4.1 Limited-Disease of Small Cell Lung Cancer Branislav Jeremi´c

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4.1 Limited-Disease of Small Cell Lung Cancer

Branislav Jeremi ´c

B. Jeremi´c, MD, PhD

Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 226, 81675 Munich, Germany

CONTENTS

4.1.1 Introduction 277 4.1.2 Treatment 278 4.1.2.1 Chemotherapy 278 4.1.2.2 Radiation Therapy 280 4.1.3 Conclusions 282

References 283

4.1.1

Introduction

Small cell lung cancer (SCLC) is a highly aggressive carcinoma and represents approximately 20% of all lung cancer cases (Grenlee et al. 2000). It is an entity of lung cancer that is biologically and clini- cally different from non-small cell lung cancer. The World Health Organization classification of 1988 and 1999 and the International Association for the Study of Lung Cancer panel divide SCLC into three subtypes: classic small cell carcinoma (combined oat-cell and intermediate-cell), mixed small cell/

large cell carcinoma (components of small cell and large cell carcinoma), and combined small cell carcinoma (small cell with a component of squamous or adenocarcinoma cells) (Zakowski 2003). The mainstay of the diagnosis is still light microscopy, either cytologic or histologic. The addition of im- munostaining and common molecular and genetic abnormalities implicated in the pathogenesis of SCLC – amplification of c-myc oncogene, allelic loss on the short arm of chromosome 3, deletion and phosphorylation, altered protein expression of retinoblastoma (Rb) gene and frequent mutations in p53, located at chromosome 17p13.1 – have in-

creased our understanding of these lesions, but have not yet replaced the use of routine microscopy (Zakowski 2003).

Cigarette smoking has long been known to be the primary risk factor for small cell lung cancer, accounting for >90% cases (Mulshine et al. 1993;

Ihde et al. 1993). The most frequent clinical signs and symptoms include cough, hemoptysis, dys- pnea, hoarseness, and dysphagia. Contrary to non- small cell lung cancer, the common paraneoplastic syndromes occur frequently in a variety of presen- tations, including the syndrome of inappropriate antidiuretic hormone (SIADH), ectopic Cushing’s syndrome, Lambert-Eaton myasthenic syndrome (LEMS), and rare neurologic syndromes, such as subacute spinal or peripheral neuropathy, cerebel- lar ataxia, limbic encephalopathy and retinal de- generation (Curran 2001).

The Veterans Administration Lung Group pro- posed a two-stage system dividing all small cell lung cancer cases into “limited disease” and “extensive disease” 35 years ago (Green et al. 1969) and the system is still used today. The vast majority of patients (approximately two-thirds) fall into the extensive disease category while limited disease occurs in approximately one-third of all small cell lung cancer cases. Limited-disease small cell lung cancer is defined as disease confined to the hemi- thorax of origin along with the involved regional lymph nodes (hilar and mediastinal), with or without ipsilateral supraclavicular lymph nodes. It can also be considered as a disease which can be in- corporated within a single, tolerable radiotherapy treatment field, and may include patients with contralateral mediastinal or hilar lymph nodes. Almost 15 years ago, the International Association for the Study of Lung Cancer recommended that limited- disease small cell lung cancer include patients with ipsilateral hilar nodes, ipsilateral and contralateral mediastinal and supraclavicular nodes, and ipsilateral pleural effusion (Stahel et al. 1989), which would correspond to stages I–IIIB.

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4.1.2 Treatment

Due to extreme chemosensitivity and a propensity for early spread beyond the thorax, chemotherapy was the mainstay of treatment several decades ago, although chemotherapy alone led to intrathoracic failure in up to 80% of cases, leading to a median survival of 10–14 months (Cohen et al. 1979). Since a number of studies showed that radiation therapy has great potential in decreasing locoregional failures it was increasingly practised in the 1970s and 1980s, but radiation therapy was introduced as a necessary part of the combined modality approach owing to the results of two meta-analyses that appeared a decade ago (Pignon et al. 1992; Warde and Payne 1992).

They both showed a small but signiﬁ cant improvement in 2-year and 3-year survival, averaging 5%–7%

and an improvement in local control rates in 25% of cases with the addition of thoracic radiation therapy.

With the widespread use of the cisplatin/etoposide regimen, and its lower toxicity (lower than that observed with the cyclophosphamide, doxorubicin, vincristine) when combined with thoracic radiation therapy, concurrent thoracic radiation therapy and platinum-based chemotherapy is now considered as the standard treatment in limited-disease small cell lung cancer. Recent meta-analysis (Auperin et al.

