Stages IA and IB

The average 5-year survival rate for patients with stage I NSCLC is approximately 65% (range 55% to 90.5%).^{19,270,310–312} Within the group, several factors appear to influence survival: T status, size independent of T status, and histology. The more favorable tumors are T1 squamous cell and T1 bronchioloalveolar cell carcinomas. Focal T1 N0 bronchioloalveolar cell carcinomas have been reported to have a 5-year survival as high as 90.5%.³¹³ Significant prognostic factors that adversely affect survival include mucinproducing tumors and diffuse invasion.

Survival of all patients with T1 N0 has been reported to be 82% at 5 years and 74% at 10 years, compared with 68% at 5 years and 60% at 10 years for patients with T2 N0 tumors.⁶⁸ In this series of 598 patients, the overall incidence of recurrence was 27% (local or regional 7%, systemic 20%). Second primary tumors developed in 206 patients (34%). Of these 206, 70 (34%) were second primary lung cancers or an overall incidence of second primary lung cancers of 11.7% (70 of 598). The findings, confirmed by other investigators, prompted division of stage I into two groups, stage IA (TI N0) and IB (T2 N0).

The median survival period for all patients with T1 N0 NSCLC is approximately 8 years.⁷⁰ The long-term prognosis for patients with T1 N0 NSCLC has been evaluated by the LCSG, which reported recurrence rates per eligible patient per year of 0.042 for patients with squamous tumors and 0.088 to 0.106 for patients with nonsquamous tumors within the first 5 years after surgery.³¹⁴ After this period, though, the rate of recurrence decreased (from 0.043 to 0.013), whereas the rate of new primary lung cancer increased (from 0.009 to 0.016) with no significant differences between the two histologic subgroups.⁷⁰

Stages IIA and IIB

The average 5-year survival for patients with stage II disease is 41.2% (range 29% to 51%). Several studies have evaluated this group to identify tumor characteristics that affect survival. The LCSG reported significant survival differences between patients with squamous carcinoma and adenocarcinoma and between patients with T1 and T2 lesions.^19,315 More specifically, patients with T1 squamous carcinoma had a 5-year survival rate of 75% compared with those with T2 adenocarcinoma, who had a 5-year survival rate of 25%. The Ludwig Lung Cancer Study Group studied 253 patients with stage II disease and also noted better survival for patients with T1 lesions than for those with T2 lesions.³¹⁶ They reported median survival periods of 4.8 years and 2.3 years for patients with T1 N1 and T2 N1 disease, respectively. A review by Martini and colleagues of 214 patients found no differences in survival on the basis of histology or T status.³¹⁷ However, tumor size and number of involved N1 nodes were identified as prognostic factors. Naruke also found no difference in survival by histology in 221 patients with stage II disease; but 5-year survival was significantly different at 52% for T1 lesions and 38% for T2 lesions.³¹⁵ Mountain reported similar 5-year survival in 317 patients: 54% for T1 lesions and 40% for T2 lesions.²⁷⁰ These persistent differences in survival based on T status led to division of stage II into IIA and IIB.

Patients with T3 N0 tumors, on the basis of chest wall invasion, have a favorable 5-year survival rate, as high as 56%.^68,319–322 However, patients with T3 N2 disease have a 5-year survival rate ranging from 16% to less than 5%.^320–326 Survival is also worse in those patients who have incomplete resections. The similarity of the outcomes for T3 N0 and T2 N1 supported its reclassification as stage IIB.³

Stage IIIA

Approximately 25% to 40% of patients with NSCLC have stage III disease.^327,328 Of these, approximately one-third will present with potentially resectable disease, stage IIIA (T1–3 N2, T3 N1). The median survival for all patients with stage IIIA (clinical or surgical stage) disease is 12 months, and the 5-year survival rate is 9% to 15%.^270,316 Within the stage IIIA subset, however, survival rates vary widely.

A review of T3 and T4 tumors that involve the mediastinum without involvement of mediastinal lymph nodes was conducted by Burt and colleagues.³²⁹ The overall 5-year survival was 19%, with median survival at 18 months. Factors that were found to affect survival were complete resectability and histologic type. The 5-year survival with complete resection was 30%, and the 5-year survival in patients with adenocarcinoma or large-cell carcinoma was 30% compared with 14% for patients with squamous cell carcinoma.

Patients with clinical (preoperative) N0 or N1 disease but pathologic (postresection) N2 disease survive longer than patients with clinical N2 disease. Martini and Flehinger noted 3- and 5-year survival rates of 47% and 34%, respectively, for such patients.³³⁰ Pearson and colleagues noted that patients with negative mediastinoscopic findings who were found to have N2 disease following resection had a 24% 5-year survival rate; the 5-year survival rate was only 9% for those who underwent resection after positive mediastinoscopy.³³¹ Patients with “completely resected” pathologic N2 disease have a median 5-year survival rate approaching 22%.^{323,328,330,332–334}

The role of combined modality treatment remains somewhat unclear. Many trials that include combinations of surgery, radiation therapy, and chemotherapy have been conducted for patients with stage III disease. The various treatment regimens and results will be discussed in later sections.

Stage IIIB

The median survival for stage IIIB patients is 8 months, and the 5-year survival rate is 5% or less.^270,335 The vast majority of these patients are treated with nonoperative therapy. There is, however, a select group of patients that can be considered for surgical resection: the rare patient with IIIB disease on the basis of a T4 tumor involving the carina and occasionally the superior vena cava, aorta, or atrium. With increased, but acceptable operative morbidity and mortality rates, extended resection and reconstruction techniques can be undertaken.^324,336,337 After carinal resection, 3- and 5-year survival is directly related to nodal status and ranges from 0% to 43%.³³⁸ Mathisen and Grillo have reported an overall 5-year survival of 19% for carinal resections.³³⁶ Extended resections for selected patients with other T3/T4 tumors has been associated with 5-year survival that varies from 0% to 18.3%, depending on the N status. Macchiarini and colleagues and Nakahara and colleagues have shown acceptable survival rates for the new patients undergoing great vessel resection, and Tsuchyia and colleagues has reported survival rates of 22% for left atrial resection.^339,340,391

Stage IV

Stage IV disease is beyond the reach of surgical cure. Treatment of this disease is well outlined in the following sections. On rare occasions, patients with solitary brain metastases and otherwise resectable lesions can undergo resection of both tumors. In this select group, surgery seems to prolong life and improve quality of life better than nonsurgical treatment, although no prospective studies have been performed.³⁴¹ The 5-year survival rate has been shown to range from 13% to 21% with median survival of 14 months.^118,341,342 Overall survival by stage (clinical and pathologic) using the recent revisions in the international system for staging lung cancer is summarized in Table 92-11.

Table 92-11

Clinical and Surgical-Pathologic Stage ^a.

History

The first lobectomy for lung cancer was performed in 1912 by Hugh Morriston Davies.³⁴³ Unfortunately, the patient died as a result of the operation. Over 15 years later, the first successful series of lobectomies was reported by Harold Brunn in 1929.³⁴⁴ His technique was one involving mass pedicle ligation instead of isolation of the hilar structures, a procedure less technically challenging than that reported by Davies. Evarts Ambrose Graham was the first to perform a successful pneumonectomy for lung cancer.³⁴⁵ This historic operation was performed in 1933 on a 48-year-old gynecologist. A simultaneous thoracoplasty was performed to avert the high risk of empyema, which occurred anyway but with no major catastrophe. The patient resumed his practice and died 30 years later at the age of 78 years, several years after the death of Dr. Graham who himself succumbed to lung cancer.

Preoperative Assessment

For any patient being considered for pulmonary resection, specific risk factors play an important role in determining operability and the chances of perioperative complications. Known factors that are associated with increased perioperative morbidity and mortality are increased age, continued cigarette use, cardiac disease, restricted pulmonary function, and pneumonectomy. In association with these factors, PS is a key general indicator of physiologic function and, as such, is another factor determining risk. With the increasing use of adjuvant and induction therapy, concurrent systemic illnesses (renal or hepatic dysfunction, weight loss, anemia, leukopenia) and a diminished PS score associated with therapy can heighten a patient's intolerance to surgical intervention. Recent reviews of preoperative therapy for patients with stage III lung cancer have noted increased rates of complications compared with historic reviews, although long-term survival appears to have been positively affected.^318,346,347 A reduction in the PS of patients after chemotherapy or chemoradiotherapy usually was seen and appeared to influence the observed perioperative morbidity. Several cooperative groups have evaluated the influence of PS and survival in large numbers of patients with inoperable lung cancer.^302,348,349 Each study found that a patient's initial PS had a definite impact, not only on prognosis, but also on the ability to tolerate aggressive therapy. A similar observation can be made in the evaluation of patients being considered for aggressive therapy in the form of surgical resection; those with a poor PS are at a higher risk than those with a good PS. In addition to other noted risk factors, consideration of operability must include careful assessment of a patient's PS.

Pulmonary Function

Most patients with lung cancer have associated chronic lung disease due to many years of smoking. The degree of underlying parenchymal pathology and abnormal chest mechanics may be subtle or subjectively insignificant because of compensatory lifestyle changes. On the other hand, concurrent benign pulmonary disease may be severely, subjectively debilitating for unclear reasons and without objective proof. Various objective studies, noninvasive and invasive, can provide good information in the overall assessment of pulmonary function and can provide the surgeon with a good estimate of risk.

Because pulmonary resection reduces lung volume, precise measurements of pulmonary function and reserve are imperative. Predicted postoperative volumes, based on spirometry, are useful in estimating the amount of lung that can be removed. Spirometric studies measure overall lung capacity, reserve volumes, functional residual capacity, and forced expiratory volumes. These simple tests give a relatively crude but highly useful estimate of lung function and pulmonary mechanics. The presence and extent of underlying disease can be quickly determined, along with any response to therapy (eg, bronchodilators).

Patients with abnormal pulmonary function are known to have an associated increase in perioperative complications. Several spirometric parameters have been analyzed by various authors and are useful in estimating patients at increased risk (Figure 92-13). No single parameter is used alone to select or exclude patients from surgery. The information is always considered collectively, along with other parameters noted below. Patients with limited pulmonary function in the noted risk categories generally are more susceptible to perioperative complications because of limited functional reserve to adapt to postresectional changes and underlying lung disease that is more susceptible to dysfunction caused by inflammation or infection. To optimize pulmonary function, patients are strongly encouraged to stop smoking 2 weeks in advance of surgery to reduce the amount of bronchorrhea and smoking-related bronchitis. Pulmonary physiotherapy is initiated with bronchodilators, incentive spirometry and coughing, appropriate antibiotics, and a walking program. Patients with poor pulmonary function test will have them repeated following this 1- to 2-week physiotherapy program. In some instances of severe bronchospasm, a short course of steroid therapy can be helpful.

Figure 92-13

Pulmonary risk based on spirometry, arterial blood gas (ABG), and oxygen consumption studies (MVO₂). CXR = chest radiography; FEV = forced expiratory volume; H & P = history and physical examination. pCO₂ = partial pressure of carbon dioxide; (more...)

Surgical technique

Standard Surgical Procedures

Pneumonectomy or the total removal of the lung is indicated for tumors that cannot be completely resected with a lesser procedure. Pneumonectomy is often indicated for central lesions that involve either the mainstem bronchus or the main pulmonary artery, tumors that are located in both the upper and lower lobes, and locally recurrent tumors. The procedure is most commonly performed through a posterolateral thoracotomy. The vascular structures are mobilized, ligated and divided either within the thoracic or pericardial cavity (for central tumors). The main bronchus is mobilized to the level of the carina and stapled (or suture closed) no more than 0.5 cm from the carina. Following division of the bronchus and removal of the specimen, a mediastinal lymph node dissection is performed.

Usually, postoperative pleural drainage is unnecessary, unless fluid or blood drainage from the hemithorax needs to be monitored. Aggressive pulmonary toilet and pain control are mandatory to reduce the incidence of pulmonary complications.

