5 Radiation Therapy for Recurrent Lung Cancer Branislav Jeremi´c

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5 Radiation Therapy for Recurrent Lung Cancer

Branislav Jeremi ´ c and Michael Bamberg

B. Jeremi´c, MD, PhD

Department of Radiation Oncology, Klinikum rechts der Isar, Munich, Germany

M. Bamberg, MD

Department of Radiation Oncology, University Hospital, Tübingen, Germany

CONTENTS

5.1 Introduction 297

5.2 External Beam Radiation Therapy for Locoregional Post-Surgical Recurrences of Non-Small Cell Lung Cancer 298 5.3 External Beam Radiation Therapy

for Local/Regional Intrathoracic Recurrences After Previous Radiation Therapy 303 5.4 Endobronchial (Endoluminal) Brachytherapy

for Locoregional Recurrent Lung Cancer 304 5.5 Conclusions 305

References 305

5.1 Introduction

The treatment of choice for early stages non-small cell lung cancer (NSCLC) is surgery (Mountain 1986, 1997; Naruke et al. 1988). This treatment modality may also be successfully applied in selected patients with stage IIIA (Mountain 1986, 1997; Naruke et al. 1988). While there is an increasing possibility of detecting early stage tumours with the use of posi- tron emission tomography, there is also an increasing possibility of using induction (neoadjuvant) chemo- therapy and surgery in selected cases of locally ad- vanced NSCLC (Pass et al. 1992; Rossell et al. 1994;

Roth et al. 1994). It is anticipated, therefore, that not only will more patients be undergoing surgery alone or combined with chemotherapy in the future than before, but that these patients will be more likely to have the stage of the disease deﬁ ned during pre- treatment investigation. Also, a number of patients with non-metastatic lung cancer are offered either radiation therapy alone or a combination with che-

motherapy. They also experience disease recurrence in high percentage of cases.

Locoregional recurrence is a well-documented event in the history of lung cancer. As the ﬁ rst site of failure, it was documented in surgical series in as low as 3%–9 %, but also as high as 32% or even 38%

(Holmes et al. 1986; Immerman et al. 1981; Ishida et al. 1990; Kaiser et al. 1989; Ludwig Lung Cancer Study Group 1987; Matthew et al. 1973; Spjut and Mateo 1965; Thomas and Rubinstein 1990). When, however, more intensive follow-up procedures after an initial operation are carried out, this rate may go as high as 52% as in one series (Westeel et al. 2000).

It is, therefore, not surprising that after curative re- section, 5-year survival can be as high as 54%–83%

for stage I squamous-cell carcinoma but as low as 10%–21% for stage IIIA adenocarcinoma (Holmes 1988; McGovern et al. 1988). Also in non-surgical studies, radical radiation therapy alone or combined with chemotherapy achieved only about 15% local control, as assessed by bronchoscopy (Arriagada et al. 1991).

Thus recurrence is still a dominating and bitter event after the treatment of lung cancer, irrespective of histology (non-small cell versus small cell), stage (early versus locally advanced versus metastatic), or initial treatment (surgery, radiation therapy, chemo- therapy or any combination of these). While some failures are reported to appear soon after the initial treatment, some manifest years later. All recurrences can be broadly divided into local (e.g. bronchial stump recurrences only or thoracic wall), regional (e.g. mediastinal lymph node), and distant (brain, liver, bones or contralateral lung). Again, any combi- nation of these may occur in a patient.

Since some recurrences may appear in lung paren-

chyma (ipsilateral or contralateral lung), it is impor-

tant to recognise the distinct features of the second

primary metachronous primary lung cancer as op-

posed to lung parenchyma recurrence occurring after

the initial treatment. A second primary metachronous

lung cancer appears after an initial treatment of the

primary lung cancer and a particular set of criteria is

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considered necessary to differentiate second primary lung cancer from recurrent or metastatic lung can- cer (Martini and Melamed 1975). A tumour was considered a second primary if it: (1) had different histology, or (2) had the same histology as the initial lung cancer but if: (a) the disease-free interval be- tween the occurrence of cancers was at least 2 years, (b) the second cancer originated from a carcinoma in situ, or (c) the second cancer was in a different lobe or lung, but neither cancer was in lymphatics common to both cancers, nor extrapulmonary metastases were found at the time of diagnosis. This entity will not be discussed in this chapter.

As recurrence may appear after any of the treat- ment modalities used in lung cancer (surgery, radia- tion therapy, chemotherapy) or any combination of these, recurrences can also be treated by any of these.

