95 - Lung Transplantation
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 110 - Radiation Therapy for Carcinoma of the Lung
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Chapter 110
Radiation Therapy for Carcinoma of the Lung
Ritsuko Komaki
James D. Cox
Carcinoma of the lung encompasses a group of diseases that require the collaboration of the thoracic surgeon, radiation oncologist, medical oncologist, pathologist, and diagnostic radiologist. Unless dramatic gains in prevention are made in the next decade, the effective interplay of these specialists represents the best hope for the millions of patients worldwide who will develop cancer of the lung.
Radiation therapy, like surgical resection, is a technically complex locoregional treatment that can be used with curative intent. The results depend on the experience of the physician-led team and the appropriate application of the treatment, that is, to those patients with disease confined to a primary tumor and regional lymph node metastasis. For patients with disease too advanced to be considered potentially curable, radiation therapy can also be used to relieve symptoms from the intrathoracic tumor and discrete metastases, especially in the brain or bones.
The end points used to evaluate the effectiveness of surgery, radiation therapy, and chemotherapy differ. In surgical management of lung cancer, the focus is on curability and the end point is survival. The most common end points used in evaluating chemotherapy for lung cancer are complete and partial response rates and median survival. Radiotherapeutic effectiveness may be assessed in terms of both sets of end points. The palliative contribution may be reported in terms of response rates and median survival. Median survival is not necessarily related to long-term survival. The lack of sensitive indicators of recurrence after radiation therapy, however, and the recognition that the treatment can cause changes in the irradiated volume that obscure response raise questions as to the value of response as a useful end point.
The standard treatments for most patients with carcinoma of the lung without distant metastasis have changed in recent years. Integration of two or all three therapeutic modalities rather than use of only a single modality is advantageous for most patients. Combinations of resection and irradiation improve local tumor control and may reduce the risk of distant metastasis. Chemotherapy has increasingly been found to be effective in eradicating subclinical metastases; it also may improve local control if used concurrently with radiation therapy.
One of the challenges in treating lung cancer is proper application of the treatments to those patients most likely to benefit. For patients with inoperable squamous cell carcinoma, adenocarcinoma, or large cell (non small cell) carcinoma of the lung, pretreatment prognostic variables probably outweigh treatment factors in their short-term survival. At least 20% of all patients with non small cell lung carcinoma (NSCLC) have unresectable tumors without distant metastasis, little loss of weight (less than 5%), and mild to moderate symptoms (Karnofsky performance status scores of 70 to 100). One of us (RK) and associates (1985) showed that disease in such patients was potentially curable with radiation therapy alone. However, the outlook for patients with relatively favorable but inoperable disease is better with induction chemotherapy followed by radiation therapy, as demonstrated by Dillman (1990), Le Chevalier (1991), and Sause (1995) and their colleagues. Chemotherapy and radiation therapy administered concurrently increase the probability of survival.
Small cell carcinoma, heretofore considered the most malignant form of cancer of the lung, is more likely to be cured than NSCLC when the tumor is limited to the primary site and regional lymph nodes. Radiation therapy to these regions, given concurrently with combination chemotherapy, has been shown by Turrisi and co-workers (1999) to cure more than 25% of patients with limited small cell carcinoma.
INDICATIONS FOR RADIATION THERAPY BASED ON FAILURE ANALYSES
Shields's (1983) failure pattern analyses of patients with resectable carcinoma of the lung suggested that a subset of patients with squamous cell carcinoma, adenocarcinoma, or large cell carcinoma of the lung could benefit from irradiation
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of the mediastinum and hila. Patients with T1N0M0 or T2N0M0 disease rarely experience failure in the thorax after complete resection of the tumor. The presence of mediastinal lymph node metastasis considerably increases the risk of local failure and also portends a higher rate of distant metastasis, especially to the brain.
Cox's (1983) failure pattern analyses of patients with inoperable or unresectable carcinoma of the lung showed that the extent of the intrathoracic tumor is a major determinant of survival after palliative irradiation or single-agent chemotherapy, especially in patients with squamous cell carcinoma. Saunders and associates (1984) studied the causes of death in patients with unresectable NSCLC who were treated with a few large fractions of radiation to the modest total dose of 35 Gy. They showed that 72% of their patients died of complications of the intrathoracic disease and only 15% died of distant metastasis. Arriagada and co-workers (1997) analyzed the effects of local failure relative to distant metastasis in a large prospective trial of induction chemotherapy. The local failure rate, 92% at 5 years, was the reason for the small survival benefit of induction chemotherapy despite highly significant reductions in the distant metastasis. Saunders and colleagues (1999) also demonstrated reductions in the incidence of distant metastasis from improved local control through the use of continuous hyperfractionated accelerated radiation therapy (CHART).
EVALUATION BEFORE TREATMENT
The evaluation of patients with carcinoma of the lung that is apparently confined to the thorax differs little regardless of whether the treatment is to be surgical resection or radiation therapy and chemotherapy. The intent of the pretreatment evaluation is to determine the extent of the local and regional manifestations of the intrathoracic tumor and to investigate the most likely sites of distant metastasis.
A complete blood count, biochemical survey, and posteroanterior and lateral chest radiographs are routine components of the evaluation. The intrathoracic tumor can be assessed well by high-resolution computed tomography (CT) with intravenous contrast administration. Multiple parenchymal lesions, pericardial involvement with effusion, and pleural effusion are signs of intrathoracic dissemination and are contraindications to aggressive locoregional therapy. Magnetic resonance (MR) imaging has not been found to be more sensitive or accurate than CT by Webb and colleagues (1991), although apical sulcus (Pancoast's) tumors are well demonstrated by MR imaging, especially in parasagittal planes (Fig. 110-1). The liver, adrenal glands, and kidneys, all common sites of distant metastasis at autopsy, can be assessed by high-resolution, contrast-enhanced CT of the upper abdomen. As reported by Pieterman and coinvestigators (2000), positron emission tomography (PET) with fluorodeoxyglucose (FDG) can reveal the intrathoracic and extrathoracic spread of disease.
