Chemoradiotherapy + Surgery for Esophageal Cancer

(NEEDS Trial)

Recruiting at 12 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Karolinska University Hospital

Disqualifiers: Metastatic cancer, Unresectable tumor, Organ impairment, others

Stay on Your Current Meds

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

NEEDS is a pragmatic open-label, randomised, controlled, phase III, multicenter trial with non-inferiority design with regard to the first co-primary endpoint overall survival and superiority for the experimental intervention definitive chemoradiotherapy. A second co-primary endpoint is global health related quality of life (HRQOL) one year after randomisation. A third co-primary endpoint is eating restictions one year after randomisation. The aim is to compare outcomes after neoadjuvant chemoradiotherapy with subsequent esophagectomy to definitive chemoradiotherapy with surveillance and salvage esophagectomy as needed in patients with resectable locally advanced squamous cell carcinoma (SCC) of the esophagus, with the aim to provide generalisable guidance for future clinical practice.

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 a clear answer based on your specific situation.

What data supports the effectiveness of the treatment combining chemoradiotherapy and surgery for esophageal cancer?

Research shows that using chemoradiotherapy with drugs like Carboplatin and Paclitaxel before surgery can improve the chances of completely removing the cancer in esophageal cancer patients. This approach, known as neoadjuvant chemoradiotherapy, has been shown to improve local control of the cancer and is considered a preferred treatment option. ^{1 2 3 4 5}

Is chemoradiotherapy with carboplatin or cisplatin safe for esophageal cancer treatment?

Carboplatin is generally well tolerated and may be a less toxic alternative to cisplatin, which can cause kidney damage. Neoadjuvant chemoradiotherapy (treatment before surgery) with carboplatin and paclitaxel has relatively low adverse events, but severe effects can occur after surgery. A study confirmed the safety of a regimen including pemetrexed, carboplatin, and radiation followed by surgery. ^{6 7 8 9 10}

How is the treatment of chemoradiotherapy plus surgery for esophageal cancer different from other treatments?

This treatment combines chemoradiotherapy (using drugs like Carboplatin and Cisplatin with radiation) before surgery, which may improve the chances of completely removing the cancer compared to surgery alone. It uses a combination of drugs and radiation to shrink the tumor before surgical removal, potentially leading to better outcomes. ^{1 4 11 12 13}

Research Team

Magnus Nilsson, MD, PhD

Principal Investigator

Karolinska University Hospital

Florian Lordick, MD, PhD

Principal Investigator

Leipzig University Medical Center

Eligibility Criteria

This trial is for adults with a specific type of esophageal cancer (SCC) that hasn't spread beyond the local area. They must be in good physical condition, have organs functioning well, and women must not be pregnant or breastfeeding. Participants should use effective birth control and commit to following the study's procedures.

Inclusion Criteria

Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment

My esophagus cancer is confirmed and in an advanced stage but hasn't spread to distant organs.

Exclusion Criteria

I have been cancer-free for at least 5 years from a previous cancer.

My cancer has spread to distant parts of my body.

My throat cancer cannot be removed without taking out my voice box.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant chemoradiotherapy followed by esophagectomy or definitive chemoradiotherapy with surveillance and salvage esophagectomy as needed

5-8 weeks

Weekly visits for chemotherapy administration

Follow-up

Participants are monitored for safety, effectiveness, and quality of life after treatment

5 years

Regular visits at 6, 12, 24, 36, and 60 months

Treatment Details

Interventions

• Carboplatin (Platinum-based Chemotherapy)
• Cisplatin (Platinum-based Chemotherapy)
• Esophagectomy (Procedure)
• Neoadjuvant radiotherapy (Radiation)
• Oxaliplatin (Platinum-based Chemotherapy)

Trial Overview The NEEDS trial compares two approaches: one group receives chemotherapy plus radiotherapy before surgery, while another gets the same treatments but only has surgery if necessary later on. The focus is on survival rates, quality of life, and eating ability after treatment.

Participant Groups

Group I: Experimental arm (B) Experimental Treatment 5 Interventions

Definitive chemoradiotherapy followed by surveillance, and esophagectomy only in case of residual or recurrent locoregional cancer. Radiotherapy: Two alternative schemes: 1. 1.8 Gy fractions five days per week in 28 fractions to a total dose of 50.4 Gy. 2. 2.0 Gy fractions five days per week in 25 fractions to a total dose of 50 Gy. Chemotherapy: Three alternative regimens: 1. Platin-Taxane Regimen: Carboplatin AUC 2 + Paclitaxel 50mg/m2 on day 1 weekly during the full course of radiotherapy. 2a. Platinum-Fluoropyrimidine Regimen: Cisplatin 75mg/m2 weeks 1 and 5 + 5-fluorouracil 1000 mg/m2/day by continuous infusion weeks 1 and 5. 2b. FOLFOX: Oxaliplatin 85 mg/m2, calcium folinate 200 mg/m2 and 5-fluorouracil 400 mg/m2 weeks 1, 3 and 5 + 5-fluorouracil 800 mg/m2 by continuous infusion weeks 1, 3 and 5.