1999) conﬁ rmed the necessity for prophylactic cranial irradiation, but its timing, dose and fractionation require further investigation.

There are, however, a number of questions which warrant further studies into this disease such as opti- misation of both chemotherapy (choice of drugs and its schedule/timing/dosing) and thoracic radiation therapy (timing of thoracic radiation therapy and dose/volume/fractionation). Some of these questions will be addressed in the following sections.

4.1.2.1

Chemotherapy

A number of chemotherapeutic agents with response rates of >30% in small cell lung cancer include cisplatin, carboplatin, etoposide, cyclophosphamide, doxorubicin, methotrexate and vincristine (Sandler 2003). Cyclophosphamide/doxorubicin/vincristine regimen was mostly used in earlier studies, while studies carried out in the 1980s frequently employed cisplatin/etoposide, the latter being not only less toxic, but also very active (Einhorn et al. 1988). The results of Einhorn et al. (1988) were subsequently

reconﬁ rmed by Fukuoka et al. (1991) in a trial with alternating cyclophosphamide/doxorubicin/vincristine and cisplatin/etoposide being superior to either cisplatin/etoposide or cyclophosphamide/doxorubicin/vincristine alone (median survival: 16.8 vs. 11.7 vs. 12.4 months). Since it was shown that cisplatin/

etoposide had less cardiac and lung toxicity, compared with cyclophosphamide/doxorubicin/vincristine, it was preferentially used with thoracic radiation therapy, providing 2-year survival rates of >40%

(Turrisi et al. 1999; Takada et al. 2002). While cisplatin/etoposide and thoracic radiation therapy is the mainstay of concurrent treatment today, carboplatin was sometimes used instead of cisplatin (Kosmidis et al. 1994; Jeremic et al. 1997), in combination with etoposide (i.e. carboplatin/etoposide) due to a similar response and survival as with cisplatin/etoposide but with less nephro- and ototoxicity than cisplatin/etoposide (Kosmidis et al. 1994; Jeremic et al. 1997).

Attempts were also made to incorporate other drugs in the treatment plan (Woo et al. 2000; Hanna et al. 2002).

One of the frequently practised approaches in the past was to treat patients for the duration of their life. Of several randomised trials to test this hypoth- esis, frequently including both stages, only one study could demonstrate a survival advantage for limited- disease small cell cancer patients (Maurer et al.

1980), which is in sharp contrast to numerous studies showing either no advantage at all (Woods and Levi 1984; Cullen et al. 1986; Bleehan et al. 1989;

Lebeau et al. 1992; Giaccone et al. 1993; Beith et al.

1996; Sculier et al. 1996) or showing even detrimen- tal effects of continuous chemotherapy (Byrne et al.

1989). Given the lack of survival improvement and increased toxicity in maintained treatment, this approach has no role in the treatment of limited-disease small cell lung cancer patients nowadays. Some studies focused on the question of an optimal number of induction chemotherapy cycles. If the option of a sec- ond line chemotherapy was offered, no survival ben- eﬁ t was seen for eight cycles of cyclophosphamide/

etoposide/vincristine compared to four cycles (Spiro et al. 1989). Indirectly, this was conﬁ rmed in as early as 1996 by results of an Intergroup 0096 study which produced convincing results with only four cycles of cisplatin/etoposide and thoracic radiation therapy (Johnson et al. 1996). It seems, therefore, that the current standard chemotherapy protocol is four (to six) cycles of a platinum-based regimen.

The dismally high recurrence rate was the impe- tus for investigating other approaches like rapid alternation or dose intensiﬁ cation, or testing the intro-

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duction of “third” generation drugs like irinotecan, topotecan and paclitaxel. The mathematical model of Goldie and Coldman (1984) indicated that rapid al- teration of non-cross-resistant chemotherapy should improve survival in SCLC. It was tested (Einhorn et al. 1988) and conﬁ rmed in practice (Fukuoka et al.

1991), to demonstrate an improvement in survival by adding cyclophosphamide/doxorubicin/vincristine and cisplatin/etoposide in a sequential protocol.

Dose intensifi cation was tested in randomised trials including either doxorubicin or alkylating-based chemotherapy in limited-disease small cell lung cancer in the 1970s and 1980s (Cohen et al. 1977; Mehta et al. 1982; Figueredo et al. 1985), or cisplatin-based chemotherapy in the 1990s (Arriagada et al. 1993), including granulocyte colony-stimulating factor support (Ardizzoni et al. 2002). Improved survival was noted in the dose-intensive arm in three studies, with two trials showing signifi cant improvement, but this was accompanied with more severe toxicity, with the result that the dose intensifi cation did not become standard treatment approach. An attempt to rectify the issue of increased dose intensity is made by reducing the interval between cycles of chemotherapy.