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Fig. 110-1. Magnetic resonance image reconstruction in the parasagittal plane showing superior extensions of adenocarcinoma of the left apical sulcus. |
The diagnosis of adenocarcinoma, large cell carcinoma, or small cell carcinoma justifies contrast-enhanced CT or MR imaging of the head to identify occult cerebral metastasis. In patients with no neurologic symptoms, the frequency of occult cerebral metastasis recorded by Jacobs (1977) and Tarver (1984) and their associates ranged from 10% to 20%. The finding of cerebral metastasis, of course, profoundly affects the prognosis as well as the plan of therapy.
RADIATION THERAPY AS A SURGICAL ADJUVANT
Radiation therapy is of clear benefit for a subset of patients with resectable carcinomas of the lung. The indications for adjuvant irradiation, the timing of the irradiation (preoperative or postoperative), and the use of chemotherapy in conjunction with radiation therapy are being refined by clinical investigations.
Radiation therapy can have an adverse effect on pulmonary function among patients who have undergone major resections of the lung, so only those patients at high risk for regional recurrence should be treated. Preoperative or postoperative radiation therapy has no place in the treatment of patients without surgical or pathologic evidence of metastasis to regional lymph nodes (pN0).
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The excellent review by Van Houtte and Henry (1985) summarized trials of both preoperative and postoperative radiation therapy. Those authors concluded that preoperative irradiation is of no benefit for patients with clearly operable tumors; on the other hand, its possible benefit for patients with marginally resectable tumors, especially those with spread to mediastinal lymph nodes, continues to be studied. Chemotherapy given concurrently with radiation therapy followed by thoracotomy and resection, as reported by Albain (1991), is being compared with chemotherapy and radiation therapy without surgery in a prospective intergroup trial.
A meta-analysis of clinical trials of postoperative irradiation by the PORT Meta-analysis Trialists Group (1998) found that it was of no value for patients with hilar lymph node involvement (pN1). However, Van Houtte and Henry (1985) concluded that the available data suggested that postoperative irradiation was of some value for patients with hilar or mediastinal lymph node involvement. Three- and 5-year survival rates in those studies ranged from 16% to 33% for patients with squamous cell carcinoma treated with surgical resection alone versus survival rates of 21% to 52% for those treated with surgery plus radiation therapy. The differences were even more striking for adenocarcinoma with hilar or mediastinal lymph node involvement: 5-year survival rates were 0% to 8% for surgery alone versus 12% to 62% for surgery and postoperative irradiation. The PORT Meta-analysis Trialists Group (1998) showed that surgical adjuvant radiation therapy was of no value for patients with pN1 tumors, but data were insufficient to draw conclusions concerning patients with mediastinal lymph node metastasis.
RADIATION IN DEFINITIVE THERAPY FOR SQUAMOUS CELL CARCINOMA, ADENOCARCINOMA, AND LARGE CELL CARCINOMA
Radiation therapy is an essential component of treatment with curative intent for patients with inoperable squamous cell carcinoma, adenocarcinoma, and large cell carcinoma of the lung. Once the determination has been made that the disease is unresectable, and a thorough evaluation including CT and PET scanning has shown no evidence of distant metastasis, technically sophisticated, high-dose radiation therapy offers the best opportunity for long-term disease-free survival. In patients with few symptoms (good performance status) and a weight loss of less than 5%, chemotherapy should be combined with irradiation. As Arriagada and colleagues (1991) pointed out, standard radiation therapy is far from sufficient local treatment. Moreover, even effective thoracic irradiation does not contribute to control of already established subclinical extrathoracic metastases. The evolution of more effective systemic therapy reinforces the importance of locoregional control: The actual cause of death is more often the result of intrathoracic complications than of distant organ involvement.
Determination of the Treatment Volume
Definitive irradiation for lung cancer is predicated on irradiation of the primary tumor and involved lymph nodes with adequate margins. Ipsilateral hilar and mediastinal lymph node regions must also be treated. Supraclavicular irradiation has not been systematically studied, but findings from biopsy studies suggest that at least 25% of patients with upper lobe tumors have disease in the scalene or supraclavicular nodes, whereas this risk is less than 10% for patients with tumors arising in the lower lobes. Irradiation of the ipsilateral supraclavicular nodes may be considered for upper lobe or middle lobe tumors. PET with FDG may allow irradiation of the supraclavicular region to be omitted if there is no suggestion of uptake of the tracer above the clavicle.
Treatment Planning
Treatment planning to achieve permanent control of intrathoracic tumors has greatly increased in sophistication and complexity. This area of intensive research and rapid change is described in detail in Chapter 109; a brief description follows here.
Three-dimensional treatment planning has the goal of increasing the dose to the tumor while sparing the normal tissues. A treatment-planning CT scan of the entire thorax permits definition of all known tumor [the gross tumor volume (GTV)] in each axial slice as well as delineation of critical normal structures (i.e., both lungs, spinal cord, heart, and esophagus) [International Commission on Radiation Units and Measurements (ICRU) (1993)]. Coregistration of FDG PET images and the planning CT scan offers improved target coverage, as suggested by Mah and associates (2002). Multiple fields may be used with individualized external blocks or machine-based collimation, which encompass the tumor but exclude all normal tissue possible.
The next step in the planning process is to expand the GTV to include sites of suspected subclinical disease. The resulting clinical target volume (CTV) usually includes the ipsilateral mediastinum and hilum. Given that parenchymal lung tumors can move with respiration by as much as 1 or 2 cm, as documented by Shimizu and collaborators (2001), studies of tumor motion have led to definition of another concept, internal target volume (ITV) ICRU, 1999). Treatment planning and treatment with respiratory gating or expansion of the GTV to include the ITV must take tumor motion into account, as noted by Vedam and colleagues (2001). Yet another variable, the planning target volume
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(PTV), is an expansion of the CTV to account for day-to-day variations in setup, including tumor motion. The use of PET CT, as suggested by Vanuytsel and associates (2000), to define the GTV, especially that which includes lymph nodes, can significantly reduce the PTV and spare the normal lung.