Patients with isolated intrathoracic recurrence have been treated with different approaches, including a more aggressive surgical approach (Gabler and Liebig 1980; Matthew et al. 1973) or endobronchial irradiation (Hilaris et al. 1979). Photodynamic therapy was shown to be ineffective in this patient population, especially those with bronchial stump re- currence. In a series by Lam (1994), as many as 75%

of patients with bronchial stump recurrence re-re- curred after photodynamic therapy, despite achieving an initial response. When several large surgical series are taken into account together (Gabler and Liebig 1980; Dartevelle and Khalif 1985; Watanabe et al. 1992; Voltolini et al. 2000), it can be observed that in more than 6000 patients recurring locally, re-operation with curative intent was managed in 1%–1.7% of patients. Results with re-operation were mostly discouraging such as 23% with 2-year sur- vival (Pairolero et al. 1984). The median survival times (MST) ranged from 7–26 months (Becker et al. 1990; Lesser et al. 1997; Voltolini et al. 2000;

Westeel et al. 2000). More recent studies reported more promising results such as 15.5% 5-year survival obtained, however, in a smaller patient population (n=12) (Voltolini et al. 2000). In early stages of re- current lung carcinoma even higher local control and overall survival rates can be achieved by completion pneumonectomy, with 5-year survival of about 50%

in stage I and 40% in stage II carcinoma (Regnard et al. 1999), although patient cohorts included those with second primary lung cancer. The poor results of some studies clearly warrant newer strategies, which may include more intensive follow-up procedures, as well as alternative treatment approaches.

There are also reports (Curran et al. 1992;

Emami et al. 1997; Green and Kern 1978; Jeremic

et al. 1999b; Kagami et al. 1998; Kono et al. 1998;

Kopelson and Choi 1980; Law et al. 1982; Leung et al. 1995) indicating the effectiveness of radiation therapy when given as a sole treatment. Since these reports covered long periods of time during which great variance in the diagnostic and radiotherapeutic approaches occurred, including a number of differ- ent recurrent tumour locations, these reports, unfor- tunately, suffer from a mixture of potentially different entities frequently treated with a wide range of doses and different fractionation patterns. Radiation ther- apy was sometimes also combined with chemother- apy (Itoh et al. 2002) or brachytherapy. All of these factors contributed to a confusing picture of the use of external beam radiation therapy in this disease, in spite of the fact that some reports clearly indicated the effectiveness of external beam radiation therapy with results showing at least similar effectiveness to those obtained with surgery.

In this chapter, we will focus on the use of radia- tion therapy in the treatment of locoregionally recur- rent lung cancer.

5.2 External Beam Radiation Therapy

for Locoregional Post-Surgical Recurrences of Non-Small Cell Lung Cancer

In contrast to surgery, which has been exclusively used to treat post-surgical recurrences, radiation therapy has been used to treat both those recur- rences occurring after initial surgery and after pre- vious radiation therapy. When used for post-surgical recurrences, the aim of radiation therapy was to treat local/regional recurrences located at various intra- thoracic sites. These were usually divided into chest wall/pleural, parenchymal, bronchial stump, and me- diastinal lymph node recurrences, but could include any combination of these.

It seems that the history of radiation therapy in

treating locoregional post-surgical recurrences of

non-small cell lung cancer starts with the ﬁ rst report

by Green and Kern (1978) on 46 patients with lo-

cal recurrence without documented metastasis. Low

doses were those which ranged from 2500–3999 cGy

and while high doses were those which ranged be-

tween 4000 and 6500 cGy. Subjective improvement

was observed in about 2/3 of patients, improvement

being dose-related. The median survival time was

11 months with a 4-year survival rate of 4%. The me-

dian survival time for patients in the high dose group

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responding to radiation therapy was 19 months, which was in sharp contrast to those radically treated with radiation therapy and having no response (8 months), or those treated with the low dose radiation therapy (4 months). The impact of response to radiation therapy on treatment outcome was also documented by Yano et al. (1994). In their study, high local con- trol rates and higher overall survival were achieved if the tumour responded to radiation treatment (the median survival time, 27 months vs. 6 months for re- sponders and non-responders, respectively).

Also, several other reports indicated effectiveness of radiation therapy alone in treating locoregionally recurrent lung cancer. Kopelson and Choi (1980) reported on 24 patients with a median survival time of 12 months and 5-year survival of 10%. Shaw et al.

(1992) reported on a series of 37 patients, the major- ity of whom were treated with 40 Gy in 10 fractions using the split-course technique. The median sur- vival time was 13.7 months and 5-year survival was 4%. It is likely that somewhat lower local control rates and lower 5-year survival in that study resulted from the inclusion of patients with hilar, mediastinal and even supraclavicular lymph node recurrence (57%

of the patients had stage IIIA and 22% had stage IIIB disease at the time of recurrence). In the study of Curran et al. (1992), who reported on 37 patients treated with external beam RT to a median dose of 56 Gy, the median survival time was 12 months and 2-year survival was 22%. Also, Leung et al. (1995) reported on 45 patients who achieved the median survival time of 10 months and 2-year survival of 27%. The radiation dose played an important role:

there was a signiﬁ cant difference between patients treated curatively (n=17) and those treated with palliative intent (n=28) (median survival time: 15.6 vs 4.0 months, respectively; p=0.02). Patients whose recurrence was conﬁ ned to the bronchial stump had a better median survival time than those with other sites of relapse (15 months vs. 9 months), and pa- tients treated with radical intent (total dose >50 Gy) did well with an estimated 2-year survival of 41%.