Group II: Control arm (A) Active Control 3 Interventions

Neoadjuvant chemoradiotherapy followed by esophagectomy. Radiotherapy: 1.8 Gy fractions 5 days per week in 23 fractions to a total dose of 41.4 Gy. Chemotherapy: Carboplatin AUC 2 + Paclitaxel 50mg/m2 weekly x 5 (day 1, 8, 15, 22, 29), starting on the first day of radiotherapy. Esophagectomy: Within 8 weeks of termination of chemoradiotherapy,

Carboplatin is already approved in Canada for the following indications:

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Karolinska University Hospital

Lead Sponsor

Trials

509

Recruited

1,319,000+

Björn Zoëga

Karolinska University Hospital

Chief Executive Officer since 2019

PhD in Medicine from the University of Gothenburg, MBBS from Reykjavik University

Christophe Pedroletti

Karolinska University Hospital

Chief Medical Officer

MD, PhD

The Swedish Research Council

Collaborator

Trials

159

Recruited

4,805,000+

Maria Eriksson

The Swedish Research Council

Chief Medical Officer

MD from Karolinska Institutet

Irene Wennemo

The Swedish Research Council

Chief Executive Officer since 2022

PhD in Sociology

University of Leipzig

Collaborator

Trials

219

Recruited

1,288,000+

Jarl Ulf Jungnelius

University of Leipzig

Chief Medical Officer since 2017

MD and Bachelor of Science from Karolinska Institute

Aram Mangasarian

University of Leipzig

Chief Executive Officer since 2017

PhD in Biology from the University of California-San Diego, MBA from INSEAD

Findings from Research

The CROSS trial is a multicenter, randomized phase III clinical trial involving 350 patients, designed to compare the effectiveness of neoadjuvant chemoradiotherapy followed by surgery against surgery alone for treating potentially curable esophageal cancer.

The trial aims to assess various outcomes, including median survival rates, quality of life, and the rate of complete R0 resections, to determine if the neoadjuvant treatment improves overall survival and locoregional control in patients with esophageal adenocarcinoma or squamous cell carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS). van Heijl, M., van Lanschot, JJ., Koppert, LB., et al.[2022]

This randomized phase II trial is comparing the efficacy and toxicity of two chemoradiation regimens, OXCAP-RT and CarPac-RT, in patients with resectable oesophageal adenocarcinoma, with a primary focus on achieving a pathological complete response rate (pCR) after treatment.

The study involves 76 patients and aims to determine which regimen is more effective and safer, potentially leading to a future phase III trial against the current standard neo-adjuvant chemotherapy in the UK.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma. Mukherjee, S., Hurt, CN., Gwynne, S., et al.[2023]

Neoadjuvant chemoradiotherapy (CTRT) is the standard treatment for locally advanced esophageal cancer, with the CROSS trial establishing the combination of radiotherapy with carboplatin and paclitaxel as the preferred regimen.

There is a need for further randomized trials to identify optimal chemotherapy and radiotherapy combinations, as well as to explore new multimodal strategies that include biological agents and immunotherapy for better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of different available chemotherapy regimens combined with radiotherapy for the neoadjuvant and definitive treatment of esophageal cancer. Tomasello, G., Ghidini, M., Barni, S., et al.[2018]

Pre-operative chemotherapy with Paclitaxel-Carboplatin followed by adjuvant immunotherapy using Nivolumab has significantly improved the management of locally advanced esophageal cancer, which historically has a poor prognosis.

Current trials are exploring the effectiveness of immunotherapy for non-operable esophageal cancers, while strategies like dose escalation and combining pre-operative chemo-radiotherapy with trastuzumab have not shown benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. Quéro, L., Besnard, C., Guillerm, S., et al.[2022]

Esophageal cancer is rapidly increasing in the U.S. and is aggressive, with poor survival rates from traditional treatments like surgery or chemoradiation alone.

New trials at Memorial Sloan-Kettering Cancer Center are exploring the use of weekly paclitaxel/cisplatin and irinotecan/cisplatin, which may reduce gastrointestinal toxicity while maintaining efficacy, compared to traditional cisplatin/5-FU regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy in esophageal cancer: the Memorial experience. Anderson, SE., Minsky, BD., Bains, M., et al.[2018]

In a study of 11 patients with advanced oesophageal cancer, carboplatin showed a partial response in 9% of patients and minor responses in 2 cases, indicating some level of antitumor activity.

Carboplatin was well tolerated, with only one case of reversible myelosuppression reported, and no nephrotoxicity or vomiting, suggesting it may be a safer alternative to cisplatin in chemotherapy regimens for oesophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin in the treatment of oesophageal cancer. Mannell, A., Winters, Z.[2014]

Cis-platinum is a highly effective chemotherapy agent used for various cancers, including testicular, ovarian, and bladder cancers, but it can cause dose-limiting kidney toxicity.

