The Contemporary Role of Radiation Therapy in the Management of Lung Cancer

PRACTICAL RADIATION ONCOLOGY FOR THE SURGICAL ONCOLOGIST

THE CONTEMPORARY ROLE OF RADIATION THERAPY IN THE MANAGEMENT OF LUNG CANCER Minesh P. Mehta, MD

Lung cancer represents one of the major oncologic problems of this centurv. Whereas the disease was almost nonexistent at the turn of the century the widespread dissemination and availability of tobacco products led to a rapid increase in the consumption of this powerful cocktail of carcinogens, leading to a rapid rise in the worldwide incidence of lung cancer. From a curiosity relegated to occasional mention in a paragraph or two at the end of book chapters in the 1920s and 1930s, this disease has soared to become the number one cancer killer in the United States. Estimates for 1999 suggest that approximately 160,000 individuals were afflicted by this disease, and unfortunately, the overall survival statistics remain grim, with 15%5-year survival.19The gender equity revolution of the 1960s had the unfortunate consequence of making tobacco consumption among women an acceptable practice. As a consequence, whereas the ratio of male to female non-small-cell lung cancer was 4:l just a quarter century ago, the ratio is almost equal today. From a practical clinical perspective, I prefer to approach lung cancer using a decision tree. The first bifurcation separates the disease histologically into either small-cell lung cancer or non-small-cell lung cancer. The former is managed primarily with chemotherapy, and a case is made for the role of thoracic radiation and prophylactic cranial radiation in patients with limited stage disease. The latter is a conglomeration of at least three

From the Department of Human Oncology, University of Wisconsin-Madison Medical School, Madison, Wisconsin SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9. NUMBER 3 JULY 2000

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histologic subtypes referred to as epidermoid carcinoma, adenocarcinoma, and large-cell carcinoma. The approach to these patients is governed by their surgical resectability, the prime definitional objective of the staging system, which divides the disease into four progressively poorer prognostic groups from stage I to stage IV. The approach to stages I, 11, and operable stage I11 patients revolves primarily around the use of surgical resection with or without adjuvant radiation and chemotherapy. More recently, preoperative neoadjuvant and postoperative adjunctive therapies have been explored and are described in this article. For the more advanced unresectable stage IIIA and IIIB patients, the backbone of therapy is radiation alone or combination chemoradiotherapy. For stage IV patients, no cure is possible, and the treatment approach is primarily palliative. The specific application of various radiation techniques for palliation is described herein. Figure l summarizes the treatment decision pathway in patients with lung cancer, and this simplified decision tree illustrates the need for asking two primary questions, that is, histology and stage, which result in five major groupings of lung cancer patients that drive treatment decisions. NON-SMALL-CELL LUNG CANCER Inoperable Early Stage Lung Cancer

Stage I lung cancer includes the categories T1 and T2, which represent relatively small tumors without evidence of involvement of lymph nodes. When lymph nodes up to the hilar region are involved for these early T1 and T2 lesions, the overall category is regarded as stage 11. Both stages I and I1 non-small-cell lung cancer are the prototypical lesions considered for surgical resection with favorable outcome in the earliest disease stages. Lung cancer frequently tends to occur in patients with significant underlying cardiac and pulmonary comorbidities, however, and despite being anatomically resectable, many of these patients have physiologically inoperable disease. The typical situation is one of a patient with significantly comprised pulmonary function or extremely poor cardiac status. For the most part, these patients are appropriately treated with definitive radiation therapy that produces survival in the 20%to 30% range. A number of single institution experiences validate this observation. In a recent review, ten studies were evaluated and the overall and disease-specific Representative studies survival rates were 15% and 40%, re~pectively.~~ are presented in Table 1. From a practical standpoint, it is important to pay attention to several key radiotherapeutic principles when managing these patients with nonsurgical approaches. First, it is important to sort out those patients whose physiologic status is so extremely poor that no therapeutic intervention is warranted. Once this extremely ill group of patients is excluded, significant caution must be paid to the volume of lung parenchyma exposed in a radiation field because the slightest degree of pulmonary injury from

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a a TTTTT Stage

Stage

Surgery ? Radiotherapy

+ Chemotherapy

Radiotherapy

Chemotherapy

Chemotherapy

Chemotherapy

e Chemotherapy

+ Radiotherapy

+ Radiotherapy

+ Radiotherapy

? Observation

Figure 1. Lung cancer treatment decision pathway. The two primary nodal points in treatment decision-making are histology and stage. For small-cell lung cancer, surgery is considered rarely. For resectable non-small-cell lung cancer, surgery is primary therapy.

radiation pneumonitis can precipitate significant complications in this already compromised groups of patients. In our practice, we tend to use treatment planning CT scans to direct our radiation portals, which are designed specifically to traverse through as much abnormal lung as possible in order to minimize the exposure of functional normal lung. We tend to treat these patients to a total dose of 70 Gy in 7 weeks, using 35 fractions of 2 Gy each. More recently, with the advent of positron emission tomography in staging nodal disease in non-small-cell lung cancer, we have begun to use this imaging technology for defining radiation portals. This helps to select out those patients who may have significant nodal or metastatic disease who would not benefit from small field radiotherapy. Table 1. DEFINITIVE RADIOTHERAPY FOR INOPERABLE EARLY STAGE LUNG CANCER Author

Year

n

Smart Schumacher Hilaris Haffty

1956 1976 1986 1988

33 42 55 37

5-Year Survival (%)

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Given the commonly encountered poor pulmonary status of many of these patients, a primary chemotherapeutic approach may be warranted if the radiation field size would be excessive; the data that support this are anecdotal. Postoperative Radiotherapy

