AFINITOR is contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives, or any excipients. There have been reports of noninfectious pneumonitis (including some with…
Advanced Pancreatic Neuroendocrine Tumor (NET)
Dr Strosberg typically starts patients with a 3-phase CT scan of the abdomen, and uses an OctreoScan™* to assess disease stage. In order to obtain an accurate diagnosis, he performs a chromogranin or synaptophysin stain. He also determines whether the patient should receive targeted (poorly differentiated tumors) or systemic treatment (well-differentiated tumors).
*OctreoScan is a registered trademark of Mallinckrodt, Inc.
Drs Strosberg and Pommier are paid consultants of Novartis.
Dr Pommier: So Dr Strosberg, as we already mentioned, patients often are diagnosed at advanced stage disease, typically with imaging. In your practice, in your opinion, do you find that patients have already received the appropriate imaging diagnostic work-up?
Dr Strosberg: Not always. We generally recommend appropriate scans of the abdomen, typically multiphase CT scans or MRIs. The standard contrast CT scan is often suboptimal for evaluating hypervascular liver metastases or identifying a small subtle tumor in the pancreas. Another common baseline imaging modality we obtain is OctreoScan™, which is useful for whole-body imaging and staging.
Dr Pommier: Functional tumors, and even with the nonfunctional tumors, biomarkers often come into an important role, so how would the biomarker work go?
Dr Strosberg: So, for functional tumors I think it’s a good idea to try and tailor the biomarker that you measured to the syndrome. So, for an example, patients with heart rate and diarrhea, one would obtain a serum gastrin. Patients that present with hypoglycemia, it is a good idea to get insulin, proinsulin, and C peptide. I prefer that to sort of a panel approach to hormones. There are of course nonspecific tumor markers such as chromogranin A, pancreastatin, pancreatic polypeptide. There is actually a very long list. I usually like to get one or two and, if they are elevated at baseline, continue to monitor them over time.
Dr Pommier: And how about the pathology?
Dr Strosberg: Pathology is really critical and it’s a good idea to try to obtain a good amount of tissue. Sometimes, we have to make do with the fine-needle aspiration but we prefer at least a core biopsy. The reason this is important is, first of all, to get the accurate diagnosis to be able to do appropriate immunohistochemical stains such as chromogranin or synaptophysin, which will help establish the diagnosis for the neuroendocrine tumor. And then, of course, for assessment of differentiation in grade which has critical prognostic implications. Differentiation really refers to the extent to which the cancer cell resembles the endocrine cell of origin. Tumors that are well differentiated tend to consist of small uniform cells often arranged in islets or trabeculae. Poorly differentiated tumors tend to be much more pleomorphic, often with large areas of necrosis. Grade refers more to the proliferative activity of the tumor which is typically measured either by the mitotic rate, number of mitosis per 10 high-power fields, or the KI-67 index, or both ideally. Well-differentiated tumors tend to be low grade and poorly differentiated tend to be high grade. But that is not always the case.
Dr Pommier: So does the pathologic grade have any impact on the treatment decisions?
Dr Strosberg: Well, it certainly does, as well as on the prognosis. High-grade tumors tend to be very aggressive. They are often treated with cytotoxic regimens, similar regimens to what we use in small-cell carcinoma. Well-differentiated or low-grade tumors are often treated with the kind of systemic targeted treatments.
Drs Pommier, Anthony, Strosberg, and Phan are paid consultants of Novartis.
Dr Pommier: Pancreatic neuroendocrine tumors or NETs are rare clinical tumors distinct from other neuroendocrine tumors. The incidence of neuroendocrine tumors is increasing in the United States, but the incidence is probably still underestimated. So, Dr Anthony, how do patients with pancreatic neuroendocrine tumors, who typically present quite late in their stage, present at the time of diagnosis and what factors do you think contribute to this late diagnosis?
Dr Anthony: Well Rod, the symptoms are fairly nonspecific and that contributes a lot to the late diagnosis. These symptoms may be intermittent pain that’s fleeting, it may be even something like hypoglycemia that are misdiagnosed or misinterpreted as being either as a psychiatric disorder or sometimes I have even seen a seizure disorder because of the hypoglycemia. So patients are misdiagnosed and then they are diagnosed when a confluence of symptoms may come together such as maybe nausea, jaundice, or weight loss so it’s typical with a delay of interpreting symptoms is not uncommon to see these patients with advanced disease come as their initial presentation. So, with this comes a worse prognosis.
Dr Pommier: What are some of the common misdiagnoses among patients with pancreatic neuroendocrine tumors?
Dr Strosberg: One common misdiagnosis of neuroendocrine tumors is adenocarcinoma which is actually not that uncommon when you’re talking about pancreatic neuroendocrine tumors. Obviously that leads to a completely different type of treatment than one would administer for neuroendocrine tumors. Another misdiagnosis is that patients present with liver metastases undergo a biopsy that simply says carcinoid tumor and the clinician fails to recognize the primary tumor is actually in the pancreas, so that happens fairly commonly.
