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Randomized phase III adjuvant capecitabine plus temozolomide versus surveillance in patients with resected stage I‑III pancreatic neuroendocrine tumors

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The condition under study is Pancreatic NeuroEndocrine Tumors, a type of tumor that forms in the pancreas and can grow quickly. The patients involved have had the tumor removed completely with clear margins (described as “R0 resected”) and the disease is classified as stage I‑III, meaning it is limited to the pancreas and nearby tissues but carries a higher risk of coming back. The treatment being tested combines two oral chemotherapy drugs, Capecitabine and Temozolomide, given in six cycles after surgery.

The purpose of the trial is to see whether adding systemic chemotherapy followed by active surveillance improves the length of time patients remain free of cancer compared with using active surveillance alone. Participants are randomly assigned to either receive the chemotherapy regimen and then regular check‑ups, or to have the same regular check‑ups without receiving the chemotherapy.

After the treatment period, all participants continue with scheduled visits and complete questionnaires that track health status and quality of life. These follow‑up visits occur over several years to monitor for any return of the disease or side effects from the treatment.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Randomization and enrollment
After consent, you are assigned to either the chemotherapy arm or the observation arm based on the study randomization process.
The date of randomization marks the start of all study related activities.
Step 2
Baseline assessments
A series of clinical evaluations, laboratory tests and questionnaires are completed before any medication is taken.
Questionnaires include quality of life forms (eortc qlq-c30, eortc qlq-ginet21, eq-5d-5l) and are recorded for future comparison.
Step 3
Initiation of chemotherapy (cycle 1)
You begin the first cycle of oral chemotherapy that combines capecitabine and temozolomide.
capecitabine is taken by mouth at a dose of 1500 mg per square meter of body‑surface area each day, usually divided into two doses.
temozolomide is taken by mouth at a dose of 200 mg per square meter each day.
The exact number of days each drug is taken during the cycle follows the protocol schedule; each cycle lasts about four weeks.
Step 4
Monthly toxicity monitoring during chemotherapy
During the first year, you attend a clinic visit each month to assess side effects using the nci ctcae v6.0 criteria.
Any new symptoms or laboratory changes are recorded and may lead to dose adjustments.
Step 5
Subsequent chemotherapy cycles (cycles 2‑6)
Cycles 2 through 6 repeat the same medication schedule as cycle 1.
Each cycle is approximately four weeks long, followed by a short rest period before the next cycle begins.
Monthly toxicity monitoring continues throughout all six cycles.
Step 6
Completion of chemotherapy and transition to active surveillance
After the sixth cycle, you stop taking the study drugs.
The study then moves you to the active surveillance phase, during which no further chemotherapy is given.
Step 7
Regular follow‑up during active surveillance
During the first year after chemotherapy, you have clinic visits every month to check for toxicity and every three months to complete quality of life questionnaires.
After the first year, visits are scheduled once a year for both toxicity assessment and quality of life evaluation.
The primary outcome measured is disease‑free survival, defined as the time from randomization to the first recurrence of disease or death.
Step 8
Study end and final data collection
The study continues to collect follow‑up data until the planned end date in 2036.
Final analyses will use all recorded information to evaluate disease‑free survival, overall survival and quality of life.

Who can join the trial?

20 criteria

Confirmed diagnosis: A tissue test must show a well‑differentiated neuro‑endocrine tumor of the pancreas.
Recent surgery: You must be within four months after having the tumor removed.
Complete removal (R0 resection): The surgeon must have removed all visible tumor with clear margins.
No spread of cancer: Scans of the chest, abdomen (CT or MRI) and any PET scan done before surgery must show no distant tumors or leftover tumor tissue.
Performance status: You need an ECOG score of 0 or 1, meaning you are fully active or able to carry out light work.
No previous cancer medicines: You must not have received any systemic (body‑wide) therapy for this cancer before.
Intermediate to high risk of coming back: Your tumor must meet one of the following risk patterns:
- Ki67 ≥ 10% (high‑grade tumor), or
- Ki67 5‑9% and tumor larger than 3 cm or cancer in nearby lymph nodes, or
- Ki67 3‑5% and tumor larger than 3 cm and cancer in lymph nodes, or
- Ki67 < 3% and tumor larger than 3 cm and cancer in lymph nodes and either blood‑vessel invasion or nerve invasion.
- Trial approval: Your case must be approved by a multidisciplinary board (RENATEN‑ENDOCAN).
- Age requirement: You must be 18 years or older; there is no upper age limit.
- Blood‑cell health: Your blood tests must show hemoglobin > 8 g/dL, absolute neutrophil count ≥ 1,500 cells/µL, and platelets ≥ 80,000 cells/µL.
- Effective birth‑control:
  - Women who could become pregnant must have a negative pregnancy test and agree to use a reliable contraceptive method for at least six months after treatment.
  - Men with partners who could become pregnant must use a reliable contraceptive method for at least three months after treatment and avoid donating sperm during that time.
  - Informed consent: You must sign a written, dated consent form before any study procedures begin.
  - Ability to follow the study: You need to be able to attend visits and follow the study instructions.
  - Social security coverage: You must be enrolled in a social security system or be a beneficiary.
  - Tumor sample available: A sample of the original tumor must be stored so it can be classified by WHO standards and tested for MGMT status.
  - Stage I‑III disease: Your cancer must be classified as stage I, II, or III according to the ENETS‑UICC 8th edition criteria.

