3.1.2 Postoperative Radiotherapy for Non-Small Cell Lung Carcinoma

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3.1.2 Postoperative Radiotherapy for Non-Small Cell Lung Carcinoma

Jeffrey C. Haynes and Mitchell Machtay

J. C. Haynes, BA, MD

Department of Radiation Oncology, The University of Pennsylvania Medical Center, 3400 Spruce Street, 2 Donner, Philadelphia, PA 19104-4174, USA

M. Machtay, MD

Associate Professor and Vice Chair, Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Hospital, 111 Sourn 11th Street, Philadelphia, PA 19107, US CONTENTS

3.1.2.1 Patterns of Failure Following Surgery Alone 189 3.1.2.2 Results of PORT in Patients

with Pathologic Stage I NSCLC 189 3.1.2.3 Results of PORT in Stage II and III (Node-Positive) NSCLC 190 3.1.2.3.1 Non-Randomized Studies 190 3.1.2.3.2 Randomized Controlled Trials 190 3.1.2.4 The PORT Meta-analysis 191 3.1.2.5 Subacute/Late Toxicity of PORT 192

3.1.2.6 Proper Radiotherapy Techniques for PORT 193 3.1.2.6.1 Fields 193

3.1.2.6.2 Radiotherapy Dose 194 3.1.2.6.3 Time Interval Between Surgery and Radiotherapy 194 3.1.2.6.4 Follow-Up/Supportive Care 195 3.1.2.7 PORT – Special Cases 195 3.1.2.7.1 Sublobar Resection 195 3.1.2.7.2 Positive Margin 195 3.1.2.7.3 Chest Wall Invasion 195 3.1.2.8 Postoperative Radiotherapy in the

Era of Chemotherapy 196 3.1.2.9 Summary/Future Directions 196

References 197

3.1.2.1 Patterns of Failure Following Surgery Alone

While lung cancer is considered a “systemic disease,”

local recurrences after defi nitive surgery are not un- common. In one series of stage I patients, 39% of fi rst failures were intrathoracic (26% ipsilateral) (Feld et al. 1984). A series from the Mayo Clinic found that 19% of fi rst recurrences in stage I NSCLC were local failures (Pairolero et al. 1984). Immerman et al. (1981) found that local failure only occurred

in 12% of patients with stage I disease, but 41% of patients with stage II disease. A cooperative group experience (the Ludwig Lung Cancer Study group) found that 41% of ﬁ rst failures were intrathoracic, while 34% were extrathoracic (Anonymous 1987).

The most common intrathoracic site was the bronchial resection line (16% of all patients), followed by the ipsilateral nodal region (13%), the contralateral intrapulmonary region (12%), and the ipsilateral intrapulmonary region (11%).

These studies suggest that local failure is a con- siderable problem among patients with resected non- small cell lung cancer (NSCLC) and that local failure often occurs as the ﬁ rst site of failure. These data imply that postoperative radiation therapy (PORT) might improve local-regional control and therefore could lengthen the survival of patients with lung cancer, particularly among stage II+ patients. The patterns of failure data have served as the primary rationale for the use of PORT over several decades of radiation oncology.

3.1.2.2

Results of PORT in Patients with Pathologic Stage I NSCLC

Patients with completely resected stage I NSCLC have a relatively favorable prognosis with surgery alone, and postoperative radiotherapy (PORT) has not proven benefi cial. Only one randomized study in the literature has demonstrated a signifi cant survival benefi t (Trodella et al. 2002). A randomized study published in 1980 demonstrated that survival among stage I (pN0) patients is shortened by PORT (24% vs.

43% at 5 years) (van Houtte et al. 1980). A second randomized study published more recently (1996) showed no benefi t to PORT and potential detriment among the subset of stage I patients with T2N0 disease (Lafi tte et al. 1996). One more recent small randomized study, however, does show a signifi cant local-regional control and survival advantage to the use

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of PORT in a highly selected population (Trodella et al. 2002).

These mixed results are not extremely surprising, since (as noted above), historical series have shown that local-regional recurrences are relatively uncom- mon after deﬁ nitive surgery. Since distant metastatic failure is substantially more likely than local-regional failure, the addition of a local modality such as postoperative radiotherapy can not be expected to improve survival.