Operative mortality and morbidity rates have improved over the last 25 years due to improvement in perioperative monitoring, anesthetic techniques, postoperative care, and antibiotics. Mortality rates vary depending on the magnitude of the resection. The 30-day mortality for limited resection, lobectomy, and pneumonectomy are 1.4% to 3.8%, 1.8% to 3.8%, and 5% to 12%, respectively.^{16,207,367–370} Mortality rates for pneumonectomy have even been reported to be as high as 21% to 43% when coupled with aggressive preoperative, concomitant chemoradiotherpy.^351,371 Complications from all causes occur in over one-fourth of all patients.^367,368 Pulmonary complications are the most frequent morbidities associated with pulmonary resection and occur in approximately 20% of patients.²²⁹ They are also responsible for the majority of the postoperative mortality.³⁷² Empyema will occur in approximately 2% of patients undergoing pneumonectomy.³⁷³ Mortality rates for pneumonectomy range from 6% to 12%. For older patients or those undergoing a right pneumonectomy, the mortality rate is higher and can approach 10.6% to as high as 37% for some high-risk patients who have undergone preoperative therapy.^350,374

Lobectomy is the most common resection performed for lung cancer and accounts for approximately 65% to 75% of all resections at our institution. Such an anatomic resection provides a method for removing the primary tumor, associated disease, and lymph node-bearing areas, while leaving a significant amount of residual functional parenchyma. Cancer survival is equivalent for patients undergoing lobectomy or pneumonectomy for all stages of disease when a complete resection is performed. Lobectomy requires isolation, ligation, and division of the individual segmental arterial and venous branches supplying the lobe. Division of the fissure between the lobes is usually performed with a stapling device to reduce the air leak that occurs from incising the pulmonary parenchyma. The lobar bronchus is closed with a stapler or sutured. For lesions that are located close to the lobar orifice, often an adequate margin of resection cannot be achieved. In such circumstances, a portion of the main bronchus must be included with the resection. This type of resection is termed a sleeve resection and is performed as a parenchymal-sparing procedure to avoid pneumonectomy. (Figure 92-14) It is most commonly performed for lesions located in the right upper lobe. However, it may be used for tumors in the left upper lobe, left lower lobe, or bronchus intermedius. The procedure is performed to include a small segment of grossly normal bronchus (5 mm) to ensure an adequate margin. Once frozen section analysis confirms negative margins, the two ends of the bronchus are re-approximated with interrupted sutures, achieving an airtight seal. In selected patients, bronchial sleeve resection has proven to be a safe and effective method for pulmonary preservation, with cancer survival rates comparable with those following pneumonectomy.^375,376 The overall 5-year survival rate in stage III disease patients who undergo sleeve lobectomy is 21%.³⁷⁷ A 5-year survival rate of 38% has been reported following sleeve resection of T3 lesions;³⁷⁸ the survival rate appears to be directly related to the extent of N2 nodal involvement.^378,379 Like pneumonectomy, pulmonary complications are the most common event after lobectomy and are the primary cause of postoperative mortality. However, the overall procedural mortality is only 1% to 3%. Sleeve resections also have low operative mortality but carry a 5% risk of anastamotic complications (leak or stricture).

Figure 92-14

A standard right upper lobectomy cannot be performed in this circumstance because residual tumor will remain in the bronchial stump. Rather than performing a pneumonectomy, a sleeve lobectomy is performed to ensure negative margins while still preserving (more...)

Limited resections include segmentectomy, wedge resection, and lumpectomy. Any segment of lung can be resected, but this form of limited resection requires a bit more tedious dissection through the lung parenchyma than does standard lobectomy. A segmentectomy indicates that a distinct anatomic resection was performed. The pulmonary artery and segmental bronchus are individually isolated and divided. The segment is removed from the remaining lobe by stapled excision or blunt dissection, and the segmental pulmonary venous branches are divided as encountered. Wedge excision, in contrast, is performed without identifying the adjacent anatomic landmarks. It is a simple and quick procedure. Usually, a stapling device is used to remove the lesion, including a rim of grossly normal lung to provide a clear margin. Wedge resections can only be used for peripherally located lesions. Lesions that reside more deeply within the pulmonary tissue often are not amenable to wedge resection and may require precise local excision with laser or electrocautery assistance (lumpectomy).^380,381 The pulmonary tissue is directly incised and the lesion is removed, with preservation of the surrounding lung. Usually, postoperative air leaks are minimal.

Over the past 35 years, lobectomy has been regarded as the procedure of choice for the treatment of early-stage lung cancer. The LCSG completed a prospective phase III trial comparing limited resection (segmentectomy or wedge resection) with lobectomy for patients with small peripheral tumors staged intraoperatively with T1 N0 malignancies.³⁸² Patients were randomized to undergo standard lobectomy, segmentectomy, or wedge resection. A significant increase in local recurrence was found following limited resection. Survival tended to favor patients treated by lobectomy, particularly those with nonsquamous tumors, but the difference was not statistically significant. There was no significant difference in either morbidity or mortality for each procedure. The conclusions were that lobectomy should remain the standard procedure for patients with early-stage disease. Limited procedures should be reserved for patients with pulmonary function problems or other illnesses that preclude lobectomy.^382,383

Extended Surgical Procedures

Chest wall resection in patients with tumors considered T3 N0 because of chest wall invasion, are 5-year survival rates ranging from 26% to 60%.^{325,326,330,384,769} In patients with T3 N2 tumors, on the other hand, the 5-year survival rate is less than 5%, although Martini has reported a 5-year survival rate of 21% for patients with regional lymph node involvement.^384,385 Other factors adversely influencing survival are incompleteness of resection and depth of invasion of the tumor into the chest wall.^{321,326,384–386} Overall 5-year survival rates for patients with surgically resected T3 tumors have ranged from 12% to 40%.^{266,321,326,330,384,387}

Tumors involving the carina are considered T4 lesions. Most lesions involving the carina are not amenable to surgical resection (Figure 92-15). There are, however, several indications for resection: (1) tumors restricted to the carina, such as rare cases of primary lung cancer arising on the carina, and less common neoplasms such as adenoid cystic carcinoma or mucoepidermoid carcinoma, (2) tumors of the mediastinal trachea that extend to involve the origin of the main bronchus or carina, (3) primary carcinoma of the lung extending proximally to involve the origin of the main bronchus and carina on either the right or left sides, which may, in very rare instances, be managed by carinal resection or sleeve pneumonectomy, and (4) rare cases of benign disease involving the carina with local destruction. These are indications that have been defined by F. G. Pearson.³⁸⁸

Figure 92-15

A sleeve pneumonectomy. The tracheal carina is resected with a small segment of distal trachea and an anastomosis is made with the proximal left mainstem bronchus.

Operative mortality for carinal resection and sleeve pneumonectomy are significantly higher than for traditional pulmonary resections and have been reported to range from 10% to 30%. In selected patients with tumors confined to the carina or tracheobronchial angle, sleeve pneumonectomy can achieve a complete resection; however, the significant 30-day mortality risk of 8% to 20.9% indicates that caution must be used in recommending such a procedure.^324,337,389 Five-year survival rates have been reported to be as high as 23% to 35%.^247,337 Survival after resection of T4 tumors that involve the carina is directly related to the extent of nodal disease; 3-year survival rates are 43% for N1 disease, 34% for disease involving only the subcarinal node, and 0% when the upper mediastinal nodes are involved.³³⁸

Tumors that involve the vena cava, aorta, main pulmonary artery, or left atrium are considered T4 tumors. If the vena cava becomes directly involved by the primary pulmonary neoplasm, the effect is compression or wall invasion. Compression or obstruction of the vena cava is manifested by distal venous engorgement, which most frequently compromises the superior vena cava, causing SVC syndrome. Although the more common cause of SVC syndrome is compression from metastatic disease to lymph nodes in the superior mediastinum, direct tumor compression can cause the same process. In most instances, such tumors represent extensive disease and carry a poor prognosis. Treatment is usually nonsurgical, although in a few cases of localized disease with vena cava involvement, the tumor can be resected by including a portion of the vessel wall.^{7,338,390,391} Similarly, a tumor that invades the aorta usually is unresectable because of extensive invasion that precludes complete extirpation.³²⁹ However, in rare instances, if a tumor locally invades the aorta and is otherwise completely resectable in a good-risk patient, en bloc resection can be performed with reconstruction of the aorta.^338,340,391 Intrapericardial extension of the tumor not uncommonly involves the left atrium, precluding resection. In some instances of local invasion of the left atrium, a complete resection can be accomplished without hemodynamic compromise. Tsuchiya and colleagues reported a 5-year survival rate of 22% after resection of the left atrium to achieve a complete resection.³⁴⁰ Such reports suggest the feasibility of aggressive approaches for selected T4 tumors and for this reason patients should not be denied a surgical evaluation based on their T status alone.

Synchronous and Metachronous Lung Primaries

The presence of synchronous lung lesions raises the suspicion of metastatic disease not only from an extrathoracic site, but also from within the lung. A concerted effort to evaluate all possibilities should be undertaken prior to the initiation of any treatment. The histology is particularly important. If adenocarcinoma is found in the lung, numerous potential extrathoracic sites of origin can exist. A complete examination that includes a thorough evaluation of the gastrointestinal tract, breast, and reproductive system is imperative. If the lung lesions are squamous carcinomas, a systematic inspection of the upper aerodigestive tract and rectum should be performed. This includes panendoscopy (nasopharyngoscopy, laryngoscopy, bronchoscopy, and esophagoscopy), with biopsies of any suspicious lesions. Only after an exhaustive search has been undertaken to rule out nonpulmonary sources should lung primaries be considered. If the lesions are present within the same lobe, these lesions probably originated from the same source. The larger of the two should be considered the primary, while the other represents a satellite lesion, an intraparenchymal metastasis. Satellite lesions are discussed in the next section.

Synchronous primary lung cancers occur in 0.26% to 1.7% of all patients with lung cancer.^7,18,392,393 Practical pathologic and clinical criteria have been proposed as guidelines to distinguish primary and metastatic tumors.^{7,18,69,72,392,394–396} Probable or definite synchronous lung cancers are physically separate and located in a different segment, lobe, or lung, with no regions of common lymphatic involvement.They have a different histologic type or are proven to arise from different endobronchial lesions by bronchoscopy or from separate foci of carcinoma in situ at pathologic examination. Patients with unilateral tumors and hilar or mediastinal lymph node metastases are not considered to have synchronous tumors. When synchronous tumors are confirmed as individual primaries, they should be staged separately and independently according to standard TNM definitions. The patient's overall tumor stage should be determined by the higher-staged lesion.

Survival rates after complete resection of synchronous lung cancers are worse than for isolated lesions of similar stage.^392,396,397 The overall 5-year survival rate for all patients with synchronous lesions ranges from 0% to 44%, and the median survival ranges from 11 to 43 months; patients with no hilar or mediastinal node metastases generally survive longer.^{393,395,396,398,399}

Metachronous (asynchronous) lesions are distinct tumors that arise in separate anatomic sites and are of different histologic types; they may be of the same histologic type if there was previous complete resection of the initial primary lung cancer without stump involvement, the tumors originated in separate lobes or lungs, there is no cancer in the common lymphatics or extrapulmonary disease at the time of diagnosis, and the site of origin of the second primary can be identified (or, if the original site is unknown, there is a 2- or 3-year interval between the two tumors).^7,72,395 As the number of patients successfully treated for lung cancer increases, the incidence of second primaries will also increase.⁶⁹ Multiple lung cancers occur in 10% to 25% of patients who survive longer than 3 years.^72,400,401 Patients in whom the multiple lesions are metachronous survive significantly longer (10-year survival rates reported at 42% for survival from time of diagnosis of the original tumor) than those in whom the multiple lesions are synchronous. This survival is strongly influenced by the interval to recurrence and the stage of the second primary.⁷² The time interval between the development of asynchronous primary lesions may exceed 10 years.^72,394

The treatment of these lesions should follow the same pattern of evaluation that has been previously discussed. The only difference pertains to evaluation of the mediastinum. If the chest CT scan does not demonstrate adenopathy and bilateral lesions exist, it has been our practice to perform mediastinoscopy to rule out occult N2 disease prior to performing pulmonary resection. The method for resection depends on the location of the disease and the degree of concomitant pulmonary disease. If clinical stage I disease is present for each lesion and the patient has normal pulmonary function tests (PFTs), either sternotomy with bilateral resection or staged thoracotomies can be performed. Because lobectomy provides the best opportunity for local control and possible cure, lobectomies are most desirable; such procedures are best performed in a staged fashion. If limited pulmonary function is present or sternotomy is performed, limited resections or a lobectomy coupled with a limited resection are probably adequate. If a pneumonectomy is contemplated, staged resections are best to reduce postoperative complications. PFTs should be repeated after the first procedure whenever staged resections are performed to ensure adequate pulmonary reserve.

If clinical N1 disease is present and the lesions are unilateral, intraparenchymal metastases are probably present, indicative of higher-stage (stage IV) disease. In the absence of N2 disease, a pneumonectomy can be considered. If clinical stage II disease is present in both bilateral lesions, such disease is probably beyond the scope of complete resectability, and a nonoperative approach should be considered. If N2 disease is present, the suspicion of intraparenchymal metastatic disease should be high, and nonoperative therapy is appropriate. These situations also pertain to metachronous lesions.

Survival rates after treatment for synchronous or metachronous primary lung lesions are better than those for metastatic or locally recurrent disease. Locally recurrent disease has been reported to develop at a median time interval of 13 months and to have a 4-year survival of 5% to 23%.^72,402

Satellite lesions

Satellite lesions are separate foci of tumors that coexist with the lung primary tumor in the same lobe and represent intraparenchymal metastases. Mountain and colleagues and Deslauriers and colleagues have noted the implications of satellite lesions in their series of patients.^397,403 In Deslauriers and colleagues series, patients with stage I, stage II, and stage III lesions that had associated satellite tumors had 5-year survival rates of only 32%, 12.5%, and 5.6%, respectively, rates that are clearly worse than expected for early stages of disease.³⁹⁷ Accordingly, Mountain has recommended that tumors with associated satellite lesions be considered T4 tumors.

Surgery for N2 Disease

The frequency of mediastinal lymph node involvement in patients with resectable NSCLC ranges from 22% to 33%.⁴⁰⁴ Approximately 33% of patients with stage IIIA disease (based on N2 nodal metastases) present with a single positive node, whereas the remainder present with multiple nodes involved at a single station or at multiple stations.^327,341 Patients with multiple-station involvement have a significantly worse prognosis than do patients with single-node involvement.^327,405

In patients with metastases involving a single station, a significant survival difference has not been demonstrated between those with subcarinal metastases and those with metastases to other stations.^327,405,406 In patients with multiple-station metastases, the significance of subcarinal involvement is uncertain.^{327,334,406,407} The significance of metastases to the highest mediastinal lymph node and the definition of an incomplete resection based on N2 lymph node metastases is unclear.⁴⁰⁶ The overall survival rate for patients with completely resected N2 disease is approximately 22% (Table 92-12).