Who cannot join the trial?

16 criteria

Having tumors that are poorly differentiated neuroendocrine carcinoma (NEC) instead of the specific type being studied.
Blood protein level (serum albumin) lower than 3.0 g/dL unless clotting time (prothrombin time) is normal.
Currently taking another experimental medication.
Still experiencing side effects from the recent surgery.
Having an active or suspected serious disease that is not well‑controlled, which the doctor believes makes the study too risky.
Having a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) or not having been tested for it.
Having taken the antiviral drug brivudine recently or at the same time as the study drugs.
Being allergic to the study drugs Capecitabine or Temozolomide or to any of the inactive ingredients (excipients).
Having mixed tumors that contain both neuroendocrine and non‑neuroendocrine cells (MiNEN).
Having received chemotherapy before surgery (neoadjuvant) or having received a chemotherapy regimen used for a different cancer.
Being pregnant or breastfeeding.
Having a performance‑status score higher than 1 on the ECOG scale, which means limited ability to carry out daily activities.
Being younger than 18 years old.
Having a pancreatic neuroendocrine tumor that occurs as part of a genetic syndrome (such as NF1, VHL or MEN) with other tumors already diagnosed.
Having had another cancer in the past, except for cured non‑melanoma skin cancer, early‑stage cervical cancer, or other cancers that have been cured and disease‑free for at least five years.
Having severe kidney problems (estimated glomerular filtration rate < 30 ml/min) or a kidney condition called nephrotic syndrome, or having severe liver problems (liver enzymes ALT/AST more than 2.5 times normal, or more than 5 times if caused by the tumor, or high bilirubin > 2.5 times normal).

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Verified
Assistance Publique Hopitaux De Marseille
Marseille, France
Verified
Assistance Publique Hopitaux De Paris
Paris, France
Responsive
Institut De Cancerologie De Lorraine
Vandoeuvre Les Nancy, France

Trial locations

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Investigated drugs

Capecitabine
is an oral chemotherapy drug that is taken by mouth in tablet form. In this study it is given together with another drug for six cycles after surgery to try to kill any remaining cancer cells and lower the chance that the tumor comes back.
Temozolomide
is also an oral chemotherapy medication, supplied as hard capsules. It works by damaging the DNA of cancer cells, making it harder for them to grow. In the trial it is used together with capecitabine for six cycles after the tumor has been surgically removed, aiming to prevent the disease from returning.
Active surveillance
means that after surgery (and after the chemotherapy cycles for the group receiving drugs) patients are closely monitored with regular check‑ups and tests, but no additional cancer treatment is given unless the disease returns. This approach is used as a comparison to see if the chemotherapy improves the time patients stay free of disease.

What is already known about the treatment

Capecitabine
This medication is taken by mouth as film‑coated tablets that are swallowed with water. It is an approved anticancer drug that is well described in medical literature and is used for several solid tumors, including pancreatic neuroendocrine tumors. Capecitabine works as a pro‑drug that is changed inside the body into 5‑fluorouracil, which blocks the building blocks needed for DNA and stops cancer cells from multiplying. It belongs to the antimetabolite class of chemotherapy agents.
Temozolomide
This drug is also taken orally, supplied as hard capsules that are swallowed whole. It is an established chemotherapy medicine with extensive clinical study and is indicated for brain tumors and for neuroendocrine cancers such as pancreatic NETs. Temozolomide adds a small chemical group (a methyl) to the DNA of cells, causing damage that leads to cancer cell death. It is classified as an alkylating agent in the chemotherapy group.

Investigated diseases

Pancreatic neuroendocrine tumor - A pancreatic neuroendocrine tumor is a growth that arises from hormone‑producing cells in the pancreas. It is usually slow‑growing and can be classified by how far it has spread, from stage I (confined to the pancreas) to stage III (involving nearby tissues or lymph nodes). When the tumor is well differentiated, its cells look similar to normal cells and tend to grow in an orderly pattern. After surgical removal with clear margins (R0 resection), the tumor may stay stable for a period, but it can later develop new growths in the pancreas or spread to other parts of the body. The disease course is monitored by looking for any signs of recurrence over time.