Conformal radiation therapy may also permit use of higher doses of cytotoxic chemotherapeutic agents. Fossella and co-workers (2001) found it possible to increase the dose of gemcitabine given concurrently with irradiation to a greater extent when three-dimensional conformal radiation therapy was used to exclude more of the esophagus than was possible with two-dimensional treatment planning.
Sophisticated treatment planning is now considered standard. There is no reason to use unshaped, square, or rectangular fields or to base treatment only on posteroanterior and lateral chest films. Careful blocking must be undertaken if the high doses thought necessary to control common epithelial tumors, including those arising in the lung, are to be achieved.
Dose Time Relations
The interplay among the individual dose of irradiation (fraction size), the frequency at which that individual dose or fraction is delivered, the total dose to the tumor and to normal tissues, and the overall time of treatment are encompassed by the terms dose time relations or fractionation.
The Radiation Therapy Oncology Group (RTOG) conducted an important multicenter, centrally randomized prospective trial to compare the effectiveness of 40, 50, and 60 Gy, delivered in 2.0-Gy fractions at five fractions per week for 4, 5, or 6 weeks, respectively. Analyses of this trial by Perez and associates (1980) revealed a dose response relation for tumor control in which higher total doses led to lower failure rates. Long-term follow-up of the patients in this study showed no difference in median survival time but showed a highly significant direct relation between 2- and 3-year survival rates and total dose. A total dose of at least 60 Gy in 30 fractions in 6 weeks subsequently became a standard for RTOG studies and for many institutions in the United States.
This fractionation schedule was also used after induction chemotherapy by Dillman (1990) and Sause (1995) and their coinvestigators, but Arriagada and associates (1991) demonstrated that rates of tumor persistence or recurrence were very high after such treatment.
Hyperfractionation with higher total doses of radiation did not improve survival, as noted by Sause and colleagues (1995), but accelerating treatment by using CHART did according to Sause (1999). Graham (1996) and Hayman (2001) and their associates found that conformal irradiation permits higher total radiation doses to be delivered, but the benefit of higher doses in terms of survival has yet to be demonstrated. Considerable interest has been expressed in using conformal techniques to increase fraction size as a means of improving tumor control. Shimizu and associates (2001) from Hokkaido have used highly conformal irradiation to deliver very large fractions to treat small lung tumors.
As one of us (JDC) (1985) observed, large-dose fractions have been used for treatment schemes involving hypofractionation (fewer than five treatments per week), rapid fractionation (large doses 5 days per week for only 3 or 4 weeks), and split-course radiation therapy in which fractions larger than 2.0 Gy are used in an attempt to compensate for a treatment interruption lasting 1 week or more. A large body of data from radiation therapy for common epithelial tumors at many sites suggests that use of fractions larger than 2.0 Gy and treatments less frequent than 5 days per week are disadvantageous. In reviewing RTOG studies conducted over a 15-year period, Perez (1989) reported significantly higher rates of late reactions in normal tissues when fractions larger than 2 Gy were used.
Proliferation of Tumor Cells during Treatment
An expanding body of evidence suggests that failure to control common epithelial tumors results, in part, from continued proliferation of surviving tumor cells during treatment. Fowler and Lindstrom (1992) reviewed 12 sets of data on radiation therapy for carcinomas of the upper respiratory and digestive tracts and concluded that interruptions of treatment reduced tumor control by approximately 14% for every week of prolongation. The adverse consequences of prolonging treatment time in NSCLC have been shown by one of us (JDC) and associates (1993) from the RTOG (Fig. 110-2). Withers and others (1988) found evidence that proliferation actually accelerated approximately 3 to 4 weeks after the start of irradiation.
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Fig. 110-2. Effect of treatment interruptions on survival in high-total-dose hyperfractionated radiation therapy patients. From Cox JD, et al: Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials. Int J Radiat Oncol Biol Phys 27:497, 1993. With permission. |
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Several means of overcoming the proliferation of clonogenic cells during treatment are being investigated. Diener-West and colleagues (1991) noted that hyperfractionation (i.e., giving larger numbers of smaller-than-standard fractions of irradiation) permits higher total doses to be delivered in the same overall treatment time. An RTOG report by one of us (JDC) and colleagues (1990) showed a higher survival rate among patients given 69.6 Gy in twice-daily 1.2-Gy fractions than among those given lower total doses. These findings led to a randomized comparison of hyperfractionation with 69.6 Gy given in twice-daily 1.2-Gy fractions and 60 Gy given in once-daily 2.0-Gy fractions (RTOG 88 08/Eastern Cooperative Oncology Group 4588). Sause and colleagues (1995) initially reported that the hyperfractionation scheme produced no improvement, but at longer follow-up one of us (RK) and associates (1997) showed that 3-year survival rates were higher in the hyperfractionated irradiation group. Lee and associates (1998) combined that fractionation schedule with concurrent cisplatin and oral etoposide and found a 5-year survival rate of 22% among a small group of patients with inoperable NSCLC.
Accelerated fractionation schemes seek to short-circuit proliferation of residual tumor cells by completing the total course of treatment in the shortest time. Such schemes typically involve delivering more than one fraction per day for all or part of the therapeutic regimen; each fraction is nearly the same dose as that used in a once-daily treatment plan, and the total dose is similar to that achieved with standard fractionation. The most accelerated regimen used to date was studied at the Mount Vernon Hospital in the United Kingdom by Saunders and Dische (1992) and associates (1999). In that CHART regimen, 1.5 Gy was delivered three times daily, with 6-hour interfraction intervals and no interruption for the weekend, to achieve a total dose of 54 Gy in 36 fractions in 12 days. Saunders and colleagues (1999) reported a significant improvement in survival among patients given CHART versus those given standard-fractionation therapy. Because most of the patients in that study had squamous cell carcinoma, the relevance of CHART for patients with adenocarcinoma or large cell carcinoma remains to be determined.
