Chemotherapy for Neuroendocrine Neoplasms

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By Ronny Allan – Living with Neuroendocrine Cancer

Chemotherapy has a long and complicated history in the management of Neuroendocrine Neoplasms (NENs) (an umbrella term for both Neuroendocrine Tumours (NET) and Neuroendocrine Carcinomas (NEC)).  Unlike many other cancers, most well‑differentiated NETs are relatively resistant to traditional cytotoxic chemotherapy. However, chemotherapy remains an important option for specific subtypes, particularly higher‑grade disease, and certain anatomical sites. 

There’s a myth that circulates the NET patient groups along the lines of “chemotherapy does not work for NETs“. That’s not entirely true or at best totally out of context.  However, it’s true to say that most lower grade (1 or 2) NET patients will not receive chemotherapy.  Some guidelines e.g. NCCN, suggest it is only an option in progressive disease where no other option is feasible but options increase for pancreatic NET. For those who do, it is normally in an adjuvant setting.  Chemo is relatively common in Grade 3 well differentiated NETs and for example, NCCN guidelines talk about “favourable biology” i.e. well differentiated Ki67 less than or equal to 55%.  This updated 2026 review reflects the latest global guidance (ENETS, NANETS, NCCN, ESMO), new evidence, and evolving clinical practice.

🎯 Where Chemotherapy Fits in the NEN Treatment Landscape

Chemotherapy is not a universal treatment for all NET patients. Its role depends heavily on:

• Differentiation (NET vs NEC)

• Grade (Ki‑67)

• Primary site

• Tumour biology and behaviour

• Previous treatments

• Patient fitness and goals

In general:

• Low‑ and intermediate‑grade NETs (G1–G2) → chemotherapy is selective, not routine.

• High‑grade NETs (G3) and NECs → chemotherapy is often central to treatment.

• Pancreatic NETs → chemotherapy is more effective than in small bowel NETs.

🧬 Chemotherapy for Well‑Differentiated NETs (G1–G2)

Pancreatic NETs (pNETs)

This is the group where chemotherapy has the strongest evidence.

Common regimens:

• CAPTEM (Capecitabine + Temozolomide)

  • Now widely used as first‑line or second‑line therapy.

  • Response rates: 30–40%

  • Particularly effective in MEN1‑associated and MGMT‑deficient tumours.

• Streptozocin‑based combinations (Streptozocin + 5‑FU or Doxorubicin) 

  • Older but still used in some centres.(mostly used in Europe)

  • Response rates: 20–40%

  • More toxicity than CAPTEM.

When used:

• Progressive disease after SSA or targeted therapy

• Bulky or symptomatic disease

• When tumour shrinkage is needed quickly

• As a bridge to PRRT in selected cases

Small Intestine NETs (SI‑NETs)

Chemotherapy has limited benefit.

• Response rates typically <10%

• Not routinely recommended

• May be considered only when all other options are exhausted

Lung NETs (Typical/ Atypical)

Chemotherapy is not very effective, but may be used when:

• Disease is rapidly progressing

• Other systemic options (SSA, everolimus, PRRT) have been used

• Tumour has atypical features or higher Ki‑67

Regimens include:

• Temozolomide‑based therapy

• Platinum + etoposide (more effective in higher‑grade disease)

🔥 Chemotherapy for High‑Grade NETs (G3) and Neuroendocrine Carcinomas (NECs)

This is where chemotherapy becomes standard of care. 

Well‑differentiated NET G3

These tumours sit biologically between G1/2 NET and NEC.

• CAPTEM is commonly used

• Platinum + etoposide may be used if Ki‑67 is high (≥55%)

• PRRT remains an option if SSTR‑positive

Poorly Differentiated NEC (any site)

Poorly differentiated NEC is an umbrella term that covers two recognised morphologies:  Small‑cell NEC — the classic small‑cell pattern. Large‑cell NEC — larger cells, prominent nucleoli, abundant cytoplasm

First‑line standard:

• Platinum (Cisplatin or Carboplatin) + Etoposide

Second‑line options (2026):

• FOLFIRI

• FOLFOX

• Temozolomide‑based regimens

• Lurbinectedin (increasing use based on small‑cell lung cancer data)

• Immunotherapy combinations in selected cases (still evolving)

🧪 Emerging and Investigational Chemotherapy Approaches (2026)