A similar effect of higher radiation disease was also observed in the study of Emami et al. (1997) who re- ported on 52 patients treated with radiation therapy doses that ranged from 16 Gy to 75 Gy with 15 (29%) patients receiving >60 Gy. The 5-year survival was 4%, with the median survival time of 8.5 months, when all patients were considered, with a signiﬁ - cantly better response obtained with increased dose of radiation therapy (p=0.02). More recently, Kagami et al. (1998) reported on 32 patients treated within a hypofractionated schedule of a daily dose of

2.5 Gy, four times per week with total radiation ther- apy doses that ranged from 47.5 Gy to 65 Gy. There were 25 patients who received >60 Gy. The median survival time was 14 months, and 5-year survival was 12.5%. More recently, Jeremic et al. (1999b) ob- served a 5-year survival rate of 14% with the median survival time of 18 months in a group of patients harbouring a variety of post-surgical locoregional recurrences of non-small cell lung carcinoma.

Of all locoregional recurrent tumour locations, high-dose radiation therapy proved to be particu- larly effective in patients with bronchial stump re- currences. In the study by Law et al. (1982), the investigators reported on their experience with post- surgical bronchial stump recurrence only. A total of 14 patients were irradiated, three by bronchoscopic implantation of radioactive gold grains and 11 by ex- ternal beam radiation therapy. Three patients were not irradiated (two with extension to tracheal wall and one with extension into the contralateral main bronchus) and they survived for 4, 8, and 10 months, respectively. Of irradiated patients, those conﬁ ned to stump alone reported 5-year local control of 100%, overall survival of 50%, and cause-speciﬁ c survival of 83%. In contrast, in cases of more extensive tumours (n=8) survival ranged from 11 to 46 months.

Curran et al. (1992) treated a total of 37 patients with post-surgical recurrences with external beam ra- diation therapy. There were 25 nodal recurrences, four in the chest wall/pleura, while eight patients had iso- lated bronchial stump recurrence. The treatment ﬁ eld encompassed all known disease, without chemother- apy or radiation sensitisers. When analysed according to the site of recurrence, patients with bronchial stump recurrence did better than those with either nodal or chest wall recurrences (median survival time: 36 vs 9 vs 7 months, respectively; 2-year survival: 50% vs 18%

vs 0%, respectively). Of the eight patients with bron- chial stump recurrence, four experienced no further evidence of lung cancer. In contrast, no patient with chest wall recurrence survived 2 years. In patients with bronchial stump recurrences locoregional recur- rence was found in 75%, while distant metastasis was found in the remaining 25%.

In the study of Leung et al. (1995), for ten pa-

tients with bronchial stump recurrences the me-

dian survival time was only 15 months and 3-year

survival was 20%. This was not signiﬁ cantly differ-

ent from the results obtained in patients with recur-

rences elsewhere (median survival time: 9 months),

which the authors attributed to the fact that 8 (80%)

of the 10 patients with local recurrence conﬁ ned to

the bronchial stump were treated with radical intent

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compared with 9 (26%) of the 34 patients with local recurrence elsewhere (p=0.007).

In the study of Kagami et al. (1998) the treatment ﬁ elds covered the clinical gross tumour with adequate margins. Ten patients had bronchial stump recurrence alone, 14 bronchial stump with mediastinal and/or supraclavicular lymph node recurrence, while eight patients had nodal recurrence only. When bronchial stump recurrences only were considered separately, the median survival time was 15 months and 3- and 5-year survival were both 30%. This was signiﬁ cantly better than results achieved in those with combined stump and node recurrences (median survival time:

8 months), with patients with node recurrence only having a prognosis similar to that of stump recur- rences only (median survival time: 14 months)(Cox- Mantel test, p<0.05).

Kono et al. (1998) reported on 46 patients with post-surgical intrathoracic recurrences which in- cluded 18 cases of bronchial stump recurrences. Of the latter, ﬁ ve patients had bronchial stump recur- rence only, while 13 patients had combined bronchial stump and mediastinal lymph node recurrences. The delivered dose ranged from 45 to 80 Gy and 19 pa- tients also underwent chemotherapy. All patients with bronchial stump recurrence received doses of

>60 Gy. For fi ve patients with bronchial stump recur- rence only, radiation therapy fi elds covered the recur- rent mass and mediastinum, including the ipsilateral hilum and subcarinal area as well as the superior me- diastinum, but excluding the supraclavicular fossa and contralateral hilum. Overall 2- and 5-year sur- vival rates were 17% and 11%, respectively, with the median survival time being 10 months for the whole group. For the group with bronchial stump recur- rence alone, median survival time was 20.9 months and 3-year survival was 20%, which was very similar to the results achieved in the stump plus node group of patients (3-year survival: 15.9%). There was no dif- ference between the groups of patients treated with 45–60 Gy and those treated with >60 Gy, probably due to a small patient number treated with high dose external beam radiation therapy. Analysis of pat- terns of failure in fi ve patients with bronchial stump recurrence only revealed that only one patient failed within the radiation therapy fi eld (accompanied by distant failure), another failed only distantly, while two patients died of other causes. One patient was alive and disease-free at the time of the report. No impact of chemotherapy was observed in this study (p=0.5695).

