Upfront resection of locally-advanced or cavitating NSCLC followed by chemoradiotherapy (and adjuvant systemic treatment); Phase 1 multicenter study to assess treatment feasibility and safety

Stage III non-small cell lung cancer (NSCLC) comprises a heterogeneous group of
patients resulting in variable prognoses depending on the size and extent of
the primary tumor and the degree of lymph node involvement. For resectable
stage III NSCLC, induction chemotherapy, radiotherapy or chemoradiotherapy
(CRT) followed by a surgical resection has been demonstrated to improve
survival in selected patients when compared to treatment with resection alone.
The recent introduction of immune checkpoint inhibitors (ICIs) as induction
therapy shows encouraging activity and preliminary results and shows a
favorable safety profile in patients with resectable early-stage or
locally-advanced NSCLC. However, outcomes of overall survival (OS) have yet to
be published. Until recently, guideline-recommended treatment of irresectable
stage III NSCLC (e.g. multilevel or bulky N2 disease or presence of N3 lymph
node metastases) was concurrent (c)CRT. Recently, ICI (durvalumab) was
successfully added to CRT, showing improved progression free survival (PFS) and
OS, now being the standard of care (SoC) treatment for these tumors. So, in
stage III NSCLC, possible resectability influences the treatment strategy,
however the definition of resectability is subject of discussion and varies
between different surgeons and multidisciplinary teams. Therefore, the role of
surgery remains unclear so far. When compared to small-sized tumors, large
volume (>700cc) and/or cavitating lung tumors are less likely to be sterilized
by CRT, increasing the local recurrence rate. After CRT, the quality of life
(QoL) might be impaired due to extensive and prolonged coughing. Cardiotoxicity
might cause problems and lung function might be seriously impaired after CRT
for a large tumor, especially in case of a centrally located tumor. Moreover,
necrosis and cavitation of the tumor can cause infectious and/or bleeding
complications, including potentially fatal pulmonary hemorrhage. It has been
suggested that upfront resection of the large tumor in the lung, with
postoperative CRT (aiming for the mediastinal lymph node metastases) in
patients who have a potentially resectable tumor could be a strategy to prevent
complications of tumor cavitation in large volume tumors. Moreover, it has been
shown that in highly selected patients diagnosed with stage IIIB NSCLC,
surgical resection as part of multimodality therapy might be associated with
improved overall survival (OS). Since (chemo)immunotherapy, or targeted therapy
in case of presence of a driver mutation, has the potential to control systemic
disease, local control of the primary tumor in the lung becomes more important.
Upfront resection of a large volume tumor in the lung might be considered to
gain this local control. Moreover, it eliminates the need for CRT on the
primary tumor in the lung and thus avoids the potentially serious or
life-threatening effects of this treatment.

The primary aim of the UPLAN-I trial is to evaluate feasibility and safety of
upfront resection of large volume or cavitating tumors in the lung (including a
hilar and/or mediastinal lymph node dissection if deemed possible by the
treating surgeon), followed by cCRT. The treatment protocol is regarded
feasible when at least 15 out 20 patients (75%) are able to undergo cCRT
without delay (of more than 10 weeks after de MDT). Secondary aims are
establishing safety and recording the incidence of complications.

When feasibility and safety are confirmed in this UPLAN-I trial, the role of
upfront resection in reducing infectious problems and subsequently improved
QoL, in combination with decreasing the risk of a local recurrence and
improving OS, are evaluated in the future UPLAN-II trial.

Multicenter, open label, intervention, feasibility & safety study

Upfront resection of the lung tumour

A possible risk of the upfront resection is a delayed start of treatment with
cCRT, as the resection precedes the start of cCRT and because possible
complications of surgery might postpone the start of further treatment.
Potential surgical complications include bleeding, wound infections, lung
infections or thrombosis. The aim is to start the cCRT within 4-6 weeks after
resection. The risk of delayed treatment with cCRT is potentially acceptable,
considering that upfront surgery might benefit patients with large volume stage
IIIB/IIIC NSCLC. One of the main benefits this treatment strategy may realise,
is a decrease in the occurence of necrosis and infection of the large-volume
tumor after treatment with cCRT. Furthermore, it is probable that the patients
will require less intensive treatment with radiotherapy due to the resected
tumour and affected lymph nodes. In conclusion, potential advantages of an
upfront resection include improved local control, reduction of radiotherapy
treatment volumes and reduction of long-term infectious problems or bleeding
complications. These advantageous outcomes possibly outweigh this risk of a
delayed start of the SoC treatment.