3.1.2.3

Results of PORT in Stage II and III (Node-Posi- tive) NSCLC

3.1.2.3.1

Non-Randomized Studies

Sawyer et al.’s (1997) retrospective review of the Mayo clinic experience showed a dramatic beneﬁ t to PORT among N2 patients. Patients receiving PORT had an actuarial 4-year survival of 43% versus 20%

for the surgery-alone group. The two groups were well balanced with respect to gender, age, histology, tumor grade, involved N1 lymph node number, and number of mediastinal lymph node stations dis- sected or involved. These results appear to conﬁ rm

the data from other retrospective reports published in the 1980s (Choi et al. 1980; Chung et al. 1982;

Kirsh et al. 1976). However, these papers can be criticized as falling short of the high level of evidence demanded by modern evaluators of medical therapeutics.

3.1.2.3.2

Randomized Controlled Trials

The results of major randomized trials of postoperative radiotherapy for NSCLC are described in Table 3.1.2.1. The best known of these studies is probably the Lung Cancer Study Group (LCSG) Trial, published in 1986 (Weisenburger et al. 1986). This trial found that PORT had no impact on survival but dramatically reduced the rate of local recurrence.

Patients with pathologic N2 disease had a reduction in the overall rate of recurrence as well. Importantly, only selected N2 patients were eligible for the LCSG trial; the most superior mediastinal node had to be proven negative after a thorough mediastinal lymph node dissection. In community practice many surgeons sample only a few mediastinal lymph nodes and thus many patients may have occult N2 disease.

Therefore, the LCSG ﬁ nding that PORT is of little beneﬁ t for N1 patients may perhaps not be generalized to all communities.

Table 3.1.2.1. Results of selected randomized trials of postoperative radiotherapy (PORT) for NSCLC

Study Number

of patients

Stage XRT dose (Gy)

Survival with XRT

Survival without XRT

LRF with XRT

LRF without XRT Belgium

(van Houtte et al. 1980)

202 I--III 60 24%^a 43%^a 2% 11%

LCSG773

(Weisenburger et al. 1986)

230 II,III 50 40% 40% 3%^a 21%^a

CAMS (Feng et al. 2000) 317 II,III 60 43% 41% 13%^a 33%^a

Lille (Laﬁ tte et al. 1996) 163 I 45--60 35% 52% 15% 17%

MRC LU11

(Stephens et al. 1996)

308 II,III 40 25% 25% 18%^a 29%^a

Austria

(Mayer et al. 1997)

155 I--III 50--56 30% 20% 6% 24%

GETCB

(Dautzenberg et al. 1999)

720 I--III 60 30%^a 43%^a 28% 34%

Slovenia

(Debevec et al. 1996)

74 III 30 32% 20% ^b ^b

Italy

(Trodella et al. 2002)

104 I 50 67%â 58%â 2%â 22%â

a Statistically signiﬁ cant difference (p<0.05) ^b Data not available.

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Several other randomized controlled trials (RCTs) demonstrated an improvement in local control but never more than a trend towards improved survival.

The MRC Lung Cancer Working Party trial found an increase in the time to “deﬁ nite” local recurrence (Stephens et al. 1996). Mayer et al. (1997) found that PORT offered a signiﬁ cant improvement in local control and almost twice the recurrence-free survival (p=0.07 for the latter).

The outcome of one RCT stands in stark contrast to those of the others. The trial by Dautzenberg et al.

(1999) not only failed to show any signiﬁ cant beneﬁ ts to PORT; it showed a dramatically inferior 5-year survival rate in the PORT arm (30% vs. 43%, p=0.002).

This study was not limited to patients with node- positive disease; approximately 30% of the patients in the trial had pN0 disease, and the study did not stratify by stage or nodal status. In addition, many of the deaths in the trial likely resulted from suboptimal radiation technique. Patients were treated to 60 Gy, a high dose usually reserved for gross disease, in daily fractions as large at 2.5 Gy. Given the association between fraction size and toxicity to the heart and lungs (Stewart et al. 1995; Movsas 1995), it is not surprising that “non-cancer-related deaths” in this study were noted to occur at a higher rate in those patients treated with >2 Gy per fraction (26% vs.

