Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma

August 16, 2022 updated by: Shereen Issa, Kuwait Cancer Control Center

Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma: A Randomized Phase III Trial

The standard of care for locally advanced nasopharyngeal carcinoma is radical chemoradiation(CRT).Recent advances in radiation techniques and supportive measures resulted in improvemnent of locoregional control and quality of life.However distant failure is still the main challenging reason of poor survival

Addition of systemic therapy to concurrent CRT is widely used and accepted as an option to reduce these failures ,however selection of chemotherapy regimen and timing in relation to CRT is controversial.

Doublet and triplet chemotherapy regimens using cisplatin and 5FU are throughly investigated in this setting.Inspite of significant improvement in disease free survival and overall survival they were poorly tolerated.Hence,minority of patients in the daily practice could tolerate those studied regimens as propsed.

Recently, in multicenter randomized trial, Zhang and his group investigated gemcitabine and cisplatin as induction chemotherapy (ICT) added to CRT.It showed improvement in recurrence free survival and overall survival.More importantly 96.7% of the experimental arm completed the treatment protocol.

This was further confirmed by an updated network of meta analysis by Bongiovanni et al.Again the question of "when" is still valid.Our proposal is to compare tolerable regimen in induction versus adjuvant settings.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Background

Nasopharyngeal carcinoma (NPC) is one of the cancers which shows significant geographic prevalence variation. Worldwide, there were 130,000 new cases in 2018.As a non-endemic region, only 35 new cases were diagnosed in Kuwait in the same year. Nevertheless, it accounts for 1.3% of cancer related mortality in Kuwait.

Radical radiotherapy (RT) is the mainstay treatment of NPC for decades. A high cure rate can be achieved for patients with early-stage. The breakthrough in the management of NPC came with the intergroup study 009 which showed significant improved progression free survival with adding chemotherapy (CTH) to the radiation.

As compared to RT alone, concurrent chemoradiation (CRT), showed significant improvement in 10-year overall survival and progression free survival in meta-analysis of nasopharyngeal carcinoma (MAC-NPC) collaborative group. Addition of systemic therapy to concurrent CRT was the proposed solution to treatment failures; whether in the induction (ICT) or adjuvant (ACT) settings. However, ICT or ACT in NPC remains controversial; largely due to inconsistent results of several prospective randomized trials.

The above-mentioned MAC-NPC group reviewed six clinical trials in which CRT followed by ACT was compared with RT alone (administrated without concurrent or adjuvant chemotherapy). Overall survival (OS) was significantly improved compared with RT alone (10-year overall survival 57% versus 43.1%, HR 0.65, 95% CI 0.56-0.76), as well as 10-year progression-free survival; PFS (53.2% versus 38.5%).

However, this was not consistent in endemic areas with high prevalence of Epstein-Barr virus (EBV); which is known causative for NPC. Chen et al reported in a Chinese phase III trial 508 patients with advanced NPC randomized to ACT (cisplatin plus fluorouracil) vs observation following CRT with weekly cisplatin. There was no improvement in the five-year failure-free rate with ACT compared with CRT alone (five-year rate 75% versus 71%, HR 0.88, 95% CI 0.64-1.22) Later, from the same endemic region, Sun Yat-sen university conducted a multi center phase III clinical trial in which 480 patients, stage III to IVB, node-positive NPC were randomly assigned to ICT followed by CRT versus CRT alone. This study showed improvement of recurrence-free survival (RFS) and distant RFS.

Another reason for reluctancy to adopt ICT or ACT in the management of advanced NPC, is the morbidity of current chemotherapy regimens. The high toxicity profile with some of these regimens was the real obstacle toward the use of them. In previous studies, the back bone for adjuvant or induction chemotherapy in NPC has been platinum and 5-fluoruracil, with or without a taxane. This regimen was poorly tolerated, with only 40-60 % of patients could complete their preplanned course of treatment in many trials.

Recently, in multicenter randomized trial, Zhang and his group compared gemcitabine and cisplatin as ICT plus CRT with CRT alone. The 3-year RFS was 85.3% in the induction group and 76.5% in the standard-therapy group (HR 0.51; 95% CI, 0.34 to 0.77; P=0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (HR 0.43; 95% CI, 0.24 to 0.77). What is more important is that 96.7% of the experimental arm completed 3 cycles of ICT.

On behalf of the Nasopharyngeal Cancer Portal Group of Investigators, Bossi colleagues from Europe, Kuwait, Jordan, Turkey and USA, assessed the impact of treatment intensity within a large retrospective multicenter cohort, nasopharyngeal cancer in non-endemic areas. Our group shared in this pooled analysis and the data showed a higher rate of death and recurrence with non-intensive treatment, (defined as no "added" systemic treatment to CRT).