Table 92-12

Five-Year Survival Rates for Patients with Completely Resected N2 Disease.

Patients with intranodal disease have a significant survival advantage compared with those patients with extranodal extension.^256,408,409 Lymph nodes that extend beyond the confines of the nodal capsule have an increased propensity to involve adjacent tissue, reducing the chances of a complete resection. Such gross perinodal spread confers the possibility of microscopic residual disease, which may account for increased local recurrence rates and carry a worse prognosis.⁴¹⁰

Positive Margins (Bronchial and Parenchymal)

At the time of resection, the bronchial margin should be assessed by frozen section to ensure a complete resection. If the margin contains evidence of disease, all reasonable attempts to achieve a negative margin should be undertaken. One can surmise that the risks of residual disease evolving into gross and potentially metastatic disease are higher in the face of an incomplete resection on the basis of a positive bronchial margin. But several studies have shown that reasonable survival rates can be achieved in the face of a positive bronchial margin. When microscopic disease or in situ carcinoma exists within the mucosa, 5-year survival can approach 24%.⁴¹¹ Shields also showed reasonable survival in patients with carcinoma in the bronchial mucosa.⁴¹² His cohort of patients, however, had poor survival when the disease was present outside of the bronchial mucosa or within the peribronchial lymphatics, which is a finding similar to those of other studies.^411,413

The role of radiotherapy in patients with positive margins of resection is unclear. Definitive studies that address this issue are difficult to perform. Currently, there is no evidence that radiation therapy provides improvement in survival or local recurrence. However, despite this fact and on the basis of success with radiation therapy in the treatment of gross disease (locally advanced and stage IV), it is assumed that radiation will reduce the increased risk of local recurrance implicated by a positive margin. At our institution, the standard of care remains radiation therapy if gross or microscopic disease remains after resection.

Surgery for Metastatic Disease

Approximately 25% to 30% of all patients who present with NSCLC have stage IV disease (any T, any N, M1). These patients, who have M1 disease are usually treated with systemic therapy or palliative radiotherapy; their 5-year survival rate is generally less than 5%.⁴¹⁴ There is one subset of patients who can be considered for surgical intervention: those with resectable lung carcinoma and a resectable solitary brain metastasis. In this select group, surgery seems to prolong life and improve quality of life better than nonsurgical treatment.^339,341 The 5-year survival rate has been shown to range from 13% to 30%, with the median survival ranging from 14 to 27 months.^{118,339,341,342} It has been suggested that resection of adrenal metastases can be performed in patients with lung cancer, but the benefit, other than local control, is unclear.^415,416 For lack of evidence to the contrary, conventional therapy for metastatic disease should not typically include the option of surgery except in highly selective cases.

Management of Malignant Pleural Effusions

Many patients will either present with malignant pleural effusions or develop them during or after therapy. Symptomatic effusions should be palliated with the greatest expediency to allow a rapid return of the patient's quality of life. Standard therapy has been thoracoscopy with talc pleuradage or tube thoracostomy with some form of chemical or talc pleurodesis. Both require hospitalization and either a general anesthetic or prolonged placement of an uncomfortable tube thoracostomy. A recent alternative is the placement of a chronic indwelling catheter that can be drained by the patient at home and achieves prompt resolution of symptoms and eventual pleural symphysis.⁴¹⁷ This system has the same success rate as tube thoracoscopy when the end point for evaluation is symptomatic relief. However, its ease of insertion, minimal patient discomfort, rapid return to an ambulatory status, and reduced cost in this usually preterminal condition makes this system a very attractive option.

Surgery for High-Risk Patients

Many patients with potentially resectable disease are excluded from surgery because of severe cardiac or pulmonary limitations. Such high-risk patients are categorized by specific objective criteria. Usual pulmonary measures of high risk include the following: (1) preoperative forced expiratory volume in one second (FEV1) less than 40% of predicted, (2) predicted postresectional FEV1 less than 33% of predicted as determined by radioisotopic ventilation-perfusion studies, and (3) resting hypercarbia on arterial blood gas analysis (PCO₂ >45). Cardiac criteria of high risk include (1) myocardial infarction 3 to 6 months before the anticipated surgery, (2) evidence of class III angina, (3) hemodynamically significant valvular heart disease, (4) atrial fibrillation, (5) age over 75 years, (6) a history of cerebrovascular accident or transient ischemic attack, and (7) an echocardiogram with an ejection fraction of less than 50%. The introduction of improved methods to assess cardiopulmonary function has helped to better assess a patient's candidacy for surgery. The increased operative mortality associated with surgery for these patients can erode the oncologic survival advantage usually achieved with surgery. For most of these patients, radiotherapy carries considerably less risk and achieves similar rates of cure. Highly selective patients with these risk factors can sometimes still be offered surgery. Some examples include resection of right upper lobe tumor in patients with severe bullos emphysema confined to the upper lobes or correction of cardiac disease immediately before or during pulmonary resection. A surgical evaluation, therefore, should not be denied solely on the presence of cardiac or pulmonary limitations.

Radiation Treatment Planning

Internal Target Volume and Tumor Motion

One other approach to tumor motion is to use the ICRU 62-defined volume “internal target volume.” As can be seen in Figure 92-16, lung tumors can move significantly and often not only along the superior-inferior axis. These CT images were obtained with the patient in the treatment position during inspiration and expiration, and the images were co-registered. Panel A demonstrates the expansion that would be used to take motion into account if only the AP view had been used (as would be typical with fluoroscopy). Had this been done, the tumor would have been outside of the target volume for part of the treatment, which would have resulted in significant underdosing. If tumor motion is measured in three dimensions as shown in Panel B, the tumor would be properly irradiated. This technique also helps with choosing beam angles because beam angles parallel to the axis of motion will usually irradiate less normal tissue. In this example, lateral fields should be avoided.

Figure 92-16

Computed tomography (CT) scans were obtained through the target volume on a representative patient at inspiration and expiration, and the images were co-registered. If the target volume had been limited to the tumor motion seen on the AP projection (A), (more...)

Primary Radiation Therapy for Stage I and II NSCLC

Patients who have surgically resectable NSCLC but are medically inoperable because of their lung function, cardiac function, bleeding tendency, or other reasons (including patient refusal of the surgery) can be treated with radiation therapy as a potentially curative approach.^435,436 Observation only is a poor choice for patients with stage I NSCLC, with most patients dying of lung cancer.⁴³⁷ Radical radiotherapy is well tolerated even in patients over 80 years old.^438–440 It must be kept in mind that such patients are always clinically staged, which makes comparison with surgically treated patients difficult. Several surgical series demonstrate a 24% to 37% upstaging of cT1–T2 N0 patients, which partially explains the poorer results seen in clinically staged irradiated patients.^308,441,442 Small early-stage NSCLC is uncommon in radiation oncology clinics. However, as we develop better screening tools for early-stage NSCLC, the number of patients with small but medically inoperable tumors will increase.¹³⁸

Hilton and Smart treated 38 NSCLC patients with orthovoltage equipment, giving 40 to 55 Gy.^443,444 This resulted in 17 of 38 (47%) patients surviving at 2 years and 8 of 38 (17%) surviving at 5 years. At the University of Texas M.D. Anderson Cancer Center, between 1980 and 1990, 19 patients with clinical T1 N0 disease and 26 patients with T2 N0 clinical disease were treated with curative intent by primary radiotherapy. The median total radiation therapy dose was 6,300 cGy with 80% of patients receiving doses exceeding 60 Gy. Radiographic response was documented at completion of radiation therapy in half the cases, and 60% of the cases showed maximum response within 6 months after completion of radiation therapy. The median follow-up time was 36 months, and the disease-specific survival rate at 3 years by T status was 49% for T1 and 47% for T2. The clinically determined local control rate at 3 years was 89% for T1 lesions and 61% for T2 lesions. The significant prognostic factors for disease-specific survival were Karnofsky performance status (KPS) of 70 or more, tumor size 5 cm or less, and a radiation dose of 50 Gy or higher. The important prognostic factors for local control were tumor size 4 cm or less, a radiation therapy dose of 60 Gy or more, and complete response as seen on the chest radiograph by 6 months after completion of radiation therapy. The coverage of nodal drainage areas did not affect survival or local control. No lethal complications were seen with radiation therapy alone, and documented symptomatic radiation pneumonitis occurred in only 7% of cases. Usually, the most important prognostic factor documented in the literature is tumor size. Dosoretz and colleagues reported distant metastatic rates were correlated to the size of the primary tumor.⁴⁴⁵ When the tumors were smaller than 3 cm, the incidence of distant metastasis was 8% in 3 years, which increased to 27% if the tumor measured 3 to 5 cm and to 50% if the tumor was larger than 5 cm. They reported that the local control rates in 3 years were 77% for 4 cm lesions compared with 48% for those larger than 4 cm. Therefore, they recommended giving definitive radiation therapy if the tumors measured 4 cm or less. Noordijk and colleagues also reported 70% local control rates with radiotherapy alone, 60 Gy by split course, for 50 patients with T1-2 N0 NSCLC.⁴⁴⁶ Distant metastases occurred in 20% to 25% of patients. Another study of 31 stage I NSCLC patients demonstrated 76% disease-specific survival 3 years after irradiation with very limited fields.⁴⁴⁷

From 1980 to 1989, 149 patients with clinical T1–T2 N0 NSCLC were treated with radiation alone.⁴⁴⁸ Fifty percent were squamous carcinomas, and 44% were adenocarcinomas. Radiation doses ranged from 55 to 74 Gy (mean 64.7 Gy). Regional lymphatics were irradiated in 66 patients, but the reasons for such irradiation were not given. Beam geometries and typical margins were not described. Actuarial 1-, 3-, and 5-year survival rates were 78%, 34%, and 22%, respectively. Forty-four percent of patients had local failure prior to death. Complications were not discussed. Elective nodal irradiation in this series increased 5-year actuarial survival from 15% to 31% (p = .022), but this survival is much more than reported by other series.

Twice-daily radiation (1.2 Gy per fraction, total 69.6 Gy) was also delivered to 49 patients with stage I NSCLC.⁴⁴⁹ The mediastinum was not included in the target volume. The five patients who had recurrences in the mediastinum also failed distantly. Five-year relapse-free survival was 41%, and clinical local failure was 45%.

Results from radiation dose escalation trials are now becoming available, and they confirm that local control remains a major problem in early stage NSCLC. For example, even after doses of 102.9 Gy, there was a clinical failure rate of 34% within the PTV.⁴⁵⁰ Lower doses generally have higher rates of local failure even with doses of 60 Gy.⁴⁵¹ However, a recent meta-analysis revealed a wide disparity in outcomes for patients treated with radiotherapy alone for early stage NSCLC.⁴⁵² In 26 nonrandomized studies, 2,003 patients were found. Outcomes were quite variable, with overall survival of 22% to 72% at 2 years and cancer-specific survival of 54% to 93% at 2 years. They conclude that potentially curative therapy (dose > 60 Gy) should be given to medically inoperable patients with early-stage NSCLC.

Hypofractionation/radiosurgery has also been attempted for early stage NSCLC.⁴⁵³ In one study, 50 patients who underwent hypofractionated treatment were reported on; 33 of these received 50 to 60 Gy over 1 to 2 weeks. With a median follow-up of 36 months, there was an 88% cause-specific survival at 3 years. A second group of researchers treated 27 lung tumors and 24 liver tumors with three 10 Gy fractions.⁴⁵⁴ With a median follow-up of 9 months, there was a 76% actuarial rate of local control. Although the follow-up is short, long-term toxicity was minimal.

These results demonstrate that patients with early-stage NSCLC can be cured with radiation therapy alone. Radiation doses in excess of 60 Gy have been shown to be more effective than lower doses (improved local control, usually with a trend toward improved survival), and several recent studies suggest that doses in excess of 65 Gy are better still. Such patients rarely fail from metastatic disease in the regional lymph nodes. In one study, there was only a 15% actuarial rate of recurrence 2 years after irradiation in previously uninvolved hilar or mediastinal nodes.⁴⁵⁵ As better noninvasive mediastinal assessment (such as FDG-PET scans) modes become more available, irradiation of these areas can be eliminated with more confidence. The survival rates and local control rates are, however, quite poor with standard therapy. Most of the recurrences are at the primary site, or patients die from intercurrent disease. The improved outcomes resulting from chemotherapy combined with surgery, as shown by the Bimodality Lung Oncology Team (BLOT) trial, suggests that chemoradiotherapy might similarly improve outcome for patients with medically inoperable NSCLC.⁴⁵⁶ Likewise, radiation dose escalation may further improve local control and survival.

