcoma experts recommend we limit surgery after observation to an area that would not cause any long-term dysfunction. The tumor might die out over time, but once we remove something surgically, we can’t bring it back. We don’t want to leave someone with a deficit.

If we do medical management, adverse events [AEs] can be reversed and, to our knowledge, we don’t see many long-term complications with most of our systemic therapies. Some [systemic options] can cause long-term complications, but they are much less than that of surgery. Systemic therapy is recommended based on where the tumor is located, how symptomatic the patient is, and whether [the desmoid tumor] is potentially organ- or life-threatening.

Mesenteric masses are probably the most dangerous, per se, and would be [treated with] sorafenib [Nexavar] in the first-line setting or chemotherapy if it is bothersome [to the patient].

The sorafenib dose is 400 mg, which is different from the cancer dose of 800 mg. It tends to be well tolerated although there are certain AEs, such as hand-foot-skin reaction, rash, elevated blood pressure, nausea, and diarrhea; however, most of those can be controlled with concomitant medications or stopping the drug for a bit then restarting. We don’t know the long-term complications of these drugs because they haven’t been around long enough.

With the chemotherapy, that is a different situation. Those patients can have more AEs, including pancytopenia, infections, hair loss, and secondary cancers about 5 years [after stopping chemotherapy]. We have to think about [those AEs] and [reserve chemotherapy] for when [a desmoid tumor] is really threatening, like intra-abdominal tumors or tumors near the neck that can press on important structures.

In terms of treatment selection, what factors need to be considered?

: Don’t make the treatment worse than the disease. Historically, we used to think of desmoid tumors [as] cancers and [use] aggressive [regimens to gain] local control at any expense. We dealt with the repercussions after, but sometimes we mutilated some of these patients all for the concept of a negative margin and left them with a worse problem than when they started.

Sometimes, a very well-intended but inexperienced surgeon in the realm of desmoid tumors treats these patients aggressively with surgery and radiation, leaving them left with disfigurement, pain, and identity issues. Don’t make the treatment worse than the problem. The take-home message for medical oncologists is to slow down, talk to someone who has experience with desmoid tumors, and then have a very informed discussion with the patient.

Historically, surgery plus or minus radiation therapy was the best treatment modality for patients with desmoid tumors. Now, surgery plays an important but less broad role in the management of desmoid tumors. Often, someone will come in with a solitary desmoid tumor. The first-line option is to watch it if it isn’t bothering them to look for progression. If it looks like it is progressing, there are a variety of noncytotoxic and cytotoxic medical therapies that can be offered.

: The most important consideration [for patients] with desmoid tumors is the course of the disease. If the patient has stable disease, they can be safely watched . If it is a disease that is rapidly progressing and causing other problems in terms of pain or dysfunction, we have to quickly think about other interventions we can do, such as surgery, radiation, or systemic therapies.

What systemic options have demonstrated efficacy in this patient population?

: Sorafenib was studied in a phase 3 trial [NCT02066181] for [patients with] desmoid tumors, which was amazing because this is a rare disease, but we were able to do a phase 3 study.

 That study was a slam dunk. Clearly, this is an active drug. There are AEs with [sorafenib], but many times, this is a great option for patients to consider.

Please speak to some of the emerging systemic therapies we’re seeing in this space.

: We have some new clinical trials with gamma-secretase inhibitors [GSIs]. We have DeFi, the phase 3 clinical trial [NCT03785964] comparing nirogacestat with placebo. That trial is currently closed to enrollment, so we are anxiously awaiting the results of that.

: We are all excited to see if [nirogacestat] could potentially be [a] drug approved for [patients with] desmoid tumors. [Nirogacestat] looked promising in older [data from] phase 2 studies and the [phase 3 data] is about to reach maturity. Interventional approaches, such as cryoablation where we can freeze the tumor, have also become exciting. These are areas of active investigation.

 Some direct inhibitors of β-catenin, which is the gene that is normally mutated in these tumors, [are under investigation]. β-catenin drives oncogenesis, and some direct inhibitors of that pathway may have some efficacy as well [for patients with desmoid tumors].

: There is another drug called tegavivint, which is also being investigated [for] the treatment of desmoid fibromatosis. That drug works a little bit differently as it is not a GSI. It is a drug that seems to directly look at the interaction between β-catenin and TBL1, which stabilizes β-catenin. Accumulation of β-catenin [results in cell proliferation]. Tegavivnt seems to reverse that accumulation [of β-catenin] through direct inhibition between β-catenin and a stabilizing protein.

What are the most pressing unmet needs in this space, and how are they being addressed?

: In general, the types of desmoid tumors that are the hardest to deal with are those that occur in conjunction with a disease called familial adenomatous polyposis [FAP]. Most desmoid [tumors] are sporadic and we don’t know what causes them. They [can] occur in one place and are sometimes associated with an injury [or surgical procedure]. However, people with FAP have an inherited tendency to develop desmoid tumors. The problem is that they can get multiple desmoids in multiple locations, often inside the abdominal cavity. These tumors can be very difficult to treat or manage.