In the study by Jeremic et al. (1999b) patients with this location had the median survival time of

38 months, and 5-year survival of 33%. Contrary to that, only one out of 27 patients with nodal recurrence remains alive with no evidence of the dis- ease for >5 years post-radiation therapy (p=0.0004).

Patients with combined stump and nodal recur- rences (p=0.0020) and those with chest wall/pleura (p=0.0054) did particularly poorly, all of them dy- ing by the second year post-radiation therapy, con- ﬁ rming previous observations about their incur- ability (Ludwig Lung Cancer Study Group 1987;

McGovern et al. 1988).

When we pooled the data on bronchial stump avail- able in the literature (Jeremic and Bamberg 2002), in 54 documented cases with no other intrathoracic component, the median survival time was estimated to be approximately 28.5 months and the 5-year sur- vival to be about 31.5%, results which clearly estab- lish external beam radiation therapy as a treatment of choice in this patient population (Table 5.1). Two studies, however, showed somewhat inferior results for patients with recurrences located at bronchial stump only. In the study by Leung et al. (1995), the median survival time of 15 months is likely to be the effect of the fact that two out of ten such patients were treated with 30 Gy in 10 daily fractions, with an accompanied fi nding that in the whole cohort of patients in that study, radically treated patients achieved signifi cantly better survival than those treated palliatively (p=0.02). Similarly, in the study of Kagami et al. (1998), besides a wide range of doses used (47.5–65 Gy), a total of seven out of 32 patients received less than 60 Gy. This was an important fi nd- ing in the study which observed signifi cantly better response on increasing the radiation therapy dose.

Also in another study (Kono et al. 1998), this may have well been the reason for overall poorer survival for the whole group of patients with locoregional re- currences (1997) where doses of <50 Gy were used in one-third of patients. Unfortunately, it is very difﬁ cult to draw ﬁ rm conclusions about the effect of dose be- cause in some studies (Jeremic et al. 1999b; Kagami et al. 1998; Leung et al. 1995) lower doses of radiation therapy have been used because of tumour volume or poor performance status, both of which might well determine the outcome.

Further evidence of the effectiveness of external

beam radiation therapy in this patient population

relates to a small (n=7) subset of “early” (i.e. stage

I: /T2N0) bronchial stump recurrences in the study

of Jeremic et al. (1999b) which achieved excellent

survival (5-year: 57%) with high-dose external beam

radiation therapy (>60 Gy). Indeed, in a very small

and highly selected patient population, these results

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are approaching those obtainable with surgery alone in newly diagnosed non-small cell lung cancer of the same stage (Mountain 1986; Naruke et al. 1988).

An interesting and still unexplained fact is that their survival seems much better than that of patients with newly diagnosed non-small cell lung cancer of a sim- ilar stage when treated with high-dose standard or hyperfractionated radiation therapy (Ono et al. 1991;

Morita et al. 1997; Jeremic et al. 1997, 1999a; Sibley et al. 1998; Hayakawa et al. 1999).

The ﬁ ndings of the study by Law et al. (1982) who also provided the data on such patients having a “more extensive” bronchial or tracheal component of the disease further support the effectiveness of external beam radiation therapy in bronchial stump recurrence. These patients achieved the median sur- vival time of 19 months and 1- and 3-year survival rates of 75% and 12.5%, respectively, showing that more extensive, but still localised (no nodes present) disease may also beneﬁ t from radiation therapy. On the other hand, three patients with “more extensive”

bronchial stump recurrence not treated with exter-

nal beam radiation therapy survived for only 4, 8, and 10 months, respectively. When stump recurrence was accompanied with other sites, such as nodes, inferior survival was clearly documented (Curran et al. 1992;

Jeremic et al. 1999b; Kagami et al. 1998; Kono et al.

1998). Taken together, these data indicate high efﬁ - cacy of external beam radiation therapy which seems to be limited to a very selected population of patients with small recurrence, and no accompanying lesions in the thorax and other extrathoracic sites.

There seems to be a dose-response effect in bron- chial stump only recurrences as well as probably in the whole group of patients with locoregional post- surgical recurrences. While some did not enable such evaluation (Curran et al. 1992; Kopelson and Choi 1980), the majority of studies unequivocally showed that higher doses enable better response (Kagami et al. 1998; Law et al. 1982; Leung et al.