Use of concurrent chemotherapy and radiation therapy is another means of accelerating treatment. Schaake-Koning and colleagues (1992) found that the addition of cisplatin, administered weekly or daily during radiation therapy for inoperable NSCLC, produced significant improvements in locoregional tumor control (Fig. 110-3A) and survival (Fig. 110-3B). In general, induction chemotherapy followed by standard radiation therapy has not improved local control rates, although Arriagada and colleagues (1991) observed an apparent elimination of distant metastasis. The possibility of increasing local control and decreasing distant metastasis by using concurrent combination chemotherapy and radiation therapy is being explored with the hope of improving survival for patients with unresectable NSCLC.
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Fig. 110-3. Effects of concomitant cisplatin and radiation therapy (RT) on inoperable non small cell lung carcinoma. A. Survival without local recurrence. Comparison of group 1 with groups 2 and 3 (P = 0.009). B. Overall survival in treatment groups. Comparison of group 1 with groups 2 and 3 (P = 0.04). From Schaake-Koning C, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326:524, 1992. With permission. |
RESULTS OF RADIATION THERAPY FOR INOPERABLE NON SMALL-CELL CARCINOMA
Potential for Cure by Radiation Therapy
The most important role for radiation therapy is its potential to cure disease in patients who have few or only mild symptoms. One of us (RK) and associates (1985) reported an improvement in 3-year survival rates among patients with inoperable carcinoma of the lung treated at the Medical College of Wisconsin from 1971 to 1975 versus from 1975 to 1978. Of 197 patients given radiation therapy alone between 1971 and 1975, 7% were alive at 3 years, a figure
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similar to many contemporary reports involving megavoltage radiation therapy. In contrast, of 213 patients treated between 1975 and 1978, 14% were alive after 3 or more years. Long-term observations of those 29 patients showed that 23 (80%) were still alive at 5 years (11% of entire group), and 18 lived for 10 years. No patient in this series had died of lung cancer at 54 months follow-up.
These important gains between treatment periods did not result from an imbalance of patients with more favorable, less extensive disease; indeed, some patients with more advanced tumors were long-term survivors (Table 110-1). Only 1% of patients with stage III tumors treated between 1971 and 1975 lived for 3 or more years, compared with 11% of those treated between 1975 and 1978. Most of the improvement in survival came from the ability to identify patients who presented with only mediastinal lymph node involvement.
Table 110-1. Percentage of Patients Surviving 36 or More Months by Extent of Tumor, Medical College of Wisconsin, 1971 1978 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In the Wisconsin study, no patient with a performance status score of less than 80 on the Karnofsky scale survived for 3 years, as compared with 7% of those with scores of 80 to 89, 25% of those with scores of 90 to 99, and 70% (7 of 10 patients) who were truly asymptomatic (i.e., those whose performance status score was 100). Moreover, none of the patients in this study had undergone pretreatment evaluation by CT and other sophisticated imaging procedures. Thus, this experience should be considered only a baseline for what can be accomplished with contemporary treatment methods and pretreatment selection.
We have been most impressed with the effectiveness of concurrent chemotherapy and radiation therapy. Lee and colleagues (1998) reported our long-term results with cisplatin, oral etoposide, and hyperfractionated radiation therapy; in that study, 5 of 23 patients treated in this manner were alive and well more than 5 years later. An update of this experience with more than 200 patients given concurrent radiation therapy and chemotherapy reported by one of us (JDC) and coinvestigators (2000) shows an actuarial 5-year survival rate of 23%. Prospective randomized studies have also demonstrated survival to be improved by concurrent chemotherapy and radiation therapy. Furuse and colleagues (1999) from western Japan demonstrated a statistically significant improvement in survival (P = 0.04) when patients with inoperable NSCLC were given concurrent cisplatin-based chemotherapy and two periods of standard-fractionation irradiation (56 Gy in 28 fractions of 2 Gy) compared with a sequential course of the same chemotherapy followed by a single course of irradiation (Fig. 110-4). Curran and colleagues (2000) from the RTOG corroborated the improvement in survival from concurrent chemotherapy and radiation therapy as compared with sequential treatment. In that study, the chemotherapy was cisplatin and vinblastine, and the comparison was between radiation therapy beginning on day 50 versus the same radiation therapy beginning on the first day of chemotherapy.
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Fig. 110-4. Overall survival in patients with non small cell lung carcinoma according to treatment group. From Furuse K, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non small-cell lung cancer. J Clin Oncol 17:2695, 1999. With permission. |
Prolongation of Survival
Radiation therapy delivered to intrathoracic tumors prolongs survival, even among patients who will eventually die
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of lung cancer. We (JDC, RK) and our associates (1983) reported that patients with tumors limited to the thorax who received no definitive treatment rarely lived for 3 years; fewer than 5% survived for even 2 years. In a retrospective evaluation of radiation therapy for inoperable carcinoma of the lung, Eisert and associates (1976) showed that survival was prolonged among patients whose intrathoracic tumors were controlled with radiation therapy compared with those whose tumors were not controlled. Perez and associates (1986) corroborated this finding in a prospective trial conducted by the RTOG. In that study, a dose response relation was apparent for radiation and 2- and 3-year survival.
