Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05620199 |
| Other study ID # |
M22UPL |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2023 |
| Est. completion date |
April 1, 2025 |
Study information
| Verified date |
November 2022 |
| Source |
The Netherlands Cancer Institute |
| Contact |
Robert Luger, Bsc. |
| Phone |
+31657341946 |
| Email |
r.luger[@]nki.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