Two trials demonstrated an improvement in survival (Steward et al. 1998; Thatcher et al. 2000) but again, however, due to increased toxicity it could not be considered as standard treatment.

Of the third generation drugs, irinotecan was combined with cisplatin and compared to cisplatin/etoposide in a Japan Clinical Oncology Group phase III study in extensive-disease small cell lung cancer only (Noda et al. 2002). A signiﬁ cant survival advantage for the irinotecan/cisplatin arm was observed (the median survival time, 390 versus 287 days; 1-year sur- vival, 58% versus 38%; p=0.002). Overall responses were also signiﬁ cantly higher in the irinotecan/cisplatin arm (83% versus 63%). High-grade diarrhoea was seen only in the irinotecan/cisplatin arm, while high-grade haematological toxicity was seen more frequently in the cisplatin/etoposide arm. Topotecan was initially shown to be effective in relapsed small cell lung cancer patients. This led to its evaluation as maintenance after initial cisplatin/etoposide in chemonaive extensive-disease small cell lung cancer patients compared to no maintenance therapy. With the addition of topotecan, progression-free survival was improved but no impact on survival (8.7 months versus 9.0 months, p=0.71) was observed (Schiller et al. 2001). Although taxanes have also been increasingly used in small cell lung cancer, only paclitaxel was tested in a phase III studies. Two recently pub- lished studies compared cisplatin/etoposide with

cisplatin/etoposide/paclitaxel. Mavroudis et al.

(2001) found no difference in response rates, median and overall survival, but observed more treatment- related deaths in the cisplatin/etoposide/paclitaxel regimen (p=0.001). Niell et al. (2002) also observed no signiﬁ cant difference in the median survival time (10.3 vs. 9.8 months, p=0.33) while toxicity was in- creased in the cisplatin/etoposide/paclitaxel arm (neutropenia: 63% vs. 44%; thrombopenia 21% vs.

11%; grade 5 toxicities: 6.4% vs. 2.7%). Gatzmeier et al. (2000) showed no difference in toxicity between paclitaxel, carboplatin and etoposide versus carboplatin, etoposide and vincristine in limited-disease and extensive-disease small cell lung cancer. Finally, a preliminary analysis of another study (Birch et al. 2000) showed only modest improvements in the overall response rate with a trend toward improvement in survival for paclitaxel, carboplatin and etoposide when compared to carboplatin and etoposide in patients with extensive-disease small cell lung cancer. Data from four phase II trials in small cell lung cancer showed only moderate success with concurrent cisplatin/etoposide/paclitaxel and thoracic radiation therapy (Levitan et al. 2000; Ettinger et al. 2000; Sandler et al. 2000; Bremnes et al. 2001), with complete response rates of 13%–81% and median survival times of about 22 months. Finally, recent analysis of the Southwest Oncology group phase II study 9713 provided another set of data on the use of paclitaxel in 87 patients with limited-disease small cell lung cancer (Edelman et al. 2004). Concurrent cisplatin/etoposide/radiation therapy as part of the combined modality program was followed by three cycles of consolidation paclitaxel/carboplatin. While the response rate was 86%, the median survival time was 17 months and the 2-year survival rate was 33%, while the progression-free survival at 2 years was only 21%. This prompted authors to conclude that paclitaxel is inactive against small cell lung cancer and suggested it’s further investigation be abandoned.

These results conﬁ rmed previously disappointing results of the Eastern Cooperative Oncology Group in a similar study (Sandler et al. 2000). Contrary to these results, the European Organization for research and treatment of Cancer (Reck et al. 2003) found an advantage in the paclitaxel-containing arm in patients with small cell lung cancer, including limited- disease small cell lung cancer patients who achieved the median survival time of 17.6 months in that study.

It must, however, be clearly stated that this result is quite similar to that of the Southwest Oncology group study cited above, as well as those achieved during the Intergroup study (Turrisi et al. 1999), and somewhat

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lower than achieved in other prospective randomised studies which used only a cisplatin/etoposide combination (Jeremic et al. 1997; Takada et al. 2002).

