Trial Title:
Upfront Resection of Locally Advanced NSCLC Followed by Chemoradiotherapy
NCT ID:
NCT05620199
Condition:
Locally Advanced Non-Small Cell Lung Cancer
Chemoradiotherapy
Cavitation Lung
Surgery
Feasibility
Safety
Conditions: Official terms:
Carcinoma, Non-Small-Cell Lung
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Upfront resection
Description:
Resection of the primary tumor
Arm group label:
Study population
Summary:
For patients with irresectable locally advanced non-small cell lung cancer (NSCLC) (e.g.
multilevel or bulky N2 disease or presence of N3 lymph node metastases), current
guidelines recommend treatment with chemoradiotherapy (CRT) followed by immune checkpoint
inhibition (ICI, durvalumab). Chances of sterilization of a large (e.g. clinically staged
T3 or T4 tumor) tumor volume by CRT alone are relatively small and these tumors are
associated with a high local recurrence rate. Moreover, necrosis and cavitation of these
tumors puts these patients at risk of fatal bleeding and might cause infectious
complications, which lead to subsequent impaired quality of life (QoL) and to
interruption of, or the need for postponing, (systemic) treatment.
Upfront resection of the tumor in the lung, followed by postoperative CRT in patients who
have a (potentially) resectable tumor could be a strategy to prevent complications of CRT
in large volume and/or cavitating tumors with extensive mediastinal disease.
Detailed description:
Stage III non-small cell lung cancer (NSCLC) comprises a heterogeneous group of patients,
with concurrent chemoradiotherapy (CRT), until recently, being considered the standard of
care (SoC) treatment for fit patients. Prognosis varies depending on the size and extent
of the primary tumor and the degree of lymph node involvement. The aim of treatment of
stage III NSCLC is to increase both locoregional and systemic control of the disease. For
resectable stage III NSCLC, resection alone is associated with poor survival because of a
high local recurrence rate and the presence of distant metastatic disease during the
course of the disease. Induction chemotherapy and/or radiotherapy followed by surgery has
been demonstrated to improve survival in selected patients. Moreover, it has been shown
that in highly selected patients with stage IIIB NSCLC, surgical resection as part of
multimodality therapy might be associated with improved overall survival (OS). Since a
large proportion of patients with stage III NSCLC develop distant disease relapse
following CRT, there is a need to treat possible presence of micrometastases and improve
systemic control of the disease. Recently, immune checkpoint inhibition (ICI, durvalumab)
has been added to CRT successfully and is now SoC treatment in irresectable (e.g.
multilevel or bulky N2 disease or presence of N3 lymph node metastases) stage III NSCLC,
leaving the role of surgery in this new treatment strategy unclear.
In large volume NSCLC and in cavitating tumors, chances of sterilization of the tumor by
CRT alone are reduced, increasing the local recurrence rate, when compared to small size
tumors. Between 10-20% of all lung carcinomas present with radiological cavitation, which
is believed to be due to tumor necrosis as a consequence of ischemia and/or bronchial
obstruction. Necrosis and cavitation of the tumor can cause infectious complications in
the short and long term with subsequent impaired quality of life (QoL) and may also lead
to interruption of, or the need for postponing, (systemic) treatment. Moreover,
cavitation is associated with bleeding complications and even fatal pulmonary hemorrhage
after CRT. Besides, lung function might be seriously impaired after CRT for a large
tumor, especially in case of a centrally located tumor. It has been suggested that
upfront resection with postoperative CRT in patients who have a potentially resectable
tumor could be a strategy to prevent complications of tumor cavitation (e.g. infectious
complications, bleeding) in large volume tumors. Moreover, in advanced NSCLC, it is
suggested that (chemo)immunotherapy (or targeted therapy in case of presence of a driver
mutation) improves systemic disease control, making local control of the disease more
important during follow-up. To decrease the risk of a local recurrence in a situation of
controlled systemic disease, local control by upfront resection of the large volume tumor
might be considered.
