Using Capecitabine/Temozolomide or 177Lu-Dotatate to Treat NETs Requires Real-World Guide

Several systemic treatments are approved or recommended by guidelines for advanced well-differentiated neuroendocrine tumors (NETs). These include somatostatin analogs, everolimus (Afinitor), sunitinib (Sutent), lutetium Lu 177 dotatate ( ¹⁷⁷Lu-Dotatate; Lutathera), and capecitabine/ temozolomide (CAPTEM). NETs are rare tumors, and few clinicians acquire broad experience with regimens such as CAPTEM and ¹⁷⁷Lu-Dotatate that are unique to these malignancies. Consequently, a real-world guide to best practices can improve patient outcomes.

Capecitabine/temozolomide

The oral chemotherapy regimen of CAPTEM is particularly effective in pancreatic NETs with objective response rates (ORRs) of approximately 50% and a median progression-free survival (PFS) of approximately 18 to 23 months.^1,2 The ECOG 2211 trial (NCT01824875) showed that CAPTEM significantly improved PFS and overall survival (OS) compared with temozolomide monotherapy in patients with advanced, progressive pancreatic NETs.¹ Lower response rates have been reported in other NET subtypes, including lung and thymus, but the evidence is limited primarily to small retrospective series.^3-6

The regimen typically consists of capecitabine 750 mg/m² twice daily on days 1 to 14 and temozolomide 200 mg/m² once daily (typically at bedtime) on days 10 to 14 every 28 days (FIGURE 1). In practice, doses usually are rounded down to minimize the use of different pills. Thus, actual starting doses are often slightly lower than target doses: 675 mg/m² of capecitabine twice a day and 180 mg/m² of temozolomide, as seen in one large institutional study.⁶

Temozolomide is highly emetogenic unless 5-HT3 blockers are administered prophylactically.^7,8 Therefore, antiemetics such as ondansetron (Zofran) must be taken before administering temozolomide. One of the chief toxicities of this regimen is myelotoxicity, which can be quite severe in approximately 10% of patients and often occurs after the initial cycle. The cytopenias are nearly always related to temozolomide and are somewhat delayed, beginning around week 4 with nadir around week.⁵

CAPTEM is a complex oral regimen that is often prescribed without a prewritten electronic order template or pharmacist oversight, leading to prescription errors as well as problems with patient adherence, which are both well-known challenges of oral chemotherapy. Several pitfalls have been associated with this:

• Failure to prescribe prophylactic antiemetics before temozolomide. One recommended option is ondansetron 8 mg given 30 to 60 minutes before temozolomide.
• Failure to check blood counts within a few days prior to each cycle. Cytopenias to 28. Therefore, complete blood count should be checked shortly before the beginning of a cycle. If platelet counts fall below 100, chemotherapy should typically be held, and blood counts should be monitored closely through nadir and recovery. Blood thinners and antiplatelet agents should be stopped, if possible, during this time. When treatment is resumed, it is essential to recognize that temozolomide (rather than capecitabine) is typically implicated in cytopenias and that doses of this drug should be reduced accordingly.
• Incorrect doses (eg, unadjusted to body surface area) or interval (eg, capecitabine cycle of 21 rather than every 28 days).

One of the chief controversies surrounding CAPTEM is the optimal duration of treatment. There are theoretical concerns regarding the potential for myelodysplastic syndrome (MDS) with long-term use of an alkylating agent (temozolomide) and debates over the necessity of treating beyond a specific fixed interval (eg, 1 year) or beyond maximal radiographic response.⁹ The randomized ECOG 2211 study recommended 1 year of treatment but allowed the continuation of therapy per investigator discretion. In practice, clinicians have found that MDS is exceptionally rare with CAPTEM and occurs primarily in patients who have also received peptide receptor radiotherapy.⁶

Specific processes can help reduce errors in physician prescription and patient adherence. These include as follows:

• prewritten order templates embedded in electronic medical records systems,
• pharmacist review, and
• prewritten patient instruction handouts.

Adopting these measures will help optimize outcomes of patients treated with CAPTEM and other complex oral anticancer regimens.