Although the survival of patients with TINO, or stage.IA, disease is excellent, the survival of other patients with resectable lung cancer is considerably lower. These patients can either fail locally in the thorax or at distant sites. In order to improve intrathoracic control, postoperative thoracic radiotherapy has been used extensively in patients with NO, N1, and N2 disease (no adenopathy, hilar adenopathy, and mediastinal adenopathy). Several retrospective single institution reviews have suggested a survival benefit with this approach. The most comprehensive randomized trial in this regard was performed by the Lung Cancer Study Group; and it demonstrated major improvement in intrathoracic disease control. For those patients who received thoracic radiotherapy, intrathoracic failure rate was only 3%, compared with 43% for patients who did not receive postoperative radiotherapy. Interestingly, in this randomized trial, no significant survival advantage was identified. The consequences of intrathoracic failure in terms of clinical symptomatology are sufficiently devastating that we believe that improved intrathoracic control is a reasonable goal and we recommend postoperative radiation therapy to our patients with involved mediastinal nodes. We do not routinely recommend this for patients without evidence of nodal involvement or for those in whom the nodal disease is limited to the hilar region. In a metaanalysis of 2128 patients in nine clinical trials of postoperative radiotherapy, a 7%survival decrement from radiation was identified. This particular analysis included a number of trials from the 1960s and 1970s, when staging was highly inaccurate and relatively outmoded radiation therapy technologies were used. In addition, several of the trials included in this report aggressively treated patients with no evidence of nodal involvement or those with early nodal involvement only, a group that by current standards would not be subjected to postoperative radiation therapy. Whereas this metaanalysis demonstrates the risks of over using postoperative radiation therapy in earlier disease stages, we remain convinced of its value in patients with more advanced nodal d i ~ e a s e . ~ The lack of a survival benefit from the Lung Cancer Study Group trial prompted the hypothesis that these patients were dying of distant metastatic disease; hence, postoperative chemotherapy in addition to radiation therapy was tested in a recently completed multiinstitutional trial. In this study, no significant survival advantage from the addition of chemotherapy was identified. We do not recommend the routine use of postoperative chemotherapy in non-small-cell lung cancer.18

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A few practical considerations are critical in the delivery of postoperative radiotherapy. First, treatment volumes, especially regarding normal pulmonary parenchyma and cardiac volume, must be minimized and excluded diligently from the radiation portals. Second, overall treatment dose should not exceed 50 to 54 Gy, generally delivered in 1.8 or 2 Gy daily fractions over 5 to 6 weeks. The treatment techniques should use the benefits of treatment planning CT scans, simulation, inhomogeneity corrections with wedges or custom compensators, and the use of megavoltage photons, preferably in the 6 to 10 megavolt range, which have appropriate penetration characteristics for the thorax. We recommend avoiding lateral fields as far as possible to protect the maximal possible volume of normal lung. Neoadjuvant Approaches

The delivery of either radiation or chemotherapy or combined chemoradiotherapy before definitive surgical resection is referred to as neoadjuvant therapy. In the 1960s and 1970s, several clinical trials of neoadjuvant radiation therapy were conducted in an attempt to downstage the disease, improve nodal control, and make tumors more resectable. None of these clinical trials showed a significant survival benefit, and preoperative radiation therapy for non-small-cell lung cancer has largely been abandoned. The one exception to this observation is the superior sulcus tumor, in which retrospective single institution trials of preoperative low-dose radiotherapy followed by definitive surgical resection have yielded long-term survival in up to one third of patients. These trials are reviewed by Sundaresan et a135and summarized in Table 2. More recently, considerable attention has been focused on the use of chemotherapy or combination chemoradiotherapy as neoadjuvant approaches. This interest has been driven primarily by two relatively small randomized trials, one from the United States and the other from Europe, both published in 1994. These trials showed a significant survival advantage for resectable stage IIIa disease from the neoadjuvant approaches compared with surgical resection alone. The extremely small patient numbers in these trials provide grounds for significant caution because it is not possible to balance for all prognostic variables in such tiny trials. An excellent example of this is the proponderance of patients in the European Table 2. SUPERIOR SULCUS TUMORS: 5-YEAR SURVIVAL Author

Year

n

5-Year Survival (%)

Paulson Hilaris Komaki Houtte Devine

1981 1981 1981 1984 1986

120 170 38 31 66

31 17 23 23 13

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trial on the surgical arm with mutations of the k-ras oncogene, which is a known biomolecular marker for poor prognosis. Additionally, the recent publication of two negative trials from neoadjuvant approaches further underscores the experimental nature of this strategy. The subject is reviewed in a recent publication.13 In our practice, we do not use neoadjuvant approaches outside the clinical trial context. The data from these four clinical trials are summarized in Table 3.

Definitive Radiotherapy for Inoperable Non-Small-Cell Lung Cancer

Given the well-accepted role of radiation therapy in unresectable non-small-cell lung cancer, no contemporary clinical trials of observation versus radiation therapy exist. A Veterans' Administration Lung Group clinical trial from the 1960s tested radiation therapy against best supportive care and demonstrated a small but consistent and statistically significant survival benefit from radiation therapy, although no long-term follow-up data were provided. A more recent three-arm randomized trial compared thoracic radiotherapy, vindesine, and thoracic radiotherapy plus vindesine. Each of the arms contained just over 100 patients, and the intent at the time of study design was to consider the vindesine arm as equivalent to the observation arm because this drug has little to no documented activity in non-small-cell lung cancer. As required by ethical trial design, patients on the vindesine only arm were permitted to switch over to radiation therapy at progression. Because most patients were rapidly switched over to thoracic radiotherapy, the trial in effect ended up being a comparison of radiation with or without vindesine rather than evaluating the value of thoracic radiotherapy.17 In the 1970s, the Radiation Therapy Oncology Group (RTOG) conducted a landmark four-arm randomized trial that explored external beam radiation doses in the 40 to 60 Gy range. Patients randomly allocated to the high-dose arm had superior short-term survival as illustrated in Table Table 3. NEOADJUVANTAPPROACHES FOR NON-SMALL-CELL LUNG CANCER Author

year

n Tm (mo) no chemotherapy chemotherapy survival (mo) no chemotherapy chemotherapy TTP

=

time to progression.

