Preoperative Therapy for Stomach Cancer

(TOPGEAR Trial)

Recruiting at 59 trial locations

Overseen By Christine Aiken

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Australasian Gastro-Intestinal Trials Group

Disqualifiers: Metastatic disease, Prior chemotherapy, Cardiac failure, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

574 Participants Needed

Trial Summary

What is the purpose of this trial?

Gastric cancer remains a significant global public health problem. Although in developed countries its incidence has dramatically decreased, on a worldwide scale it is still a leading cause of cancer-related deaths. Surgery is the only potentially curative treatment for gastric cancer. Although the survival rates for patients with early stage disease (stage 1A and 1B) are good, this subgroup of patients constitutes only 20% of those undergoing resection. The majority of patients will have locally advanced or metastatic disease at presentation, which has an extremely poor prognosis. The current five-year survival rate for gastric cancer in Western countries is approximately 20-30%, a figure that has improved little over the past 30 years. The intervention arm in TOPGEAR consists of pre-operative chemotherapy, pre-operative chemoradiotherapy, surgery and post-operative chemotherapy. The control arm consists of pre-operative chemotherapy, surgery and post-operative chemotherapy. The primary objective of TOPGEAR is to investigate whether the addition of chemoradiotherapy to chemotherapy is superior to chemotherapy alone in the neoadjuvant setting by improving pathological complete response rates in the first instance, and subsequently overall survival, in patients undergoing adequate surgery (D1+ dissection) for resectable gastric cancer.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor to get specific guidance based on your situation.

What data supports the effectiveness of the drug combinations used in the Preoperative Therapy for Stomach Cancer trial?

Research shows that chemotherapy before surgery for stomach cancer can improve survival rates and reduce cancer recurrence. Studies have found that drug combinations like 5-FU, cisplatin, and epirubicin, as well as docetaxel, oxaliplatin, and capecitabine, are effective in increasing the chances of successful surgery and improving long-term outcomes for patients. ^{1 2 3 4 5}

Is the preoperative therapy for stomach cancer generally safe for humans?

The preoperative therapy for stomach cancer, including combinations like FLOT and ECF, has been studied for safety. While these treatments can cause side effects, such as nausea or fatigue, they are generally considered manageable. Studies show that preoperative therapy does not significantly increase surgery-related risks. ^{4 6 7 8 9}

How does the preoperative therapy for stomach cancer differ from other treatments?

This preoperative therapy for stomach cancer is unique because it combines multiple chemotherapy drugs, such as epirubicin, cisplatin, and 5-fluorouracil, to shrink tumors before surgery, potentially improving the chances of complete tumor removal and increasing survival rates. It is specifically designed for patients with locally advanced gastric cancer and aims to reduce recurrence and improve long-term outcomes. ^{1 2 3 10 11}

Research Team

Trevor Leong, MBBS, MD

Principal Investigator

Peter MacCallum Cancer Centre, Australia

Eligibility Criteria

This trial is for adults over 18 with certain stages of stomach cancer (Stage IB-III) that can potentially be removed by surgery. Participants must have a good performance status, meaning they're able to carry out daily activities with minimal assistance. They need normal blood counts and liver function, adequate kidney function, and if there's a history of heart disease or they are over 60, their heart pumping function needs to be confirmed as sufficient.

Inclusion Criteria

My cancer is between stage IB (only T1N1) and IIIC according to AJCC 7th edition.

My liver tests are within the required range.

Bone marrow: Haemoglobin >=90 g/L, Absolute neutrophil count (ANC) >=1.5 x 10⁹ /L, White blood cell count >=3 x 10⁹ /L, Platelet count >=100 x 10⁹ /L

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative Chemotherapy

Participants receive 2-3 cycles of preoperative chemotherapy with epirubicin, cisplatin, and 5-fluorouracil or alternative regimens

6-9 weeks

Preoperative Chemoradiotherapy

Participants in the experimental arm receive 5 weeks of preoperative chemoradiotherapy

5 weeks

Surgery

Participants undergo gastric resection surgery

Postoperative Chemotherapy

Participants receive 3-4 cycles of adjuvant chemotherapy with epirubicin, cisplatin, and 5-fluorouracil or alternative regimens

9-12 weeks

Follow-up

Participants are monitored for disease progression, survival, and toxicities

Up to 5 years

Treatment Details

Interventions

• Epirubicin + cisplatin + 5-fluorouracil OR epirubicin + cisplatin + capecitabine OR epirubicin + oxaliplatin + capecitabine OR 5-Fluorouracil + leucovorin + oxaliplatin + docetaxel
• Gastric resection
• Post-operative chemotherapy
• Preoperative chemoradiotherapy
• Pre-operative chemotherapy

Trial Overview The TOPGEAR trial is testing whether adding chemoradiotherapy (a combination of chemotherapy drugs and radiation therapy) before surgery improves outcomes compared to just chemotherapy before surgery in patients with resectable gastric cancer. After the initial treatments, all patients will undergo surgery followed by more chemotherapy.