To summarise the preceding part on chemotherapy in limited-disease small cell lung cancer, there is no ﬁ rm basis to recommend either dose intensiﬁ cation or the integration of new drugs into actual regimens, due to the risk of severe toxicity and the lack of clearly demonstrated improvement in overall survival, and particularly due to a lack of data on chemotherapy combined with thoracic radiation therapy. It has already become policy, however, in the testing of new drugs and combinations in this disease and the long-term data from the completed studies, as well as those still underway, will help identify those drugs/

regimens which may be useful in further clinical testing for cisplatin/etoposide and thoracic radiation therapy to treat this disease.

4.1.2.2

Radiation Therapy

Thoracic radiation therapy issues have mainly focused on timing, dose and fractionation and treatment volumes. In relation to timing, a combination of thoracic radiation therapy and chemotherapy can be deﬁ ned as either concurrent, sequential or alternating. Regarding concurrent thoracic radiation therapy and chemotherapy, earlier studies used non-platinum regimens, or mixed regimens with cisplatin/etoposide, while newer ones used exclusively platinum-based regimens. Some studies (Perry et al. 1987; Schultz et al. 1988; Work et al. 1997) suggested that thoracic radiation therapy delayed until the fourth cycle of chemotherapy (Perry et al. 1987) or until day 120 (Schultz et al. 1988) may be superior to initial radiation therapy or suggested no difference when compared to early thoracic radiation therapy and chemotherapy (Work et al. 1997). One possible explanation lies in the marked reduction of chemotherapy dose in the Cancer and Leukemia Group B (Perry et al. 1987) and the Danish trial when thoracic radiation therapy was applied early.

Also, the Danish trial (Work et al. 1997) can not re- ally be considered as a concurrent thoracic radiation therapy and chemotherapy study because sequential radiation therapy was used before and after chemotherapy. Newer studies using cisplatin/etoposide or cisplatin/etoposide alternating with cyclophosphamide/doxorubicin/vincristine (Murray et al. 1993;

Jeremic et al. 1997; Takada et al. 2002) showed clear superiority for early (cycle one or two of chemo-

therapy) administration of thoracic radiation therapy. These studies have also reconﬁ rmed in clinical practice an original Goldie and Coldman (1979) theoretical consideration that early administration of both treatment modalities leads to the best outcome on both a local and distant level (Table 4.1.1), with only early concurrent thoracic radiation therapy and cisplatin/etoposide being capable of achieving 5-year survival of >20%, whilst late delayed thoracic radiation therapy usually obtained only about 10%.

Therefore, it became common practice to offer thoracic radiation therapy with curative doses world- wide (cycle one or two of chemotherapy) as early as possible. Others have also proved this in an institu- tional setting. Kamath et al. (1998) showed in a small study of 48 patients that early concurrent thoracic radiation therapy/cisplatin/etoposide offers an advantage over sequential chemotherapy and thoracic radiation therapy in terms of overall survival and decreased distant metastasis in patients with limited- disease small cell lung cancer. Most recently, Fried et al. (2003) performed a meta-analysis evaluating the timing of thoracic radiation therapy in combined modality therapy for limited stage small cell lung cancer. Seven trials with a total of 1524 patients met inclusion criteria. A signiﬁ cantly higher 2-year survival was observed in the early group and there was a suggestion of a similar trend at 3 and 5 years. This advantage was a consequence of signiﬁ cantly better outcome for studies employing hyperfractionated radiation therapy and platinum-based chemotherapy.

Contrary to that, once-daily regimens and doxorubicin-based chemotherapy brought no improvement for early regimens.

With regard to thoracic radiation therapy dose and fractionation, the doses used for small cell lung can- cer were usually about 50 Gy, standard fractionation.

Even in the era of concurrent thoracic radiation therapy and chemotherapy one major site of recurrence continues to be in-ﬁ eld (about 30% pure and 20%

combined with systemic progression). The majority of studies evaluating this issue are retrospective, with one study (Choi and Carey 1989) observing a better local control for doses of 40–50 Gy than with doses

<40 Gy (>50% versus 30%). Another study indicated excellent local control after 60 Gy, being 97% (Papac et al. 1987). Recently, however, Choi et al. (1998) from the Cancer and Leukemia Group B identiﬁ ed at least 70 Gy using standard fractionation as the maximum tolerated dose for combination with chemotherapy.

More recently, the Cancer and Leukemia Group B (Bogart et al. 2002) reported on the preliminary analysis of their phase II trial in which 70 Gy thoracic

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radiation therapy was shown to be feasible and effective when given concurrently with an initial three cycles of carboplatin and etoposide, following an induction with two cycles of paclitaxel and topotecan.

