Head and Neck Cancers Coverage from Every Angle

Lenvatinib (Lenvima®) (Thyroid Cancer)

Posted: Tuesday, September 25, 2018

RAI-Refractory Differentiated Thyroid Carcinoma: Rare and Indolent Cancer

Differentiated thyroid cancer represents about 90% of all cases of thyroid cancer and is usually curable with surgery followed by radioactive iodine (RAI) ablation.1,2 In rare cases, tumors become refractory to RAI therapy, and standard treatment approaches such as thyroid-stimulating hormone (TSH) suppression and external radiation may no longer be effective. Such cancers are characterized as RAI-refractory differentiated thyroid cancer, which has an estimated incidence of 4 to 5 cases in 1 million per year.3 Many patients with refractory differentiated thyroid cancer survive for years, even decades, without treatment, because the disease remains stable or grows slowly. However, a few patients have clearly progressive disease and/or a large tumor burden.

In view of the pathways involved in the cellular control of differentiation, proliferation, and survival of differentiated thyroid cancer, some agents that target angiogenesis, particularly those with multiple targets, such as lenvatinib and sorafenib, have been studied and approved for this small but challenging patient cohort.1,2,4 Other drugs, although not labeled for this indication, may also provide some benefit if applied sequentially.4

When to Consider Targeted Therapy

Metastatic, refractory differentiated thyroid cancer is a generally indolent disease, so the decision to start targeted therapy must be carefully considered. As with all such treatment decisions, assessment of the potential benefit must be weighed against the inevitability of treatment-related adverse effects and other treatment-related sequelae.

Experts have defined refractoriness to RAI in a number of ways: some tumors do not take up RAI at all from the first treatment, whereas other lesions may develop resistance over time.1,2 On the basis of results from the pivotal phase III SELECT trial, which compared lenvatinib and placebo in patients with RAI-refractory differentiated thyroid cancer, the investigators observed that the category of refractoriness without consideration of other factors seemed irrelevant to outcomes. In contrast, the critical prerequisite for benefit in terms of the primary endpoint of progression-free survival was pre-existing disease progression. They wrote, “Initiation of treatment with a [tyrosine kinase inhibitor] should be done in order to achieve a specific patient-related outcome, such as tumor response or symptom control.…”2

Eric J. Sherman, MD, a medical oncologist who specializes in the treatment of thyroid and squamous cell carcinomas of the head and neck at Memorial Sloan Kettering Cancer Center (MSK) in New York, explained to JNCCN 360 that “although there are roughly 55,000 cases of thyroid cancer in the United States per year, only about 5,000 to 8,000 end up being RAI-refractory.” Nevertheless, unlike those with lung or pancreatic cancer, for instance, these patients tend to live for many years, he pointed out. “Most thyroid cancer is curable. Even those patients with RAI-refractory disease are usually fit, with only minor, if any, disease-related symptoms at the time metastatic disease is diagnosed,” he said. “The reality is that these patients will cycle through many different regimens over the course of 3 to 5 years. Moreover, although individuals of any age or sex may have thyroid cancer, many of those being treated are younger and may still be fairly active and employed.”

Lenvatinib: A Multitargeted TKI

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), was approved in 2015 for the treatment of locally recurrent or metastatic, progressive RAI-refractory differentiated thyroid cancer.5 The second TKI to be approved in this setting [Editor’s Note: Sorafenib was the first approved TKI6], lenvatinib targets VEGFR1-3, FGFR1-4, PDGFR-α, RET, FRS2α (FGF-receptor substrate 2α), and c-KIT.2,4,7 Lenvatinib is currently preferred by the NCCN Guidelines Panel for Thyroid Carcinoma.4

Unlike in kidney cancer, where lenvatinib has been successfully combined with everolimus, in thyroid cancer, it is used as a single agent. Nevertheless, the potential for improving outcomes by using it in combination is of interest. An ongoing phase II trial8 is exploring the feasibility and efficacy of combining lenvatinib with pembrolizumab in RAI-refractory differentiated thyroid cancer.

According to Melissa Collins, RN, BSN, a nurse on Dr. Sherman’s team at MSK, the decision to begin treatment with lenvatinib is usually determined by evidence of disease progression either on imaging or from symptoms. Despite progressive disease, she observed, “Most of these individuals are in pretty good shape, particularly compared with patients who have refractory disease from other types of tumors.”

The key point to remember about treating thyroid cancer, according to Dr. Sherman, is that it is not as aggressive or rapidly growing as other tumors. Therefore, initiating treatment is not usually an emergency.