Ongoing Phase 3 Trials exploring ICT or ACT in NPC:

There are multiple phase 3 trials ongoing to refine the ICT or ACT approach. Sun Yat-sen University is conducting a study comparing TPF with PF as ICT regimen in stage IVa-b NPC (NCT02940925). They also explore the effect of triple combination of ICT, CRT and ACT in high risk NPC (NCT02621970). Another comparison between induction TPF vs adjuvant PF is recruiting (NCT03306121). Fudan University also from China exploring maintenance gemcitabine after radical treatment in N3 disease (NCT03403829). Jiangxi Provincial Cancer Hospital testing adding neoadjuvant and adjuvant PD-1 inhibitor to ICT-CRT (NCT04557020) Another promising strategy to control the distant failures in locally advanced NPC, is to employ immunotherapy in the primary treatment. There are many ongoing trials exploring this strategy, mainly in China. However, the validity in endemic vs non-endemic regions should be taken with caution.

Aim of the study In our proposal we are trying to compare the efficacy and tolerability of ICT followed by CRT with CRT followed ACT in locally advanced NPC

Study Type

Interventional

Enrollment (Anticipated)

120

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Kuwait
      • Kuwait, Kuwait, 11911
        • Recruiting
        • Kuwait Cancer control center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Mohamed Ashour, MD
        • Principal Investigator:
          • Mustafa Elsherify, MD
        • Principal Investigator:
          • Khaled Alsaleh, MD
        • Sub-Investigator:
          • Hamdy Sakr, MD
        • Sub-Investigator:
          • Amany Beshir, MD
        • Sub-Investigator:
          • Sudhan Rajan, MD
        • Sub-Investigator:
          • Eman Almoghazy, MD
        • Sub-Investigator:
          • Jitendra Shete, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with newly histologically confirmed Nasopharyngeal carcinoma (according to World Health Organization (WHO) 2. The patient has stage III except T3N0 or IVA disease (according to 8th American Joint Committee on Cancer staging system) 3. WHO performance status 0-1 . 4. The patient must have achieved lawful age to provide informed consent according to local or national law .

    5. Laboratory values performed within 14 days prior to concurrent chemotherapy should be as follows: i) Absolute neutrophil count (ANC) ≥ 1500/mm ii) Platelet count ≥ 100.000/mm iii) Hemoglobin ≥ 8g/dl iv) Urea and serum creatinine ≤ 1.5 mg/dl. (for cisplatin) v) Creatinine clearance ≥ 60 ml/min. (for cisplatin) vi) SGOT and SGPT ≤ 2 × upper limit of laboratory normal 6. Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy

Exclusion Criteria:

  1. Age ≥70 or <18
  2. The patient has evidence of distant metastatic disease.
  3. The patient has received prior systemic chemotherapy within the last three years.
  4. The patient has undergone previous surgery for the tumor, other than biopsy.
  5. The patient has received prior radiation therapy to the head or neck
  6. The patient is pregnant or breast feeding.
  7. The patient has a medical (e.g. renal impairment) or psychological condition that would not permit the patient to complete the trial or sign informed consent.
  8. Has known history of Human Immunodeficiency Virus (HIV)
  9. Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy,
  10. Has a history of severe hypersensitivity reaction to Cisplatin, Gemcitabine or radiotherapy or their analogs
  11. Unstable cardiac disease requiring treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Induction Arm
patients will receive three cycles of IC Gemcitabin/Cisplatin followed by radical CRT
Drug: Gemcitabin/cisplatin
chemotherapy combination
Active Comparator: Adjuvant Arm
Patients will receive radical CRT followed by three cycles of AC Gemcitabin/Cisplatin
Drug: Gemcitabin/cisplatin
chemotherapy combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute and late toxicity assessment
Time Frame: 3-5 years
Incidence of acute toxicity is calculated for each adverse event respectively, and severity evaluated on based of common terminology criteria for adverse event (CTCAE)
3-5 years
Late radiation toxicity
Time Frame: 5-7 years
assessed using the radiation therapy oncology group and Europe organization for research and treatment of cancer late radiation morbidity scoring scheme
5-7 years
Loco regional control rates (LCR)
Time Frame: 3-5 years
Defined as the time from the date of randomization to 1st failure in nasopharynx or neck lymph nodes
3-5 years
Progression free survival (PFS)
Time Frame: 3-5 Years
Defined as the time from the date of randomization to 1st failure locally or systemically
3-5 Years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: 5 years
Defined as the time from the date of randomization to death from any cause
5 years
Distance Metastasis free survival (DMFS)
Time Frame: 5 years
It is evaluated and calculated from the date of random assignment until date of first distance metastasis or until the date of last follow-up visit
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kuwait Cancer Control Center

Investigators

  • Principal Investigator: Shereen Issa, MD, KCCC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2021

Primary Completion (Anticipated)

April 30, 2025

Study Completion (Anticipated)

April 30, 2026

Study Registration Dates

First Submitted

May 13, 2021

First Submitted That Met QC Criteria

May 18, 2021

First Posted (Actual)

May 24, 2021

Study Record Updates

Last Update Posted (Actual)

August 17, 2022

Last Update Submitted That Met QC Criteria

August 16, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HNIC-NP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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