Those are the patients who I’ve had the biggest challenges with creating meaningful quality of life because they go through multiple surgeries and may have long-term issues from bowel obstructions or resections. Our hope is that newer drugs will prove to be just as effective in that group of patients, but that is an area where we still have big challenges to help our patients live better lives and control the disease.

What does the future look like in this space?

: We have a lot more tools for [desmoid tumors] than we used to. Some of these new systemic therapies have demonstrated efficacy or are currently in clinical trials, which will give us new tools. We now know also that watchful waiting can be an effective way to follow and manage these patients.

What would be helpful are algorithms to evaluate patients so that we [can identify] which [optimal treatment strategies for] patient. Right now, the default, unless we can’t do otherwise, is watchful waiting. Then, as the biology of the disease reveals itself, we start thinking about what interventions we could use to benefit the patient. 

Gounder MM, Mahoney MR, Van Time BA, et al. Sorafenib for advanced and refractory desmoid tumors. 

. 2018;379(25):2417-2428. doi:10.1056/NEJMoa1805052

Articles

Despite their rarity, the management of desmoid tumors has been an area of significant clinical change as the field has shifted away from aggressive surgical interventions to active surveillance and systemic therapies that are less morbid for patients.

Current Management Strategies for Desmoid Tumors Are Marked by Less Surgery, More Systemic Options

Alexander J. Lazar, MD, PhD, academic surgical pathologist, professor, Department of Pathology, Division of Pathology/Lab Medicine, director, Sarcoma and Melanoma Clinical Genomics Program, director, Selective (Soft Tissue) Pathology Fellowship Training Program, The University of Texas MD Anderson Cancer Center, discusses the current state of diagnosis and treatment in desmoid tumors.

Desmoid tumors are rare and look like reactive fibrosis or scarring, so they can be challenging to diagnose, Lazar explains. Unless desmoid tumors are included as potential diagnoses in the differential, clinicians who do not have a lot of experience with these tumors may diagnose them as being the reactive part of another process. 

However, improvement in tools to differentiate spindle-cell neoplasms, misdiagnoses are not as common with desmoid tumors. Despite this, delays in diagnosis remain because desmoid tumors can be challenging to recognize as definitive tumors, Lazar adds. 

Historically, patients with desmoid tumors were treated aggressively with surgery and sometimes radiation, Lazar explains. However, it’s been shown that patients can receive active surveillance and that early surgical interventions are not needed for all patients. Moreover, emerging oral or intravenous systemic therapies have the potential to further minimize the need for surgical interventions, which pose a morbidity and mortality risk to patients, Lazar says. 

Although active surveillance is the standard therapy for patients diagnosed with desmoid tumors, determining which patients require more aggressive treatment remains an area of unmet need, Lazar says. Oftentimes, patients with stable disease are best suited for active surveillance, but patients with disease-related pain or dysfunction should receive surgery or radiation. 

Moreover, emerging systemic therapies, such as sorafenib (Nexavar), gamma-secretase inhibitors, or beta-catenin inhibitors, may be indicated for patients in need of more aggressive therapies, Lazar concludes. 

Alexander J. Lazar, MD, PhD, discusses the current state of diagnosis and treatment in desmoid tumors.  



Dr. Lazar on the Current State of Diagnosis and Treatment in Desmoid Tumors 

Breelyn Wilky, MD, director, Sarcoma Medical Oncology, deputy associate director, Clinical Research, associate professor, Medicine-Medical Oncology, University of Colorado Medicine, discusses the diagnosis and management of desmoid tumors.

Desmoid tumors are a type of soft tissue tumor that often occur spontaneously and are localized to one area of the body, such as the leg, arm, or trunk, Wilky says. Like sarcomas, desmoid tumors are rare, so patients are often misdiagnosed with a bone spur or cyst. As such, it is critical for patients to seek a second opinion from a soft tissue tumor specialist to confirm an accurate diagnosis.

Historically, surgery was the mainstay of treatment for patients with desmoid tumors. However, surgical resection can trigger recurrences of desmoid tumors in up to 50% of patients. Alternative options, such as observation or systemic therapy, should be considered as approximately 20% of desmoid tumors regress without surgical or therapeutic intervention, Wilky explains.

If patients require treatment because they have pain or their tumor is in a potentially life-threatening location, such as the abdominal wall or chest, hormone-blocking agents, traditional chemotherapies, and targeted therapies, such as sorafenib (Nexavar), are potential systemic options, Wilky says. Additionally, novel agents, such as nirogacestat, and interventional approaches, such as cryoablation, are being evaluated to expand the therapeutic paradigm.

Notably, desmoid tumors that occur in conjunction with familial adenomatous polyposis are particularly challenging to manage because patients have an inherited tendency to develop multiple desmoid tumors in multiple areas, such as the abdominal cavity. In these cases, it can be difficult to maximize quality of life as many patients have undergone multiple surgeries and have complications from bowel obstructions or resections. Although the field hopes that novel agents like nirogacestat will be effective in this patient population, this subgroup represents an area of unmet need, Wilky concludes.

Breelyn Wilky, MD, discusses the diagnosis and management of desmoid tumors.  