For stage III NSCLC, immunotherapy can be added prior (neoadjuvant) or following
(adjuvant) CRT. In the neoadjuvant setting, several studies have been done or are
ongoing, including ICI (single agent or a combination of 2 agents) or ICI in combination
with chemotherapy, radiotherapy or CRT followed by resection as a possible treatment for
stage III NSCLC (NADIM(-II) trial, LCMC3 trial, NEOSTAR trial, KEYNOTE-671 trial,
IMpower-030 trial, CheckMate-816, 77T trial, AEGEAN). So far, most of these studies
included only a small number of patients and endpoints have been major pathological
response (MPR) (<10% vital tumor present) and complete pathological response (pCR), both
being surrogate markers for progression free survival (PFS) and OS. The added toxicity of
ICI, especially in combination with chemotherapy, radiotherapy or CRT, still needs to be
elucidated and in case of a large volume or cavitating tumor, toxicity might be related
to infection and necrosis of the large tumor mass and/or an increase in radiation dose to
the organs at risk such as the lungs.
Upfront surgery might benefit patients with large volume stage IIIB/IIIC NSCLC and the
potential advantages, e.g. improved local control, reduction of radiotherapy treatment
volumes and reduction of long term infectious problems or bleeding complications because
of necrosis of the primary tumor, may possibly outweigh the risk of a delayed start of
the SoC treatment. A possible drawback of an upfront resection approach is the risk of
(locoregional or systemic) tumor progression when delaying planned CRT and adjuvant ICI.
The intervention should not prevent the patient from receiving the SoC treatment, so a
safety and feasibility check is necessary in evaluating the role of upfront resection in
these patients with large volume stage IIIB/IIIC NSCLC.
Aim of the UPLAN-I trial is to evaluate feasibility and safety of upfront resection of
the large volume or cavitating tumor in the lung (including hilar with/without
mediastinal lymph node dissection if deemed possible by the treating surgeon), followed
by concurrent CRT. The role of upfront resection in reducing infectious problems (and
bleeding complications) and subsequent impaired QoL, in combination with decreasing the
risk of a local recurrence (PFS) and improving OS, are evaluated in the future UPLAN-II
trial, however feasibility and safety of this treatment regimen need to be established
first (UPLAN-I). Moreover, the role of ctDNA in relation to treatment response and
outcome of this treatment regimen will be evaluated in the consecutive UPLAN-II trial.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Provision of signed, written and dated IC prior to any study specific procedures.
- Male or female aged at least 18 years.
- Eastern Cooperative Oncology Group (ECOG)/WHO performance status of 0 or 1.
- A pretreatment PET/CT scan (of the thorax and upper abdomen) and an MRI (or CT scan)
of the brain is considered SoC and must be done prior to start of treatment.
- Pathologically proven NSCLC, staged according to the 8th edition of the AJCC Staging
Manual, with a clinical indication for concurrent CRT (according to current
guidelines).
- Pathology proven N2 or N3 lymph node metastasis.
- Patients should be able to receive concurrent CRT.
- Patients should be operable to the discretion of the treating pulmonary physician,
surgeon and anesthesiologist, based on lung function testing and performance
scoring.
- EGFR/ALK mutations and never-smokers may be included in the study (since endpoints
are settled after finishing CRT and before starting adjuvant systemic treatment).
Exclusion Criteria:
- Irresectable primary lung tumor before start of concurrent CRT.
- Pneumonectomy deemed necessary (by the treating surgeon) to achieve a complete
resection (R0).
- Sulcus superior tumor with invasion of the thoracic wall.
- cT3-4 based on satellite nodus/lesion in the ipsilateral lung.
- Patients with a locoregional recurrence or a second primary lung cancer.
- Patients with prior treatment with radiotherapy on the lung.
- Patients with a history of other malignancies, except:
- adequately treated non-melanoma skin cancer
- curatively treated in-situ cancer, or
- other malignancies curatively treated with no evidence of disease for >5 years
following the end of treatment and which, in the opinion of the treating
physician, do not have a substantial risk of recurrence of the prior
malignancy.
- Small cell lung cancer or a pulmonary carcinoid tumor.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
April 1, 2023
Completion date:
April 1, 2025
Lead sponsor:
Agency:
The Netherlands Cancer Institute
Agency class:
Other
Collaborator:
Agency:
Leiden University Medical Center
Agency class:
Other
Collaborator:
Agency:
Radboud University Medical Center
Agency class:
Other
Collaborator:
Agency:
University Medical Center Groningen
Agency class:
Other
Collaborator:
Agency:
Erasmus Medical Center
Agency class:
Other
Collaborator:
Agency:
Maastricht University Medical Center
Agency class:
Other
Collaborator:
Agency:
Zuyderland Medical Centre
Agency class:
Other
Collaborator:
Agency:
Maxima Medical Center
Agency class:
Other
Source:
The Netherlands Cancer Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05620199