Radiotherapy Techniques for Medically Inoperable T1–T2 N0 Lesions

An adequate staging work-up is critical before the treatment of small primary lesions because every effort should be made to avoid mediastinal treatment. This work-up includes CT scans of the chest, with biopsy of questionable (1 to 2 cm) adenopathy, if medically possible. Pretreatment FDG-PET scanning with careful attention to the mediastinum can also be helpful, particularly if the primary tumor actively accumulated FDG.⁴⁵⁷ Improvements in image co-registration have allowed PET and CT data to be compared more easily, ensuring that suspicious areas are included within the high-dose radiation volume.⁴⁵⁸ MRI of the brain is more sensitive than CT and is preferred. Patients are usually treated with megavoltage irradiation using 6- to 18-MV beams, but energies from 4 to 10MV are preferred if the tumor is surrounded by lung. We recommend the routine use of lung heterogeneity corrections for treatment planning.

Postoperative Elective Nodal Irradiation

Postoperative radiotherapy (PORT) is currently contraindicated in patients with stage I completely resected disease on the basis of the PORT meta-analysis.⁴⁵⁹ Data for stage II and higher-stage patients neither support nor refute the use of postoperative radiation (because the hazard ratio error bars include 1.0), and regional control is clearly improved.

The use of PORT for stage II and III NSCLC was first tested in a controlled trial by the LCSG, who randomized 210 patients to either 50 Gy in 25 fractions or to observation.^460,461 Local recurrence was significantly reduced (3% vs 41%), but there was no effect on overall survival or disease-free survival because of the high rate of distant failure. This study and many other similar studies demonstrate that no amount of local therapy can cure most patients with advanced disease. Several approaches have been taken in the treatment of stage III patients to address the issue of systemic failure: combinations of chemotherapy with surgery (which will be dealt with elsewhere in this chapter) for patients with resectable disease and combinations of chemotherapy and radiation for those patients with unresectable disease.

Resectable or marginally resectable NSCLC 5-year survival rates and collective results of surgery alone for stage III (N2) of NSCLC ranged from 14% to 30%.^461–463 As discussed above, many patients who are clinically N0 (even when staged by mediastinoscopy) will be found to have occult mediastinal lymph node metastases. Approximately 15% of resected patients with T1 tumors will have N2 disease and 40% to 45% of patients with T2-T3 tumors will have N2 disease. Patients with incomplete resection, such as positive margins, multiple levels of lymph node involvement, bulky extracapsular extension and nonsquamous cell carcinoma usually have a poor prognosis. PORT for N1 and N2 patients with squamous cell carcinoma has been studied and reported, with reduction of the local regional recurrence for both groups.⁴⁶⁰ These patients need PORT with or without chemotherapy.

If N2 disease is bulky and the tumor is questionable for complete resection, patients can be treated by neoadjuvant chemotherapy followed by surgery. At the University of Texas M.D. Anderson Cancer Center, 60 patients were randomized to chemotherapy and surgery or surgery alone. Three cycles of cyclophosphamide, etoposide, and cisplatin followed by surgery were given to 28 patients, and they were compared with 32 patients treated with surgery alone. The median survival was 64 months versus 11 months, favoring neoadjuvant chemotherapy. Two-year survival was 56% in the neoadjuvant group, compared with 15% in the surgery-alone group (p = .008). In this study, the patients who had positive margins, multiple levels of positive lymph nodes, or extracapsular extension received PORT between 50 and 60 Gy, and there were only two patients who developed local recurrences in the entire group. Rosell and colleagues from Barcelona randomized 60 patients treated with or without mitomycin C, ifosfamide, and cisplatin as neoadjuvant chemotherapy.⁴⁶⁴ Thirty patients had neoadjuvant chemotherapy followed by surgery, and the other half had surgery alone, with 26 months median survival among the neoadjuvant group and 8 months median survival without neoadjuvant chemotherapy. Two-year survival revealed 29% among the patients who received neoadjuvant chemotherapy and no survivors among the patients who received surgery alone, although both groups had PORT of 50 Gy in 5 weeks. The neoadjuvant chemotherapy group had improved 2-year survival (p = .001).

Increasing numbers of stage III patients are now undergoing induction chemotherapy, followed by surgery, on the basis of the work of Rosell and colleagues and Roth and colleagues.^464,465 There is no clear consensus on the treatment of those patients who are found to have residual nodal disease at the time of resection. At M.D. Anderson Cancer Center, the authors have taken the approach that such patients should be evaluated by a radiation oncologist. We recommend, on the basis of data from earlier-stage patients, that radiotherapy is likely to dramatically improve intrathoracic control and so should be offered to all patients with positive mediastinal lymph nodes. There are no data to support improved survival with thoracic irradiation in such patients. However, all patients with positive surgical margins or extracapsular nodal disease should be irradiated because of the very high incidence of local recurrence. The Southwest Oncology Group (SWOG) studied concurrent induction chemotherapy, cisplatin, and etoposide with thoracic radiation therapy in 74 patients with biopsy-proven stage IIIA (N2) NSCLC.³⁴⁷ After two cycles of chemotherapy, complete responders, partial responders, or patients with stable disease underwent resection. Of 74 patients, 55 (74%) had complete resection. Grade 4 or greater acute toxicity was reported in 13% of patients from induction chemotherapy, and 2 patients died of treatment-related causes. Eight patients died postoperatively. Late pulmonary toxicity was reported in 10 patients. Pathologic complete response was seen in 22% of the resected cases. Median survival was 13 months, 2-year survival was 37%, and 3-year survival was 27%. Median survival of patients who had pathologic complete response of the nodal disease was 30 months compared with 10 months among the patients with residual nodal disease (p = .0005). On the basis of the results from this study, the National Cancer Institute (NCI) has launched a phase III multicenter trial for patients with biopsy-proven N2 disease and potentially resectable NSCLC. (NCI Protocol INT 139). Patients are stratified by good performance status and weight loss of less than 5%. Patients on the experimental arm receive 45 Gy in 5 weeks with concurrent cisplatin and etoposide followed by surgery or 60 Gy in 1.8 Gy daily fractions with concurrent cisplatin and etoposide. This protocol has been activated since 1994, with targeted accrual of over 600 patients. Although results from this study are not yet available, another intergroup study with 488 patients demonstrated that the addition of chemotherapy to PORT did not improve survival, local control, or DM rate.⁴⁶⁶

PORT may be given as early as 2 weeks after resection if there have been no complications. Postoperative CT scanning is required for planning purposes to define the anatomic relationship between tumor and normal tissue, which changes from the preoperative relationships, and to minimize lung volume in the radiotherapy ports.

The technique of PORT for positive margins or positive lymph nodes encompasses mediastinal and ipsilateral hilar lymph nodes with a 1- to 1.5-cm margin of normal tissue around the tumor region and 5 cm below the carina. If the margin of the primary tumor is negative, the original tumor bed is not covered. The dose of PORT would be 2 Gy per fraction and 50 to 60 Gy, depending on completeness of surgery, positivity of the margins, or presence of extracapsular extension (with 60 Gy delivered as a continuous course under these latter conditions).⁴⁶⁷ Radiation dose to the spinal cord is limited to 44 to 45 Gy by using oblique fields followed by a boost field to the target to give an additional 10 to 20 Gy to the positive margin or lymph node regions.

The importance of the quality of radiation therapy cannot be underestimated. Emami and colleagues demonstrated that survival and local control are both significantly worse if careful attention is not paid to tumor/mediastinal volumes to ensure adequate coverage by the 90% isodose line.⁴⁶⁷ This is consistent with the findings of the International Association for the Study of Lung Cancer consensus report.⁴⁶⁸

Radiation Therapy for Unresectable Stage III NSCLC

A radiation dose escalation trial (RTOG 73-01) was begun in 1973 to determine the optimal radiation dose using single daily fractions.⁴⁶⁹ Local control and 3-year relapse-free survival were improved with doses of 60 Gy compared with lower doses; however, a very high incidence of local failure was seen (>70%), even in this pre-CT era study. In an attempt to increase local control and cure, a nonrandomized radiation dose escalation trial using twice-daily radiotherapy (RTOG 83-11) was performed. This demonstrated improved survival and local control with doses of at least 69.6 Gy (delivered at 1.2 Gy per fraction, twice daily), but only about half the patients on each arm were in stage III. There was no survival advantage with doses higher than 69.6 Gy because of the high rate of systemic failure.

While these studies using radiation alone were underway, several large studies explored different combinations of radiation and chemotherapy. Induction chemotherapy with cisplatin and vinblastine added approximately 4 months to the median survival compared with radiation alone (60 Gy in 2 Gy fractions). ^470,471 Although a thorough analysis of intrathoracic control was not performed, 80% to 90% of relapses had an intrathoracic component with no difference between the treatment arms. A second study compared radiation treatment (65 Gy in 2.5 Gy fractions) with radiation treatment plus concurrent vindesine, cyclophosphamide, cisplatin, and lomustine.⁴⁷² Despite very poor compliance in the combined-therapy group (32% did not receive complete radiotherapy), there was a trend toward better survival, with a 2-year survival rate of 21% in the combined-therapy arm versus 14% in the radiation-alone arm. Again, local control was only 15% to 17% as determined by bronchoscopic biopsy. Treatment modality did not affect local control or the rate of distant metastases.

A third study compared split course radiation (55 Gy delivered as 3 Gy × 10 doses followed by 2.5 Gy × 10 doses with a 4-week break between courses) with the same radiation combined with weekly or daily cisplatin.⁴⁷³ Overall survival and local control were significantly improved in the cisplatin-containing arms compared with radiation alone, with the daily cisplatin arm demonstrating a 2-year survival of 26% and improved local control. Local failure was still a significant problem, with 70% to 80% of patients having some component of local failure. Cisplatin given with this regimen did not affect the rate of distant metastases. A fourth study compared induction chemotherapy (cisplatin and vinblastine) followed by “standard” radiotherapy (60 Gy in 2 Gy fractions) with standard radiotherapy alone or hyperfractionated radiotherapy (69.6 Gy at 1.2 Gy per fraction twice daily).⁴⁷⁴ Induction chemotherapy increased median survival by 2.4 months over radiation alone. Longer follow-up confirmed the benefits of chemotherapy, but local control was not discussed.⁴⁷⁵ Additional analysis of this data showed that outcome depended on tumor histology such that patients with large cell or adenocarcinoma had more distant (especially brain) metastases, and these patients had improved survival with induction chemotherapy followed by irradiation.

Recent meta-analyses of phase III trials have demonstrated the benefit of combined modality therapy in the treatment of unresectable NSCLC. Marino and colleagues studied outcomes of 14 trials published between 1980 and 1994 containing 1,887 patients.⁴⁷⁶ Cisplatin-based chemotherapy reduced mortality by 24% and 30%, respectively, 1 and 2 years following treatment. Unfortunately, the risk reduction was not seen beyond 2 years, suggesting that chemotherapy may simply delay progression, not increase cure. Another meta-analysis of combined chemoradiotherapy was performed in 1996.⁴⁷⁷ They reviewed the same 14 articles and compared survival by treatment category. Their assessment was that radiation (doses from 55 to 65 Gy) combined with chemotherapy (either concurrent or sequential) resulted in a gain in median survival of approximately 2 months over similar radiation without chemotherapy. A third meta-analysis was performed by the Non-Small Cell Lung Cancer Collaborative Group.⁴⁷⁸ After analyzing 3,033 patients from 22 randomized trials, they concluded that chemotherapy reduced the risk of death (hazard ratio 0.90) corresponding to a benefit of 3% at 2 years and 2% at 5 years, with the bulk of this benefit from trials that used cisplatin. Thus, combinations of radiation and chemotherapy seem to offer the best hope of long-term disease-free survival in unresectable stage III NSCLC today, and this is consistent with the American Society of Clinical Oncology Guidelines.⁴⁷⁹ It should be noted that the local control rates, when reported, were quite poor in these studies and ranged from 15% to 50%. Despite some improvement in outcome, much better therapy is needed. Towards this end, induction chemotherapy followed by concurrent chemoradiation has been found to be tolerable.⁴⁸⁰

Radiation Techniques

For many years, the standard of treatment for patients with unresectable stage III NSCLC was high-dose radiation therapy alone. Even now, patients who are ineligible for aggressive combination therapy usually receive a total dose of 60 Gy at 2 Gy per fraction or 63 Gy at 1.8 Gy per fraction in 6 or 7 weeks, respectively; this therapy is delivered to the primary tumor and regional lymph nodes. For upper lobe lesions, the supraclavicular regions are covered by the fields of radiation, and the lower border of the mediastinal radiation fields extends at least 5 cm below the carina. The fields are designed to extend to the diaphragm when the primary tumor arises in the lower lobe. If chemotherapy is given concurrently, radiation toxicity (esophagitis and bone marrow suppression) is significantly higher. Consequently, the field of radiation is reduced, and the lower border of the radiation port rarely extends to the diaphragm, even when the primary lesion is in the lower lobe.

The RTOG has pooled its results of combined chemotherapy-radiotherapy studies of 461 unresectable stage II-IIIB NSCLC patients.⁴⁸¹ These results suggest that concurrent chemoradiotherapy can be tolerated, although it is more toxic than sequential therapy. Three treatment strategies were compared: (1) induction chemotherapy followed by radiotherapy, (2) induction chemotherapy followed by concurrent chemoradiotherapy, and (3) concurrent chemotherapy with hyperfractionated radiotherapy. No clear survival or disease-free survival advantage was seen in any group. An update of RTOG 92-04 revealed that accelerated hyperfractionated radiotherapy with concurrent chemotherapy results in much better local control, with higher rates of acute and chronic esophageal toxicity but without improved survival compared with standard therapy.⁴⁸²

RTOG 94-10 was designed as a prospective randomized trial to answer the question of radiotherapy timing with respect to chemotherapy. Patients were randomized to cisplatin/vinblastine followed by radiotherapy, radiotherapy with concurrent cisplatin/vinblastine, or hyperfractionated radiotherapy with concurrent cisplatin/etoposide. Unfortunately, results from RTOG 94-10 are not yet available for analysis.