1995) and better local control (Jeremic et al. 1999b), leading to better survival (Jeremic et al. 1999b;

Leung et al. 1995). However, the “optimal” dose level for bronchial stump recurrence remains imprecisely

Table 5.1. Outcome of patients with bronchial stump recurrence treated with external beam radiation therapy

Author Location n RT

Total dose (cGy)/n of fx

MST (months)

Survival (%)

1-year 2-year 3-year 4-year 5-year

Law et al.

(1982)^a

Stump only Stump/extension^b

6 8^c

5000–6100/25–35 5000–6100/25–35

>60 19

83 75

83 37.5

83 12.5

83 0

50 0

Curran et al.

(1992)

Stump only 8 5600 Gy^d/25–31 36 50

Leung et al.

(1995)

Stump only 10 3000–6000^e 15 60 40 20 10 10

Kagami et al.

(1998)

Stump only Stump/mediastinal nodes

10 14

4750–6500/19–24 4750–6500/19–24

14 8

80 36

30 21

30 7

30 0

Kono et al.

(1998)^f

Stump only Stump/mediastinal nodes

5 13

>6000 4500–8000

21 5.5

60 32

40 16

20 16

Jeremic et al.

(1999b)^g

Stump only Stump/lymph- nodes

15 5

5500–6000/26–30 5500–6000/26–30

38 16

93 80

73 0

60 0

33 0

Pooled data Stump only 54 28.5 81.5% 55% 40% 30%^h 31.5%^h

RT, radiation therapy; MST, median survival time; fx, fractions.

a Includes three patients not irradiated and three patients who received bronchoscopic implantation of radioactive gold grains.

b Extensions into main bronchus, lateral tracheal wall or contralateral principal bronchus.

c Three additional patients not irradiated.

d Median delivered dose.

e Two patients treated with 30 Gy in 10 daily fractions.

f All patients with stump recurrences treated with >60 Gy.

g Data for patients treated with 55–60 Gy.

h Due to small patient numbers.

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deﬁ ned. Available evidence in non-small cell lung cancer seems to suggest that the dose necessary for tumour control should be at least 60 Gy, and pref- erably 65–70 Gy with standard fractionation. Some of the studies reported herein, however, also used 55 Gy, described as “high” dose level, which may not be high enough for permanent tumour control, regardless of recurrent tumour stage. This particu- lar dose may actually be one of the reasons for the inferiority of the overall results in studies which grouped patients receiving it with those receiving 60 Gy or more. In the study of Jeremic et al.(1999b) patients treated with 55 Gy tended to have worse sur- vival than those treated with 60 Gy (median survival time: 20 vs. 13 months; 5-year survival: 16% vs. 0%;

p=0.31), which would probably have reached signiﬁ - cance if more than only four patients treated with 55 Gy would have been encountered. Additionally, patients with larger tumours are usually adminis- tered palliative therapy, whereas those with less ad- vanced disease are approached with higher doses.

The dose-effect could, therefore, be, at least in part, a consequence of tumour size and not just of the dose itself.

It is interesting to observe a similar incidence of local failure after external beam radiation therapy in the majority of these studies, when all patients with post-surgical recurrences are considered. While Kopelson and Choi (1980) observed local failure in 48%, both Shaw et al. (1992) and Leung et al. (1995) in 64% and Kagami et al. (1998) in 66%, Curran et al. (1992) observed it in 57% patients, an identi- cal fi nding to that of Jeremic et al. (1999b), show- ing that the primary pattern of failure in this patient population remains local. Another consistent fi nding was that there was no difference between the vari- ous locations of locoregional recurrences (e.g. stump vs. other). It is unknown which (if any) particular biological property leads bronchial stump and other post-surgical locoregional recurrent tumours to re- cur locoregionally. This fi nding remains to be investi- gated in future studies because, together with the re- sults obtained with external beam radiation therapy to doses >60 Gy (especially in stump recurrences), it may indicate a possibility for dose escalation which should nowadays be easier to achieve by using three- dimensional treatment planning and conformal RT.

To further extend this, some (Yano et al. 1994) noted that the subsequent appearance of metastatic disease did not affect the survival time after local recurrence, implying the crucial importance of locoregional spread of the disease and its control, even if tempo- rary.

Another issue not well deﬁ ned is the “optimal”

treatment fi eld. Owing to the long time periods, it frequently varied not just between institutions, but also intra-institutionally, ranging from local fi elds with wide margins to prophylactic inclusion of nodal areas thought to be at risk. Due to the lack of knowl- edge of precise biological behaviour of these recur- rent tumours and treatment inconsistencies, suggest- ing one approach or another regarding the treatment fi elds remains purely speculative. However, the “lo- cal” nature of these recurrences, both post-surgery and post-radiation therapy, could favour the use of more “localized” radiation therapy fi elds, the precise defi nition of which remains to be investigated in the future.

