Carcinoid Lung Tumors Treatment & Management
- Author: Mary C Mancini, MD, PhD, MMM; Chief Editor: Jeffrey C Milliken, MD more...
No medical therapy exists for the primary treatment of carcinoid tumor of the lung. Chemotherapy and radiation therapy have been used in the treatment of metastatic disease but have met with virtually no success. A response rate of 30-35% has been reported with a combination of 5-fluorouracil and streptozotocin. Symptomatic relief of carcinoid syndrome from metastatic disease has been achieved with octreotide, which can be administered subcutaneously.
In February 2016, everolimus (Afinitor) was approved by the US Food and Drug Administration (FDA) for progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of lung origin that are unresectable, locally advanced or metastatic. Approval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (p<0.00001).
Surgical resection is the primary mode of therapy for carcinoid tumors of the lung. Various forms of resection have been utilized successfully and with excellent long-term results.
Some 40-50 years ago, in an era when these tumors were considered more benign in their activity, bronchotomy with local excision of the tumor mass was used for resection of carcinoid tumors located in larger bronchial structures. Within the past two decades, a greater understanding of the malignant nature and biologic activity of these tumors has been acquired, and surgical resection has become more radical, now more closely resembling that for primary carcinoma of the lung.
At present, anatomic lobectomy is the most commonly performed procedure for resection of pulmonary carcinoid tumors. Larger or more proximal lesions may require bilobectomy or pneumonectomy. Smaller lesions in peripheral locations and contained within a single pulmonary segment may be treated with segmentectomy or wedge resection.
Because of the intrabronchial location and slow rate of growth of most carcinoid tumors, a variety of parenchymal-sparing procedures, including sleeve lobectomy and sleeve pneumonectomy, have been proposed and performed successfully with excellent long-term results.
In a large review of the Surveillance Epidemiology and End Results (SEER) database, sublobar resection of carcinoid tumors was not found to compromise oncologic outcomes; rather, factors such as age, sex, race, stage, and histologic types were direct influences on survival rates and the likelihood of patients acquiring other types of cancer. As long as complete resection and adequate mediastinal staging are performed, it is not necessary to perform a lobectomy on typical carcinoid tumors.
There is a resurgence of interest in local resection of carcinoid tumors. Most of these local resections are bronchoplastic procedures without any parenchymal resection, in which the section of bronchus containing the tumor is excised and the divided ends of the bronchus are reanastomosed.
A renewal of the use of bronchotomy and local excision has been proposed for specific carcinoid tumors that are polypoid in configuration. Regional lymph node dissection at the time of primary tumor resection is advocated by an increasing number of authors for both staging and treatment. A number of patients in several series had a favorable long-term outcome after resection of pulmonary carcinoid tumors and regional lymph nodes, even when lymph node metastases were present.
Because of their more biologically aggressive nature, greater tendency to metastasize, and poorer general prognosis, it is recommended that atypical carcinoid tumors be treated very aggressively. In general, the same surgical approach should be used for these aggressive forms of carcinoid as for cases of pulmonary carcinoma; this includes radical resection with frozen section evidence of tumor-free bronchial margins plus hilar and mediastinal lymphadenectomy.
Wedge resection of small peripheral typical carcinoid tumors without evidence of lymph node metastases may be acceptable in selected cases; however, a more radical resection is indicated for a similar mass found to be atypical.
Bronchoscopic resection using a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, with or without photodynamic therapy, also has been utilized in selected cases. As yet, these forms of treatment have been reserved for preresection reduction of intrabronchial tumor mass or for palliative management of airway obstruction in cases where the patient was considered otherwise inoperable.
In the former case, this form of treatment is helpful in reducing bronchial obstruction and clearing postobstructive pneumonia prior to formal surgical resection. In addition, some experts believe that preresection tumor reduction may allow a more conservative surgical resection. To date, series utilizing this form of therapy have been quite small, and long-term results have yet to be determined. This area has been controversial.[20, 21]
The surgeon must have a clear preoperative understanding of the location of the tumor (particularly if it is intrabronchial) and, to the degree possible, its extent. Many surgeons revisualize the tumor with the bronchoscope in the operating room immediately prior to the resection. This may facilitate decision-making regarding the choice of surgical procedure.
Preoperative evaluation of patients for resection of carcinoid tumors is identical to that for those with carcinoma of the lung.
Evaluation of pulmonary function should be performed prior to any procedure that may require resection of a portion of lung tissue. The same pulmonary function criteria used for patients undergoing pulmonary resection for any other reason applies to individuals having surgery for carcinoid tumors.
