The Answer to How to Continue Pancreatic Neuroendocrine Tumor Treatment After Smart Drugs Has Been Found

Neuroendocrine tumors are difficult even for pathologists to classify, and their treatment is always debated. Cells in poorly differentiated, high-grade tumors have aggressive biology.

The less cancer cells resemble their tissue of origin, the more poorly differentiated the tumor. Such rapidly growing/proliferating tumors are called high grade . High-grade neuroendocrine tumors are treated more with conventional chemotherapies such as cisplatin, etoposide and carboplatin than with hormonal somatostatin analogs. However, in metastatic cases, the best objective response rates were only %31 (the largest retrospective NORDIC Group Study, 252 patients), with progression-free survival of 4 months and overall survival of 11 months.

Despite cytotoxic (cell-killing) chemotherapy, metastatic (stage 4) cases have recurrence risk above 50 percent, and retreatment with the same agents gives objective responses only around %15. Chemotherapy also carries risks of alopecia (hair loss), nausea and febrile neutropenia and similar side effects at %35-40.

In the early 2000s, the Human Genome Project and discovery of our genetic map greatly increased biological agents called smart drugs in cancer treatment. Particularly for low or intermediate grade pancreatic neuroendocrine tumors, treatment began using new blood vessel formation inhibitors (vascular endothelial pathway inhibitors) such as sunitinib (Sutent), pazopanib (Votrient), and everolimus (Afinitor), an inhibitor of another cancer development pathway, mTOR. These smart molecules are used particularly in tumors that are not high grade, meaning low or intermediate differentiation, and have fewer side effects than conventional chemotherapy. A major advantage is oral administration, reducing hospital visits.

Despite chemotherapy and smart molecules, in stage 4 pancreatic neuroendocrine tumors progression-free survival does not exceed 4-6 months and objective responses in recurrent cases remain % 10-15. Until recently, our general understanding was that chemotherapy had no place in low- or intermediate-grade tumors. Therefore, “which agent should follow smart drug treatment?” had no clear answer.

For patients with metastatic pancreatic neuroendocrine tumors progressing despite these agents but with good general performance, at ASCO 2018 the ECOG ACRIN clinical trial was presented.

Patients previously receiving the smart drugs described above were assigned;

• in one arm, to temozolomide , an oral chemotherapy (72 patients),
• and in the other arm to temozolomide and capecitabine , combined oral chemotherapies (72 patients). Ü

Both drugs can be taken orally, allowing treatment at home. Contrary to general medical understanding, the study examined whether conventional chemotherapy works despite low- or intermediate-grade tumors. Participants were also allowed the standard neuroendocrine tumor drug, somatostatin analog therapy .

According to the Research Results;

• Progression-free survival was 22.7 months with temozolomide plus capecitabine versus 14.4 months with temozolomide alone.
• Overall survival had not yet been reached in the combination arm, an extremely favorable result.
• Objective response favored the combination, at %33.3 versus %27.8.
• Despite these favorable responses, not achieved in earlier studies, severe side effect rates in the combination arm were %44, as expected.

Conclusion / Comment

For the first time in low- or intermediate-grade pancreatic neuroendocrine tumors progressing despite smart drugs, this highly important study achieved progression-free survival approaching 22 months, objective responses reaching %33 and an overall survival advantage. It is also extremely valuable for overturning the hypothesis that conventional chemotherapy is ineffective in this group.

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