16%–18%) (Dautzenberg et al. 1999). Furthermore, the authors note that “an additional dose of 20 Gy was delivered by lateral and/or oblique ﬁ elds.” As noted later in this chapter, lateral ﬁ elds may increase serious pulmonary complications. The results of the Dautzenberg trial can probably not be generalized to modern radiotherapy for stage II and III patients.

3.1.2.4

The PORT Meta-analysis

In response to the lack of statistical power of the existing RCTs, the PORT Meta-analysis Trialists Group attempted to bring together all the existing randomized data in an effort to settle the question of PORT in NSCLC (PORT 1998). It should be noted that the Dautzenberg trial (described in the meta-analysis as being two trials) weighs heavily in the meta-analysis, accounting for 728 of the 2128 patients considered.

The meta-analysis found that PORT had a signiﬁ cant adverse effect on survival, with a hazard ratio of 1.21 (95% CI 1.08–1.34) (PORT 1998). This result trans- lates into a 7% decrease in absolute survival, from 55% to 48%. Subgroup analysis reveals that the sur-

vival disadvantage is concentrated in the N0 and N1 patients. Among patients with pathologic N2 disease, a statistically insigniﬁ cant trend toward better survival with PORT was observed (hazard ratio=0.96).

There are a number of problems with the design and interpretation of the PORT meta-analysis;

these shortcomings have been detailed elsewhere (Machtay et al. 1999). Brieﬂ y, these problems include the following:

– Inappropriate lumping (including patients with pathologic stage I disease along with node-positive disease in the same meta-analysis).

– Unexplained exclusion of at least one randomized trial that appeared to demonstrate a trend toward improved outcome with PORT (Mayer et al. 1997).

– Limited information to conﬁ rm that patients in the randomized trials included in the meta-analysis met the usual medical criteria to safely receive PORT.

– Limited information regarding the surgical techniques used in the randomized trials included in the meta-analysis; as shown in Table 3.1.2.2, an unusually large number of patients underwent pneumonectomy.

– Fifth and most importantly, the studies in the meta-analysis probably utilized radiotherapy techniques that would today be considered out- dated and unsafe. These include the use of lateral radiation ﬁ elds, Cobalt-60 source radiotherapy, large daily radiation fraction size, and high total PORT doses.

All of these biases conspire to efface any possible survival beneﬁ t of PORT for NSCLC in the meta-analysis. Even apart from the question of bias, a meta- analysis should not be regarded as the ﬁ nal word on a subject. The history of meta-analysis makes clear the fallibility of the process (LeLorier et al. 1997).

The meta-analysis of PORT for breast cancer found that postmastectomy irradiation for breast cancer worsened survival (Cuzick et al. 1987). Subsequent well-designed randomized trials have subsequently demonstrated a survival beneﬁ t when patients are appropriately selected and treated with modern techniques (Ragaz et al. 1997; Overgaard et al. 1997).

The postmastectomy example is not unique. In the treatment of lung cancer with chemotherapy, a summary of studies using suboptimal chemotherapy (i.e.

alkylator agents alone) showed a decremental effect on survival, while treatment with modern (cisplatin- based) chemotherapy shows an advantage (Stewart 1995).

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Finally, even though no randomized study shows a clear survival advantage to PORT for patients with stage II and III disease, PORT may provide ben- eﬁ ts that can not be measured in a meta-analysis.

Speciﬁ cally, the prevention of local-regional relapse may be an important component of quality of life for patients with cancer. Mediastinal relapse can cause airway obstruction, hemoptysis, dysphagia, and/or chest pain and is rarely controllable.

3.1.2.5

Subacute/Late Toxicity of PORT

While the acute toxicity of PORT is relatively modest (Keller et al. 2000), the potential for subacute and/or late toxicity (cardiopulmonary) appears to be signiﬁ - cant. Despite all of the problems with the PORT meta- analysis described above, the data strongly suggest an unrecognized, important potential for severe toxicity with PORT. In the meta-analysis, 19% of 548 coded deaths in the PORT group were due to causes other than lung cancer (PORT 1998). In contrast, in the non- PORT group, only 11% of 522 coded deaths were due to causes other than lung cancer. The Dautzenberg trial reported that at 5 years, the rate of death from intercurrent disease (DID) was 32% for PORT vs. 8% (surgery alone control group) (Dautzenberg et al. 1999). It is plausible that some cases of serious radiation pneumonopathy were mistaken for bronchopneumonia or other forms of cardiorespiratory failure.