Roth

Rosell

Elias

Wagner

1994 60

1994 60

1997 57

1994 57

9

5 20

12 9

-

8 26

23 19

12 12

>37

11 64

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4.26With the improved survival in the 60 Gy arm, this has become the accepted US standard for unresectable, locoregionally advanced nonsmall-cell lung cancer. The paradigm established by this seminal RTOG trial was the treatment of micrometastatic disease to 50 Gy and boosting gross disease to 60 Gy. By definition, this resulted in the inclusion of large volumes of the mediastinum, lung, and frequently, the supraclavicular fossae in the treatment portals. Because radiation toxicity is a function of both dose and treatment volume, the large radiation fields used in RTOG 73-01 precluded significant dose escalation beyond 60 Gy using conventional approaches, and an apparent impasse appeared to have been reached. This impasse was bridged with two different philosophies, each resulting in a new paradigm as outlined later.

The Altered Fractionation Paradigm

From a radiotherapeutic perspective, the failure to achieve local control remains a significant issue. Using data from 353 randomized patients treated at the Institut Gustave Roussy in Paris, Le Chevalier et alZ0evaluated patterns of relapse and concluded that whereas a measurable reduction in distant metastases was achieved with combination therapies, local failure remained an extremely common and important consideration. Using posttreatment bronchoscopic evaluation, they were able to demonstrate that actual complete response rate at the primary site was only 16.5%. Of several possible radiotherapeutic approaches to dose escalation, altered fractionation has been evaluated most comprehensively. The biologic rationale that underscores this approach is based on the recognition that the mechanisms for acute and chronic radiation toxicities are different. In fact, acutely responding tissues behave in a fashion similar to most rapidly proliferating tumors. Escalation in total dose is likely to enhance tumor control as well as acute toxicities. Late toxicities appear to correlate significantly with the fraction size (i.e., the amount of radiation per fraction). Dose intensification by increasing conventional daily fraction sizes from 1.8 to 2 Gy to 3 Gy, for example, would enhance tumor control as well as both acute and chronic toxicities, thereby negating any improvement in the therapeutic index, unless significant volume reduction accompanied the increase in fraction size. Total dose can be escalated without increasing late toxicities by simply using more daily single fractions; however, there is a rapid limit to this benefit as well, because prolongation of Table 4. RADIATION THERAPY ONCOLOGY GROUP 73-01: THE IMPACT OF DOSE

LF

=

Dose

3-Year % LF

3-Year % S

40 Gy 60 G y

63 36

10 20

local failure, S

=

survival.

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the therapeutic duration may result in loss of tumor control. Hyperfractionation using multiple daily fractions, each typically smaller than the conventional 1.8 to 2 Gy fractions, that are spaced approximately 6 to 8 hours apart and delivered over a total treatment duration of approximately 6 weeks, not dissimilar to conventional schedules, holds the promise of improving the therapeutic index by increasing the overall effective tumor dose without increasing late toxicities. The RTOG has contributed substantially in designing and conducting prospective trials that explore hyperfractionation.A large trial, RTOG 8311, evaluated doses in the 60 to 79.2 Gy range in 884 patients. The 69.6 Gy arm was believed to provide the best survival, and a subsequent threearm randomized trial, RTOG 88-08, compared standard fractionation to 60 Gy, hyperfractionation to 69.6 Gy, and combined chemoradiotherapy. The results, presented in Table 5, favored the combination arm initially, but this benefit did not persist beyond 2 years, which suggests that hyperfractionation may be able to achieve outcomes similar to combination ~hemoradiotherapy.~~

Accelerated Hyperfractionation

A second major radiotherapeutic altered fractionation concept that has been tested recently is based on the recognition from tumor cell kinetic studies that several primary lung carcinomas have extremely short (less than 5-7 days) potential doubling times.39The rapid repopulation from these tumor cells would have a major detrimental impact on conventional 6-week-long radiation schedules, which would start losing their effectiveness within a couple of weeks of initiation of therapy. To overcome this, it would be necessary to shorten the overall treatment time considerably (i.e. acceleration). From a practical standpoint, the easiest way to accelerate is to use multiple daily fractions of less than 1.8 to 2 Gy each but with the daily cumulative dose more than 1.8 to 2 Gy, a biologically comparable total dose, and a significantly shortened overall treatment duration. This concept marries acceleration with hyperfractionation, which is known as hyperfractionated accelerated radiotherapy (HART).When weekend breaks are eliminated so that there is no interruption, the word continuous is added, which results in the well-known acronym CHART. Table 5. RADIATION THERAPY ONCOLOGY GROUP 88-08: CYEAR SURVIVAL ANALYSIS % Survival b y Year

radiotherapy 60 Gy (RTOG) radiotherapy 69.6 Gy (RTOG) chemoradiotherapy (RTOG)

n

MS (mo)

1

2

3

4

153 156 152

11.4 12.3 13.8

46 51 60

19 24 32

6 13 15

4 9 11

MS (mo) = median survival in months.

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Clinical trials of CHART in non-small-cell lung cancer were first piloted in England by Saunders et a130and, based on their encouraging preliminary data, a large, multicenter randomized European trial has been completed recently. A total dose of 54 Gy was delivered over 12 continuous treatment days at 1.5 Gy three times daily, separated by intervals of 6 hours, resulting in an 18-hour treatment day, weekends included. The initial results of this randomized trial demonstrate a statistically significant 10% survival benefit at 2 years compared with a standard 60 Gy schedule. The odds ratio in favor of the CHART regimen was 0.75, which suggests a 25% decline in the risk of death. The CHART regimen has not gained popularity in the United States because of manpower and other logistic constraints imposed by the lengthy treatment days. An alternative, more practical regimen spaced over 15 days, including two weekend breaks, has been piloted by Eastern Cooperative Oncology Group (ECOG) (ECOG 45-93) with median and 1year survival of 13.5 months and 57%.24Based on the favorable results of these trials, a major US randomized trial testing HART has been initiated by ECOG (ECOG 25-97). This trial uses the concept of combined chemoradiotherapy with carboplatin and tax01 given for two cycles, following by a randomization to once daily radiation therapy to 64 Gy or threetimes daily radiotherapy over a 2.5-week period to 57.6 Gy. Concomitant Boost