Median failure-free survival was 12.9 months and the median overall survival was 19.8 months with a 1-year survival rate of 70%. Only one treatment-related death occurred during this study. Good toler- ability of higher thoracic radiation therapy doses was recently conﬁ rmed by Miller et al. (2003) who retrospectively evaluated the data from 65 patients from the Duke University in which 58–66 Gy standard fractionation was used with either concurrent (n=32) or sequential (n=33) chemotherapy. The somewhat lower (30%) 2-year survival rate was ex- plained by the fact that less than one-half of patients received concurrent thoracic radiation therapy and chemotherapy and only 26% received prophylactic cranial irradiation. The toxicity was low. Similarly, in a cohort of limited-disease small cell lung cancer treated between 1987 and 2000 with >50 Gy, Roof et al. (2003) observed that overall survival, local control and disease-free survival compared favourably with the historic controls. More recently, Komaki et al.

(2003) reported on the Radiation Therapy Oncology Group 9712 study which was a phase I dose-escalation study of thoracic radiation therapy with concurrent cisplatin/etoposide in limited-disease small cell lung cancer. Thoracic radiation therapy was given in the form of 1.8 Gy daily to 36 Gy followed by small boost ﬁ elds encompassing only the gross disease

delivered with escalations of 1.8 Gy b.i.d. during the ﬁ nal days to establish the maximum tolerated dose.

Escalations of twice-daily thoracic radiation therapy during the last 5, 7, 9 and 11 days permitted doses of 54 Gy, 57.6 Gy, 61.2 Gy and 64.8 Gy. The maximum tolerated dose was determined to be 61.2 Gy in 34 fractions of 1.8 Gy when given concurrently with two cycles of cisplatin/etoposide and followed by two additional cycles of cisplatin/etoposide.

While earlier studies mostly employed conven- tional fractionation (once a day, ﬁ ve times a week), a few of them used somewhat hypofractionated radiation therapy regimens, thought to cause more damage to small cell lung cancer cells. A recent study showed that shifting from hypofractionated to conventionally fractionated thoracic radiotherapy in a single institution’s 10-year experience in limited stage small cell lung cancer did not alter outcomes because the survival, thoracic control and toxicity rates were statistically similar (Videtic et al. 2003).

With more pronounced interest for the altered fractionated regimens, however, accelerated hyperfractionation seemed the logical choice due to the high sensitivity of small cell lung cancer to radiation therapy, the sparing effect of twice-daily fractionation and the possible effect of dose acceleration to combat rapid proliferation thought to occur in small cell lung cancer. In the Intergroup study (Johnson et al. 1996; Turrisi et al. 1999), 45 Gy given in 30 fractions in 3 weeks (1.5 Gy b.i.d. fractionation) was compared with the same dose given once daily. With

Table 4.1.1. Prospective randomised trials investigating optimal timing of concurrent thoracic radiation therapy and chemo- therapy in limited-disease small cell lung cancer

Author CHT RT RT timing Survival Outcome

(5-year)

Perry et al. (1987) 6 × CEV + 50 Gy/24 fx Cycle 1 7% Trend for improved survival for late RT CEV/CAV (once daily) Cycle 4 13% (p=0.08)

Murray et al. (1993) 6 × CAV/PE 40 Gy/15 fx Week 3 20% Improved survival for early RT

(once daily) Week 15 11% (p=0.008)

Work et al. (1997) 3 × PE + 40–45 Gy/22 fx Week 1 11% No difference 6 × CAV (once daily) Week 18 12% (p=0.4)

Jeremic et al. (1997) CpE with RT + 54 Gy/36 fx Week 1 30% Improved survival for early RT 4 × PE (twice-daily) Week 6 15% (p=0.052)

Takada et al. (2002) 4 × PE 45 Gy/30 fx Cycle 1 24% Trend for improved survival for early RT

(twice-daily) Cycle 4 18% (p=0.097)

CHT, chemotherapy; CEV, cyclophosphamide, etoposide, vincristine; CAV, cyclophosphamide, doxorubicin, vincristine; PE, cisplatin, etoposide; CpE, carboplatin, etoposide; fx, fraction; RT, radiation therapy.