Second, careful examination of the survival curves in the meta-analysis reveals that the survival curves begin to separate at 3 months following treatment and continue to widen until the 1-year mark, after which they remain parallel. Death between 3 and 12 months following radiotherapy is consistent with radiation pneumonopathy (see Fig. 3.1.2.1) and perhaps the development of radiation cardiac injury.

Table 3.1.2.2. Type of surgery used in selected randomized trials of postoperative radiotherapy (PORT) for NSCLC Study Surgical procedure (%) Radical hilar/mediastinal lymph node dissection?

(yes/no/unknown) Less than

Pneumonectomy

Belgium

(van Houtte et al. 1980)

60 40 Unknown

LCSG773

(Weisenburger et al. 1986)

45 55 Yes; most cephalad node removed must be negative

Lille (Laﬁ tte et al. 1996) 80 20 Yes

MRC LU11

(Stephens et al. 1996)

48 52 No

GETCB

(Dautzenberg et al. 1999)

58 42 No

Slovenia 58 42 Yes

Austria

(Mayer et al. 1997)

76 24 Yes

Italy[5] 91 9 Yes

Fig. 3.1.2.1. This patient was treated to 60 Gy postoperatively after lobectomy revealed pathologic stage T3N1M0 disease with a positive resection margin. Several months after com- pleting PORT, he began having progressive respiratory in- sufﬁ ciency, culminating in severe respiratory distress. The thoracic CT scan shown here demonstrates severe radiation pneumonitis and evolving ﬁ brosis of the ipsilateral lung and a contralateral pneumothorax. The patient was treated with corticosteroids, antibiotics, and contralateral chest tube place- ment and recovered satisfactorily after hospitalization

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These data strongly suggest that potential ben- eﬁ ts of PORT (reduction of local recurrence and improved lung cancer-speciﬁ c survival) have been offset by life-threatening toxicity, particularly in stage I and II NSCLC. This pattern was also observed in early randomized studies of postmastectomy chest irradiation for breast cancer (Cuzick et al. 1987; Marks and Prosnitz 2000).

If severe toxicities from postoperative radiotherapy can be prevented, it is possible that the oncologic beneﬁ ts of PORT may be better realized. Non-randomized data suggest that with the use of modern radiotherapy techniques, the risk of intercurrent deaths after PORT is comparable to that seen in an age-matched population (Machtay et al. 2001).

3.1.2.6

Proper Radiotherapy Techniques for PORT 3.1.2.6.1

Fields

The currently accepted fi eld arrangement delivers approximately 40 Gy in opposed AP/PA fi elds and then spares the spinal cord by delivering the remaining dose with opposed oblique fi elds offset 20º–35º from mid- line (see Fig. 3.1.2.2). Linear accelerator based therapy is utilized; retrospective data suggest that the use of Co- 60 source radiotherapy is associated with a higher rate of death from non-cancer cause (Philips et al. 1993), perhaps related to increased scatter to normal lung

Fig. 3.1.2.2a–c. These images depict radiotherapy dosimetry for typical postoperative treatment to 54 Gy. a Treatment with 40 Gy via AP-PA tech- nique, followed by an opposed-oblique boost to 54 Gy, all treatment administered via 6-MV pho- tons from a linear accelerator. b The identical treatment plan administered via Co-60 photons;

note the increased radiation dose scatter into uninvolved lung parenchyma, despite less satisfac- tory clinical target volume coverage as determined by dose volume histogram analysis. c The use of a lateral radiotherapy beam as part of the boost ﬁ eld is shown; although target volume coverage is adequate, excessive uninvolved lung parenchyma is exposed

a

b

c

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tissue. Field arrangements should not include lateral ﬁ elds. Lateral ﬁ elds dramatically increase the volume of irradiated lung tissue, which is generally considered the pivotal factor in the prediction of radiation pneumonopathy (Graham et al. 1999; Marks et al. 1997).