A number of potential factors infl uencing sur- vival were examined. Unfortunately, the results are confl icting and multivariate analysis which could have helped to indicate if any of these factors may be considered are lacking. Some of these factors such as the time from initial surgery to documented recur- rence or histology may indicate different biological behaviour of these tumours, while others such as age, performance status, weight loss, stage or presenting symptoms may indicate that there is a need for a dif- ferent approach or modifi cation of the intent of ad- ministered radiation therapy.

While in the vast majority of studies chemotherapy was not used (Curran et al. 1992; Emami et al. 1997;

Jeremic et al. 1999b; Kagami et al. 1998; Kopelson and Choi 1980; Law et al. 1982; Leung et al. 1995), in some it was given (Green and Kern 1978; Kono et al.

1998; Yano et al. 1994) and in none was it shown that it contributes to the overall effect of radiation therapy alone. Its role, at present, remains outside the major focus of interests, except perhaps if given as a radio- enhancing agent (e.g. low-dose, protracted adminis- tration during the radiation therapy course).

Curative, high-dose (>60 Gy) radiation therapy can be recommended as an effective treatment in patients with isolated locoregional recurrent non- small cell lung cancer, particularly if located at the bronchial stump after curative resection. In the lat- ter cases, it can produce the median survival time of approximately 30 months and 5-year survival of approximately 30%. However, further studies with high-dose external beam radiation therapy which may help clearly deﬁ ne a subset of patients most likely to beneﬁ t from this approach, similar to newly diagnosed non-small cell lung cancer, are warranted.

It is necessary to distinguish between these as well

as to address numerous questions in both patients

with bronchial stump and other post-surgical recur-

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rences after complete resection in non-small cell lung cancer. Then, patients not suitable for a curative ap- proach, mostly those with other than stump or stump plus other intrathoracic recurrence may appropri- ately be treated with a palliative approach. Although prospective studies will be difﬁ cult to perform given the small number of eligible cases, they are urgently needed.

5.3 External Beam Radiation Therapy

for Local/Regional Intrathoracic Recurrences After Previous Radiation Therapy

External beam radiation therapy was also used to treat local/regional intrathoracic recurrences after previous radiation therapy for lung cancer, mostly non-small cell histology. Feasibility and efﬁ cacy of re-irradiation was clearly documented in sev- eral reports on treatment of recurrent lung can- cer (Green and Melbye 1982; Jackson and Ball 1987; Montebello et al. 1993; Gressen et al. 2000;

Okamoto et al. 2002). These studies were retrospec- tive in nature with inherent bias including patients with post-surgical relapses, postoperatively irradi- ated patients, those with metastasis and those with second primary lung cancer. Doses of the initial course of radiation therapy ranged from 25 Gy to 80 Gy, while those administered at the time of recur- rence ranged from 6 Gy to 70 Gy. Therefore, cumula- tive doses ranged from 43 Gy to 150 Gy. Few patients underwent even a third course of radiation therapy (second re-irradiation). Contrary to radiation ther- apy treatment portals used during the initial course of radiation therapy, which usually included more or less uninvolved (prophylactic) nodal regions, those used at the time of re-irradiation were obviously limited, in general only including visible recurrence with a safety margin of 1–2 cm (Green and Melbye 1982; Jackson and Ball 1987; Montebello et al.

1993; Gressen et al. 2000; Okamoto et al. 2003). Fear of excessive toxicity, primarily that which may have occurred in lung and spinal cord, clearly governed the choice of both total dose and treatment ﬁ eld used during the re-irradiation. Symptom relief was the main goal of re-irradiation. In a comprehensive review from the year 2000 (Gressen et al. 2000), clinical data from original articles were summarised, indicating a control of hemoptysis in 83%, cough in 65%, dyspnea in 60% and pain in 64% of cases. Re- irradiation seemed to be less hazardous than antici-

pated with a mere 5% complication rate (Green and Melbye 1982; Jackson and Ball 1987; Montebello et al. 1993; Gressen et al. 2000; Okamoto et al. 2003).

The most frequent event was radiation pneumonitis appearing in 3% of cases, with radiation myelopathy and rib fracture being a rare event. Although a higher incidence of radiation pneumonitis was noted in the recent study (Okamoto et al. 2002), described as grade 2 (moderate) and occurring after cumulative RT doses of 12–150 Gy, in that study (Okamoto et al. 2002), a somewhat different policy was instituted resulting not only in symptomatic, but also asymp- tomatic patients being re-irradiated. This has given the authors an opportunity to use higher radiation therapy doses. Patients received a median radiation therapy dose of 45 Gy. While symptomatic response in earlier studies ranged from 48% to 72% with an av- erage cumulative dose of 30 Gy (Green and Melbye 1982; Jackson and Ball 1987; Montebello et al.