Monitoring Blood Pressure on a Daily Basis

Lenvatinib treatment should not be initiated in any patient with uncontrolled or poorly controlled hypertension and should be considered only in those whose blood pressure is well controlled, Dr. Sherman asserted. Patients should be thoroughly instructed in how to use a blood pressure cuff at home. “It’s extremely important for patients to measure blood pressure every day, at around the same time,” he explained. “We emphasize to our patients that they should call us any time the reading exceeds 140/90 mm Hg. We want blood pressure to be reported on a daily basis, because if we don’t hear about significant elevations for even a week, the situation could already represent a hypertensive crisis.”

The potential for elevated blood pressure is correlated with existing hypertension, Ms. Collins told JNCCN 360. If patients already are being treated for hypertension, “we definitely expect blood pressure to increase once they start lenvatinib.”

Although some patients prefer to work with their primary care physician or cardiologist to maintain blood pressure, Dr. Sherman observed that nononcology practitioners “may not grasp the importance of strict control of blood pressure on a daily basis when TKIs are on board. That’s why we prefer to manage the blood pressure ourselves, by staying in close contact with the patient,” he said.

Describing his team’s approach to an increased blood pressure reading, Dr. Sherman said that if blood pressure goes up to 150/90 mm Hg, “we might continue treatment but initiate an antihypertensive regimen. However, if blood pressure is 180/100 mm Hg, we would hold lenvatinib, start antihypertensive treatment, and wait for the blood pressure to stabilize before restarting lenvatinib.”

Elaborating on the team’s response to treatment-related hypertension, Ms. Collins noted that if blood pressure increases again, “we might make some other adjustments to the antihypertensive regimen. But if it becomes clear that the blood pressure spikes every time the full dose of lenvatinib is tried, we will reduce the dose.”

If it becomes clear that the blood pressure spikes every time the full dose of lenvatinib is tried, we will reduce the dose.

Managing Loss of Appetite and Fatigue

A key aspect to caring for patients on lenvatinib, according to Ms. Collins, is managing loss of appetite. “We encourage small, frequent meals and educate patients about diet,” she told JNCCN 360. She advises patients to avoid fried and greasy foods, as they can also add to nausea and anorexia, and encourages small amounts of lean meats, fruit, complex carbohydrates, and vegetables. One of the most helpful tips, she said, is that patients should try to eat a little bit throughout the day, rather than larger, heavier meals. If the loss of appetite is persistent, “we might try an oral megestrol suspension.”

For fatigue, which is a common complaint in patients treated with TKIs, “we suggest that patients listen to their bodies and rest when they need to,” Ms. Collins said. “On the other hand, we encourage patients to increase their physical activity and not become too sedentary because that often results in worsened fatigue.” She noted that sometimes fatigue responds to a simple increase in fluid intake, including beverages such as coconut water, which can be beneficial. However, if fatigue is persistent and distressing, “we also consider holding the drug to allow for recuperation and will consider dose reduction if indicated.”

Effects on Extremities, Gastrointestinal Tract, Kidneys, and Liver

Hand-Foot Syndrome

Unlike with sorafenib, “we do not begin prophylaxis for hand-foot (palmar-plantar erythrodysesthesia) syndrome when patients start lenvatinib,” Dr. Sherman said. “Nevertheless, we instruct patients to call us as soon as they note any symptoms, so we can start treatment before a severe situation develops.” 

If tenderness or soreness of the extremities is reported or if patients notice difficulty with buttons or a different sensation in their fingers and toes, Ms. Collins added, “we usually use steroid creams (and pain medication, if needed) and try to get the palmar-plantar erythrodysesthesia under control as soon as it appears.” Gel insoles and comfortable shoes may also be helpful. “It’s easier to manage these symptoms if you catch them early,” Ms. Collins stressed. “This is an important point because it is difficult to bring palmar-plantar erythrodysesthesia under control once it has become severe.” When necessary, she pointed out, “we also refer the patient to dermatology colleagues for their expertise and continued management.”

Nausea, Diarrhea

If queasiness is an issue, Ms. Collins recommends taking lenvatinib with food or after a meal. “We provide a prescription for an antiemetic, so patients will have it on hand, just in case it is needed,” she said. Loperamide may help to keep diarrhea under control.

Renal, Hepatic Dysfunction

At the start of treatment, patients should be seen every 2 weeks to make sure they are tolerating the medication well at home; urinary protein and creatinine levels should be checked at each of those early visits. Values out of the normal range will trigger additional tests, such as a 24-hour urine collection. If those tests demonstrate persistently abnormal results, “we may need to consider discontinuing lenvatinib treatment,” Ms. Collins said.