Graham et al. (1999) strongly recommend that the V20 (the volume of lung irradiated to 20 Gy or above) be kept

<25% to maintain a low risk of radiation pneumonopathy and warns that when the V20 exceeds 35%, the risk of life-threatening pneumonopathy rises exponentially.

These criteria are likely to be particularly relevant to the postoperative patient, who already has impaired pulmonary reserve due to the rigors of surgery, missing lung tissue, and probable underlying chronic lung disease.

In order to minimize the volume of lung irradiated, the clinical target volume (CTV) for PORT should not include large portions of the lung parenchyma but in- stead focus on the bronchial stump, the ipsilateral hi- lum, and mediastinum. These correspond to the sites most at risk for local recurrence, particularly the most highly symptomatic and unsalvageable types of local recurrence.

More controversial is the question of whether or not to irradiate the ipsilateral supraclavicular fossa.

Supraclavicular nodal involvement is not uncom- mon when rigorously assessed by imaging (Fultz et al. 2002) and is strongly related to the presence of positive mediastinal nodes. An autopsy study of 203 patients with NSCLC who died within 1 month after deﬁ nitive surgery showed that 5% harbored occult supraclavicular disease (Matthews et al. 1973).

However, most studies have been unable to conclude a beneﬁ t to elective supraclavicular irradiation. In a retrospective study of over 1000 patients with inoperable NSCLC treated with radiotherapy on RTOG protocols, Emami et al. (2003) showed that the failure to adequately irradiate the supraclavicular fossa rarely resulted in clinical supraclavicular recurrence (2%). In the Chinese randomized trial of PORT, the rate of supraclavicular nodal failure was the same in the irradiated versus unirradiated groups (13.4% vs.

11.7%) (Feng et al. 2000). In that study, supraclavicular irradiation was used in the PORT arm only if the very high (level 1--2) mediastinal nodes were positive. The decision on whether or not to include the supraclavicular fossa should be highly individualized.

3.1.2.6.2

Radiotherapy Dose

Because many patients would not suffer local recurrence even if no radiotherapy were given, a goal in

PORT is to minimize cardiopulmonary complications. Higher doses to the heart have been clearly associated with cardiac mortality amongst Hodgkin’s disease patients (Hancock et al. 1993; Zinzani et al.

1996). In canine models radiation damage to myocar- dial connective tissue increases signiﬁ cantly above a threshold dose of 62 Gy in 2-Gy fractions and heart failure ensues (McChesney et al. 1992). As noted above, radiation pneumonopathy is closely related to radiotherapy dose-volume relationships (Graham et al. 1999). Table 3.1.2.1 shows that the randomized trials that showed statistically signiﬁ cant detrimental effect of PORT used the highest radiotherapy doses (60 Gy).

A study at the University of Pennsylvania suggested that while overall there was no signiﬁ cantly increased risk of death from intercurrent disease (DID) after PORT (compared with the expected rate for age-matched controls), there was a trend toward more DID in patients treated to higher cumulative radiotherapy doses. The crude risk of death by intercurrent disease was 2% among patients treated to <54 Gy but 17% among those treated to >=54 Gy, which bordered on signiﬁ cance (p=0.06) (Machtay et al. 2001).

In the Penn experience, there was no noticeable relationship between the rate of local-regional control and radiotherapy dose. In another retrospective series, Emami et al. (1987) found a trend toward better local-regional control with 60+ Gy, but the results were not statistically signiﬁ cant (p=0.53).

We currently recommend a dose of approximately 50 Gy in standard fractionation for most patients treated with PORT. The LCSG randomized trial utilized this dose and had excellent local-regional control (Weisenburger et al. 1986). This dose was also used in the recent Intergroup randomized trial and demonstrated a high rate of local-regional control (Keller et al. 2000). Selected patients felt to be at particularly high risk for local-regional recurrence may be considered for additional boost radiotherapy dose if carefully given via highly conformal techniques.

3.1.2.6.3

Time Interval Between Surgery and Radiotherapy

Hypothetically, a longer interval between surgery and radiotherapy is detrimental. The tumor cells would have a greater opportunity to repopulate, and radiation is less effective against a larger mass of tumor cells. Data from sites other than the lung suggest a

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detrimental effect from a long interval; a review of the literature by Huang et al. (2003) found that there was strong evidence of a decrease in local control with long intervals in radiation in breast cancer or head and neck cancer (Huang et al. 2003).