Because of poor local control, radiation dose escalation has been attempted using three-dimensional conformal and intensity-modulated radiation therapy. Radiation doses above 90 Gy have been reported to be tolerable when small lung volumes are irradiated.⁴⁸³ Radiation dose- escalation studies are underway to determine the optimal dose for NSCLC; however, until tumor motion can better be taken into account, such studies seem premature.⁴⁸⁰ The normal tissue complication probability (NTCP) model can help with the analysis of dose-volume histograms and suggests that radiation pneumonitis risks (and likely other normal tissue complication risks) can be assessed and minimized.^484,485 Hyperfractionated radiation and concurrent chemotherapy can be delivered safely to regions of the spinal cord up to doses of 50.4 Gy in 1.2 Gy twice daily fractions.⁴⁴⁹ Esophageal toxicity can be minimized, even in the setting of concurrent therapy, by limiting both the longitudinal and circumferential dimensions of the esophagus within the radiation fields.⁴⁸⁶

Because of the toxicity of concurrent chemoradiotherapy (especially during dose-escalation trials), attempts have been made to limit irradiation of normal tissues as much as possible. Unfortunately, many cancers lie near vital structures, such as the esophagus, that must be included in the high-dose region. We and others have attempted to ameliorate these symptoms with the radioprotector amifostine.⁴⁸⁷ Recent studies with the radioprotector amifostine have demonstrated benefit in the treatment of NSCLC without an increase in local failure.^488,489 Both esophageal and pulmonary toxicity is reduced by Amifostine, but hypotension is increased. The results of a large multicenter study (RTOG 98-01) are pending. Also, weight loss and fatigue are independent problems that must be addressed proactively in the clinic by experienced personnel.⁴⁹⁰ Megace use can decrease chemoradiation-induced weight loss and improve quality of life scores.⁴⁹¹

Special Considerations

Superior Sulcus Tumors

Superior sulcus tumors (SSTs) represent an uncommon presentation of lung cancer, accounting for approximately 3% of all lung cancers.⁴⁹⁹ SSTs with associated Pancoast syndrome, Horner syndrome, pain in the C8-T1 distribution, and atrophy of the intrinsic muscles of the hand (usually extrinsic involvement of the brachial plexus) represent a unique subset of SSTs. Irrespective of vertebral body or vascular invasion, tumors with Pancoast syndrome (true “Pancoast tumors”) carry a poor prognosis and should be classified as T4 lesions. The T3 descriptor is appropriate when the rib, intercostal muscle, sympathetic chain, stellate ganglion, or the lowest cord of the brachial plexus is involved. Other poor prognostic findings include N2-3 status, the use of wedge resection instead of lobectomy with en bloc chest wall resection, and an incomplete resection. The majority of tumors are of non-small-cell histology, but occasionally SCLC occurs.¹⁴⁶ The diagnosis can usually be established by FNA. SCLCs are treated with nonoperative therapy by standard small-cell protocols, whereas NSCLCs are usually treated with combined modality therapy. Magnetic resonance angiography (MRA) can also be helpful in determining the extent of tumor.

In many cases, SSTs can be completely resected, including the lowest chord of the brachial plexus, the sacrifice of which causes minimal neurologic compromise. Tumors that invade the vertebral body, subclavian vessels, or deep aspects of the brachial plexus present difficult surgical problems that may be ameliorated by induction chemotherapy. In some circumstances of limited invasion, however, the subclavian artery can be resected and reconstructed.^407,500 When the tumor is adherent to the vertebral body, a portion can be removed with an en bloc resection, or the entire vertebral body can be removed and reconstructed.^407,501

For patients who have potentially resectable lesions, the best timing for radiotherapy is unknown. Certainly, radiation therapy can diminish the size of the tumor and perhaps improve respectability, particularly in patients who have improvement in their pain during the course of their preoperative radiation therapy. Radiation has its greatest effect when a full and uninterrupted dose can be delivered in the range of 60 to 65 Gy. When radiation therapy is given preoperatively, the usual dosage ranges are from 30 to 45 Gy.⁵⁰² Higher preoperative radiation doses generally increase the perioperative complication rate, although a 5-year survival rate over 60% with full-dose preoperative therapy over 55 Gy, with conventional fractionation of 175 to 200 Gy/day versus high-dose fractionation of 275 to 300 Gy/day, has been reported in association with minimal perioperative morbidity.⁵⁰³ It should be kept in mind that split course techniques generally have been found to be inferior to continuous course irradiation.⁵⁰⁴ A retrospective analysis at the Massachusetts General Hospital suggested that induction chemoradiation was superior to radiation alone prior to resection, although the radiation dose was 12 Gy higher in the combined group.⁵⁰⁵ A prospective phase II intergroup study demonstrated that induction chemoradiation followed by surgery can result in significant complete pathologic responses and very good survival, especially for patients with T2, N0 disease.⁵⁰⁶

At our institution, we feel that potentially resectable candidates are best managed by immediate thoracotomy followed by PORT. A retrospective study was undertaken of all previously untreated patients with SSTs who received definitive management at the M.D. Anderson Cancer Center between January 1977 and December 1987.⁵⁰⁴ Eighty-five patients had been treated in that period. The male to female ratio was 2.7 to 1, and the ages ranged from 35 to 80 (median 59) years. KPS was 80 or more in 70 patients (82%). Thirty patients (35%) had 5% or more loss of body weight. All had histologic or cytologic confirmation of carcinoma: 25% were squamous cell, 2% small-cell, 54% adenocarcinoma, 6% large-cell carcinoma, and 12% unclassified. After complete evaluation, 43 patients were classified as clinical stage IIIA, and 42 were stage IIIB. One stage IIIA patient had surgery, 13 surgery plus radiation therapy, 2 surgery plus radiation therapy plus chemotherapy, 17 radiation therapy plus chemotherapy, and 4 chemotherapy alone. Surgery was a component of therapy more frequently in stage IIIA than in stage IIIB (p = < .05), and systemic treatment was used significantly more often in stage IIIB (p = .0042). The 1 patient treated with surgery alone lived 2 years. Twenty-three percent (7 of 31) of patients who had radiotherapy alone and none of the 4 patients who had chemotherapy lived 2 years. When surgery was a component of treatment, 52% (13 of 25) lived over 2 years, compared with 22% (13 of 60) when surgery was not part of the treatment. When radiation therapy was part of the treatment, 31% lived 2 years, and when chemotherapy was used, 18% lived 2 years. Fifty-two patients (61%) had local control of the tumor; their survival was significantly greater (p = < .01) than those who had local failure. In patients with unresectable tumors, total dose of radiotherapy was important (p = < .01) in achieving local control; patients treated with more than 65 Gy had a 38% local control rate compared with those treated with more than 65 Gy and achieved a 69% local control rate. Ten of 11 patients treated with neutron beam therapy had good local control. Split-course radiotherapy was disadvantageous. High performance status, weight loss of less than 5%, and no involvement of the vertebral bodies were significant factors (p = < .01) in better survival.

The conclusions of the study were that surgical resection should be used whenever possible for SSTs. Patients with unresectable disease should receive high-dose photon or neutron radiotherapy, if available. Because there is a high likelihood of close or positive surgical margins postoperatively for SSTs, we have generally preferred induction chemotherapy followed by postoperative radiation to 50 Gy if surgical margins are adequate, 60 Gy for microscopically positive margins, and at least 66 Gy for grossly positive margins (all delivered at 2 Gy per day). This approach was supported by the LCSG as well as an update by our institution.^460,482 Others have used preoperative radiation followed by intraoperative brachytherapy.⁴⁴² There was no established role for chemotherapy alone for these tumors.

The overall 5-year survival for patients with resected SSTs ranges from 28% to 56% (Table 92-13).^{407,410,500,507–513} The presence of nodal disease significantly shortens survival. For all patients who receive radiotherapy alone, the 5-year survival rate ranges from 1.6% to 23%.^508,514,515

Table 92-13

Superior Sulcus Tumors: 5-Year Survival after Resection.

In summary, combinations of surgery and radiotherapy have been the hallmark of the treatment of SSTs. Aggressive surgery with lobectomy and en bloc chest wall resection and lymphadenectomy is still essential. However, the use of neoadjuvant chemotherapy followed by surgery and radiotherapy has the potential to improve outcome as it has for other stage III NSCLC.

Brachytherapy

Endobronchial or endotracheal lesions can cause life-threatening symptoms including shortness of breath, postobstructive pneumonitis, and hemoptysis. Endobronchial brachytherapy has been used to achieve high radiation doses to these relatively accessible tumors, either as a component of potentially curative therapy or, more commonly, in the palliative setting after external radiotherapy has failed. The majority of patients with lung cancer have either locally unresectable, medically inoperable, or metastatic disease. Radiation therapy is able to control local symptoms, although external beam radiotherapy requires longer time to alleviate the symptoms compared with endobronchial brachytherapy. High-dose rate brachytherapy has been shown to accomplish rapid alleviation of symptoms and improve functional status without causing esophagitis, pneumonitis, or the bone marrow suppression seen with external irradiation. High-dose rate brachytherapy is ideal for patients who either need short-term palliation or need quick resolution of symptoms before they have definitive treatment (such as chemotherapy and radiation therapy with or without surgery). In theory, low-dose rate brachytherapy offers the advantage of better tolerance of normal tissues, although it has not shown a clinical benefit for endobronchial treatments when compared with high-dose rate therapy. Low-dose rate therapy requires hospitalization and displacement of the catheter in patients with respiratory distress, and cough would be a major concern. There has been proof that rapidly proliferating tumors might be more beneficially treated by rapid radiation therapy to overcome proliferation of malignant cells. Palliative results with low- or high-dose rate brachytherapy showed symptomatic relief between 50% and 70%.^516–519

Primary endobronchial irradiation can provide excellent local control for those rare patients found to have small (< 1 cm) primary endobronchial tumors with no evidence of metastases in whom other treatment options are medically contraindicated.^520,521 Doses of 35 to 42 Gy in 7Gy weekly fractions have been delivered to such tumors using high-dose rate brachytherapy remote afterloading techniques. Pathologic local control at 1 year was 75%, with actuarial 1- and 2-year survival rates of 78% and 58%, respectively, in these medically fragile patients. Narrowing of the irradiated bronchial walls was noted on bronchoscopy in most patients, but they were asymptomatic. An incidence of fatal hemorrhage was noted to be approximately 10% and was associated with longer implant lengths and upper lobe lesions. Catheter centering is also important to limit the dose to normal mucosa.

Primary intraoperative brachytherapy has been performed on patients with peripheral lesions but who are otherwise poor operative candidates. Hilaris reported that patients treated with interstitial¹²⁵ I via thoracotomy could achieve excellent local control and survival.⁵²² Five-year disease-free survival was 63% and overall survival was 32%. Brachytherapy, either by high-dose rate or permanent implant, can also be used in more advanced tumors to improve local control. This was particularly effective for T3-T4 N0 patients, with local control of 71%. Similar techniques can be applied to SSTs as well.

The addition of brachytherapy to external beam irradiation improves local control but does not improve survival. Permanent implants using I-125 or Pd-103 have also been safely performed in selected patients with positive margins after resection⁵²³ or following wedge resection in patients with poor pulmonary reserve.^523,524 Local control rates in these studies are encouraging on the basis of comparison with historic controls. Paclitaxel can also be safely added to endobronchial brachytherapy.⁵²⁵ A recent study randomized mostly stage III NSCLC patients to receive either radiation alone or radiation and endobronchial brachytherapy and found no difference in survival or local control.⁵²⁶ Airway obstruction was relieved more rapidly in patients undergoing brachytherapy.

Because the majority of patients with bronchogenic carcinoma have either locally inoperable or metastatic disease, radiation therapy is often used to alleviate local symptoms. External beam radiotherapy is most commonly used and is effective in relieving dyspnea and hemoptysis in the majority of patients treated. Limitations in this modality are the toxicity of treatment, which is not negligible, including radiation esophagitis, pneumonitis, myelitis (rarely), and other toxicities in surrounding-tissue. Brachytherapy to treat endobronchial lesions has been available for many years but has grown substantially because of the development of equipment that allows for safe and efficacious methods of delivering this treatment.

Between 1988 and 1993, 81 patients with lung cancer underwent endobronchial brachytherapy at the M.D. Anderson Cancer Center.⁵²⁷ Of the patients, 54 were male and 27 were female. The age range was 28 to 77 years, with a median age of 59 years. KPS was 90 in 15 patients, 80 in 24 patients, 70 in 20 patients, 60 in 11 patients, 50 in 9, and 40 in 2 patients. The presenting symptoms were shortness of breath in 65 patients, cough in 53, hemoptysis in 22, wheezing in 31, and chest pain in 11. The degree of shortness of breath showed 8 patients with severe, 13 with moderate, and 44 with mild dyspnea. Sixteen (20%) did not have shortness of breath at presentation. The histology or cytology showed 37 patients with squamous cell carcinoma, 14 with adenocarcinoma, 13 with NSCLC without specific cell types, 7 with adenoid cystic carcinoma, 5 with SCLC, 3 with large-cell carcinoma, and 2 with carcinoid tumor.