The value of chemotherapy in prolonging survival among patients with NSCLC is discussed elsewhere (see Chapters 111 and 112). Dillman and colleagues (1990) from the Cancer and Leukemia Group B demonstrated that survival was prolonged when chemotherapy with cisplatin and vinblastine was administered for 6 weeks before radiation therapy. Sause and associates (1995) from the RTOG and the Eastern Cooperative Oncology Group confirmed the Cancer and Leukemia Group B findings. Le Chevalier and associates (1991) from France also found survival to be prolonged when cisplatin-based combination chemotherapy was given before thoracic irradiation. Arriagada and colleagues (1991) showed that this benefit resulted from a reduction in rates of distant metastasis (Fig. 110-5A); no improvement in local tumor control was apparent from induction chemotherapy (Fig. 110-5B). One of us (RK) and colleagues (1997) from the RTOG and Eastern Cooperative Oncology Group also found that induction chemotherapy was valuable in eliminating distant metastasis but had no effect on local tumor control (Fig. 110-5).
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Fig. 110-5. A. Distant metastasis rate by treatment arm. Arm A, standard radiation therapy; Arm B, induction chemotherapy plus radiation therapy plus adjuvant chemotherapy. B. Local control by treatment group. Arm A, standard radiation therapy; Arm B, induction chemotherapy plus radiation therapy plus adjuvant chemotherapy. From Arriagada R, et al: ASTRO plenary: effect of chemotherapy on locally advanced non small cell lung cancer: a randomized study of 353 patients. Int J Radiat Oncol Biol Phys 20:1183, 1991. With permission. |
Palliation
Slawson and Scott (1979) suggested that symptomatic relief by radiation therapy for locoregional manifestations of squamous cell carcinoma, adenocarcinoma, and large cell carcinoma of the lung can be predicted fairly accurately. Superior vena caval obstruction can be relieved more than three-fourths of the time, and hemoptysis can be eliminated with similar consistency. Pain in the chest, shoulder, and arm can usually be reduced or eliminated, although in general the more vague and nonspecific the discomfort, the less predictable the relief. In contrast, bronchial obstruction with atelectasis (which is usually complicated by obstructive pneumonitis) can be ameliorated in only one-fourth of patients so affected. The longer the atelectasis has been established, the greater the opportunity for infectious complications and the more remote the possibility of effective relief from local radiation therapy. Paralysis of the vocal cords resulting from involvement of the recurrent laryngeal nerve at the aortic pulmonary window is rarely relieved even when long-term control of the tumor is achieved. Whether this paralysis is caused by destruction of the nerve through direct invasion or through entrapment of the nerve in the tumor with subsequent fibrosis is not clear.
SPECIAL CONSIDERATIONS
Several special circumstances may be encountered among patients with lung cancer that might lead to the appropriate use of radiation therapy.
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Apical Sulcus (Pancoast's) Tumors
Tumors in the extreme apex of either lung may cause shoulder or arm pain; sensory and motor dysfunction, especially along the distribution of the ulnar nerve; destruction of ribs, or, less frequently, vertebral bodies; and Horner's syndrome. Paulson's recommendations (1966, 1968) have been followed for more than two decades: a brief course of preoperative radiation therapy followed by thoracotomy, mediastinal exploration, and definitive resection if regional lymph node metastasis is not evident (see Chapter 35). This approach was justifiable when surgical resection was the only tenable treatment. However, several series have now demonstrated the efficacy of definitive radiation therapy for such tumors, which seem to have a lesser propensity for extrathoracic dissemination than other presentations of lung cancer. The disadvantages of hypofractionation or split-course radiation therapy have been noted previously. Those patients who undergo preoperative irradiation and then are found to have unresectable tumors are placed at a great disadvantage; subsequent radiation therapy after such a long interruption is of little use, as it is often merely being applied to an already progressing tumor. Martini and McCormack (1983) reported that fewer than 20% of patients who underwent exploration at the Memorial Sloan-Kettering Cancer Center were able to have complete surgical resection of the tumors. Preoperative selection of patients through the use of contemporary CT and MR imaging can improve this percentage. Rusch and colleagues (2001) from the Southwest Oncology Group, in studying induction chemotherapy and concurrent radiation therapy before surgical resection, were impressed with the efficacy of that treatment.
One of us (RK) and associates (2000) retrospectively studied 143 patients with superior sulcus tumors who fulfilled the original criteria for Pancoast's tumor who were seen at the M. D. Anderson Cancer Center between 1977 and 1994. Adenocarcinoma was found in more than 50% of the patients studied. Favorable survival was associated with high performance status, weight loss of 5% or less, lack of vertebral involvement, and control of the primary tumor and its extensions. A higher probability of local control was associated with treatment by surgical resection. No advantage was noted in the use of preoperative versus postoperative irradiation. For patients with unresectable tumors, high total doses of radiation therapy (more than 65 Gy) resulted in better local control rates.
The most appropriate approach for the entire spectrum of apical sulcus tumors is therefore immediate surgical exploration of those tumors thought to be resectable. If the tumors prove to be unresectable, the patients can still benefit from postoperative radiation therapy in the most effective manner.
Superior Vena Caval Obstruction
Obstruction of the superior vena cava is usually caused by a malignant neoplasm, most often of the lung. Approximately 5% of all patients with carcinoma of the lung present with superior vena caval obstruction. The common presentation of dyspnea with swelling of the face, neck, and upper extremities and collateral venous circulation in the upper thorax, although often a radiotherapeutic emergency, is rarely ominous enough to preclude cytologic diagnosis by needle aspirate or even by fiberoptic bronchoscopy. Such evaluations are important because the discovery of a neoplasm other than lung cancer can change both the therapeutic options and the prognosis. Moreover, treatment for superior vena caval obstruction from small cell carcinoma is different than for that caused by NSCLC.