This technique of accelerating radiotherapy dose delivery reduces the overall treatment time by 1 to 2 weeks by giving the boost as a second fraction during the normal course of standard radiotherapy. Phase I and I1 studies have been carried out by the RTOG. In the largest such report, 355 patients received 1.8 Gy fractions to standard large fields, followed 4 to 6 hours later by 1.8 Gy boost field radiation, given 2 to 3 times each week.9 The total dose was escalated from 63 to 70.2 Gy in 5 weeks. Although there was some increase in acute toxicity in the higher dose arm, late toxicities were not enhanced. Median survival remained at 9 months for the various cohorts, but in the high-dose arm, 1- and 2-year survival rates were 44% and 22%, respectively, comparable to what is contemporarily achieved with combination therapy. This approach has not been tested further in a randomized fashion. Three-Dimensional Conformal Radiation Therapy

Based on the well-documented knowledge that local relapse is the predominant mode of failure in lung cancer, it is logical to attempt to increase total dose to overcome this problem. The advent of sophisticated computers for treatment planning, advanced software, and the widespread reliance on CT scans has spawned this entirely new field of threedimensional conformal radiation therapy. The principles are elegantly

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simple: precise anatomic delineation of the target and identification of surrounding normal critical structures permit the design of multiple radiation therapy portals or fields, approaching the tumor from almost any theoretical direction, thereby ensuring noncoplanarity. Theoretical modeling studies that compare such three-dimensional plans with conventional two-dimensional plans have indicated the potential for escalating dose. In a recent update of a multiinstitutional three-dimensional dose escalation study, Martel et a123 reported promising initial results that suggested that the local progression-free survival is clearly a function of dose. Their data suggest that doses in excess of 80 Gy are necessary to achieve 50% local progression-free survival at 2.5 years. These data are summarized in Table 6.23Spurred by this exciting prospect of substantial increase in dose, the RTOG has initiated a multiinstitutional phase 1/11 trial with doses in the range of 64.5 to 90.3 Gy. Combination Chemoradiotherapy

Combination chemoradiotherapy is an active area of investigation. Several large randomized trials have tested preradiation induction chemotherapy over the last 10 years. The hypothetical benefits of this approach include targeting potential sites of micrometastatic disease at the earliest clinically detectable phase, thereby accomplishing the goals of treating minimal disease and avoiding several generations of cell division and possible development of drug resistance. There is also the expectation that the primary site of disease may respond to cytotoxic agents, thereby improving the efficacy of subsequent radiation. Sequential delivery was adopted to avoid overlapping toxicities and to ensure that both modalities could be delivered near the planned maximal doses. Cancer and Leukemia Group B 8433: Randomized Trial of Radiotherapy Alone versus Chemoradiotherapy

The landmark clinical trial that has lifted induction chemotherapy from the investigative realm to clinically accepted standard practice was conducted by the Cancer and Leukemia Group B (CALGB) from 1984 to 1987, with 7-year follow-up demonstrating survival irnpro~ement.'~ Patients with stage I11 disease with favorable prognostic features, including Table 6. NON-SMALL-CELL LUNG CANCER: IMPACT OF DOSE ON LOCAL CONTROL

LPFS % at Dose

12 mo

24 mo

30 mo

65 Gy 75 Gy dose for 50% LPFS

53 81 64 Gy

26 61 72 Gy

26 38 85 Gy

LPFS

=

local progression-freesurvival.

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performance status 0 or 1, less than 5% body weight loss, and normal hematologic and serum chemistry parameters, were randomized to 60 Gy alone or the same radiation therapy preceded by two cycles of vinblastine (5 mg/m2) as a weekly intravenous bolus x 5 and cisplatin (100 mg/m2) on days 1and 29. One hundred fifty-five eligible patients were evaluated, with overall and median survival for the combination arm demonstrating superiority over radiation therapy alone. For the entire cohort, median survival was 11 months; 13.7 months for the combination compared with 9.6 months for radiotherapy alone. The 7-year survival figures are presented in Table 7 and indicate that after 5 years, the survival probability was 2.8 times greater for patients in the combination arm. Whereas the magnitude of benefit as a ratio is quite impressive, absolute numbers provide a sobering picture. Only 14 of 78 patients from the combination arm and 5 of 77 in the radiation alone arm survived beyond 4 years. No survival benefit accrued from the combination arm for the 44 patients with large-cell carcinoma. Radiation Therapy Oncology Group 88-08/ECOG 45-88: Confirmatory Trial for Cancer and Leukemia Group B 8433

This major intergroup randomized trial was conducted not only to verify the results observed in the CALGB 8433 trial but also to explore the potential role of hyperfractionated radiation therapy. Between 1989 and 1992,452 eligible patients who were selected using criteria similar to the CALGB shtdy were randomized to standard radiotherapy (60 Gy in 30 fractions of 2 Gy each), hyperfractionated radiotherapy (69.6 Gy in 58 fractions of 1.2 Gy each, given twice daily), or standard radiation with the same preradiation chemotherapy as in CALGB 8433. In 1995, with a potential median follow-up of 33 months, the study results demonstrated the superiority of the combined modality arm over both radiation regim e n ~The . ~ median ~ and percent survival for the first 4 years are presented in Table 5. The improvement in median survival in the combination arm to 13.8 months was not only comparable to the 13.7months in the CALGB study but also was superior to 11.4 months from 60 Gy and 12.3 months from 69.6 Gy. Metaanalysis of Randomized Combination Therapy Trials

Whereas the large randomized intergroup trial verified the initial survival benefit from combination therapy, it once again dramatically illusTable 7. CANCER AND LEUKEMIA GROUP B 8433: 7-YEAR SURVIVAL ANALYSIS % Survival by Year of Follow-Up

radiotherapy chemoradiotherapy

77 78

9.6 13.7

MS (mo) = median survival in months.

