Dexamethasone, Flurbiprofen Axetil and Long-term Survival After Lung Cancer Surgery

Impact of Perioperative Dexamethasone and Flurbiprofen Axetil on Long-term Survival After Surgery for Non-small Cell Lung Cancer: A 2x2 Factorial Randomized Controlled Trial

Surgical resection is the first choice treatment for patients with non-small-cell lung cancer. Despite of advances in surgical techniques, the long-term survival rate of postoperative patient is far from optimal. In a recent retrospective cohort study of the applicants, 588 patients after surgery for non-small-cell lung cancer were followed up for a medium of 5.2 years. The results showed that perioperative use of dexamethasone was associated with prolonged survival; perioperative use of flurbiprofen axetil was also associated with a slightly longer survival but not statistically significant. Further analysis showed that combined administration of dexamethasone and flurbiprofen axetil had additive effect in prolonging survival. We hypothesize that, for patients undergoing surgery for non-small-cell lung cancer, perioperative administration of dexamethasone and flurbiprofen axetil may improve long-term survival. However, evidences from randomized controlled trials are still lacking in this aspect.

Surgical resection is the first choice treatment for patients with non-small-cell lung cancer. Although improvements of surgical techniques have reduced the incidence of complications, the long-term survival rate of postoperative patient is far from optimal. Cancer metastasis and recurrence are the main reasons that lead to long-term postoperative death. It is unavoidable that some cancer cells will be disseminated into the blood circulation or the lymphatic systems during surgery. The development of metastasis and recurrence are dependent on the balance between the immune function of the body and the cancer-promoting factors during the perioperative period.

Studies showed that surgical stress inhibits the cytotoxic effects of natural killer cells and the activity of T cells, and thus leads to immunosuppression of the body. Furthermore, perioperative management such as anesthetic techniques, anesthetics and related drugs, blood transfusion and hypothermia can also affect immune function. For example, studies showed that inhalational anesthetics and opioids aggravate immunosuppression, and may lead to worse outcome; whereas regional anesthesia and non-steroid anti-inflammatory drugs relieve immunosuppression, and thus may improve outcome. Glucocorticoids (mainly dexamethasone) are frequently used for prevention of postoperative nausea and vomiting. A recent retrospective study showed that, for patients undergoing surgery for pancreatic cancer, perioperative use of dexamethasone was associated with improved long-term survival. However, prospective randomized controlled trials are still lacking to demonstrate the relationship between perioperative management and long-term outcome in cancer patients.

A recent retrospective cohort study of the applicants recruited 588 patients after surgery for non-small-cell lung cancer and performed a postoperative follow-up for a medium of 5.2 years. After adjusting the confounding factors with multivariate logistic regression model, perioperative use of dexamethasone (medium dose 10 mg, for prevention of postoperative nausea and vomiting) was associated with prolonged survival (HR 0.70, 95% CI 0.54-0.89; P = 0.004); perioperative use of flurbiprofen axetil (medium dose 200 mg, for postoperative analgesia) was also associated with a slightly longer survival but not statistically significant (HR 0.81, 95% CI 0.63-1.03; P = 0.083). Further analysis showed that combined administration of dexamethasone and flurbiprofen axetil had additive effect in prolonging survival (compared to no use of both: adjusted HR 0.57, 95% CI 0.38-0.84, P = 0.005).

The investigators hypothesize that, for patients undergoing surgery for non-small-cell lung cancer, perioperative administration of dexamethasone and flurbiprofen axetil may improve long-term survival. However, evidences from randomized controlled trials are still lacking in this aspect.

Inclusion Criteria:

1. Age from 18 to 85 years old;
2. Diagnose as non-small-cell lung cancer (stage IA-IIIA);
3. Plan to undergo surgical resection;
4. Provide written informed consents.

Exclusion Criteria:

1. Clinical evidences suggest remote metastasis of the primary cancer; have received radiotherapy, chemotherapy or targeted therapy before surgery; have received previous surgery for lung cancer; diagnosed with other cancer (other than lung cancer) currently or previously;
2. History of therapy with glucocorticoids or immunosuppressants within 1 year, or therapy with non-steroidal anti-inflammatory drugs (NSAIDs) within 1 month;
3. Allergy to glucocorticoids or NSAIDs;
4. Contraindications to dexamethasone or flurbiprofen axetil, such as asthma or hives urticaria induced by aspirin or other NSAIDs; active digestive tract ulcer or bleeding, or history of repeated digestive tract ulcer or bleeding; coagulopathy (platelet count < 50*10^9/L, International Normalized Ratio > 1.4, or activated partial thromboplastin time > 4 seconds above upper limit); current therapy with lomefloxacin, norfloxacin, or enoxacin; severe cardiac dysfunction (New York heart association class 3 or above, or Left Ventricular Ejection Fraction less than 30%) or myocardial infarction within 3 months; liver injury (transaminase higher than 2 times of upper limit); kidney injury (creatinine higher than 1.5 times of upper limit); uncontrolled severe hypertension before surgery (> 180/120 mmHg);
5. ASA physical status class IV or higher;
6. Refuse to use patient-controlled analgesia pump after surgery;
7. Other conditions that are considered unsuitable for study participation.