1993; Gressen et al. 2000), in that study (Okamoto et al. 2002), palliation was achieved in 75%. Again, this may indicate that higher doses may lead to a higher palliation rate at no cost of increased high- grade (>3) radiation pneumonitis. Indeed, whereas earlier reports achieved the median survival time of approximately 5 months (Green and Melbye 1982; Jackson and Ball 1987; Gressen et al. 2000), this study (Okamoto et al. 2002), reported on the median survival time of 8 months and a 2-year sur- vival of 27%, being as high as 15 months and 51%, respectively, for patients treated with curative intent and higher radiation therapy doses. Of additional importance was the fact that no difference in the treatment outcome between patients <70 years and those >70 years was observed (Gressen et al. 2000), indicating greater applicability of external beam ra- diation therapy in this disease, in particular when palliative intention is pursued and when severe late effects become less important. Finally, the most re- cent study of Kramer et al. (2004) conﬁ rmed this observation, using 2 fractions of 8 Gy given with a 1-week split, a practical and comfortable regimen for both patients and hospitals. The median sur- vival time was 5.6 months and 71% of patients had partial or complete relief of one or more of their symptoms. Relief of dyspnea, hemoptysis, and cough was observed in 35%, 100% and 67%, respectively.

The Karnofsky performance status score improved in 45% patients. The overall median duration of symptom relief was 4 months.

A recent study by Wu et al. (2003) was the ﬁ rst ever

to address the issue of re-irradiation of locoregion-

ally recurrent lung cancer after previous external

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beam radiation therapy through a prospective phase I–II study. Of a total of 23 patients in that study (age range, 43–79 years; median age, 68 years), there were nine patients with squamous cell carcinoma, seven with adenocarcinoma and seven patients with small- cell carcinoma. Initial tumour staging included stage II in seven and stage III in 16 patients. The interval between the ﬁ rst course of RT and recurrence var- ied from 6 to 42 months (median, 13 months). While the median dose of the ﬁ rst course of RT was 66 Gy (range, 30–78 Gy), re-irradiation was carried using a 3D-CRT to deliver a median dose of 51 Gy (range, 46–60 Gy), using standard fractionation, to a radio- graphically visible recurrent lesion. After re-irradia- tion, the median survival time was 14 months and the 2-year survival rate was 21%, while 2-year lo- coregional progression-free survival was 42%. Grade 1–2 esophagitis occurred in 9% of patients and grade 1–2 pneumonitis in 225 of patients. No grade >3 toxicity was reported during the follow-up (median 15 months after the end of re-irradiation). A total of 17 (74%) patients had either grade 0 or 1 late toxicity.

Of six (26%) patients with pulmonary ﬁ brosis on CT scan, two patients were observed to be symptomatic (grade 3). This pioneering study on the use of novel and widely available technology, holds promise for further use in this disease, targeting a huge number of patients experiencing a locoregional recurrence regardless of the initial treatment, although longer follow-up (at least for late toxicity) is necessary for deﬁ nitive conclusions.

In cases of small cell lung cancer, radiation therapy was not frequently used to treat locoregional recur- rence. This was especially true in cases of limited disease previously treated with a combined radioche- motherapy approach, because of the fear that it may add only toxicity without clear beneﬁ t for patients.

For extensive disease, radiation therapy at the time of recurrence after initial chemotherapy can also be con- sidered, but this was mostly related to a symptomatic patient. Retrospective studies (Ihde et al. 1979; Ochs et al. 1983; Salazar et al. 1991) used the doses rang- ing 21–60 Gy in patients harbouring recurrences from both limited and extensive disease small cell lung can- cer. Although a response rate observed within the ra- diation therapy ﬁ eld was seen in 52%–77% of patients, the median survival times ranged only between 3 and 4 months, which is also likely to have been the cause of early systemic progression. Nevertheless, the wide range of doses used gave the authors an opportunity to speculate about higher doses (>40 Gy) producing better palliation, an important issue in patients with limited remaining lifetime.

5.4 Endobronchial (Endoluminal) Brachytherapy for Locoregional Recurrent Lung Cancer

Besides external beam radiation therapy, endobron- chial brachytherapy was used to treat recurrent bronchogenic carcinoma, particularly when previ- ous external beam radiation therapy had been given.

Here as well, the vast majority of reports included the mixture of histologies with only a minority of patients having small cell histology. Some reports even included patients with primary lung carcino- mas. First reports more than 20 years ago provided different aspects of endobronchial radiation therapy with different sources such as 137-CS 198-Au, or 192- Ir combined with low-dose external beam radiation therapy to treat recurrent bronchogenic carcinoma (Mendiondo et al. 1983) with satisfactory palliative results. These two decades witnessed studies with en- doluminal brachytherapy using different dose rates in this disease. The vast majority of reports included the use of high dose rate brachytherapy (Seagren et al. 1985; Mehta et al. 1989; Bedwinek et al. 1991;

Sutedja et al. 1992; Gauwitz et al. 1992; Gustafson et al. 1995; Delclos et al. 1996; Hatlevoll et al.