40 54

13 26

10 24

7 19

6 17

6 13

6 13

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trated the minimal overall gains, as measured by the fact that by 3 years, more than 85% of all patients had died. Interestingly, it also raised the issue of altered fractionation, because the survival advantage from combination therapy appeared to have vanished by year 3 (3-year survival of 15%from the RTOG combination therapy arm compared with 13%from the RTOG hyperfractionation arm). This is of major concern, because both the CALGB and the intergroup trials were conducted in extremely wellselected patients, and extrapolation of these results to patients with inferior prognostic features has never been validated in the context of randomized, controlled clinical trials. Unfortunately, this approach appears to have become rather popular in day-to-day practice for all advanced lung cancer patients. Opponents of combination therapy regimens also point to a number of negative trials that have failed to demonstrate survival benefit from this approach. For example, in a recent large randomized trial of 302 patients from Sweden treated either with 56 Gy alone or 56 Gy preceded by three cycles of cisplatin (120 mg/m2) and etoposide (100 mg/m2 intravenously for 3 days), no survival advantage was detected. This negative result is particularly alarming given the 80% increase in total cisplatin dose compared with the CALGB trial.7 In this context, it is useful to review the three recently published metaanalyses that have attempted to address this question. In 1995, Marino et alZ2analyzed 14 randomized trials composed of 1887 patients, estimating survival from published reports. This report was based on a Medline search in all languages, and all studies included IIIa/b patients and compared radiotherapy plus chemotherapy to radiotherapy alone. Ten of the 14 trials used a cisplatin-based chemotherapy regimen, and for this group, the estimated pooled odds ratio of death at 1 and 2 years was 0.76 and 0.70, respectively, compared with radiotherapy alone. This translates to a reduction in mortality at 1 and 2 years of 24% and 30%,respectively. For the non-cisplatin regimens, the mortality reduction of 5% and 18%at 1 and 2 years was less impressive. Unfortunately, in keeping with the intergroup study findings, no significant survival advantage from combination therapy was detected at 3 and 5 years, implying that the modest survival benefit does not carry through past the second year of survival.22 In 1995, Stewart and Pignon from the British Medical Research Council and the Institut Gustave Roussy, on behalf of the Non-Small Cell Lung Cancer Collaborative Group, published a metaanalysis using updated data on 9387 individual patients from 52 randomized clinical trials in order to evaluate the effect of cytotoxic chemotherapy on survival in patients with non-small-cell lung c a n ~ e rThis . ~ analysis contained 22 trials with 3033 patients comparing radical radiotherapy with combination regimens, 11 of which were cisplatin based. The overall odds ratio of death of 0.9 indicated a 10%reduction in the risk of death for the combination regimens, with an overall absolute survival benefit at 2 and 5 years of a mere 3% and 2%, respectively. The strongest survival trend was observed

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in the cisplatin-based trials, with an odds ratio of death of 0.87 (13% reduction in risk of death) and an absolute survival benefit at 2 and 5 years of 4% and 2%, respectively. The most recent of these metaanalyses was published by Buccheri and Ferrignos in 1996, evaluating 17 randomized trials with 1355 patients, all treated with cisplatin-based regimens. The mean radiotherapy dose was 54 Gy. Nine of the 17 trials demonstrated a survival benefit from the combination approach, whereas the other 8 did not. Overall survival was superior in the combination group, with 1- and 2-year survival rate figures of 44% and 41%, respectively, for the combination arms versus 19% and 14%, respectively, for the radiotherapy arms.8 Other Chemoradiotherapy Combinations

Five major themes emerge from the induction chemotherapy trials: (1)a modest survival benefit accrues from this approach; (2) metaanalysis reveals that for the most part, this survival benefit is restricted to the first 2 years; (3) cisplatin-based regimens appear to be superior to other types of chemotherapy; (4) toxicities are not substantially enhanced; (5) failure pattern analysis of these trials reveals mixed results. Although there is some indication of a decrease in distant metastatic disease, locoregional failure remains a major issue, thereby reinforcing the notion that further approaches would have to control both local and systemic disease. Broadly speaking, these strategies fall into the categories of concomitant chemoradiotherapy or sequential chemoradiotherapy followed by chemotherapy dose intensification (i.e., consolidation). Concomitant Chemoradiotherapy This approach was developed with the expectation that not only would distant micrometastasesbe eliminated but also that the problem of locoregional failure would be addressed. Several cisplatin-based trials have been undertaken and three of the four major trials failed to demonstrate a statistically significant survival advantage. The most widely quoted positive trial, reported by Schaake-Koning et a1,32was conducted by the European Organization for Research and Treatment of Cancer (EORTC) and compared the addition of daily or weekly cisplatin to 55 Gy radiotherapy alone, with the daily cisplatin (6 mg/m2) arm yielding a statistically superior 2-year survival rate of 26% compared with 13%with 55 Gy alone. As expected, this approach resulted in net radiosensitization with improved locoregional control but did not influence metastatic patterns. The time to local recurrence was significantly longer in the group receiving daily cisplatin. Daily cisplatin provided additional local control at 1 and 2 years of 18% and 12%,re~pectively.~~ Although this approach provides possible clues for future exploration, confirmatory evidence has not been forthcoming. A similar trial by Trovo et a136comparing 45 Gy with the same radiation plus daily cisplatin (6 mg/m2) showed no differ-

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ences in overall response, pattern of relapse, or median survival but doubled the incidence of grade 3 esophagitis. The more aggressive concomitant regimens have attempted to combine conventional chemotherapy with radiation, and several phase I1 reports have been published. In one such relatively mature study reported by the Southwest Oncology Group (SWOG 8805), the combination of concurrent cisplatin and etoposide with thoracic radiotherapy was associated with severe toxicity.' In a recent phase I1 study, 50 patients with inoperable stage I11 non-small-cell lung cancer were treated with concurrent chemoradiotherapy to determine the feasibility, toxicity, response rate, local control, and survival of concurrent chemotherapy with cisplatin-etoposide and radiotherapy. Thoracic radiotherapy was administered to a total dose of 60 Gy. Concurrent chemotherapy consisted of cisplatin 20 mg/ m2/d plus etoposide 50 mg/m2/d from day 1 through day 5, every 4 weeks for four cycles. The overall response rate was an impressive 84%, including 68% complete response, providing proof of principle that such therapy can enhance local control. With a minimum follow-up of 23 months, overall survival rate was 70% at 1 year, 40% at 2 years, and 35% at 3 years. Median survival was 18 months. Major hematologic toxicity occurred in 24% of the patientsz9 The most significant data supporting concomitant chemoradiotherapy recently have been presented by a Japanese group.14This group has reported results from a randomized trial conducted in more than 300 patients who either received concurrent chernoradiotherapy or sequential chernoradiotherapy. The results are presented in Table 8. They demonstrate significant improvement in median as well as 3- and 5-year survival for concurrent chernoradiotherapy,thereby providing the first major randomized evidence in support of this strategy. The RTOG recently has completed a randomized trial also attempting to address the schedule question. In this trial, patients received either preradiation chemotherapy or concurrent chernoradiotherapy with standard fractionation or concurrent chernoradiotherapy with hyperfractionated radiation. The latter concept of chemotherapy plus altered fractionation is clearly a significant new direction in non-small-cell lung cancer. Consolidation Chemoradiotherapy The desire to use postradiation chemotherapy emerged from the recognition that most non-small-cell lung cancer patients fail at distant sites, despite up-front chemoradiotherapy. The strategy of consolidation has been incorporated in some of the combined modality trials but has not been validated fully in a randomized context. Its value remains questionable, particularly as significant toxicity questions remain. Proof of principle was provided by a large randomized trial incorporating preradiation and postradiation chemotherapy and reported by Le Chevalier et a120in 1991. Three hundred fifty-three patients were randomized to 65 Gy alone or the same radiotherapy preceded and followed by three cycles each of vindesine, lomustine, cisplatin, and cyclophospha-