¹⁷⁷Lu-Dotatate ¹⁷⁷Lu-Dotatate is a radiolabeled somatostatin analog approved for the treatment of progressive, well-differentiated gastroenteropancreatic NETs.¹⁰ The primary registrational trial evaluating this drug, NETTER-1 (NCT01578239), resulted in substantial improvement in PFS with a hazard ratio of 0.21.

An 11.7-month increase in median OS also was reported with long-term follow-up. This was clinically meaningful but not statistically significant.¹¹

A standard regimen of ¹⁷⁷Lu-Dotatate consists of 4 treatments (200 mCi) administered every 8 weeks for a total duration of 24 weeks (FIGURE 2). Prophylactic amino acids are administered intravenously before and during each treatment to reduce nephrotoxicity.¹² Although the NETTER-1 study used commercial amino acid formulations, numerous studies have demonstrated that arginine and lysine are sufficient to minimize renal toxicity without causing significant nausea or vomiting.^13,14 Some investigators strongly recommend using compounded arginine/ lysine as prophylactic amino acids and administering 1 liter over 4 to 6 hours starting 30 to 60 minutes before ¹⁷⁷Lu-Dotatate infusion. Prophylactic ondansetron is typically sufficient to control nausea.

Although previous studies of ¹⁷⁷Lu-Dotatate typically mandated a creatinine clearance above 50 to 60 mL/min, approximately 10% of patients on the NETTER-1 trial had a lower clearance of 30 to 50 mL/min.¹⁵ Although moderate renal insufficiency does not appear to be a contraindication to treatment, renal outlet obstruction may represent a significant risk. Therefore, hydronephrosis or bladder outlet obstruction should be managed before ¹⁷⁷Lu-Dotatate treatment.

Radiation peritonitis/mesenteritis A recently recognized complication of ¹⁷⁷Lu-Dotatate is radiation peritonitis/ mesenteritis.^16,17 Patients with a high burden of peritoneal or mesenteric disease appear to be at risk of bowel obstruction. Evidence suggests that corticosteroids can be effective at treating this complication and potentially effective prophylactically. Patients can be treated judiciously with prophylactic dexamethasone. We consider high peritoneal tumor burden to be a contraindication to treatment.

Hepatotoxicity does not appear to be a significant risk with ¹⁷⁷Lu-Dotatate, even among patients with very high liver tumor burden, as long as baseline liver function is adequate.¹⁸ An exception may be patients with high liver tumor burden and extensive prior liver-directed therapy.

When selecting patients to prescribe ¹⁷⁷Lu-Dotatate, it is vital to verify that all tumors express somatostatin receptors strongly. Typically, this means that measurable tumors (eg, >1 cm) should have evidence of somatostatin receptor expression greater than normal liver on a somatostatin receptor scan such as a 68Ga or 64Cu-dotatate PET/ CT or PET/MRI. Heterogeneity of somatostatin receptor expression is particularly prevalent in lung NETs or aggressive pancreatic NETs and rarely seen with midgut NETs.^19-21 Some experts recommend obtaining both fluorodeoxyglucose (FDG) and somatostatin receptor PET scans to ensure no FDG-positive, somatostatin receptor–negative lesions.²²

One common question that arises involves the coordination of ¹⁷⁷Lu-Dotatate with somatostatin analog therapy. Past conventional wisdom held that somatostatin analogs interfere with ¹⁷⁷Lu-Dotatate and that long-acting octreotide LAR or lanreotide should be held at least 6 weeks prior to each ¹⁷⁷Lu-Dotatate infusion. However, it is increasingly unclear whether these drugs truly interfere with ¹⁷⁷Lu-Dotatate. Whether somatostatin analogs should be continued beyond progression in patients with nonfunctional (non–hormone producing) NETs is a matter of debate.

In summary, there are unique challenges associated with the CAPTEM regimen and with ¹⁷⁷Lu-Dotatate. A familiarity with key toxicities, logistical issues, and ancillary drugs holds the key for optimizing patient care.

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