Dr Pommier: Dr Phan, what are the common syndromes that we see when patients with functional pancreatic neuroendocrine tumors are diagnosed?
Dr Phan: That’s a very good question. Patients that have functional neuroendocrine tumor of the pancreas typically present with symptoms that are typical or specific to the hormone that is being overproduced. For example, a patient can present with very refractory gastric reflux from gastrinoma. Or patients can have symptoms of hypoglycemia from insulinoma. Occasionally, patients will have symptoms from dehydration, electrolyte abnormalities from diarrhea, watery diarrhea from VIPoma. Other patients will have symptoms related to rashes, that’s from typically glucagonoma. So those are the typical symptoms that patients come in with that are functional neuroendocrine tumor.
Dr Pommier: Ok. But most of the tumors are actually nonfunctional. So in contrast, how do the patients with nonfunctional pancreatic neuroendocrine tumors come to diagnosis?
Dr Phan: So nonfunctioning pancreatic neuroendocrine tumors in my practice, typically come in after they have symptoms related to obstructive jaundice, new onset diabetes, vague symptoms of abdominal pain, nausea, and even weight loss and abdominal bloating. These are symptoms that are oftentimes misconstrued for other types of diseases, which leads patients with nonfunctioning neuroendocrine tumors to be more likely to be diagnosed later in their stage of disease.
Dr Anthony explains that the RADIANT-3 is the largest phase 3 clinical trial in the treatment of advanced, progressive PNET. The primary object response was progression-free survival. Other end points included response rates, overall survival, and safety signals. The major finding of RADIANT-3 was a significant increase in progression-free survival among the AFINITOR patients.
Drs Pommier and Anthony are paid consultants of Novartis.
Dr Pommier: All of us here were involved in the RADIANT-3 Trial, which stood for RAD 001, which was the initial name of AFINITOR in advanced neuroendocrine tumors. And Dr Anthony, what were the key criteria in the terms of design of the RADIANT-3 Trial?
Dr Anthony: Rod, the RADIANT-3 Trial was the largest randomized, placebo-controlled study that was done in this rare disease. This was a global trial, approximately 410 subjects were randomized 1:1, either to AFINITOR at 10 mg per day, or placebo.
Dr Pommier: Was there any crossover for the placebo group?
Dr Anthony: When patients progressed on placebo, 85% actually went on to receive active drug.
Dr Pommier: So how are the patients monitored during the trial?
Dr Anthony: These patients were seen in the clinics at least monthly and scans were done every 3 months.
Dr Pommier: Alright, and then what were the outcome parameters that were monitored in the trial, and the key end points?
Dr Anthony: The primary object response was progression-free survival. Other secondary end points included response rates and overall survival, as well as safety signals. The major finding of the RADIANT-3 Trial was there was a significant increase in the progression of free survival.
Dr Pommier: And what were those numbers?
Dr Anthony: The patients on the placebo arm had a rate of around 4.3.
Dr Pommier: So that was just like one scan and a little bit more on average.
Dr Anthony: Absolutely and the patients saw in the AFINITOR arm went 11.0 months.
Dr Pommier: And that was a highly significant difference?
Dr Anthony: That was a highly significant difference. It had a hazard ratio that resulted in approximately 65% reduction of risk of progression.
Dr Pommier: And were there any subgroup analyses about which patients might have benefited or not benefited as well as others?
Dr Anthony: There were, Rod. These subgroup analyses show that all subgroups have benefited.
Important Safety Information
AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.
Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids. Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases. For patients who require use of corticosteroids, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose.
Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.
PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required.
Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.
Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.
Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR.
Impaired Wound Healing: Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period.
Laboratory Tests and Monitoring: Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function.
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.
Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter.
Drug-Drug Interactions: Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less.
Hepatic Impairment: Exposure to everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.
Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR.
Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential of the potential risk to a fetus and to use effective contraception while using AFINITOR and for 8 weeks after ending treatment.
Adverse Reactions: The most common adverse reactions (incidence ≥30%) were stomatitis (70%), rash (59%), diarrhea (50%), fatigue (45%), edema (39%), abdominal pain (36%), nausea (32%), fever (31%), headache (30%), and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were stomatitis (7%) and diarrhea (5.5%). Deaths primarily due to adverse events during the double-blind treatment phase occurred in 7 patients taking AFINITOR.
Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥50%, all grades) were: decreased hemoglobin (86%) and bicarbonate (56%); increased fasting glucose (75%), alkaline phosphatase (74%), cholesterol (66%), and aspartate transaminase (56%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were: decreased hemoglobin (15%), lymphocytes (16%), and phosphate (10%), and increased glucose (17%) and alkaline phosphatase (8%).
Please see full Prescribing Information.
AFINITOR is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease.
AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.
Reference: Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016.