Participant Groups

Group I: Preoperative chemoradiotherapy Experimental Treatment 3 Interventions

2 cycles preoperative chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 3 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel 5 weeks preoperative chemoradiotherapy. Gastric resection. 3 cycles adjuvant chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel

Group II: Preoperative chemotherapy Active Control 2 Interventions

3 cycles preoperative chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel Gastric resection. 3 cycles adjuvant chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine) OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel

Who Is Running the Clinical Trial?

Australasian Gastro-Intestinal Trials Group

Lead Sponsor

Trials

26

Recruited

8,000+

National Health and Medical Research Council, Australia

Collaborator

Trials

167

Recruited

473,000+

Trans Tasman Radiation Oncology Group

Collaborator

Trials

50

Recruited

16,600+

European Organisation for Research and Treatment of Cancer - EORTC

Collaborator

Trials

417

Recruited

166,000+

NCIC Clinical Trials Group

Collaborator

Trials

190

Recruited

145,000+

Findings from Research

Chemotherapy significantly increases survival and improves quality of life in patients with advanced gastric carcinoma compared to supportive measures alone.

Current standard treatments include infusional 5-FU combined with cisplatin or ECF, while newer third-generation combinations with taxanes and irinotecan show similar effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Patient with stomach cancer with metastases. What is the value of chemotherapy?]. Wilke, H., Stahl, M., Vanhoefer, U.[2013]

The biweekly FLOT chemotherapy regimen, which includes oxaliplatin, leucovorin, fluorouracil, and docetaxel, showed a 57.7% objective response rate in 54 patients with metastatic gastric cancer, indicating its efficacy.

Despite some significant side effects like neutropenia and leukopenia, the treatment demonstrated a favorable safety profile, with only 3.8% of patients experiencing complicated neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Al-Batran, SE., Hartmann, JT., Hofheinz, R., et al.[2022]

A patient with HER2- and PD-L1-positive locally advanced gastric carcinoma achieved a pathologic complete response after receiving a neoadjuvant therapy regimen that included toripalimab, Herceptin, and FLOT chemotherapy, followed by surgery.

This case suggests that combining immunotherapy with chemotherapy may be an effective neoadjuvant treatment strategy for gastric carcinoma, but further large-scale phase III clinical trials are needed to confirm the safety and efficacy of such approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report. Liu, R., Wang, X., Ji, Z., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

[Surgery after chemotherapy: gastric cancer]. [2011]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Preoperative or Perioperative Docetaxel, Oxaliplatin, and Capecitabine (GASTRODOC Regimen) in Patients with Locally-Advanced Resectable Gastric Cancer: A Randomized Phase-II Trial. [2020]

3. Greece pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy versus surgery alone for locally advanced gastric cancer: a retrospective comparative study. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Pathological response and outcome after neoadjuvant chemotherapy with DOC (docetaxel, oxaliplatin, capecitabine) or EOF (epirubicin, oxaliplatin, 5-fluorouracil) for clinical T3-T4 non-metastatic gastric cancer. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

[Patient with stomach cancer with metastases. What is the value of chemotherapy?]. [2013]

6. Japan pubmed.ncbi.nlm.nih.gov

Phase II study of docetaxel, oxaliplatin, and S-1 therapy in patients with metastatic gastric cancer. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

COMplot, A Graphical Presentation of Complication Profiles and Adverse Effects for the Curative Treatment of Gastric Cancer: A Systematic Review and Meta-Analysis. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Response to docetaxel and cisplatin induction chemotherapy of locally advanced head and neck squamous cell carcinoma: a multicenter, non-comparative, open-label interventional pilot study. [2018]

10. Tunisia pubmed.ncbi.nlm.nih.gov

Perioperative chemotherapy in locally advanced gastric cancer. A retrospective study about 25 cases. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report. [2022]