Dr. Wilky on the Diagnosis and Management of Desmoid Tumors

Gina Z. D’Amato, MD, associate professor, assistant director of clinical research, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses optimizing treatment for patients with desmoid tumors.

All patients with desmoid tumors should be observed initially until they develop indications for treatment, D’Amato says. Indications for treatment include tumor growth that could impede or threaten quality of life or cause deformity, dysfunction, or pain. Additionally, growing tumors may be observed, unless they are in areas such as the intra-abdominal wall where other organs can be affected, the head or neck where major blood vessels are involved, or the appendages where they may hinder activity, D’Amato explains.

Historically surgery was the mainstay of treatment for patients with desmoid tumors; however, the field is significantly limiting surgery now because these tumors may regress or disappear without therapeutic intervention, D’Amato says. Now, based on recommendations from the Desmoid Tumor Working Group guidelines, surgery is indicated only in cases where resection will not cause deformity, such as the intra-abdominal wall.

If treatment is indicated, systemic therapy offers patients a less morbid alternative to surgery, D’Amato says. Systemic treatment selection is based on factors, such as tumor location and patient symptoms. Typically, sorafenib (Nexavar) is the recommended first-line therapy and is generally well tolerated. Systemic chemotherapy can also be considered, although it is associated with substantial toxicities, D’Amato concludes.

Gina Z. D’Amato, MD, discusses optimizing treatment for patients with desmoid tumors.   



Dr. D’Amato on Optimizing Treatment for Patients With Desmoid Tumors  

Richard F. Riedel, MD, associate professor of medicine, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, medical oncologist, Duke Cancer Center, Duke Health, discusses the challenges of diagnosing and treating patients with desmoid tumors.

Desmoid tumors are bland in appearance and can occur spontaneously anywhere in the body, Riedel says. The tumors are often indolent and cannot metastasize; however, they can grow to be locally invasive and aggressive. Although uncommon, patients who seek medical attention and undergo a biopsy could be misdiagnosed with low-grade sarcoma, for example. As such, pathologic confirmation of the diagnosis with immunohistochemistry is recommended.

Research is ongoing to evaluate gamma-secretase inhibitors as potential therapeutic options in patients with desmoid tumors, Riedel explains. These agents inhibit the Notch pathway, which may prevent tumor growth in these patients. Nirogacestat, a gamma-secretase inhibitor, is being evaluated in the phase 3 DeFi trial (NCT03785964) in patients with desmoid tumors or aggressive fibromatosis. Other agents, such as AL102, are being investigated. Finally, combination therapies could emerge as options to improve upon single-agent systemic and chemotherapeutic regimens, Riedel adds.

Notably, to mitigate some of the diagnostic and therapeutic challenges experienced in the field, education in community practices is needed, Riedel says. It should be underscored in clinical practice that surgical resection may not be the optimal treatment approach because desmoid tumors may disappear with observation and surgery can cause unnecessary complications. Additionally, patients should be treated by a multidisciplinary care team that includes medical, surgical, and, in some cases, radiation oncologists, to individualize patient care, concludes Riedel.

Richard F. Riedel, MD, discusses the challenges of diagnosing and treating patients with desmoid tumors.   



Dr. Riedel on the Challenges of Diagnosing and Treating Patients With Desmoid Tumors  

R. Lor Randall, MD, FACS, professor and The David Linn Endowed Chair for Orthopaedic Surgery and professor and chair of the Department of Orthopaedic Surgery, University of California Davis Health, discusses initial considerations when treating patients with desmoid tumors, a type of soft tissue sarcoma.

It is important to establish up front whether a patient with a diagnosed desmoid tumor harbors an 

 mutation, which would put them at risk for Gardner syndrome, multiple desmoid fibromatosis, and polyps, Randall explains. Patients with Gardner syndrome need to be monitored aggressively because they tend to have multiple relapses at multiple sites because they have several desmoids. As such, genetic counseling should be strongly considered for patients with a solitary desmoid tumor, particularly if they have a family history of colon cancer, Randall says.

Additionally, it is critical to weigh the risks and benefits of treatment for patients with desmoid tumors to ensure the treatment doesn’t cause more harm to the patient than surveillance, Randall says. Notably, not all patients with a desmoid tumor require aggressive local treatment, which was standard of care historically. In the past, some patients would be disfigured from aggressive treatment with the goal of negative margins; however, their disease likely didn’t require such interventions.

This concept has been observed in patients with desmoid tumors of the chest wall or breast implant–associated desmoid tumors, Randall explains. Moreover, treating patients with desmoid tumors with aggressive surgery and radiation therapy can lead to disfigurement, identity issues, and pain. Therefore, it is critical to get insight from a provider who has substantial experience in managing desmoid tumors before making treatment decisions for patients, Randall adds.

Historically, patients with desmoid tumors who required treatment underwent surgery with or without radiation therapy. Although surgery still plays an important role in the management of desmoid tumors, it has become less prominent. As such, the guidelines now are to monitor patients when their tumor is not progressing. If they have progressive disease, several noncytotoxic and cytotoxic therapies can be considered, Randall concludes.

R. Lor Randall, MD, FACS, discusses initial considerations when treating patients with desmoid tumors.