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survival signiﬁ cantly better in the b.i.d. arm (5-year, 26% versus 19%). This, however, was achieved with a somewhat higher incidence of acute toxicity. Another study investigating this issue was a North Central Cancer Treatment Group study which compared concurrent two cycles of cisplatin/etoposide and either b.i.d., split-course thoracic radiation therapy (48 Gy in a total of 5.5 weeks) or once-daily thoracic radiation therapy (50.4 Gy), both given after three cycles of cisplatin/etoposide (Bonner et al. 1999). There was no difference in a 3-year overall and locoregional control. After 5 years (Schild et al. 2003), the median and 5-year survival were 20.4 months and 22% for b.i.d. versus 20.5 months and 21% for once-daily tho- racic radiation therapy, respectively (p=0.7). Having these two studies together, a possible explanation may lie either in the inferiority of the split-course regimen (which undermined the effect of hyperfractionation) or the effects of acceleration outweighing those of hyperfractionation. Extending the overall treatment time, therefore, which allows tumour cell regeneration, may have been the reason for this ﬁ nd- ing due to a delay in thoracic radiation therapy either by long lasting induction chemotherapy or by split-course protocol for thoracic radiation therapy.

A quality-adjusted reanalysis of a phase III trial comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with limited stage small cell lung cancer using ‘quality time without symptoms or toxicity’ methodology showed no difference in survival after adjusting for toxicity and progression (Sloan et al. 2002).

A number of groups and institutions world-wide accepted the policy of accelerated hyperfractionated thoracic radiation therapy, and the accumulated data show different outcomes (Johnson et al. 1996; Ali et al. 1998; Mennecier et al. 2000; Segawa et al. 2003) and toxicity proﬁ les. The future studies directly comparing b.i.d. to once-daily fractionation will bring deﬁ nitive answers about optimal total dose and fractionation regimen preferentially used. While this task is already underway, the “third” generation of drugs eagerly awaits its place and time in this disease and the data are slowly emerging (Sandler et al. 2000).

With the change of practice from sequential to concurrent thoracic radiation therapy and chemo- therapy, the issue of thoracic radiation therapy vol- umes became particularly important in the latter case, while it is of no importance if one use early (cycle one) concurrent thoracic radiation therapy and chemotherapy. Several questions provide an in- teresting framework for further investigation, such as whether one should treat pre-chemotherapy or

post-chemotherapy visible volumes, and what should be the safety margin around the visible tumour and which, if any, elective nodal coverage should be used.

There is no consensus to date, although common policy is to include the original tumour with 1.5–2.0 cm safety margin. One prospective study showed no difference between large ﬁ eld thoracic radiation therapy and limited ﬁ eld thoracic radiation therapy (Kies et al. 1987), but others showed the opposite (Perez et al. 1981; White et al. 1982). Larger thoracic radiation therapy volumes will inevitably lead to more toxicity, but this must be carefully balanced against the increased risk of high incidence of local recurrence.

Any appropriate solution of this question must take the dose/fractionation regimen used into account.

It is also expected that newer diagnostic tools such as positron emission tomography and newer, more powerful, computer-driven radiation therapy tech- nologies may help solve the problem of optimal thoracic radiation therapy volumes.

To further extend this, three-dimensional treatment planning and delivery using conformal tech- niques are increasingly used. Intensity-modulated radiation therapy and stereotactic fractionated radiation therapy are expected to fully bloom in the near future. It is reasonable to expect that they will be introduced in clinical practice to treat limited-disease small cell lung cancer, as a tool for both tumour dose increase and the dose normal tissue receives. This is an important issue since toxicity during concurrent thoracic radiation therapy and chemotherapy may lead to poor compliance and may necessitate treatment interruptions to palliate existing symptoms. As recently shown they result in poorer local control and decreased survival (Videtic et al. 2001).

4.1.3 Conclusions

The standard treatment for the majority of patients with limited-disease small cell lung cancer is a combination of thoracic radiation therapy and cisplatin/

etoposide, given concurrently, with thoracic radiation therapy being started early. While the majority of institutions world-wide use four cycles of cisplatin/etoposide, numerous thoracic radiation therapy and chemotherapy issues remain unsolved. Ongoing studies will help clear up these important issues in optimising the treatment approach and outcome in this disease. The lessons we have learned from opti- misation of the treatment approach in limited-dis-

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ease small cell lung cancer also served as an attempt to optimise the treatment in extensive-disease small cell lung cancer. As we have recently shown in a prospective randomised trial, thoracic radiation therapy can play an important role in extensive-disease small cell lung cancer, provided that suitable patients are identiﬁ ed (Jeremic et al. 1999). We have focused on those patients who have the most favourable progno- sis after induction chemotherapy, i.e. those achieving complete response at distant sites accompanied with either complete response or partial response intratho- racically. They were chosen as a subject of our study because they most closely resembled limited-disease small cell lung cancer patients. In these patients, after three initial cycles of cisplatin/etoposide, accelerated hyperfractionated thoracic radiation therapy offered a survival advantage over that achieved with chemotherapy alone (the median survival time: 17 vs. 11 months; 5-year survival rates: 9.1% vs. 3.7%, respectively; p=0.041) due to an improvement in the local recurrence-free survival (p=0.062). Patients treated with thoracic radiation therapy achieved better results than those treated with chemotherapy only regarding both median time to ﬁ rst relapse (13 vs.