The finding of squamous cell carcinoma, adenocarcinoma, or large cell carcinoma of the lung with superior vena caval obstruction justifies immediate treatment with three or four large radiation fractions (3.5 to 4.0 Gy per fraction) followed by more typical fractionation with 1.8 to 2.0 Gy per fraction. The destruction of tumor cells from the initial large fractions leads to more immediate relief of symptoms than the smaller fractions can provide. The number of large fractions given in such circumstances is sufficiently small that the late effects on normal tissues do not become a serious problem. More than 80% of patients with superior vena caval obstruction experience rapid relief of symptoms after such treatment; the remaining patients probably derive no benefit because of thrombosis of the superior vena cava.
Treatment of Metastases
In addition to relieving symptoms caused by the intrathoracic tumor, radiation therapy is often useful for the palliation of symptoms caused by distant metastases from carcinoma of the lung. The most common extrathoracic symptoms that can be alleviated by radiation therapy are neurologic dysfunction resulting from metastasis involving the central nervous system and pain from metastasis to bones or, less often, to soft tissues.
Central Nervous System Metastasis
Approximately 10% of all patients with cancer of the lung present with cerebral metastasis, and in most cases these metastases had resulted in neurologic symptoms and signs that suggested the need for further evaluation. Small cell carcinoma, adenocarcinoma, and large cell carcinoma of the lung cause cerebral metastasis so often (Table 110-2) that CT or MR imaging of the brain is worthwhile even for asymptomatic patients. The yield of occult metastasis in such patients is approximately 10%.
Table 110-2. Frequency of Brain Metastasis at Autopsy by Histopathologic Type of Lung Cancer | |||||||||||||||||||||
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Borgelt and associates (1980) suggested that relief of symptoms from brain metastasis by radiation therapy is reasonably consistent and predictable. Seizures and impaired mentation are reversible more often than are specific motor deficits.
At least half of all patients who develop brain metastasis from carcinoma of the lung die as a direct result of central
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nervous system involvement. Without aggressive intervention, the median survival time is little more than 3 months, as we (RK, JDC) and our associates have noted (1977). Patients who have cerebral metastasis at the time of initial diagnosis have a somewhat worse prognosis than those who do not, but those who develop cerebral metastasis after initial surgical resection or radiation therapy of the intrathoracic tumor have a slightly better prognosis than those who present with cerebral involvement. Indeed, as we (RK, JDC) and our associates (1983) have suggested, some such patients, most often those with metastasis exclusively to the brain in the absence of other extrathoracic dissemination, live for years after aggressive surgical intervention or irradiation for the cerebral metastasis. This phenomenon is more common with adenocarcinoma and large cell carcinoma than with squamous cell carcinoma or small cell carcinoma. The prognosis for patients with single metastatic foci in the brain can be improved by surgical resection followed by whole brain irradiation, as observed by Patchell and colleagues (1998). Sheehan and coinvestigators (2002) have demonstrated that stereotactic radiosurgery can effectively control brain metastases and improve survival, especially among patients with adenocarcinoma. Hoffman and associates (2001) report that whole brain irradiation may further improve control of central nervous system disease over that obtained by radiosurgery alone.
Skeletal Metastases
The two of us (RK, JDC) and our colleagues (1977) reported that at least one-third of patients with disseminated lung cancer have symptomatic involvement of the skeletal system, which usually manifests as pain. A high probability of pain relief can be expected from palliative irradiation of symptomatic bony metastases, but complete relief of pain is less common than partial relief. Tong and associates (1982) and Blitzer (1985) concur that brief but intensive courses of radiation therapy are indicated for the palliation of pain because of the desirability of minimizing the amount of time patients spend undergoing treatment when their life expectancy is short. For the uncommon situation in which multiple sites of symptomatic metastases are present simultaneously, single-dose hemibody irradiation can be considered. Upper-body irradiation with 6 or 7 Gy in a single fraction or lower-body irradiation with 8 Gy produces remarkable, if brief, palliation.
Paraneoplastic Syndromes
Radiation therapy, like surgical resection, can reduce or eliminate paraneoplastic effects. Some paraneoplastic syndromes are more readily reversible than others; endocrinologic syndromes, including adrenocorticotropic hormone and antidiuretic hormone overproduction, can be reduced or eliminated by locoregional radiation therapy. Hypercalcemia is more complex and less consistently reversible with radiation therapy. Paraneoplastic neurologic symptoms and signs and hypertrophic pulmonary osteoarthropathy are rarely affected by radiation therapy.
Chronic Obstructive Pulmonary Disease and Pulmonary Infection
Chronic obstructive pulmonary disease is rarely a contraindication to radiation therapy for inoperable cancer of the lung. Choi and associates (1985) used serial pulmonary function studies to show that judiciously applied radiation therapy rarely causes acute or late pulmonary effects greater than those already caused by the tumor. Because effective radiation therapy in this situation involves doses higher than those tolerated by normal lung tissue, the high-dose area must be minimized and confined to a volume that sharply circumscribes the intrathoracic tumor. With careful treatment planning using three-dimensional conformal techniques, the primary tumor and involved regional lymph nodes can be irradiated adequately with few serious effects in the adjacent lung. Indeed, three-dimensional conformal radiation therapy may allow higher total doses of radiation and concurrent chemotherapy to be delivered while protecting normal lung tissue in patients with limited pulmonary reserves.
Many pulmonary tumors with a significant endobronchial component result in obstruction, distal atelectasis, and subsequent bacterial infection. This condition is a clear indication for urgent radiation therapy; once atelectasis is well established, reversal is not easy to achieve.
Active tuberculosis in a patient with carcinoma of the lung was previously considered a contraindication to radiation therapy. With current antituberculous drug therapy, however, treatment for the tuberculosis and radiation therapy can both be initiated immediately if indicated. No evidence shows that radiation diminishes the effectiveness of antimicrobial therapy. Anecdotal evidence suggests that radiation therapy may reactivate tuberculosis; this phenomenon, if real, is so rare that it is of little practical consequence.