Although hepatic dysfunction is less likely with lenvatinib than with pazopanib, Dr. Sherman told JNCCN 360, “we check liver enzymes regularly. Likewise, it’s important to check for proteinuria about a month after starting treatment and then every couple of months by doing a spot urine protein and urine creatinine. Other methods may be used, but we have found this method to be quick and sensitive. If the ratio of the urine protein over the urine creatinine is above 1 mg/dL, we would next order a 24-hour urine collection for protein. Neglecting to do so can result in nephrotic syndrome,” he cautioned.  

Red Flags

In some cases, Dr. Sherman indicated that he may order magnetic resonance imaging of the brain before starting lenvatinib “because we worry about bleeding in the brain with TKIs. It’s not a common finding, but it’s prudent to rule it out,” he added. Once treatment has started, “we want to be vigilant about blood clots, so if patients report chest pain, difficulty breathing, or swelling in a leg, we need to check them immediately.”

Ms. Collins listed the “red flags” she reviews with patients and instructs them to call about right away: persistent headache, dizziness, or balance/coordination issues; swelling and/or pain in the lower extremities; chest pain/pressure; or persistent high blood pressure. “Any of these symptoms would cause us to be concerned about a bleed, blood clot, or dangerously high blood pressure that could result in a cardiac event such as a stroke,” she explained to JNCCN 360.  

Maintaining Low Threshold for Dose Reduction

“We want patients to have a reasonable quality of life during treatment,” Dr. Sherman stressed. “It is not necessary for patients to ‘push’ through miserable adverse effects. We know that 70% of patients in lenvatinib studies eventually required dose reduction. Our threshold for reducing the dose, therefore, is low.” In addition, he noted, unless a patient has an aggressive tumor, dose reduction should be considered to help patients stay functional and comfortable. “We have had patients come to us from the community, struggling with miserable adverse effects from full-dose treatment when it is not necessary,” he related. 

The other benefit of having a low threshold for holding or reducing the dose is that patients trust the provider to help them manage whatever discomforts develop. This is important for proper adherence. “If patients think the practitioner will urge them to continue treatment despite adverse effects, they are more likely to skip pills or adjust the dosage themselves,” Dr. Sherman observed. However, if patients know the provider is “on his or her side” and is willing to make dose adjustments, they may be more likely to be honest and to follow instructions, he suggested.

If patients think the practitioner will urge them to continue treatment despite adverse effects, they are more likely to skip pills or adjust the dosage themselves.

Tips for Practitioners

A portable blood pressure machine is usually included with the lenvatinib medication kit sent to patients when they start treatment, Ms. Collins explained. “If not, we advise patients to obtain a machine and instruct them to measure their blood pressure at home daily, keeping a record of each reading, which they should bring with them to each doctor visit. This way, we can see how their blood pressure has been trending at home. We give patients parameters for their blood pressure, educating them to contact the doctor’s office for any readings higher than 140/90 mm Hg.”

Adherence is always a concern with oral medication, so Ms. Collins recommends that patients take their medication around the same time every day. Most of these patients are on multiple medications, she noted, so any schedule that works and makes sense to them should be fine, provided it is consistent. 

Providers and patients need to recognize “there will definitely be some adverse effects with lenvatinib, especially in the beginning of treatment,” Dr. Sherman said. Close communication should be maintained, and patients should be helped to manage any symptoms that develop as early as they are reported. “After a few months,” he continued, “you and the patient know what to expect.” But, in the beginning, he advised watching the patient carefully for hypertension, hand-foot syndrome, and diarrhea as well as having a low threshold for reducing the dose. It is often better to hold the dose and let the patient recover from a symptom than to maintain treatment while trying to manage the symptom, he recommended. “It is usually not necessary to maintain treatment at the highest dose level if quality of life and/or function is affected,” he explained.

Although lenvatinib and sorafenib are approved for RAI-refractory differentiated thyroid cancer, Dr. Sherman noted there are other drugs (eg, pazopanib, axitinib, sunitinib, cabozantinib) that affect the same targets and may be considered sequentially. And, “lenvatinib has proven efficacy when other TKIs have failed,” he said. “Therefore, as an overall strategy, it may be reserved for a later line of therapy.”

It is often better to hold the dose and let the patient recover from a symptom than to maintain treatment while trying to manage the symptom.



Eric J. Sherman, MD, disclosed that he has served as a consultant for Eisai, Goldilocks Therapeutics, Bristol-Myers Squibb, Novartis, and Cota Healthcare and has received research funding from Roche and Plexxikon.

Melissa Collins, RN, BSN, disclosed no relevant relationships.



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