Because tissue-sparing procedures can be performed for some carcinoid tumors that are contained entirely within a bronchial structure, the limits of acceptable postoperative pulmonary reserve may be extended for patients with marginal pulmonary function in these cases. However, such procedures should be performed by thoracic surgeons experienced in bronchoplastic techniques.
Cardiac function should be assessed before any intrathoracic procedure.
Only obtain blood or serum assay of serotonin or 5-hydroxyindoleacetic acid (5-HIAA) if carcinoid syndrome is suspected clinically. If this study result is positive, further metastatic workup, especially evaluation for hepatic metastases, should be performed. Evidence of distant metastases often alters the decision about resection.
Evaluation of the extent of local disease and the existence of nodal disease must be performed so that the proper choice of procedure can be made. This is especially important in bronchoplastic cases and parenchymal-sparing procedures.
In cases where a solitary pulmonary nodule is resected, accurate frozen section diagnosis is important because the extent of the subsequent resection may vary depending upon the histologic findings. A small, peripheral typical carcinoid tumor may be treated with a more conservative resection, while an atypical carcinoid tumor requires a more radical resection. Hilar and mediastinal nodes also should be sampled and resected if necessary.
Operative procedures are conducted in much the same fashion as other pulmonary resections. At most major centers, a double-lumen endotracheal tube is used to allow single-lung ventilation and facilitate visualization of the surgical field. Intra-arterial monitoring lines are placed for continuous blood pressure monitoring. Continuous transcutaneous oxygen saturation and end-tidal carbon dioxide monitoring is routine.
Careful intraoperative management of fluids is extremely important to avoid fluid overload and pulmonary edema in lung resection cases, especially pneumonectomy. A preoperative understanding between the surgeon and anesthesiologist to limit crystalloid infusion and maintain the patient in a relatively even fluid balance is advisable.
When not contraindicated, placement of an epidural catheter, ideally in the thoracic position, for postoperative pain management is advisable. If this is not possible, an intercostal block using a longer-acting local anesthetic, such as bupivacaine, is helpful for immediate postoperative pain control, though its effective duration is not longer than 4-6 hours.
Postoperative management is identical to that employed for any patient undergoing pulmonary resection for any reason.
In the vast majority of cases, discontinuance of assisted ventilation and extubation is possible at the completion of surgery or very shortly thereafter. Most patients who undergo pulmonary resection do not require postoperative ventilation, though patients with significant chronic obstructive pulmonary disease (COPD) or other diseases associated with marginal pulmonary function may require it.
Patients who undergo any formal pulmonary resection or thoracotomy without major resection should be placed in an intensive care setting for at least 24 hours. Intensive care monitoring may not be needed for those who undergo less invasive procedures, such as thoracoscopic biopsy, but this should be decided on an individual basis.
A chest radiograph should be obtained immediately after surgery in the recovery room or intensive care unit (ICU) and daily thereafter. Additional films are warranted if any change in pulmonary status occurs in the course of recovery. A chest radiograph should be obtained immediately after thoracostomy tubes are removed.
Chest tube patency must be maintained, and constant suction with -20 to -25 cm under H2 0 seal suction should be established. Chest tubes are removed when the lung is fully expanded on chest radiograph and no evidence of air leak exists.
Pulmonary toilet and pain management are vital for successful management. Incentive spirometry and assisted coughing at scheduled intervals can be very helpful for prevention of atelectasis and clearing of secretions. Nasotracheal suctioning may be required in some patients for aspiration of secretions and to stimulate an effective cough effort. If atelectasis is significant or major amounts of secretions cannot be cleared, bronchoscopy may be needed.
Other forms of pulmonary toilet, such as chest physiotherapy or intermittent positive pressure breathing, have variable results in patients who undergo pulmonary resection.
Pain management via epidural catheter is ideal in these patients because this method controls pain well without altering the sensorium or diminishing the respiratory effort of the patient as significantly as IV narcotics may. If epidural analgesia is not possible, patient-controlled analgesia (PCA) with well-defined parameters may be used, though it may not be as effective.
The judicious fluid management begun in the operating room should be continued in all patients who undergo a major resection. Volume overload must be avoided. If excessive fluids were administered during the operative procedure, administration of a diuretic may be needed.
If the volume status of a postoperative patient is in question or if cardiac disease is present, placement of a pulmonary artery catheter may be necessary. Some surgeons advise performing this procedure with fluoroscopic guidance after major lung resection to assure proper positioning of the catheter into the nonoperated pulmonary artery.