• Temozolomide + PARP inhibitors (e.g., olaparib)

• Chemotherapy + immunotherapy combinations

• Chemotherapy + targeted agents

• Neoadjuvant CAPTEM for borderline‑resectable pNETs

• Adjuvant chemotherapy after surgery for high‑risk NEC (still debated)

⚖️ Balancing Benefits and Side Effects

Chemotherapy side effects vary by regimen but may include:

• Fatigue

• Nausea

• Low blood counts

• Hair thinning (rarely full hair loss except with platinum regimens)

• Hand–foot syndrome (capecitabine)

• Renal toxicity (streptozocin)

• Neuropathy (oxaliplatin)

NET patients often tolerate CAPTEM relatively well compared to older regimens.

🌍 Global Guideline Summary (2026)

Across ENETS, NANETS, NCCN, and ESMO:

• CAPTEM is now the most widely endorsed chemotherapy for pNETs and NET G3. ENETS still lists Streptozocin‑based regimens as a valid chemotherapy option for pancreatic NETs.

• Platinum + etoposide remains the backbone for NEC.

• Chemotherapy is rarely used for small intestine NETs.

• Chemotherapy is selective for lung NETs.

• MGMT testing is increasingly used to predict CAPTEM response.

• Sequencing chemotherapy and PRRT is now a major strategic consideration in MDTs managing well differentiated NETs.

📝 Key Takeaways

• Chemotherapy is not a one‑size‑fits‑all treatment in NENs.

• It is most effective in pancreatic NETs, NET G3, and NEC.

• CAPTEM has become a modern standard for many NET subtypes.

• Small Intestine NETs remain chemotherapy‑resistant.

• Treatment decisions must be individualised, ideally in a specialist NET centre.

Addendum – Misc items

Chemo Embolization

My Oncologist did mention Chemotherapy at my initial meeting which was a shock and a realisation I had something serious. However, that never transpired but I was once scheduled to have a chemoembolization (or TACE, Trans-arterial Chemo Embolization). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that was what my Oncologist meant. The chemo-embolization never transpired either (long story). Read more about liver direct therapy here.

PRRT and Chemo Combo Treatment

In Australia, they trialled a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this in 2016 click here. Includes 2026 follow on data.

PRRT plus chemotherapy combinations Early Australian data (AGITG CONTROL NET) combining PRRT with CAPTEM showed high response rates, particularly in pancreatic NETs, but at the cost of substantial haematologic toxicity and without a clear progression‑free survival advantage strong enough to change guidelines.

More recent trials are revisiting PRRT–chemotherapy and PRRT–systemic combinations using refined dosing, sequencing, and partner drugs, aiming to capture the activity seen in CONTROL NET while reducing long‑term marrow risk. These approaches remain investigational and are generally recommended only within clinical trials.

A more recent, mature publication from the same Australian CONTROL NET programme has confirmed the earlier signal: combining PRRT with CAPTEM produces high response rates, particularly in pancreatic NETs, but at the cost of substantially increased haematologic toxicity and no clear, durable survival advantage strong enough to change guidelines.

The updated data have shifted expert opinion away from routine concurrent PRRT–chemotherapy and towards smarter sequencing and carefully selected combinations, ideally within clinical trials.

“Chinese Dumplings”

Interest only.  Innovation is always welcome.  There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.

Nomenclature:  Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues

I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as “chemotherapy” but that isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo.

Use of the term “chemotherapy” is often used widely by healthcare professionals and insurance companies, the latter wants to group everything under the chemo banner for ease of their databases.  Healthcare professionals may be trying the simple explanation by saying “chemo” rather than (e.g.) “Tyrosine kinase inhibitors (TKI)” or “Vascular endothelial growth factor (VEGF)”).  However, the use of the term “chemo” or “chemotherapy” can strike unnecessary fear into people given its association with aggressive cancers and nasty side effects.

See my article “Chemo or not Chemo” (click here).

Future of Chemo?

A lot is written about how much longer chemo will be around. It gets a bad press – I suspect due to the side effects. There are suggestions that it will eventually be replaced by Immunotherapy and other treatments downstream. However, immunotherapy is still in its infancy and there remains a lack of long-term data on success rates and side effects. I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO. Cancer experts continue to insist that chemo will be around for a long time yet – read more here.

Finally check out this useful summary from US, click here

Disclaimer

I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.

Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.

Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.

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