1999; Kelly et al. 2000). In the majority of reports previous external beam radiation therapy was used with median doses mostly ranging between 54 and 58 Gy (Bedwinek et al. 1991; Sutedja et al. 1992;

Gauwitz et al. 1992; Gustafson et al. 1995). Only a few studies reported on the use of a single frac- tion of endobronchial irradiation of either 10 Gy (Seagren et al. 1985; Hatlevoll et al. 1999) or 20–30 Gy (Mehta et al. 1989), the majority of other reports using 2–3 fractions given in weekly inter- vals. The dose per fraction/session ranged from 6 to 15 Gy. Subjective response to treatment was observed in 66%–94%. Objective response measured during bronchoscopy was observed in 72%–100% patients, while radiologic documentation of re-aeration was observed in 64%–88% patients. Duration of response ranged between 4.5 and 6.5 months. Survival was rarely reported, being approximately 25% at 1 year (Bedwinek et al. 1991). The median survival time ranged from 5 to 8 months (Bedwinek et al. 1991;

Gauwitz et al. 1992; Delclos et al. 1996) with two

studies reporting identical ﬁ nding of the median sur-

vival time of 7 months for responders (Sutedja et

al. 1992; Kelly et al. 2000). Although a number of

different treatment-related complications have been

observed, the most feared was fatal bleeding. Whilst

initial reports (Seagren et al. 1985; Bedwinek et

al. 1991; Sutedja et al. 1992) stated an incidence

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of severe pulmonary bleeding of 25%–32%, those reported in the last decade (Gauwitz et al. 1992;

Gustafson et al. 1995; Delclos et al. 1996; Kelly et al. 2000) reported on signifi cantly lower incidence of this complication ranging from 0% to 7%. A num- ber of factors were investigated in relation to their infl uence on the incidence of fatal bleeding. No fi rm conclusion could be drawn due to the varying na- ture of reporting (crude versus actuarial), and due to frequently lacking pre-treatment patient and tu- mour characteristics. Regardless of these shortcom- ings, endobronchial brachytherapy remains one of the cornerstones of successful palliative approaches in patients with symptomatic endobronchial recur- rences of lung cancer.

5.5 Conclusions

Recurrence is a frequent observation during the course of lung cancer, regardless of its initial treat- ment. While the recurrences occurring after chemo- therapy for metastatic disease are instantly incur- able, there is still some hope for patients recurring locoregionally after initial treatment for either early or locally advanced non-small cell lung cancer; small cell lung cancer has only sporadically being investi- gated regarding this issue, mostly in cases of exten- sive disease when radiation therapy had been given to control locoregional recurrences.

It is for this reason that the search for better (ear- lier) recognition and more successful treatment of locoregional recurrence must start as soon as initial treatment has been completed. This means close fol- low-up, which has been shown to be rewarding in di- agnosing early post-treatment recurrences and also in detecting early metachronous second primary lung cancer. When done properly, it results in more early stages of recurrent/metachronous lung can- cer which are more easily locally controlled, a pre- requisite for treatment success. But even before the intensive follow-up starts, mostly occurring during prospective clinical studies, information can be gath- ered to identify patients more likely to experience re- gional intrathoracic recurrence. In such an attempt, Sawyer et al. (1999) used the ﬁ ndings of preopera- tive bronchoscopy, tumour size, grade and histology from 346 patients undergoing complete resection of early clinical stage (I/II) NSCLC to create risk groups for N1/N2/local/regional recurrence. The risk of sub- clinical nodal involvement was >15.6% in the low

risk subgroup, while all other patients had >35% risk.

Increasing risk correlated with increasing size and grade of tumour, accompanied with positive ﬁ ndings of bronchoscopy. Thus, groups with different risk could be identiﬁ ed and different (risk-adapted) fol- low-up strategies implemented. Hopefully, this could result in better (earlier) detection of recurrences (or second metachronous primary lung cancer) in earlier stages, being more suitable for curative intervention.

This must be one of the major goals of future stud- ies, in particular those dealing with the treatment of early stages of non-small cell lung cancer.

Also, novel technologies, such as three-dimen- sional treatment planning and delivery could enable successful dose escalation and provide the neces- sary tools for treating those recurrences which are presumably “more local” (e.g. bronchial stump) and, therefore, need only radiation therapy. It is also not unrealistic to expect that other technological ad- vances in radiation therapy, such as intensity modu- lated radiation therapy or stereotactic fractionated radiation therapy become indispensable tools in treating these patients with more success. In contrast, it became clear that other-than-stump recurrences may require a different approach, including possible administration of chemotherapy concurrently with radiation therapy or chemotherapy preceding con- current radiation therapy and concurrent chemo- therapy, due to poor results obtained with radiation therapy alone.

Finally, as became clear in other tumour entities, the best way to ask interesting questions and get an- swers which may be used in a clinical setting, is to perform prospective clinical studies. This is particu- larly the case for tumour entities which have previ- ously been largely denied an adequate diagnostic and treatment approach, a fate which should no longer fall to locoregionally recurrent lung cancer.

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