Postoperative ileus is not common in patients who undergo pulmonary surgery; consequently, oral fluids often can be administered within 24 hours. Maintenance IV fluids should be all that are required until oral intake is adequate, and IV fluids should be discontinued thereafter.
Because airway structures containing secretions and bacteria are divided in pulmonary surgical cases, most surgeons administer a broad-spectrum antibiotic preoperatively and for 2-3 days postoperatively. This coverage is administered primarily to reduce the risk of infection within the pleural space. Wound infections in thoracotomy patients are quite rare.
After discharge from the hospital, surgical follow-up for observation of wound healing and determination that no intrathoracic complication has occurred is conducted for 8-12 weeks.
Oncologic follow-up is conducted in a fashion similar to that for pulmonary carcinoma after resection. Patients' cases are followed clinically and by plain chest radiograph examination every 2-3 months for the first year after surgery. If no evidence of recurrence is discovered within this period, surveillance intervals are extended to every 6 months. Additional studies, such as CT scan, are only performed if suspicion of recurrence arises.
Complications that can arise after surgery for resection of pulmonary carcinoid tumors are similar to those that may occur after pulmonary resection for other reasons. In the immediate postoperative period, bleeding, atelectasis, and prolonged air leak are the most common complications.
Bleeding generally is an early postoperative complication and most often manifested is by copious or persistent amounts of blood from the thoracostomy tubes.
In some cases, the measured amount of bleeding from the chest tubes does not itself appear to herald a problem. Other clinical signs (eg, hypotension, tachycardia, decreased urine output, or inordinately low hematocrit) in the immediate postoperative period may alert the physician to significant undrained blood loss. In such cases, chest tubes may not be in proper position for drainage or may be partially clotted, preventing complete evacuation of the chest. A retained hemothorax in these cases is evident on chest radiograph.
Bleeding that is massive, requires large amounts of crystalloid or blood replacement to maintain hemodynamic stability, or is persistent over a number of hours and indicates that re of the thorax is needed.
Some degree of atelectasis is present postoperatively in all patients undergoing chest surgery. Adequate pain control and vigorous pulmonary toilet are mandatory in order to avoid major problems with atelectasis. If the patient is unable to clear his or her own secretions adequately, nasotracheal suctioning is an effective method of assisting the patient. Bronchoscopy may be used for clearing secretions if nasotracheal suction is unsuccessful or if major areas of lung are collapsed.
Air leak is a common postoperative problem after pulmonary resection and usually is produced by the raw surfaces of the lung parenchyma that are created during resection, such as the area in the major fissure. In the vast majority of cases, if the lung is fully expanded on chest radiograph, air leak diminishes over a period of a few days and ceases. Persistent air leak is a frustrating problem and may result from a number of causes, including the following:
Persistent air leak may be caused by a leak within the chest tube drainage system or improper positioning of the chest tube within the thorax; for example, when some of the chest tube openings are located outside of the pleural space, there may appear to be an air leak when none is present
Incomplete reexpansion related to persistent atelectasis may be the cause of persistent air leak
In individuals with underlying restrictive lung disease, the remaining lung may not be able to expand enough to completely fill the thoracic space
Pulmonary resection performed on a lung that has significant emphysematous changes also can result in prolonged air leak
Unlike the leaks that are from the raw, resected parenchymal surface, more serious air leaks arise from lesser bronchial structures within the raw parenchymal tissue in the area of resection or from the bronchial stump or anastomosis itself. These usually persist as leaks of significant volume and may be associated with an incompletely expanded lung on chest radiograph.
Bronchial stump disruption may present as a pneumothorax on chest radiograph or as a new air leak at an interval after surgery, usually about 5-8 days postoperatively. This picture also may be present if a leak occurs at the bronchial anastomosis of a sleeve resection of other bronchoplastic procedures.
Large, prolonged air leaks producing some degree of persistent collapse of the lung usually require reoperation for closure. Thoracoplasty may be considered in cases in which a leak persists in the face of restrictive lung disease.
Postoperative respiratory insufficiency
This a devastating postoperative complication that, at best, may result in the patient becoming pulmonologically crippled with extremely limited functional reserve and, at worst, requiring some permanent form of ventilatory support.
This complication largely can be avoided by prudent preoperative examination of the pulmonary function and circulatory status of the patient. By doing this, the vast majority of individuals who would not have sufficient pulmonary reserve after the required resection are identified in advance and not subject to this devastating complication.
Postoperative pulmonary edema usually related to injudicious administration of intravenous fluids represents one cause of respiratory insufficiency. This can be a very serious, and even lethal, postoperative problem and needs to be addressed aggressively when found.