9 months, respectively) and 1-5 year ﬁ rst relapse-free survival (p=0.045). Interestingly, after initial 3 cycles of cisplatin/etoposide, thoracic radiation therapy offered higher response rate than additional cisplatin/

etoposide. When further response was evaluated, additional cisplatin/etoposide (in both groups) offered nothing but a few percent of additional response, an indirect evidence of the necessity of limiting of the number of chemotherapy cycles to 4–6. Results of this study await further veriﬁ cation, an important task for the future endeavours in small cell lung cancer.

References

Ali MA, Kraut MJ, Valdivieso M, Herskovic AM, Du W, Kalem- kerian GP (1998) Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer. Lung Cancer 22:39- 44

Ardizzoni A, Tjan-Heijnen VCG, Postmus PE, Buchholz E, Biesma B, Karnicka-Mladowska H, Dziadziuszko R, Burghouts J, van Meerbeck JP, Gans S, Legrand C, Debru- yne C, Giaccone G, Manegold C (2002) Standard versus intensiﬁ ed chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for research and treatment of cancer – Lung Cancer Group phase III trial – 08923. J Clin Oncol 20:3947-3955

Arriagada R, Le Chevalier T, Pignon JP, Riviere A, Monnet I, Chomy P, Tuchais C, Tarayre M, Rufﬁ e P (1993) Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 25:1848-1852 Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A,

Stephens RJ, Kristjansen PE, Johnson BE, Ueoka H, Wagner H, Aisner J (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.

Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484

Beith JM, Clarke SJ, Woods RL, Bell DR, Levi JA (1996) Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung. Eur J Cancer 32A:438-443

Birch R, Greco F, Hainsworth J (2000) Preliminary results of a randomized study comparing etoposide and carboplatin with or without paclitaxel in newly diagnosed small cell lung cancer. Proc Am Soc Clin Oncol 19:490 (abstract) Bleehan NM, Fayers PM, Girling DJ, Stephens RJ (1989) Con-

trolled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 59:584-590

Bogart JA, Herndon JE, Lyss AP, Watson D, Miller AA, Lee ME, Turrisi AT, Green MR (2002) 70 Gy thoracic radiotherapy (TRT) is feasible concurrent with chemotherapy for limited stage small cell lung cancer (L-SCLC): preliminary analysis of a CALGB phase II trial. Int J radiat Oncol Biol Phys 54:

S103 (abstract 173)

Bonner JA, Sloan JA, Shanahan TG, Brooks BJ, Marks RS, Krook JE, Gerstner JB, Maksymiuk A, Levitt R, Mailliard JA, Tazelaar HD, Hillman S, Jett JR (1999) Phase III com- parison of twice-daily split-course irradiation versus once- daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 17:2681-2681

Bremnes RM, Sundstrom S, Vilsik J, Aasebo U (2001) Multi- center phase II trial of palcitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small cell lung cancer. J Clin Oncol 19:3532-3538

Byrne MJ, Van Hazel G, Trotter J, Cameron F, Shepherd J, Cassidy B, Gebski V (1989) Maintenance chemotherapy in limited small cell lung cancer: a randomised controlled clinical trial. Br J Cancer 59:584-590

Choi NC, Carey RR (1989) Importance of radiation dose in achieving improved locoregional tumor control in small- cell lung carcinoma: an update. Int J Radiat Oncol Biol Phys 17:307-310

Choi N, Herndon J, Rosenman J, Carey RW, Chung CT, Bernard S, Leone L, Seagren S, Green M (1998) Phase I study to determine the maximum tolerated dose of radiation in standard daily and accelerated twice daily radiotherapy schedules with concurrent chemotherapy for limited stage small cell lung cancer: CALGB 8837. J Clin Oncol 16:3528-3536

Cohen MH, Broder LE, Fossieck BE, Ihde DC, Minna JD (1977) Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61:349-354

Cohen MH, Ihde DC, Bunn PA Jr, Fossieck BE Jr, Matthews MJ, Shackney SE, Johnston-Early A, Makuch R, Minna JD (1979) Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 62:163-170

Cullen M, Morgan D, Gregory W, Robinson M, Cox D, McGivern

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D, Ward M, Richards M, Stableforth D, Macfarlane A (1986) Maintenance chemotherapy for anaplastic small cell carcinoma of the bronchus: a randomised, controlled trial.