RADIATION EFFECTS ON NORMAL TISSUES OF THE THORAX
A detailed description of radiation effects on normal tissues that could be encountered during high-dose, definitive radiation therapy of lung cancer is provided in Chapter 109. One of us (RK) and associates (2003) also reviewed this subject recently.
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The most sensitive structure irradiated in the course of treating bronchopulmonary carcinoma is the lung itself. Given in single doses, 8 to 10 Gy predictably produces radiation pneumonitis. Common fractionation schemes in which 1.5 to 1.8 Gy are delivered per day allow some repair of radiation effects; pneumonitis occurs in fewer than 5% of patients receiving total doses of 18 to 20 Gy in such standard fractions. Irradiation for lung cancer, which incidentally treats some normal lung tissue as well, usually results in improvement in pulmonary function because of the response of the tumor, followed by some degradation in function resulting from radiation pneumonitis and subsequent scarring. To limit the adverse effects of radiation therapy on the lung, the volume irradiated must be limited. Techniques that use multiple field arrangements, shrinking fields, and individualized blocking are essential. Our own findings, reported by Geara and others (1998), suggest that variations in late effects of treatment, at least in the lungs, could be related to inherent differences in individual sensitivities. Prior, concurrent, or even subsequent chemotherapy may enhance or recall radiation effects and lessen the total dose needed for radiation-induced inflammation and scarring. Drugs that notably increase radiation effects in the lung include dactinomycin, bleomycin, carmustine, cyclophosphamide, and methotrexate.
The normal tissue that most often gives rise to symptoms during the course of irradiation is the esophagus. The germinal layer of the squamous epithelium lining the esophagus is affected by doses between 15 and 20 Gy. By 10 to 14 days after the start of treatment, pseudomembranous inflammation results in dysphagia. Although dysphagia improves as the treatments continue, it increases during the fourth week and again during the sixth week because of the cyclic nature of the accelerated proliferation of the viable germinal cells. Dietary modifications and analgesics usually prevent significant weight loss, but percutaneous endoscopic gastrostomy may be required, especially when chemotherapy is given concurrently with radiation therapy. Late effects of radiation on the esophagus (i.e., stenosis or complete obstruction) are rare with typical fractionation unless one or more of the aforementioned chemotherapeutic agents is used in combination with the radiation therapy.
Radiation myelopathy is unquestionably the most serious potential result of radiation therapy. Experiences with large-dose fractionation reported by Hatlevoll (1983) and Dische (1981) and their associates revealed many cases of radiation myelopathy. Symptoms consist of weakness of the lower extremities and Brown-S quard syndrome beginning 6 to 36 months after completion of radiation therapy. Wollin and Kagan (1976) suggested that this grave late effect of radiation therapy can be avoided entirely by careful attention to individual fraction size and overall treatment time. Use of three-dimensional conformal radiation therapy techniques can further decrease the risk of damage to the spinal cord.
Finally, with rare exceptions some of the heart must be included within the field of irradiation. Stewart and Fajardo (1971) reported that treating the entire heart with doses of 40 Gy in 4 to 5 weeks led to symptomatic radiation pericarditis in approximately 5% of patients. Because most pulmonary neoplasms arise in the upper lobes, it is usually necessary to treat only the atria and great vessels. When a significant amount of the ventricles must be included within the field of irradiation, the dose must be limited, and treatment plans that sharply confine high doses to a minimal volume must be sought.
RECURRENT CANCER OF THE LUNG
Lung cancer can recur in the thorax after definitive surgery or definitive radiation therapy performed with the intent of complete eradication. In many cases, the recurrence takes the form of diffuse parenchymal metastases or pleural involvement with effusion. Radiation therapy has little, if anything, to offer patients with these manifestations of intrathoracic tumor progression. Less often, the tumor may progress in the lung or mediastinum adjacent to the site of the primary tumor or in the regional lymph nodes. This appearance is an indication for locoregional radiation therapy, but the expectations for success with such treatment are necessarily limited. A tumor that regrows within an operative bed can rarely be controlled. This circumstance is similar to that of macroscopic residual tumor after subtotal resection.
Although the precise reasons why external radiation therapy can have only limited effects are not known, they presumably relate to changes in tumor vasculature in which broad areas of hypoxia confer resistance to the effects of ionizing radiation. Interestingly, Green and Melbye (1982) reported that postirradiation recurrences have a somewhat less grave outlook than postsurgical recurrences, and limited success has been achieved with repeat irradiation. Hilaris and Martini (1979) suggested that operative intervention with implants (i.e., brachytherapy) is rarely beneficial.
Patients who experience tumor recurrence after external irradiation to high total doses can be offered palliative endobronchial irradiation. This procedure is indicated only if the patient has significant endobronchial or endotracheal disease as determined by bronchoscopy. In our practice, we further require that no bleeding disorder be present and no systemic chemotherapy planned for at least a month. If sufficient occlusion is present, laser resection may be indicated, because attempts to force a catheter through an obstructing tumor may produce uncontrollable bleeding. We use a high-dose-rate afterloading unit with a single high-specific-activity iridium 192 source that produces a dose rate of 15 Gy at a distance of 6 mm from the source in less than 15 minutes. A second and occasionally a third procedure
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are used if symptoms are not relieved after the first application. Our experience with 81 patients, reported by Delclos and colleagues (1996), has now been extended to more than 100 patients; at least 75% of these patients had radiographic or bronchoscopic evidence of response, and the same proportion had symptomatic improvement as well.