Eleven percent (9 of 81) of the patients had endobronchial treatment three times at 2-week intervals, and 67% (54 of 81) had treatment twice with 2-week intervals between the endobronchial brachytherapy. Twenty-two percent (18 of 81) of the patients had only one application because they had excellent responses after one application. About one half could not receive the second round of endobronchial brachytherapy because of rapid deterioration due to progression of their disease. Ninety-three percent of the patients received 1,500 cGy calculated at a distance of 0.6 cm from the center of sources for mainstem lesions, and the rest of the patients had the same dose calculated at a distance of 0.75 cm from the center of the sources for the tracheal lesions.

Twenty-six patients (32%) showed improvement, and 25 patients had moderate improvement. Seventeen patients had minimal improvement, and 11 patients showed no change. Five patients became slightly worse, and 2 became much worse after the endobronchial brachytherapy. Thus, 85% achieved some response, including 32% of all patients who had an excellent response. The median duration of responses was 4.5 months, and the patients who had an excellent response had much longer survivals. Median survival was 5 months for all patients, ranging from 0.5 months to 43 months. There was no significant difference on the basis of histology, although SCLC patients appeared to be worse in terms of symptomatic relief and survival because they were referred to us at their terminal stage and they had a more extrinsic component from mediastinal nodal disease rather than endobronchial lesions. The survival time was correlated to duration of palliation, especially for shortness of breath. The 16 patients who had excellent relief of shortness of breath after the treatment had a median survival of 13.3 months compared with 65 patients who had little or no response of symptoms. Their median survival was 5.4 months (p = .0135). Other symptomatic relief was not significantly correlated with survival.

Thirty-one patients had lesions on the left side, 48 patients had lesions on the right side (1 patient had bilateral lesions), and 2 patients had main lesions at the carina. The location of the tumor was correlated to the complication rate. The 2 patients who had lesions at the carina developed fatal complications that were due to tracheal malacia in 1 patient and fistula in 1 patient. Three patients developed pneumothorax, which resolved after insertion of a chest tube. However, the pneumothoraxes did not cause fatal complications. One patient developed a severe complication due to tumor necrosis, although it did heal. Two patients developed stenosis of the trachea, and 1 patient developed hemorrhage.

Survival was correlated to improvement of symptoms, especially dyspnea. To prolong the duration of palliation as well as hasten the degree of improvement, we are now trying to give taxol infusion for 24 hours, followed by endobronchial radiotherapy according to our institutional protocol. Some investigators treated patients with locally advanced lung cancer by using combined external radiation therapy and endobronchial brachytherapy. The external radiation therapy was given with a dose between 57 and 66 Gy followed by two to four Ir ¹⁶¹endobronchial treatments delivering 5 to 15 Gy at the distance of 1 cm from the center of sources, which resulted in 77% of patients having a complete response and 13% of patients having a partial response.⁵²⁸ Endobronchial brachytherapy can be used as a boost technique for patients with prominent endobronchial lesions without distant metastases to improve local control as well as to reduce complications to the surrounding normal tissue from external radiation therapy, especially in patients treated with combined chemotherapy and radiation therapy. The last follow-up analysis revealed 6 patients alive with disease and 1 patient alive without any evidence of disease 43 months after completion of treatment. Seventy patients died of disease, 3 patients died of intercurrent disease, and 1 patient died of a second malignancy.

A retrospective analysis has also been performed on the first 406 patients treated at Christie Hospital, Manchester, UK.⁵²⁹ Patients were treated palliatively with a number of fractionation schemes (97% of patients received 15 or 20 Gy as a single fraction, with the dose prescribed at 1 cm from the central axis of the source). Stridor and hemoptysis were well palliated, with 89% of patients demonstrating improvement within 6 weeks of treatment. Dyspnea and cough were also well palliated, with approximately 60% of patients showing improvement within 6 weeks. Pain and lung collapse were improved in about 43% of patients. If patients demonstrated symptomatic improvement within 6 weeks of treatment, their symptoms were likely to be controlled for the remainder of their lives, even if that was more than 12 months. However, survival was poor, with only about 12% alive 1 year after treatment.

Techniques

A history is obtained and a physical examination including performance status, routine blood work, lung function tests, and CT scans are performed; these are reviewed by the radiation oncologist and thoracic surgeon to assess the suitability for endocavitary therapy and the thickness of the tumor. Bronchoscopy is performed by the thoracic surgeon or pulmonologist, usually as an outpatient procedure under sedation and local anesthesia. Tumors that protrude into the lumen are considered suitable, as opposed to extrinsic, which compress the bronchus. The location of the tumor, its length along the bronchus or trachea, and the percent occlusion of the lumen are estimated by the surgeon and radiation oncologist and recorded. The distance from the nostrils is noted, and the tumor is photographed for future comparisons.

In theory, low-dose rate brachytherapy delivering 50 to 100 cGy per hour offers the advantage of better tolerance of the normal tissue, although for endobronchial treatments, it has not been shown that complications are less in series using low-dose rate than in those series using high-dose rate delivering 100 to 500 cGy per minute. Compared with high-dose rate, low-dose rate treatments are in the order of days (median duration of 50 hours) rather than minutes (median duration of 20 minutes for high-dose rate), thus requiring hospitalization. There are also concerns that the catheters could be dislodged from their accurate placement during this long period of time in a patient who has respiratory distress from an obstructive lesion. High-dose rate offers the benefit of outpatient treatment because of short treatment time. Treatment units permit the source to be inserted in a specified location and are able to withdraw the source in a stepwise manner through the treatment volume. Computer software has been developed to allow for dose optimization. This prevents the higher doses that are seen centrally when linear sources are left in the entire treatment volume for a specified time.

Afterloading techniques for endobronchial irradiation were developed during the last decade. Catheters (5–7 French [Fr]) can be guided endoscopically and placed past obstructing lesions. A common technique is to pass the catheters through the instrument channel of a flexible fiberoptic bronchoscope, visualizing their placement, and then removing the bronchoscope, leaving the catheters in place. The catheters can then be loaded with the radioactive sources, most frequently Ir¹⁶¹, when the patient is safely in a radiation-protected environment. We prefer a transnasal approach for placement of catheters, although transoral and transtracheal approaches have also been described.

One or more 6-Fr catheters are placed through the suction channel, with the tips 2 to 4 cm beyond the most distal part of the tumor. The catheter is secured by being taped to the nostril, and the patient is taken to the simulator in the radiation oncology department where films are taken to verify placement and to permit dosimetric calculations (Figures 92-17 and 92-18).

Figure 92-17

Patient with a 6-Fr catheter placed through the nostril, with the tip of the catheter 4 cm beyond the tumor.

Figure 92-18

Isodose curves delivering 1,500 small cGy at a distance of 0.6 cm from the center of the sources.

If there is sufficient occlusion that a 6-Fr catheter (outside diameter 2 mm) cannot be placed beyond the tumor, laser resection is performed, and the procedures for endocavitary irradiation are postponed for at least 72 hours. Attempts to force a catheter through the obstructing tumor increase the risk of bleeding, which may be difficult to control.

At the M.D. Anderson Cancer Center, endobronchial irradiation is administered at high dose rates, using a remote afterloading unit (microSelectron-HDR, manufactured by the Nucletron Corporation of Columbia, Maryland), which uses a single Ir ¹⁶¹ source attached to a stainless steel cable. The Ir ¹⁶¹ source has an active length of 3.5 mm and an active diameter of 0.6 mm. The source has an activity of approximately 370 GBq (10 Ci) at the time of placement and is replaced at roughly 3-month intervals, because the half-life of this isotope is 74 days. The machine permits the positioning of the source within the catheter along a 24-cm path at 2.5-mm intervals.

The total dose and resulting time of administration are determined. Anterioposterior and lateral radiographs of the catheters within the position permit orthogonal reconstruction using a special treatment-planning program. Determinations are made of the exact source positions and duration of exposure at each position to obtain the desired dose distribution within the tumor volume. To achieve a relatively uniform dose within the tumor at a specified distance away from the catheter, the treatment times at distal positions within the treated region are longer than those in the central region. The dose rate in the tumor volume at the reference point is around 200 cGy per minute. Typical treatment times to deliver l,500 cGy at a distance of 0.6 cm from the source are less than l5 minutes (see Figure 92-18).

Patients are observed closely because most have at least moderate symptoms. Two weeks after the first endobronchial irradiation, physical examination and chest radiography are performed to determine whether a planned second brachytherapy application is contraindicated. In general, the second procedure is performed within the following 2 weeks. Infrequently, patients have such dramatic relief of symptoms that a second procedure is considered unnecessary. Somewhat more often, patients are given a third application to relieve recurrent symptoms. The specific indications for endobronchial irradiation, as practiced at the M.D. Anderson Cancer Center, are as follows:

1.

Patients with symptomatic NSCLC with a significant endobronchial or endotracheal component who are not candidates for other potentially curative therapies or patients with previous external beam radiation therapy of sufficient total dose to preclude further treatment of this type

2.

Patients able to tolerate bronchoscopy

3.

Those with no bleeding disorder

4.

Sufficient life expectancy (usually > 3 months) to benefit from therapy

Severe complications have been reported in up to 17% of patients. Our results showed that 9 of 81 patients developed complications, with 2 patients having fatal complications, although both of them had lesions at the carina extending to the main bronchus or trachea. When the patients received two or more catheters, the complication rate appeared to be higher compared with one-catheter application. This might be related to the location of the tumor as well as the volume of the tumor. It seemed that the patients who had lesions at the carina developed more complications compared with the rest of the lesions, although the number was too small to draw any definitive conclusions. All right-side lesions had more complications compared with those on the left side. We did not appreciate differences in the complication rate on the basis of upper and lower lobe lesions, although Bedwinek reported higher complications in upper lobe lesions.⁵³⁰ The incidence of fatal hemoptysis can also be minimized by keeping fraction sizes to 10 Gy and by keeping the brachytherapy catheter as far as possible from the bronchial wall if it is near major vessels.⁵³¹

Summary

In the future, it is likely that radiotherapy for NSCLC will become even more complex. A study from Germany demonstrates that proton therapy of lung cancers can be quite tolerable, with minimal effects on lung function when proton-only therapy is used.⁵³² This suggests that if motion effects can be adequately taken into account, proton therapy has a role in lung cancer treatment. Better information must also be obtained regarding the timing of radiation therapy with respect to chemotherapy and biologic agents. For example, there is evidence that very low doses of taxanes can synchronize tumor cells in G2/M, a radiosensitive phase of the cell cycle, and provide improved cell killing with little additional toxicity.⁵³³ We must understand how to integrate novel therapies into conventional treatment for lung cancer.⁵³⁴ We must develop better ways to assess local-regional failure patterns, perhaps with FDG-PET scanning.⁴³³ In summary, we have made progress in the treatment of NSCLC with radiation, but more needs to be done. It is both encouraging and daunting that so many new therapeutic approaches are becoming available. Clearly, experienced teams will be required to manage patients optimally.

Single Agents

The clinical development of chemotherapeutic agents has traditionally been in the setting of stage IV disease. Customarily, drug activity has been reported with respect to response rate, and of the many drugs tested in the early 1980s, six have been found to have predictable and reproducible antitumor activity with response rates in excess of 15%: cisplatin, ifosfamide, mitomycin C, etoposide, vindesine, and vinblastine. Variability in dose and schedule, of course, relate to response rates observed. Interpretation of early trial data is further complicated by the heterogeneity of the patient populations tested, especially with regard to major prognostic factors. Nonetheless, these six drugs were considered to be “active” in the early 1990s.^535,536

More recently a new generation of compounds has been demonstrated to possess significant activity against NSCLC. These include topoisomerase I inhibitors, taxanes, and active analogues of previously established chemotherapeutic compounds (ie, gemcitabine, and vinorelbine).^{472,537–548} Irinotecan (CPT-11) is a water-soluble camptothecin shown to achieve response rates in excess of 30% in one Phase II trial.⁵³⁸ When used in combination with other active agents such as the platinums, response rates have exceeded 50% in pilot studies. Topotecan has shown more mixed results.^549,550 Of the taxanes, docetaxel has had response rates of approximately 30% in multiple trials and paclitaxel, rates in excess of 20%.^{539,540,542–544} Gemcitabine (deoxyfluorocytidine) is a fluoridated derivative of cytosine arabinoside with a greater than 20% single-agent activity documented in a series of clinical trials.^545,546 Myelosuppression is not the dose-limiting toxicity, and therefore this agent has become quite useful in combination with others. Vinorelbine is a synthetic vinca alkaloid with less neurotoxicity than vinblastine but still an active agent.⁵⁴⁷ Alimta is a newer multitargeted anti-folate, also with demonstrated Phase II activity in NSCLC. Response rates in the range of 20% have been observed, and this agent is now undergoing systematic testing in drug combinations.⁵⁴⁸

Combination Chemotherapy

Because single agents have generally modest activity, combination chemotherapy regimens have developed, with the majority including a platinum compound. Early combinations are listed in Table 92-14 and in summary, these drug combinations consistently produce objective tumor response rates in 20% to 40% of patients with advanced NSCLC and a median survival duration of 6 to 8 months in most randomized trials.^551–554 However, the achievement of a complete tumor response is quite uncommon, and no single regimen has emerged as the standard treatment approach. The Eastern Cooperative Oncology Group (ECOG) recently conducted a randomized Phase III study to determine if one of four platinum-based schedules was superior in patients with advanced NSCLC.⁵⁵⁵ This trial involved 1,207 patients randomly assigned to the control combination of cisplatin and paclitaxel versus cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The results of this modern trial are notable, because the overall response rate was only 19%, with a median survival of 7.9 months. The 1-year survival was 33%, with a 2-year survival rate of 11%. Neither response rate nor survival differed significantly between the treatment arms. Patients with an ECOG performance status of 2 had a lower rate of survival than those with a performance status of 0 or 1. The carboplatin and paclitaxel treatment arm was associated with less toxicity overall, particularly with respect to febrile neutropenia and nausea. None of these chemotherapy regimens emerged as superior.