However, the only study to examine the question in NSCLC found that a longer delay (>36 days versus

<36 days) after surgery resulted in a higher probabil- ity of local-regional control and lung cancer-speciﬁ c survival (Wurschmidt et al. 1997). This study was retrospective, and it is possible that selection bias ac- counted for patients with more negative prognostic factors being referred to start PORT more rapidly.

3.1.2.6.4

Follow-Up/Supportive Care

Close follow-up is probably important after PORT for NSCLC. Prompt recognition and treatment of radiation pneumonopathy could reduce morbidity and mortality. A patient who presents with pulmonary symptoms greater than grade 1 after recent thoracic irradiation should undergo an intense diagnostic workup to identify pulmonary infection, pulmonary embolism, or recurrent cancer. This may include high-resolution CT scan, bronchoscopy, and/or PET scan. If grade 2 or greater radiation pneumonitis is di- agnosed, corticosteroids should be started promptly and the patient referred to a pulmonologist for help in management (Movsas et al. 1995; Machtay 2004). Particular attention and prophylactic medica- tions should be used to prevent steroid-related complications including infection, diabetes, gastritis, and osteoporosis.

3.1.2.7

PORT – Special Cases 3.1.2.7.1

Sublobar Resection

Some patients are medically unable to undergo a lobectomy and thus undergo sublobar resection such as wedge resection or segmentectomy. Attempts at these lesser resections have been associated with high rates of local recurrence, as documented in a randomized trial by the LCSG (Ginsberg and Rubinstein 1995).

A prospective non-randomized trial by the CALGB investigated the use of PORT (Bogart et al. 2000).

While the postoperative radiotherapy treatment was

feasible, it was felt that the amount of lung irradiated in order to cover the operative bed (staple line and surrounding tissue) was excessive for this fragile patient population and further prospective studies of this design are not planned (Bogart et al. 2000).

Several studies have attempted intraoperative brachytherapy to improve local control following sublobar resection. Lee et al. (2003) implanted io- dine-125 seeds along the resection margin after limited resection in 33 stage I patients who were not candidates for lobectomy or pneumonectomy. After a median follow-up of 51 months, the authors observed a 5-year survival of 67% for T1N0 patients and 39%

for T2N0 patients, with two local recurrences in the group. Encouraging results with sublobar resection plus brachytherapy were also reported by Chen et al. (1999), and the American College of Surgeons Oncology Group (ACOSOG) is developing a phase II multicenter randomized trial to rigorously assess this technique.

3.1.2.7.2 Positive Margin

There are very little data analyzing the role of PORT for patients who underwent resection with a positive resection margin(s). While common sense would dictate that PORT should be mandatory after incom- plete resection, results have been inconsistent (Law et al. 1982; Kaiser et al. 1989; Gebitekin et al. 1994).

Techniques similar to that described above would seem appropriate, with boost to as small a radiotherapy ﬁ eld as possible to approximately 59.4 Gy in standard fractionation. A retrospective review of the University of Pennsylvania experience suggested no signiﬁ cant differences in outcomes between patients irradiated for positive versus negative margins (Machtay et al. 1998).

3.1.2.7.3

Chest Wall Invasion

Patients with chest wall invasion but negative nodes (T3N0) are still candidates for aggressive resection, but they do not appear to gain signiﬁ cant beneﬁ t from external beam radiotherapy. A small retrospective study of 35 patients with chest wall invasion found that those receiving radiation had a higher survival than those treated with surgery alone (56% vs. 38%, no p value published) (Patterson et al. 1982). While patients were not randomly assigned to radiation,

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the radiated patients were more likely to have residual disease or mediastinal node involvement. In the Sloan-Kettering series of 69 patients with chest wall invasion from Pancoast tumors, the addition of brachytherapy resulted in a trend towards improved survival following complete resection (35% vs. 54%

at 5 years, p=0.15) (Ginsberg et al. 1994).

