DREAM: Double Lung Transplant REgistry Aimed for Lung-limited Malignancies

This is a prospective observational registration trial for patients who undergo lung transplantation for the treatment of the select groups of medically refractory cancers affecting the lungs alone without extrapulmonary nodal and distant metastasis.

Ever since human lung transplantation was first performed in a patient with advanced lung cancer in 1963 \[1\], it has emerged as a well-established treatment for patients suffering from a variety of end-stage pulmonary diseases. While lung transplant continues to be performed for refractory lung-limited malignancies that do not have extrapulmonary disease \[2-6\], given the perceived risks of tumor recurrence following transplantation and potentially reduced survival compared to patients with chronic end-stage lung diseases, transplants for cancer constitutes less than 0.5% of all such procedures (www.srtr.org). The need for lung transplantation is not only confined to patients with primary lung cancers. There are unmet needs for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). Indeed, successful reports of lung transplantation for lung only metastasis that are refractory to standard of care treatment has been demonstrated \[3\] and proposed by international experts in highly selected patients \[6\]. Solid organ transplantation for both primary and metastatic cancers has been demonstrated in liver transplantation \[7, 8\]. While uncommonly performed, for patients with refractory lung cancer or those with concomitant respiratory failure, lung transplantation may be the only treatment option. The 5-year overall survival of patients in some prior reports who underwent double lung transplantation (DLT) for lung cancer was 39-57%\[2, 9\], compared to those with non-malignant diseases 50-59%\[10, 11\]. Indeed, lung transplants have been steadily increasing for cancers, as evident in the International Society of Lung Transplantation (ISHLT) \[4-6\]. However, the reported cases represent heterogeneity in the surgical technique, patient selection, and post-operative management.

This prospective observational registry aims to better understand the long-term outcomes in patients undergoing double lung transplantation for lung-limited cancers in the clinical programs at Northwestern Medicine and participating centers. We aim to study the impact of a standardized approach to patient selection, tumor staging, surgical technique, and post-operative management on the long-term survival following lung transplantation in patients with lung-limited malignancy. Specifically, this study aims to investigate the clinical outcomes of patients who undergo lung transplantation for treatment of a select group of medically refractory cancers affecting the lungs without extrapulmonary metastases. Patients will undergo transplantation if they have failed standard of care treatments and do not have further curative treatment/trials options. Their clinical courses including overall survival, disease-free survival, and graft failure will be monitored as well as the molecular and genetic biomarkers to investigate the correlation with the prognosis.

Eligibility Criteria:
Inclusion Criteria:

Any patient who is undergoing double lung transplantation as part of the clinical program, consents for this prospective observational trial, and has one of the following conditions will be eligible.

* Common Inclusion Criteria

  * Adults of Age ≦ 80
  * Resistant or refractory to or without available standard of care treatment options or experimental treatment options that are known to increase survival outcome
  * Patients without any extrapulmonary disease
  * Patients with good general health with an ability to withstand physiologic stressors and undergo psychosocial evaluation by the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) or other assessment tools
  * Patients to meet all other criteria for lung transplantation including insurance approval and United Network for Organ Sharing (UNOS) registration

Inclusion Criteria for Cohort A

* Histologically confirmed selected lung non-small cell lung cancer including but not limited to:

  o according to the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification

  - Lepidic dominant pattern
* Adenocarcinoma in situ
* Minimally invasive adenocarcinoma
* Non mucinous lepidic predominant invasive adenocarcinoma

  o based on 2015 World Health Organization (WHO) classification of lung tumors including

  - Invasive mucinous adenocarcinoma
* Mixed invasive mucinous and mucinous adenocarcinoma

  * Colloid adenocarcinoma
  * Enteric adenocarcinoma
  * Minimally invasive adenocarcinoma
* Nonmucinous
* Mucinous

  - Preinvasive lesions
* Atypical adenomatous hyperplasia
* Adenocarcinoma in situ

  * Nonmucinous
  * Mucinous
  * based on the 2004 WHO classification of lung tumors including - Bronchioloalveolar carcinoma
* Nonmucinous
* Mucinous
* Mixed nonmucinous and mucinous or indeterminate
* Without any distant metastasis confirmed by standard staging work-up
* Without brain metastasis confirmed by brain imaging
* Without unidentified primary site of cancer

Inclusion Criteria for Cohort B

* Metastatic cancers to lung alone - including but not limited to germ cell tumors, head \& neck tumors, colorectal tumors, renal cell tumors, testicular cancer
* Without any other distant metastasis confirmed by standard staging work-up

Inclusion Criteria for Cohort C

* Respiratory failure with a history of cancer in the last 5 years - including, but not limited to interstitial lung disease (ILD), pulmonary fibrosis (idiopathic or secondary), advanced chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH)
* Without any other distant metastasis confirmed by standard staging work-up

Exclusion Criteria:

* Exclusion criteria

  * Adults unable or unwilling to consent
  * Individuals who are not yet adults (infants, children, teenagers)
  * Pregnant women
  * Prisoners
  * Vulnerable Populations
  * Presence of extrapulmonary disease or mediastinal nodal disease at the time of transplant referral
  * Small Cell Cancers
  * Unidentified primary site of cancer for Cohort A
  * Progression of disease or confirmed distant metastases or mediastinal nodal disease at any point during transplantation work-up
  * Medical ineligibility for lung transplantation after multidisciplinary assessment
  * Not a suitable candidate according to the lung transplantation protocol for treatment of lung confined primary or metastatic tumors
* Body mass index more than 35 kg/m2
* Evidence of co-existing malignancies for Cohort A
* Untreatable significant dysfunction of another major organ system including heart, liver, kidney, or brain unless combined organ transplantation can be performed
* Uncorrected atherosclerotic disease with suspected or confirmed end-organ ischemia or dysfunction and/or coronary artery disease not amenable to revascularization
* Uncorrectable bleeding diathesis
* Evidence of active Mycobacterium tuberculosis infection
* Significant chest wall or spinal deformity expected to cause severe restriction after transplantation