A variety of other factors also must be noted in patients postresection who have difficulty weaning from ventilatory support or oxygen. Full lung or lobar expansion must be present and no residual pneumothorax present. Lung condition must be optimal and without infection, and pain management must be adequate.
Slow weaning from the ventilator may be required and, if successful, long-term oxygen therapy still may be required.
Pleural infection and empyema
Postoperative intrathoracic infections almost always are related to the presence of a bronchopleural fistula. The diagnosis can be made using culture of the pleural fluid.
Complete lung expansion must accompany adequate drainage of the space for successful resolution of this problem. Adequate drainage by means of properly placed thoracostomy tubes or ultrasound- or computed tomography (CT)-guided aspiration may be successful, but reoperation for clearance of the infection and decortication and, if necessary, closure of the fistula may be needed. Various thoracoplasty techniques can be employed to reduce the size of the thorax if full expansion of the remaining lung cannot completely fill the space.
Infection in the postpneumonectomy space is a true challenge and may require a Clagett procedure or the rotation of chest wall muscle flaps into the chest to obliterate the thoracic cavity after the empyema is drained.
Atrial fibrillation or flutter is a well-known complication after pneumonectomy or upper lobectomy, especially in older patients. Prompt identification of the arrhythmia and appropriate medical management is indicated. Electrical cardioversion may be required if the patient is unstable.
Some surgeons administer digitalis to their patients preoperatively in an attempt to avoid this complication. If this is instituted, patients should be fully digitalized and on maintenance therapy with laboratory evidence of therapeutic digitalis levels before the surgical procedure. An attempt at rapid digitalization 24-48 hours before operation usually is not effective.
Outcome and Prognosis
Carcinoid tumors of the lung generally have a better prognosis than other forms of pulmonary malignancy. They have an overall 5-year survival rate of 78-95% and a 10-year survival rate of 77-90%.
Typical carcinoid tumors have been found to have a much better prognosis than do the atypical variety. Atypical carcinoid tumors have been associated with a 5-year survival rate of 40-60% and a 10-year survival rate of 31-60%, depending on the series.
Regardless of histologic type, the presence of lymph node metastases at the time of resection has a significant effect on prognosis in many series, producing 5-year survival rates of 37-80% and 10-year rates of 22-80%. This wide variation is likely related to the percent of atypical carcinoid tumors present in each analyzed series. N1 disease does not affect prognosis in typical carcinoids, and it tends to decrease survival in atypical carcinoids; however, N2 disease has a dismal prognosis.
The presence of tumorlets associated with the primary tumor appears to worsen the prognosis. In a retrospective single institution study from Australia, age greater than 60 years and atypical histology were negative predictors of survival; patients in the atypical subgroup were found to be significantly older. Whether or not tumor size is a prognostic risk factor is uncertain.
The presence of carcinoid syndrome or other paraneoplastic syndromes in the absence of lymph node or distant metastases does not seem to affect prognosis adversely.[20, 24, 25, 26, 27]
With respect to postoperative surveillance, a multi-institutional study showed that recurrence was rare in typical carcinoids. Recurrence is more common in atypical carcinoids (26%), yet most recurrences were not detected by routine surveillance protocols; instead, they appeared either after symptoms developed or incidentally on studies done for other reasons. Hence, there are no set recommendations for routine follow-up in patients with pulmonary carcinoid after surgical treatment.
Future and Controversies
The exact determination of the specific histologic entities within the spectrum of pulmonary neuroendocrine tumors is an area of considerable controversy.
Several authors have renamed the entire spectrum of pulmonary neuroendocrine neoplasms on the basis of more advanced histologic study. One classification system labels typical carcinoid tumors as type 1 Kulchitsky cell carcinoma, atypical carcinoids as type 2 Kulchitsky cell carcinomas, and small cell carcinoma as type 3. Another defines these as well-differentiated, intermediate cell, and small cell neuroendocrine carcinomas.
Additional changes in tumor classification also have been proposed specifically with respect to atypical carcinoid tumors. Several subcategories of atypical carcinoid have been described on the basis of identification of genetic molecular abnormalities.
The addition of genetic marker identification to previous methods of tumor analysis has resulted in further subclassification for some of the more aggressive types of these neuroendocrine tumors. Large cell neuroendocrine and mixed small-large cell neuroendocrine carcinomas have been proposed as high-grade tumors more closely related to small cell carcinoma than to carcinoids, falling into the disease spectrum between atypical carcinoid and small cell carcinoma.
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