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Table 8. CONCURRENT VERSUS SEQUENTIAL CHEMORADIOTHERAPY

n RR (%) MS (mo) 2-year survival (%) 3-year survival (%) 5-year survival (%) RR (%)

=

response rate %, MS (mo)

=

Concurrent

Sequential

156 84 16.5 37 27 16

158 66 13.3 26 13 9

median survival in months.

mide. One-, 2-, and 3-year survival rates were 41%, 14%,and 4%, respectively, for radiotherapy alone, compared with 51%, 21%, and 12%, respectively, for the combined modality arm. The relative distant metastasis rate in the radiotherapy-only arm was twice as high as that observed in the combination arm, thus validating the hypothesis. Unfortunately, local control at 17% and 15% was poor in both arms, and the survival figures were not impressively superior to other combination trials not using consolidation. It is premature to conclude that major gains have been achieved from consolidation, and the issue still remains investigational. Chemotherapy Plus Altered Fractionation

Based on the principles and results outlined thus far, it is clearly logical to consider a combination of chemotherapy and altered fractionation. Several phase 1/11 trials have been reported. The most impressive results in this setting were reported in a North Central Cancer Treatment Group (NCCTG) study reported by Shaw et a1.33These investigators treated 23 patients with split course hyperfractionated radiotherapy using 1.5 Gy twice daily to a total of 30 Gy followed by a 2-week break and an additional 30 Gy using a similar schedule. Two cycles of etoposide and cisplatin were given, one with commencement of the first radiation session and the other when the second half of the radiotherapy course was commenced. Although toxicities were considerable with 26% grade I11 or more acute pneumonitis, the overall median and 1- and 2-year survival figures were an impressive 26 months and 74% and 51%, respectively. The RTOG has tested the 1.2 Gy twice daily regimen to 69.6 Gy with vinblastine (5 mg/m2 weekly X 5) and cisplatin (75 mg/m2 on days 1,29, and 50) in their trial 90-15. Enhanced acute toxicities were substantial with 45% grade IV or more hematologic and 24%grade I11 or more esophagitis. The median and 1- and 2-year survival were 12.2 months, 54% and 28%, respectively. In a subgroup with prognostic features similar to CALGB 8433, these survival figures were 17.5 months and 60% and 30%, respectively.1° These rather excessive toxicities led to RTOG 91-06, which substituted etoposide in place of vinblastine, because this regimen previously had been tested and better tolerated in small-cell lung cancer. Seventynine patients received two cycles of oral etoposide 100 mg/d, intravenous

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cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy to 69.6 Gy. The median survival for patients comparable to CALGB 8433 was an impressive 21 months, with 1-and 2-year survival figures of 70%and 42%, respectively (these values for CALGB 8433 were 13.7months and 54% and 26%, respectively). Unfortunately, the associated toxicities from this regimen were also substantial with 57% grade IV hematologic toxicity, 53% grade I11 or more esophagitis, and 25% grade 111 or more pulmonary toxicity.21 The first statistically significant survival advantage (median survival 34 versus 77 weeks; P = 0.003) from chemohyperfractionated radiotherapy was reported by Jeremic and Shibamoto16in a three-arm randomized trial in the group receiving 100 mg/d carboplatin on days 1 and 2 with 100 mg etoposide on days 1 to 3 of each week during the course of radiotherapy (64.8 Gy; 1.2 Gy twice daily) compared with the same radiation alone. Both acute and late toxicities were increased with this approach, however. Grade IV acute toxicities were seen in 2%, 4%, and 11% of patients receiving radiation alone, radiation with weekly chemotherapy, and radiation with chemotherapy on alternate weeks, respectively; the late toxicity values were 2%, 4%, and 9%, respectively. Jeremic's group then conducted a subsequent phase I11 follow-up study with an interesting design change. To investigate the efficacy of concurrent hyperfractionated radiation therapy and low-dose daily chemotherapy in stage I11 non-small-cell lung cancer, 131 patients were randomly treated as follows: group I, 1.2 Gy twice daily to 69.6 Gy, and group 11, same radiation with 50 mg of carboplatin and 50 mg of etoposide given on each day of radiotherapy. Group I1 patients had a significantly longer survival time than group I patients, with a median survival of 22 versus 14 months and 4-year survival rates of 23% versus 9% (P = 0.021). The median time to local recurrence and 4-year local recurrence-free survival rate were also significantly higher in group I1 than in group I (25 versus 20 months and 42% versus 19%,respectively; P = 0.015). In contrast, the distant metastasis-free survival rate did not differ significantly in the two groups. The two groups showed similar incidence of acute and late highgrade t~xicity.'~ Whereas the results from Jeremic's trials are encouraging, further supportive evidence is necessary before combination chemoaltered fractionation radiotherapy can be recommended outside a protocol context. The RTOG has completed an important three-arm randomized trial (RTOG 94-10) comparing the gold standard of sequential chemoradiotherapy with concurrent chemoradiotherapy in one experimental arm and concurrent chemoradiotherapy with twice daily radiation in the other arm, and results of this trial are eagerly awaited. SMALL-CELL LUNG CANCER The Case for Thoracic Radiotherapy The primary therapeutic approach for patients with limited stage small-cell lung cancer revolves around platinum-based chemotherapy.