3.1.2.8

Postoperative Radiotherapy in the Era of Chemotherapy

Until the 1990s, NSCLC was considered highly chemo- resistant and the role of chemotherapy was primarily for palliation of visceral metastatic disease. However, the role of chemotherapy in combination with radiotherapy for inoperable stage III disease has been unequivocally conﬁ rmed (Marino et al. 1995), and data suggest that preoperative chemo or chemoradiation for resectable stage III disease improves survival over local therapy alone (Rosell et al. 1994).

The data have been more controversial in the postoperative setting. Several trials have investigated postoperative chemoradiation versus PORT alone in NSCLC. These studies, including a meta- analysis (Stewart 1995) and a subsequent large US Intergroup randomized trial (Keller et al. 2000), have shown no signiﬁ cant beneﬁ ts to postoperative combined modality therapy over PORT alone. Subgroup analysis of a randomized European trial comparing pre-PORT multiagent chemotherapy to PORT alone suggested improved disease-free survival among 137 patients with pathologic N2 disease (Dautzenberg et al. 1995).

In 2003, results became available from the largest randomized study ever done comparing adjuvant chemotherapy versus control for resected NSCLC (LeChevalier 2003). This study, the International Adjuvant Lung Trial (IALT) did not specify the use or non-use of PORT but did stratify appropriately for its use in its statistical design. The IALT showed a statistically signiﬁ cant improvement in overall survival with adjuvant chemotherapy, with an absolute beneﬁ t of approximately 4.5% at 5 years. All stages of disease appeared to have similar gains; most patients with pathologic N2 disease received PORT in this study.

Further clinical trials of chemotherapy with PORT are ongoing. The RTOG recently completed a phase II trial combining PORT (50.4 Gy) with concurrent and consolidation carboplatin/paclitaxel for stage II and IIIA resected NSCLC (Graham et al. 2003). The

3-year actuarial survival was 61%, which compares quite favorably with the results from the previous US Intergroup study (Keller et al. 2000) (52%) and the IALT study (LeChevalier 2003) (45%).

As an alternative to delivering therapy after surgery, some centers aggressively try to identify patients with resectable stage IIIA/N2 disease preoperatively and offer them induction therapy. This induction or neoadjuvant therapy may include chemoradiotherapy (Albain et al. 1997, 2003) or chemotherapy alone (Rosell and Felip 2001; Roth et al. 1998). If chemotherapy alone is used preoperatively, the question remains whether or not to utilize postoperative radiotherapy. A retrospective study at M. D. Anderson considered PORT in combination with preoperative chemotherapy and showed that PORT improved lo- cal-regional control (81% vs. 54% at 5 years, p =0.07) (Taylor et al. 2003). However, survival was not improved, and was actually numerically lower in the PORT group, perhaps reﬂ ecting adverse selection bias (patients with a large amount of residual cancer after preoperative chemotherapy/surgery were more likely to be offered PORT).

3.1.2.9

Summary/Future Directions

The outcomes of currently published randomized trials of PORT could probably be improved upon simply by using modern treatment and planning equipment and adhering to the techniques outlined in this chapter. However, there remains a severe lack of high-level medical evidence to demonstrate an improvement in survival by adding PORT to complete surgical resection for NSCLC, particularly for early stage disease.

Available data strongly suggest that PORT is contra- indicated after complete resection of pathologic stage I NSCLC. Outside of the clinical trials settings, the use of PORT should probably be limited to patients with pathologic N2 disease or N1 disease characterized by one or more high risk factors for local recurrence such as the absence of a complete mediastinal lymph node dissection. Additional prospective trials study- ing PORT, perhaps postoperative chemoradiotherapy versus chemotherapy alone for selected patients, are indicated.

Future trials investigating PORT, in combination with systemic therapy, are clearly indicated but must utilize meticulous radiotherapy techniques. Gains in PORT could be obtained by reducing the potential for cardiopulmonary toxicity by strictly minimizing

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the volume of heart and lung irradiated. This might be achieved by using improved radiotherapy planning techniques (e.g. multiﬁ eld 3-D and/or intensity modulated radiation therapy) and/or improvements in radiotherapy delivery (e.g. respiratory gating tech- nology). These technological advances must be combined with better means of predicting which patients harbor the greatest risk of local-regional recurrence, as identiﬁ ed via conventional and/or molecular prognostic markers.

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