Table 92-14

Older Chemotherapy Regimens.

Several studies have compared cisplatin-based two-drug combination regimens with single agents, and on balance, combination regimens appear to fare better, with improved survival. Cisplatin and vindesine or vinorelbine produced improved survival over the comparator arms with vinorelbine or vindesine alone, respectively.^472,556 However, other investigators could not confirm these results.^557,558 Similarly, randomized trials have failed to demonstrate a survival advantage for cisplatin and etoposide over cisplatin or etoposide given as single agents.^559,560 Nonetheless, more recent trials have shown differences, and a compilation of these studies is offered in Table 92-15. Combinations with cisplatin appear to consistently improve response rate over cisplatin alone. This improvement is modest but still has translated into a survival advantage, at least for vinorelbine and gemcitabine. A more recent trial with tirapazamine has also resulted in improved response rate and survival when given in combination with cisplatin.⁵⁶¹ In aggregate, these studies indicate that two-drug regimens appear to be significantly more active in the treatment of NSCLC patients receiving chemotherapy in comparison to cisplatin given alone.

Table 92-15

Results of Selected Randomized Trials of Chemotherapy.

Chemotherapy for Advanced NSCLC

First-Line Therapy for Advanced NSCLC

Although existing data clearly indicate that chemotherapy is warranted in appropriately selected patients with advanced lung cancer, an optimal chemotherapy regimen has not been identified. Until the mid 1990s, regimens of cisplatin in combination most often with a vinca alkaloid or etoposide were most commonly used. More recently, drug regimens with a platinum, either cisplatin or carboplatin, and a second newer drug with known activity are more widely used. That second agent could be a taxane, vinorelbine, gemcitabine, or a camptothecin. However, choosing one regimen from among many has been a difficult task since there is no clearly documented survival advantage for one drug program versus the others. Table 92-16 offers a listing of the results of selected randomized trials with comparison of combination regimens in previously untreated patients. At times, subtle differences in eligibility criteria (eg, inclusion of patients with stage III tumors or those with poor PS) make it difficult to directly relate the results among trials. Nonetheless, there is a trend indicating that regimens containing platinum with a taxane or gemcitabine probably produce higher response rates and also better survival outcome in some series when compared with older regimens such as cisplatin/etoposide or cisplatin/Adriamycin/cyclophosphamide. (Please see our previous discussion of the recent ECOG trial.)⁵⁵⁵

Table 92-16

Results of Selected Randomized Trials Evaluating Chemotherapy Regimens in NSCLC.

Vinorelbine was among the first of the so-called third-generation agents to demonstrate substantial activity against NSCLC, both as a single agent and in combination with a platinum compound. The European multicenter trial reported by Le Chevalier showed results favoring the cisplatin/vinorelbine combination (NVB-P) over single-agent vinorelbine (NVB) alone and a vindesine plus cisplatin (VDS-P) combination.⁴⁷² Vinorelbine was administered at a dose of 30 mg/m² weekly, cisplatin at 120 mg/m² on days 1 and 29 and then every 6 weeks, and vindesine at 3 mg/m² weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. An objective response rate was observed in 30% of patients in the NVB-P arm versus 19% in the VDS-P arm (p = .02) and 14% in the NVB alone arm (p < .001). The median survival duration of 40 weeks in the NVB-P arm was significantly longer than 32 weeks in the VDS-P arm (p = .04) and 31 weeks for the NVB alone arm (p < .001). This trial, however, did not confirm the role of vinorelbine in NSCLC therapy, even though it helped to establish the role of cisplatin.

To address this issue, the SWOG conducted a study comparing cisplatin alone with NVB-P combination as shown in Table 92-15.⁵⁷⁴ This SWOG trial reported by Wozniak and colleagues enrolled 432 NSCLC patients and treated them either with cisplatin alone (100 mg/m² every 4 weeks) or vinorelbine (25 mg/m² weekly × 3, every 4 weeks) plus cisplatin (NVB-P).⁵⁷⁴ The survival outcome was analyzed for 415 patients of whom 92% had stage IV tumors. The NVB-P regimen significantly improved progression-free survival (median 2 months vs 4 months; p = .0001) and overall survival (median 6 months vs 8 months; 1-year survival 20% versus 36%; p = .0018). Given the findings of the NCI Canada trial that VDS-P combination improved survival compared with BSC, it seems logical to conclude that NVB-P is a reasonable choice for the treatment of advanced NSCLC. In this context, the SWOG trial has not only firmly established the role of vinorelbine in NSCLC therapy, but it also sends a message that it is no longer acceptable to conduct randomized trials comparing chemotherapy with BSC.

There have been a number of studies with paclitaxel in combination with cisplatin or carboplatin, and other agents. In a three-arm randomized ECOG trial (ECOG 5592), 560 eligible previously untreated patients were randomized to a combination of cisplatin plus etoposide versus either low-dose (135 mg/m² over 24 hours) or high-dose (250 mg/m² over 24 hours with growth factor) paclitaxel in combination with cisplatin (75 mg/m²).⁵⁷⁵ The response rates for the low-dose and high-dose paclitaxel arms were 26.5% and 32.1%, respectively, significantly better than the cisplatin/etoposide arm. There was also an improvement in overall survival, but it reached statistical significance only when the two paclitaxel arms were combined into a single group and compared with the third arm. In a European trial of similar design, cisplatin plus paclitaxel led to improved response rate and quality of life parameters, but there was no overall survival difference compared with a standard regimen of cisplatin and teniposide.⁵⁷⁶

In a recent survey, paclitaxel plus carboplatin was found to be the most widely favored option for first-line chemotherapy in all stages of NSCLC among United States medical oncologists.⁵⁷⁷ This relates to ease of administration on an outpatient basis, with manageable toxicity profiles compared with other cisplatin-containing regimens, and to promising Phase II trial results. Langer and colleagues, in one such Phase II trial, reported a response rate of 62% and a 1-year survival rate of 54%.⁵⁷⁸ However, a more recent randomized trial failed to demonstrate a survival advantage over the standard cisplatin plus etoposide regimen, and a SWOG trial showed equivalent survival results in a comparison of paclitaxel and carboplatin with vinorelbine and cisplatin.^579,580 The SWOG investigators concluded that both regimens provide effective palliation in advanced NSCLC, but they favor the paclitaxel plus carboplatin regimen for future studies due to a favorable toxicity profile and better tolerability and compliance.

Like vinorelbine and paclitaxel, gemcitabine is also approved by the US Food and Drug Administration (FDA) for use against NSCLC. A series of successful Phase II trials of cisplatin plus gemcitabine led to pivotal Phase III studies.^551,581,582 The Hoosier Oncology Group compared gemcitabine plus cisplatin with cisplatin alone and showed a modest improvement in median and 1-year survival rates.⁵⁵¹ On the other hand, the Spanish and Italian trials that compared gemcitabine plus cisplatin with another regimen of cisplatin plus etoposide or mitomycin plus ifosfamide plus cisplatin, respectively, failed to demonstrate survival benefit, although there was a significant improvement in overall response rates.^581,582 Because gemcitabine is relatively well tolerated without dose-limiting myelosuppression, like vinorelbine, it is being considered for use as a single agent in older or medically compromised patients.⁵⁸³ Georgoulias and colleagues have compared cisplatin/docetaxel with gemcitabine/docetaxel in a prospective randomized multicenter trial.⁵⁸⁴ Four hundred forty-one patients were entered, and there were no apparent differences in overall response rates or median survival. The interpretation of the authors was that both drug combinations had comparable activity. Masuda and coworkers compared cisplatin/irinotecan with cisplatin/vindesine and irinotecan alone, finding no significant differences in survival.⁵⁸⁵

Fossella have reported a multicenter, multi-national study of two docetaxel/platinum regimens for NSCLC.⁵⁸⁶ In a three-arm project comparing docetaxel/cisplatin, docetaxel/carboplatin, and vinorelbine/cisplatin (VC) involving 1,218 patients with advanced NSCLC, median survival was best for the docetaxel/cisplatin arm, 11.3 months, with 1-year survival at 46% (vs 41% for VC) and 2-year survival at 21% (vs 14% for VC) (p = .03). A recent Japanese trial compared docetaxel/cisplatin with vindesine/cisplatin in 311 patients.⁵⁸⁷ The docetaxel/cisplatin produced significantly higher response rates, 37.1% versus 21.2% (p < .01), and the duration of response trended longer (13.1 vs 9.3 wk). Many Phase II studies are under way in attempts to identify increasingly active three-drug regimens, non-platinum-containing combinations, and non-platinum/non-taxane schedules. To date, a standard “best” regimen has not emerged for the treatment of NSCLC. Still it seems reasonable to offer therapy to select groups of patients with advanced disease. In the absence of curative therapy, prolongation of survival is a reasonable objective.

Certainly, quality of life concerns should enter the treatment decision-making process, and this area is now receiving increasing scrutiny. With respect to ideal duration of chemotherapy, there are probably no clear guidelines because the nature of treatment itself is rapidly changing. However, the American Society of Clinical Oncology has recommended that not more than eight cycles of currently accepted chemotherapy regimens be administered to individual patients. Socinski and colleagues recently addressed this issue in a prospective Phase III trial comparing a defined duration of therapy with carboplatin/paclitaxel versus continuous treatment in advanced NSCLC.⁵⁸⁸ Two hundred thirty patients were randomized. Despite differences in the median number of treatment cycles delivered, there were no significant differences in overall response time or 1-year survival. A general consensus is that most conventional chemotherapy regimens should be given for a finite number of cycles and that continuing a maintenance approach is not beneficial. After four to six cycles, chronic treatment-related toxicity may outweigh benefits.

Second-Line Chemotherapy for Advanced NSCLC

With the gradual increase in the efficacy of systemic therapy, NSCLC patients are increasingly demanding thoughtful consideration of alternative chemotherapy programs in the setting of progressive or recurrent disease following first-line treatment. This problem has been ably addressed by Fossella and colleagues.⁵⁸⁹ The most extensive experience with second-line chemotherapy is with docetaxel. In an early trial, good performance level patients who had had previous cisplatin-containing chemotherapy were treated with this single agent and achieved a partial response rate of 17%, with a median survival of 39 weeks. One-year survival was 40%, comparing quite favorably with historic controls (10% to 15%).⁵⁹⁰ The use of paclitaxel in this setting is not so clearly defined because the experience with this compound is much greater as a component of first-line therapy. Experience with other active agents, including vinorelbine and irinotecan, has been disappointing in this setting.⁵⁸⁹

Two recently completed large randomized trials have shown further evidence supporting the role of second-line chemotherapy (Table 92-17). Fossella and coworkers studied 373 patients with randomization either to docetaxel (100 or 75 mg/m²) or a control regimen of vinorelbine or ifosfamide at the choice of the investigators.⁵⁹¹ Treatment groups were well balanced. Response rates were low at 10.8% and 6.7%, respectively, in the docetaxel arms (0.8% response with vinorelbine or ifosfamide), but patients receiving docetaxel achieved a longer time to tumor progression and superior 1-year survival at the 75 mg/m² dose (32%). Previous exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it appear to impact survival. Treatment appeared to be well tolerated. Conclusions were that the 75 mg/m² every-3-week schedule offers meaningful benefit to patients with advanced disease. A second Phase III trial was reported by Shepherd and colleagues.⁵⁹² In this multicenter international study, patients with advanced NSCLC who had progressed on or after at least one cisplatin-containing chemotherapy regimen were randomly assigned to either docetaxel or best supportive care. A total of 204 patients were enrolled. The initial dose of docetaxel was 100 mg/m², but because of toxicity there was a reduction to 75 mg/m². The overall response rate was only 6%. However, time to progression and survival were significantly longer for docetaxel-treated patients. Patients receiving 75 mg/m² achieved a median survival of 7.5 months compared with 4.6 months (p = .01). A striking finding was that the 1-year survival rate for patients receiving docetaxel at 75 mg/m² was 37% compared to 12% for patients in the best supportive care arm (p = .003). qualtiy of life analyses have also provided evidence favoring treatment with docetaxel in selected patients.

Table 92-17

Results of Phase III Trials of Docetaxel as a Second-Line Treatment for NSCLC.