Recent advancements have identified methods to mitigate these toxic effects, allowing for the safe use of higher doses (up to 200 mg/m2) that significantly improve outcomes in patients with poor prognostic testicular cancer compared to standard doses (100 mg/m2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and clinical applications of cis-platinum. Javadpour, N.[2019]

In a study of 96 esophageal cancer patients treated with a neoadjuvant chemoradiotherapy regimen, there was a significant increase in postoperative complications such as pneumonia (51.0% vs. 27.1%), pleural effusion (24.0% vs. 12.5%), and arrhythmia (34.4% vs. 20.4%) compared to patients who underwent surgery alone.

Despite the higher rates of cardiopulmonary complications in the neoadjuvant CRT group, there were no differences in the length of hospital or intensive care unit stays, nor in short-term mortality, indicating that while neoadjuvant CRT may increase certain risks, it does not affect overall survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of neoadjuvant chemoradiotherapy on postoperative course after curative-intent transthoracic esophagectomy in esophageal cancer patients. Bosch, DJ., Muijs, CT., Mul, VE., et al.[2022]

In a safety analysis of 6 patients with locally advanced esophageal cancer, the combination of pemetrexed, carboplatin, and radiation followed by surgery showed a favorable safety profile, with only one patient experiencing a severe adverse event (grade 4 neutropenia).

The treatment resulted in promising outcomes, with one patient achieving a complete pathologic response and three showing partial responses, indicating potential efficacy that warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed, Carboplatin, and Concomitant Radiation followed by Surgery for Locally Advanced Esophageal Cancer: Results of a Planned Interim Toxicity Analysis of North Central Cancer Treatment Group Study N044E. Katipamula, R., Jatoi, A., Foster, NR., et al.[2021]

In a study of 201 patients with locally advanced esophageal squamous cell carcinoma, the chemotherapy regimen of carboplatin plus paclitaxel (TP) resulted in significantly higher rates of severe adverse events compared to carboplatin plus cisplatin (TC), particularly with a higher incidence of grade 3 or higher febrile neutropenia.

Despite the differences in safety, both TP and TC regimens showed comparable overall survival and progression-free survival rates, suggesting that TC is the preferred option due to its better safety profile without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of paclitaxel plus carboplatin versus paclitaxel plus cisplatin in neoadjuvant chemoradiotherapy for patients with locally advanced esophageal carcinoma: a retrospective study. Jiang, L., Zhu, J., Chen, X., et al.[2023]

The combination of oxaliplatin, docetaxel, and capecitabine (ODC) with radiation therapy showed a high pathologic complete response (pCR) rate of 49% in patients with resectable esophageal cancer, indicating its efficacy as a preoperative treatment.

The treatment was found to be relatively safe, with no dose-limiting toxicities in the initial phase and manageable side effects, suggesting it can be administered effectively within 8 weeks before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction. Spigel, DR., Greco, FA., Meluch, AA., et al.[2018]

Neoadjuvant chemoradiotherapy with the paclitaxel plus platinum regimen significantly improves overall survival in patients with locoregional esophageal cancer compared to surgery alone, with a hazard ratio of 0.63 for the entire population.

In particular, this regimen is especially effective for patients with squamous cell carcinoma, showing a hazard ratio of 0.50, indicating a substantial reduction in the risk of death compared to surgery alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer. Huang, TC., Hsu, CH., Lin, CC., et al.[2022]

Preoperative chemotherapy or chemoradiation is beneficial for patients with operable esophageal cancer, particularly for those with more advanced stages of the disease.

Further research is needed to explore modern chemotherapy combinations and to develop methods for predicting patient outcomes from neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy or chemoradiotherapy for locally advanced esophageal cancer. Smithers, BM., Thomson, I.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS). [2022]

2. England pubmed.ncbi.nlm.nih.gov

NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Overview of different available chemotherapy regimens combined with radiotherapy for the neoadjuvant and definitive treatment of esophageal cancer. [2018]

4. France pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. [2022]

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

Combined modality therapy in esophageal cancer: the Memorial experience. [2018]

6. South Africa pubmed.ncbi.nlm.nih.gov

Carboplatin in the treatment of oesophageal cancer. [2014]

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

Pharmacology and clinical applications of cis-platinum. [2019]

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

Impact of neoadjuvant chemoradiotherapy on postoperative course after curative-intent transthoracic esophagectomy in esophageal cancer patients. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Pemetrexed, Carboplatin, and Concomitant Radiation followed by Surgery for Locally Advanced Esophageal Cancer: Results of a Planned Interim Toxicity Analysis of North Central Cancer Treatment Group Study N044E. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of paclitaxel plus carboplatin versus paclitaxel plus cisplatin in neoadjuvant chemoradiotherapy for patients with locally advanced esophageal carcinoma: a retrospective study. [2023]

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

Phase I/II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer. [2022]

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

Neoadjuvant chemotherapy or chemoradiotherapy for locally advanced esophageal cancer. [2022]