RADIATION THERAPY FOR SMALL CELL CARCINOMA
Small cell carcinoma consistently displays overt or subclinical dissemination at presentation. Radiation therapy and single-agent cytotoxic drugs, administered separately, often produced responses but showed little long-term benefit. Combination chemotherapy was demonstrably superior to single-agent chemotherapy in terms of rate of response and median survival time, and radiation therapy was temporarily thought to be unnecessary. Retrospective studies suggested that survival rates at 2 or more years were superior when radiation therapy of the intrathoracic tumor was integrated with combination chemotherapy. At that time, several prospective, randomized trials were launched to assess the role of thoracic irradiation for small cell carcinoma. Among the findings of those trials was the recognition that quality control in radiation therapy profoundly influences the results of treatment in this type of carcinoma. White and colleagues (1982), in assessing the importance of compliance with protocol specifications in Southwestern Oncology Group trials, showed that full compliance with radiation therapy specifications was the single most important prognostic factor. Failure to mandate rigorous protocol compliance with regard to radiation therapy is a likely reason why some studies have shown little effect from combining thoracic irradiation with chemotherapy.
An independent meta-analysis by Warde and Payne (1992) included 11 prospective comparative trials of chemotherapy for limited-stage small cell lung cancer, with or without thoracic irradiation therapy. They found that the addition of thoracic irradiation increased local control rates at 2 years from 15% to 40% and improved survival rates at 2 years from 15% to 20%. Pignon and co-workers (1992) performed a meta-analysis of 2,140 patients enrolled in 13 prospective, randomized trials initiated between 1976 and 1986 that were designed to compare chemotherapy alone with chemotherapy plus thoracic irradiation. The 14% reduction in mortality associated with the combination of the two methods was highly significant (P = 0.001).
The optimal means of integrating radiation therapy into the management of small cell carcinoma remains to be defined. Perry and associates (1987) reported Cancer and Leukemia Group B findings suggesting that delaying radiation therapy until after three or more cycles of chemotherapy was associated with lower toxicity and better long-term outcome than giving radiation and chemotherapy together immediately after diagnosis. Bunn (1987), reporting findings from the U.S. National Cancer Institute, showed that aggressive initial therapy with radiation and simultaneous chemotherapy was superior to chemotherapy alone. McCracken and colleagues (1990) from the Southwest Oncology Group combined intravenous etoposide and vincristine in two 4-week cycles with concurrent radiation therapy (45 Gy in 1.8-Gy fractions given once a day for 5 weeks); prophylactic cranial irradiation was given with a third cycle of cisplatin and etoposide, followed by cycles of methotrexate, doxorubicin, and cyclophosphamide for 12 weeks. Among the 154 patients so treated, 42% were alive at 2 years and 30% lived for 4 years.
Turrisi and Glover (1990) treated 32 patients with intravenous cisplatin and etoposide concurrently with accelerated radiation therapy (45 Gy in 1.5-Gy fractions twice daily for 3 weeks). Initially, two cycles of chemotherapy were given at 3-week intervals, and then these two drugs were alternated with cyclophosphamide, doxorubicin, and vincristine for six additional cycles. Prophylactic cranial irradiation was given to those who showed complete response after the chemotherapy was completed. Turrisi (1992) reported that the 2-year survival rate was 54% and the 4-year survival rate was 36%. A comparative trial of the regimen reported by McCracken and colleagues (1990) and that reported by Turrisi (1992) was undertaken by the RTOG and the Eastern Cooperative Oncology Group. Patients with limited-stage small cell carcinoma were treated with etoposide and cisplatin and randomized to receive concurrent radiation therapy with either 45 Gy in 1.5-Gy fractions twice daily or 45 Gy in 1.8-Gy fractions once a day. Turrisi and co-workers (1999) noted that this trial produced the best short-term survival reported to date in a multiinstitutional trial: 44% at 2 years for the two arms combined. At 5 years, survival in the once-daily irradiation group was 16% and that in the accelerated twice-daily group was 26% (Fig. 110-6).
 |
Fig. 110-6. Accelerated treatment for small cell lung cancer. From Turrisi A, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340: 269, 1999. With permission. |
Goto and colleagues (1999) from the Japanese Clinical Oncology Group reported a prospective comparative trial in which thoracic irradiation was given to 45 Gy at 1.5 Gy twice a day and chemotherapy consisting of paclitaxel and etoposide was given every 3 weeks; outcome was compared between delayed radiation (started after two cycles of chemotherapy) and concurrent chemotherapy and radiation therapy (both starting on day 1). The median survival time was 27.2 months in the concurrent-therapy group and 19.5 months in the sequential-therapy group.
In summary, no doubt remains as to whether radiation therapy is important in the management of small cell carcinoma that is clinically confined to the thorax. Patients with disseminated disease at presentation may also benefit from radiation therapy. Livingston and associates (1984) showed that the number of such patients who have clinical complete responses to combination chemotherapy only to develop thoracic recurrence later is sufficient to warrant further study of thoracic irradiation in combination with systemic therapy.
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CLINICAL RESEARCH IN RADIATION THERAPY FOR CANCER OF THE LUNG
The aforementioned results described in this chapter are encouraging. Cancer of the lung has long been considered curable only if the tumors were resectable. Reports from large cooperative trials show that radiation therapy clearly improves survival for some but not all patients with inoperable NSCLC or small cell carcinoma. Clearly, radiation therapy, as currently used, addresses only part of the multifaceted problem of lung cancer. Efforts are under way to enhance the effectiveness of local radiation therapy in eradicating the intrathoracic tumor, particularly by intensifying treatment by means of concurrent chemotherapy. Systemic chemotherapeutic agents, when optimally combined with radiation therapy, may not only enhance tumor control within the irradiated volume but also reduce or eliminate disease that has disseminated beyond the irradiated volume. Roth and colleagues (1996) reported using gene therapy to correct acquired genetic abnormalities of lung cancer cells. New studies are also under way by our team that have been reported by Swisher and colleagues (2003) to combine gene therapy such as this with radiation therapy. Mauceri and associates (1998) are studying combinations of antiangiogenesis factors with radiation therapy. Biological response modifiers may also enhance effects on the local tumor and simultaneously enhance host defenses to permit eradication of subclinical disease. Clinical research in lung cancer has an exciting future.
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