There are multiple reasons for considering chemotherapy in patients with advanced NSCLC. Evidence is accumulating that there may be a response and survival benefit, and it is important to continue the search for more effective therapy in the context of organized clinical trials. Moreover, palliation of these patients is a compelling clinical issue. On balance, it can be said that chemotherapy still has limited efficacy and that patient entry into clinical trials remains the most appropriate option for those who satisfy eligibility requirements. Patients with nonmeasurable but clinically evaluable disease are also appropriate candidates to receive such treatment, because time to tumor progression and survival may be similar to those of patients with measurable lesions. Outside of clinical trials, the criteria for administering chemotherapy in lung cancer should remain conservative. Administration of a published regimen is most appropriate for fully ambulatory patients with clinically evident disease so that ineffective treatment can be readily identified and discontinued. This concept has recently been supported in the large ECOG trial in which patients with performance level 2 fared poorly.⁵⁵⁵ Patients should be well counseled and understand the limitations of chemotherapy in this setting. Most often, treatment for 2 to 3 cycles is sufficient for a clinical and radiographic assessment of efficacy in an individual patient. Patients free of cancer-related clinical signs or symptoms may very well be monitored clinically without active treatment.

Combined Modality Treatment of NSCLC

Lung cancer patients are at high risk of distant disease recurrence even after complete surgical resection. Except for patients with prognostically favorable T1 N0 M0 cancers, considerable effort has been directed toward improving therapeutic outcomes with the administration of systemic chemotherapy and/or radiotherapy after surgery. However, results from older chemotherapy trials have been disappointing, in some cases reflective of even shorter survival in chemotherapy groups compared with controls.^593–595 Despite this, there remains much interest in developing effective systemic treatment strategies because lung cancer is largely a systemic disease.

Neoadjuvant Chemotherapy

The prognosis for patients with clinical stage IIIa NSCLC is poor.³³⁰ Median survival following surgery is 12 months, with 3-year survival in the range of 10% to 20%. Disease recurrence in distant sites occurs in two of three patients, and this has suggested that the addition of systemic chemotherapy to surgery for patients with potentially resectable disease may improve overall prognosis. In accordance with the Goldie-Coldman hypothesis, earlier initiation of systemic treatment may reduce the absolute numbers of drug-resistant cells, which occur over time with continued somatic mutations.⁶⁰⁴ There are now two published prospective randomized trials providing data that indicate the potential usefulness of induction combination chemotherapy in patients with clinical IIIa disease (Table 92-18).^464,465 Although the number of patients studied was small, there appears to be a clear effect of induction chemotherapy for selected patients with resectable disease. It is conceivable that the early introduction of systemic treatment may be more effective at eradicating microscopic foci of metastatic tumor cells than surgical adjuvant treatment or in the setting of clinically evident metastatic disease. Moreover, the improved tolerance and probable efficacy of newer chemotherapy regimens further argues for continued study of this strategy.

Table 92-18

Results of Selected Randomized Trials of Neoadjuvant Combination Chemotherapy for Clinical Stage IIIa NSCLC.

Pisters and colleagues recently conducted a Phase II trial assessing the feasibility of perioperative paclitaxel and carboplatin chemotherapy in patients with early stage non-small-cell carcinoma.⁶⁰⁵ Ninety-four patients with clinical stages Ib, II, and IIIa lesions were treated with two chemotherapy cycles as initial therapy. Fifty-six percent of patients had a major response, and 94% of enrolled patients proceeded to thoracotomy with a complete resection performed in 86%. Treatment-related toxicity was quite acceptable, with promising 1- and 2-year survival rates of 85% and 56%, respectively. This has led to a Phase III North American Intergroup trial comparing primary surgery alone with induction chemotherapy followed by surgery. This study is ongoing.

A recently published French Thoracic Cooperative Oncology Group paper by Depierre and colleagues is of much interest.⁶⁰⁶ This randomized trial compared preoperative chemotherapy with mitomycin C, ifosfamide, and cisplatin given for two cycles with two additional postoperative cycles for responding patients to surgery alone in patients with early stage NSCLC. In both arms with pathologic T3 or N2 disease thoracic radiotherapy was later administered. Three hundred fifty-five eligible patients were randomized. The overall response rate to chemotherapy was 64%, and postoperative mortality between the two treatment arms was comparable. Median survival was 37 months for the experimental arm versus 26 months for surgery alone (p = .15). A quantitative interaction between N status and treatment was observed, with evidence that induction chemotherapy conferred statistically significant survival benefit for patients with N0/1 disease. The authors concluded that preoperative chemotherapy appeared to be more beneficial for stage I and II patients based on the subset analysis.

Unresectable Stage III NSCLC

Thoracic irradiation has been the standard therapy for patients with inoperable IIIa/IIIb NSCLC in the United States for many years. Although chest radiotherapy improves cancer-related symptoms and reduces the frequency of local tumor regrowth, no randomized studies demonstrate that chest radiotherapy improves median survival compared with no therapy, and immediate radiation therapy is not associated with better long-term survival. The median survival duration in patients with inoperable disease is only approximately 10 months after chest irradiation, and the 5-year survival rate is less than 5%.

Efforts to improve these results have included altered radiation dose-fractionation schedules and combined chemoradiation approaches. Unfortunately, numerous randomized trials evaluating the benefits of chemotherapy combined with chest irradiation have yielded negative results until recently. With the incorporation of cisplatin-based chemotherapy in combined modality programs, improved survival results are now reported in the literature and have been further substantiated by randomized trials. Table 92-19 summarizes the results of selected randomized trials.

Table 92-19

Results of Selected Randomized Trials of Chemoradiation Therapy for Stage III NSCLC.

A significant improvement in overall survival duration favoring combined-modality treatment was first reported by the Cancer and Leukemia Group B (CALGB) (median survival duration 9.7 vs 13.8 mo, p = .007).^470,471 Long-term survival was also prolonged after chemoradiation therapy (5-year survival 7% vs 19%). The experimental regimen consisted of induction chemotherapy, with cisplatin and vinblastine given for two cycles before conventiaonal radiotherapy. The results of the CALGB trial have been corroborated by the subsequent RTOG 88-08 trial, in which the sequential chemoradiation program of the CALGB was compared with standard radiation therapy and hyperfractionated high-dose radiation therapy.⁴⁷⁴ Patients in the chemoradiation arm achieved a median survival duration of 13.8 months, the same as that reported by the CALGB group, which was significantly better than 11.4 months and 12.3 months for the standard radiotherapy and the hyperfractionated high-dose radiotherapy arms, respectively. Le Chevalier and colleagues compared radiotherapy alone with radiotherapy plus vindesine/cyclophosphamide/cisplatin/lomustine, and also showed a significant survival advantage for the combined-modality approach.^607,608 A small trial evaluated the role of radiation therapy following induction chemotherapy.⁶⁰⁹ Although there was no difference in median survival (461 days in the chemotherapy plus radiation therapy group vs 447 days in the chemotherapy-alone group), the 2- and 3-year survival rates were significantly better in the combined-modality treatment group (36% and 29% vs 9% and 3%, respectively) over chemotherapy given as a single modality.

There are theoretical reasons to favor chemotherapy given early in the treatment course and concurrently with radiation therapy. The mathematical model of Goldie and Coldman has suggested that the most effective regimens should be given early to prevent the emergence of resistant clones.⁶⁰⁴ Chemotherapy may sensitize the cancer cells to radiation therapy and with increased cell killing, oxygenation of necrotic/hypoxic tumor fractions may improve. In addition, with a reduction of chemotherapy resistant cells, radiation therapy may improve vascular access for the delivery of subsequent chemotherapy.

The European Organization for the Research and Treatment of Cancer compared chest radiotherapy alone (55 Gy split course) with chest radiotherapy plus daily (6 mg/m²/d) or weekly (30 mg/m²/wk) cisplatin.⁴⁷³ The 2- and 3-year survival rates were significantly improved in the daily-cisplatin arm compared with the radiation-alone arm, but no significant difference was achieved with weekly cisplatin. Another randomized trial by Jeremic and colleagues showed that a low-dose chemotherapy regimen (ie, carboplatin 100 mg on days 1 and 2 plus etoposide 100 mg on days 1 to 3 of each week) given concurrently with hyperfractionated radiation therapy significantly prolonged the overall survival duration as compared with radiation therapy alone (18 vs 8 mo, p = .0027).⁶¹⁰

With respect to the issue of sequential versus concomitant chemoradiation, available data indicate that the concurrent approach improves the overall outcome. The West Japan Group performed a Phase III trial designed to test sequential versus concomitant chemoradiation in unresectable stage III patients.⁶¹¹ Three hundred twenty patients were entered. The sequential arm consisted of induction chemotherapy consisting of mitomycin C, vindesine, and cisplatin followed by daily radiotherapy compared with concurrent chemoradiation with the same chemotherapy schedule delivered with split-course radiotherapy. Patients receiving concomitant treatment did better, with a median survival of 16.5 months (vs 13.3 mo, p = .04). Three-year survival was also superior (22.3% vs 14.7%). The RTOG has also compared sequential versus concomitant chemoradiation in unresectable stage III NSCLC.⁶¹² In a preliminary report, the standard arm consisted of sequential chemoradiotherapy with induction cisplatin and vinblastine followed by once daily radiotherapy. The concomitant arm consisted of the same elements, and at the same dose level but with chemotherapy and radiotherapy given simultaneously. The third treatment arm coupled a different chemotherapy schedule consisting of cisplatin and oral etoposide with twice daily radiotherapy. The most recent analysis indicates the superiority of the experimental arm two over sequential chemotherapy and radiation (median survival 17 vs 14.6 mo, p = .04). The hyperfractionated radiotherapy arm appeared to improve local disease control, decreasing in-field failure from 38% in the sequential treatment arm to 25%. Also observed was increased locoregional toxicity, especially esophagitis and pneumonitis.

Recently, several newer chemotherapeutic agents with differing mechanisms of action have shown promising antitumor activity against NSCLC. Interaction with radiotherapy also may differ, and combined modality trials are underway, with promising early survival data and acceptable toxicity. Most notable among these are the results of concurrent chemoradiation therapy with paclitaxel and carboplatin. At the University of Pittsburgh, Belani and Ramanathan, employing seven weekly doses of paclitaxel (45 mg/m² over 3-h infusion) and carboplatin (100 mg/m²) with 60 to 65 Gy of thoracic radiotherapy, reported a 3-year actuarial survival rate of 54% in 38 patients with locally advanced NSCLC.⁶¹³ Choy and coworkers reported similarly promising results after concurrent chemotherapy, with slightly different dosing schedules of weekly paclitaxel (50 mg/m² over 1-h infusion) plus carboplatin (area under curve [AUC] =2) and standard thoracic radiotherapy (66 Gy in 2-Gy fractions).⁶¹⁴ The median survival time was 20.5 months, with 1-year survival rate of 56.3% in 39 patients.

More recent trials have focused on the potential role of induction or consolidation chemotherapy added to concomitant chemoradiation with the intent of improving distant disease control and, ultimately, survival. This allows the use of full-dose chemotherapy in order to potentially sterilize micrometastases. Langer and colleagues administered two cycles of paclitaxel (175 to 225 mg/m² over 3-h infusion) plus carboplatin (targeted AUC of 7.5) on days 1 and 22 followed by thoracic radiotherapy (60 Gy in 2-Gy fractions), starting on day 43, given concurrently with paclitaxel plus carboplatin chemotherapy on days 43 and 64.⁶¹⁵ The 1-year survival rate was 62% in the first 21 patients accrued in this trial.⁶¹⁵

Gemcitabine has been shown to have marked radiosensitizing potential but was considered too toxic when combined with radiotherapy. However, in a recently completed randomized Phase II trial, gemcitabine was safely administered during thoracic radiotherapy.⁶¹⁶ In this large cooperative group Phase II trial, patients received two cycles of induction chemotherapy with gemcitabine plus cisplatin, paclitaxel plus cisplatin, or vinorelbine plus cisplatin, and two additional cycles of chemotherapy at reduced doses during thoracic radiotherapy (66 Gy in 2-Gy fractions). The dose schedule of chemotherapy during radiotherapy was cisplatin 80 mg/m² on day 1 of each cycle plus one of the following: gemcitabine 600 mg/m² on days 1 and 8, paclitaxel 135 mg/m² on day 1, or vinorelbine 15 mg/m² on days 1and 8 of a 3-week cycle. Gemcitabine was associated with more grade 3 or 4 toxicity during the concurrent radiotherapy than paclitaxel and vinorelbine (esophagitis 52%, thrombocytopenia 56%, and granulocytopenia 53%). The reported median survival for all patients was 17 months, and the 1-year survival rate was 68% for the gemcitabine arm.

The Southwest Oncology Group has tested the concept of administering “consolidation” chemotherapy after a concomitant chemoradiation. Gandara recently reported promising results in a Phase II trial consisting of 83 patients with pathologically staged IIIb disease. Patients received concomitant cisplatin, etoposide, and thoracic radiation to 61 Gy followed by docetaxel given for three cycles. Median survival has been an encouraging 26 months, with a 2-year survival of 53%.⁶¹⁷ Treatment was reasonably well tolerated, with expected severe-grade myelosuppression and grade 4 esophagitis occurring in only 6% of patients. Furthermore, this treatment schema is now being tested in an intergroup project for patients with unresectable stage III disease. Patients in both arms will receive therapy as outlined above, and there will be a randomization to receive or not to receive maintenance ZD1839, an experimental EGFR antagonist.