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This disease is highly responsive to chemotherapy, with extremely high rates of complete remission. Despite recent advances, however, long-term survival remains elusive in most patients with limited stage small-cell lung cancer, and a substantial proportion of these patients relapse at the original site of disease within the thorax. In order to improve intrathoracic local control, radiotherapy has been used. The primary value of thoracic radiation is in enhancing local tumor control, and several studies have demonstrated that chest failures can be decreased from 72% to 43% with the addition of thoracic radiation." Data from prospective randomized trials have provided mixed conclusions regarding its value in improving survival. In a recent attempt to answer this question better, two major metaanalyses were p e r f ~ r m e d . Pignon ~ ~ , ~ ~et alZ8evaluated more than 2000 patients in 13randomized studies and demonstrated that the addition of radiotherapy resulted in a 14%decrease in the risk of death. Similarly, Warde and P a ~ n observed e ~ ~ a 25% reduction in mortality with the addition of thoracic radiotherapy. When taken together, these two metaanalyses provide conclusive evidence for a slightly better than 5%overall survival improvement with the addition of thoracic radiotherapy. In a disease in which long-term survival is poor, such an increase is clearly of significant value. Several questions regarding volume, dose, and sequence remain unanswered. Most of the recent data appear to suggest that the highest likelihood of benefit from thoracic radiotherapy results from earlier incorporation of this modality in the treatment regimen. For example, in a Canadian randomized trial, patients received radiotherapy concurrently with chemotherapy either with the first or fourth cycle. The delay of radiotherapy until the fourth cycle resulted in decreased failure-free survi~a1.~~ The most recent clinical advance in thoracic radiotherapy for smallcell lung cancer has been the use of accelerated fractionation. In a major national randomized trial reported by Turrisi et al,37patients were randomized to 45 Gy thoracic radiotherapy concurrent with the first cycle of chemotherapy delivered using either 25 fractions of 1.8 Gy each or 30 fractions of 1.5 Gy given twice daily over a 3-week period. In this clinical trial, 206 patients received once daily radiation compared with 211 patients who received twice daily radiotherapy. At a median follow-up of 8 years, a 10% overall survival advantage at 5 years was noted. Patients who received the twice daily radiation had a 5-year survival rate of 26% compared with 16% for patients who received once daily radiotherapy. This is a relative survival improvement of 62.5% and represents a major clinical gain (Table 9). The Case for Prophylactic Cranial Radiation

One of the major clinical differences between small-cell and nonsmall-cell lung cancer is the extremely high potential for patients with small-cell lung cancer to develop brain metastases. The actuarial risk of

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Table 9. SMALL-CELL LUNG CANCER: ACCELERATED FRACTIONATION

n grade 3 esophagitis response rate median survival 2-year survival 5-year survival

Once Daily XRT

Twice Daily XRT

206 11% 87% 19 mo 41% 16%

211 27% 87% 23 mo 47% 26%

developing brain metastases is a function of length of survival. Patients who survive 2 years or longer have an 80% cumulative probability of developing brain metastase~.~~ It is presumed that this high rate of brain metastases is a consequence of preexistent micrometastases in the brain that are not controlled with systemic chemotherapy because of the presence of the blood-brain barrier. Because of its exquisite radiosensitivity, the use of radiation therapy was proposed, with the postulate that it would decrease the overt manifestation of brain metastases. In this context, prophylactic cranial radiation is being used realistically as elective brain radiation for micrometastatic disease to the brain. Several randomized trials of prophylactic brain irradiation have been conducted, and these consistently show a significant decrease in the overall incidence of subsequent brain metastases. Because several of these trials failed to show a survival benefit, significant questions regarding its use have been raised. In one of the largest and most recently completed clinical trials evaluating this issue, the use of prophylactic cranial radiation resulted in a reduction in the incidence of brain metastases, which was an improvement in overall survival, and favorable impact on neuropsychological effects6 One of the most significant observations from the French prophylactic cranial irradiation trial was the lack of excess neurotoxicity in the radiation arm. This is a particularly important observation in light of the fact that concerns about neurotoxicity, raised as a consequence of retrospective single institution data, to a significant extent posed a barrier to the widespread acceptance of this therapeutic approach. What was most important was the documentation that a significant proportion of patients had abnormal neuropsychologic evaluations before randomization on the study, which indicates that this disease process itself is responsible for neurocognitive deficits in several patients. The most interesting observation regarding prophylactic cranial irradiation was presented recently in the form of a metaanalysis of the major randomized trials evaluating this question. Whereas the individual studies were not powered sufficiently to detect a survival advantage, the overall metaanalysis showed a statistically significant survival advantage with the use of prophylactic cranial irradiation5 In our practice, we recommend the use of prophylactic cranial irradiation in all patients with small-cell lung cancer irrespective of stage as long as they achieve a complete response to initial therapy.

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PALLIATIVE RADIATION THERAPY External Beam Radiation

External beam radiotherapy is a highly effective palliative modality in several clinical scenarios for patients with advanced lung cancer. Patients who present with extremeiy poor performance status &d have limited thoracic disease are poor candidates for definitive high-dose irradiation. These patients, however, may derive a palliative benefit from a short course of radiation therapy, typically 30 Gy in 10 fractions of 3 Gy each. Symptoms that can be palliated effectively include pain, hemoptysis, dyspnea as a consequence of obstructive lesions, cough that arises from mucosal tumors, postobstructive pneumonia, superior vena cava compression, and occ~sionallynerve or nerve root compression such as recurrent laryngeal, phrenic, or the brachial plexus. In some of these situations, higher radiation doses may be required, such as in the context of chest wall pain for tumors invading into the chest wall, involvement of the brachial plexus, and significant compression of the superior vena cava. Additionally, external beam radiotherapy is effective in palliating the metastatic consequences of lung cancer, including bony pain, brain metastases, and painful metastases to viscera such as the liver and adrenals. These patients typically have relatively short life expectancy, usually in the range of months, leading to the selection of as short a treatment schedule as feasible. Individualization of the treatment avvroach to each vatient's disease and clinical status is a key feature of thi:alliative approich. Endobronchial Irradiation

Approximately 40% to 50% of patients with lung cancer experience malignant airway occlusion. Although brief and minor palliation can be achieved with external beam radiotherapy, more sustained and rapid palliation may be achieved in appropriately selected patients with the use of endobronchial brachytherapy. This technique is typically performed in concert with a pulmonologist and requires the placement of one or more catheters within the endobronchial tree using a flexible fiberoptic bronchoscope. These catheters can be left in place for either a few hours or a couple of days, depending on the selection of the brachytherapy modality. If patients are treated with low-dose rate radiotherapy, radioactive seeds, typically iridium 192, are afterloaded into the endobronchial catheters and left in place for 24 to 48 hours. If high-dose-rate remote afterloading devices are used, the treatment duration is only a few minutes, and significantly shorter catheter placement times are required. These techniques effectively palliate hemoptysis, postobstructive pneumonia, and frequently dyspnea. They form an important treatment option for patients with malignant airway occlusion. Although endobronchial radiotherapy has a well-defined role in the palliation of malignant airway occlusion, its up-front incorporation as a

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dose escalation technique awaits completion of better designed clinical trials. Preliminary data from the literature suggest that patients with squamous cell carcinoma with a significant endobronchial component may in fact benefit both from the perspective of local control and survival with the incorporation of an up-front boost as part of their treatment regimen. Further extrapolation of this technique is occurring in patients with in situ or early disease who are not eligible for surgical resection. CONCLUSIONS

The most recent US projections indicate that in keeping with the decline in tobacco consumption, the overall incidence of lung cancer has started to decline. A substantial proportion of these patients still present with locoregionally advanced disease, however. Although the overall prognosis for most of these patients remains dismal, concerted effort over the last two decades has yielded some promising advances, based primarily on an understanding of the disease process. Surgical resection is the mainstay for patients with early stage nonsmall-cell lung cancer. Both neoadjuvant and adjuvant approaches have been explored in these patients. Neoadjuvant radiotherapy or chemoradiotherapy has not, to date, demonstrated significant survival advantage, with the possible exception of superior sulcus tumors. Adjuvant approaches also have not yielded a survival advantage, but the seminal adjuvant radiation therapy trial for node-positive patients indicated a major decrease in intrathoracic failure. Unfortunately, this trial did not demonstrate a survival advantage because of distant metastatic spread, and a recently completed randomized trial that incorporated chemotherapy to diminish this also failed to show a survival advantage. In more advanced but still resectable lung cancer, neoadjuvant strategies with or without radiotherapy have been investigated and preliminary results are encouraging. This approach continues to be tested in a larger, national randomized trial. Early therapeutic strategies were predicated on the assumptions that local control was of paramount significance, high rates of local control could be achieved with conventionally fractionated radiation to 60 Gy, and chemotherapy was minimally active, with no impact on micrometastatic disease. Randomized induction chemoradiotherapy trials belied this assumption by demonstrating a small but measurable survival gain that resulted primarily from control of metastatic disease. Simultaneously, better assessment of local control indicated that radiographic evaluation was extremely inaccurate and falsely inflated previously reported control rates, which in reality hovered around 20%. This observation led to renewed efforts at controlling the disease locally, and of several such strategies, altered fractionation has been demonstrated in controlled randomized trials to provide statistically significant and meaningful survival benefit. Combinations of chemotherapy and altered fractionation repre-

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sent the new frontier, and although it is too preliminary to judge its overall impact, this strategy certainly has resulted both in increased toxicity and improved survival in preliminary phase I11 trials. For small-cell lung cancer, the most important recent observations have included the recognition of a survival advantage from the incorporation of both thoracic radiotherapy and prophylactic cranial irradiation as integral to the management of patients with limited stage disease. In addition, for both small-cell and non-small-cell lung cancer, hyperfractionated, accelerated treatment approaches have demonstrated survival benefit in randomized clinical trials. The appropriate incorporation of chemotherapy with these altered radiotherapeutic regimens remains the focus of current clinical trials. Are we reaching a therapeutic ceiling? Future progress in this disease must balance toxicities with outcome, measured not only in survival terms but also as it pertains to quality of life. As health care reform policies continue their increasing grip on medical decisions, the societal impact in terms of cost effectiveness will become a critical question. For example, how justifiable is it to treat most advanced, nonmetastatic lung cancer patients with poor prognostic features with aggressive therapies when they have been excluded from the randomized trials? If the hyperfractionation results hold up as being equivalent to combination therapy results, should one or the other strategy be abandoned? Will new advances in terms of drug development and gene therapy make these issues redundant? References 1. Albain K, Rusch V, Crowley J, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for Stages IIIA (N2) and IIIB non-small cell lung cancer: Mature results of Southwest Oncology Group Phase I1 Study 8805.J Clin Oncol13:18801892,1995 2. Anonymous: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials: Non-Small Cell Lung Cancer Collaborative Group. BMJ 311:899-909,1995 3. Anonymous: Effects of post-operative mediastinal radiation on completely resected stage I1 and stage I11 epidermoid cancer of the lung: The Lung Cancer Study Group. N Engl J Med 315:1377-1381,1986 4. Anonymous: Post-operative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomized controlled trials: PORT Meta-analysis Trialists Group. Lancet 352:257-263,1998 5. Arriagada R, Auperin A, Pignon TP: Prophylactic cranial irradiation overview (PCIO) in patients with small cell lung cancer (SCLC) in complete remission (CR).J Clin Oncol 17:1758, 1998 6. Arriagada R, LeChevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87:183-190,1995 7. Brodin 0, Nou E, Mercke C, et al: Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. Eur J Cancer 32:1893-1900,1996 8. Buccheri G, Ferrigno D: Therapeutic options for regionally advanced non-small cell lung cancer. Lung Cancer 14281-300,1996

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Address reprint requests to Minesh P. Mehta, MD Department of Human Oncology University of Wisconsin-Madison Medical School 600 Highland Avenue, K4/312-3684 Madison, WI 53792 e-mail: [email protected]