Cancer Chemother Pharmacol 17:157-160

Curran WJ (2001) Combined-modality therapy for limited- stage small cell lung cancer. Semin Oncol 28:14-22 Edelmen MJ, Chansky K, Gaspar LE, Leigh B, Weiss GR, Taylor

SA, Crowley J, Livingston R, Gandara DR (2004) Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: southwest Oncology Group 9713. J Clin Oncol 22:127-132

Einhorn LH, Crawford J, Birch R, Omura G, Johnson DH, Greco FA (1988) Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 6:451-456

Ettinger DS, Seiferhals WF, Abrams RA (2000) Cisplatin, etoposide, paclitaxel, and concurrent hyperfractionated thoracic radiotherapy for patients with limited disease small cell lung cancer: Preliminary results of RTOG 96009. Proc Am Soc Clin Oncol 19:490a

Figueredo AT, Hryniuk WM, Strautmanis I, Frank G, Rendell S (1985) Cotrimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer. J Clin Oncol 3:54-64 Fried DB, Morris DE, hensing TA, Poole C, Halle JS, Rosenman

JG, Socinski MA. (2003) A meta-analysis evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small cell lung cancer. Int J Radiat Oncol Biol Phys 57 [Suppl 2]:S139-S140 (abstract 26) Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura

T, Shimoyama M, Suemasu K (1991) Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83:855-861 Gatzmeier U, von Pawel J, Macha H (2000) A phase III trial of

taxol, etoposide phosphate and carboplatin (TEC) versus carboplatin, etoposide phosphate, and vincristine (CEV) in previously untreated small cell lung cancer. Proc Am Soc Clin Oncol 19:483 (abstract)

Giaccone G, Dalesio O, McVie GJ, Kirkpatrick A, Postmus PE, Burghouts JT, Bakker W, Koolen MG, Vendrik CP, Roozendaal KJ (1993) Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. J Clin Oncol 11:1230-1240

Goldie JG, Coldman AJ (1979) A mathematical model for relat- ing the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1735

Goldie JG, Coldman AJ (1984) The genetic origin of drug resistance in neoplasms: Implications for systemic therapy.

Cancer Res 44:3643-3653

Green RA, Humphrey E, Close H, Patno ME (1969) Alkylating agents in bronchogenic carcinoma. Am J Med 46:516-525 Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer sta-

tistics 2000. CA Cancer J Clin 50:7-33

Hanna N, Ansari R, Fisher W, Shen J, Jung S-H, Sandler A.

(2002) Etoposide, ifosfamide and cisplatin (VIP) plus concurrent radiation therapy for previously untreated limited small cell lung cancer (SCLC): a Hoosier Oncology Group (HOG) phase II study. Lung Cancer 35:293-297

Ihde DC, Pass HI, Glatstein EJ (1993) Small cell lung cancer.

In: DeVita V, Hellman S, Rosenberg S (eds) Cancer - prin- ciples and practice of oncology. Lipincott, Philadelphia, PA, pp 723-758

Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S (1997) Ini- tial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small cell lung cancer. J Clin Oncol 15:893-900

Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S, Dagovic A, Aleksandrovic J, Radosavljevic-Asic G (1999) The role of radiation therapy in the combined modality treatment of patients with extensive disease small-cell lung cancer (ED SCLC): a randomized study. J Clin Oncol 17:2092-2099

Johnson BE, Bridges JD, Sobezeck M, Gray J, Linnoila RI, Gazdar AF, Hankins L, Steinberg SM, Edison M, Frame JN, Pass H, Nesbitt J, Holden D, Mulshine JL, Glatstein E, Ihde DC (1996) Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14:806-813

Johnson DH, Kim K, Sause W (1996) Cispaltin (p) & etoposide (e) + thoracic radiotherapy (TRT) administered once or twice daily (bid) in limited stage (LS) small cell lung caner (sclc): ﬁ nal report of intergroup trial 0096. Proc Am Soc Clin Oncol 15:374

Kamath SS, McCarley DL, Zlotecki RA (1998) Decreased metastasis and improved survival with early thoracic radiotherapy and prophylactic cranial irradiation in combined modality treatment of limited-stage small cell lung cancer.

Radiat Oncol Invest 6:226-232

Kies MS, Mira JG, Crowley JJ, Chen TT, Pazdur R, Grozea PN, Rivkin SE, Coltman CA Jr, Ward JH, Livingston RB (1987) Multimodal therapy for limited small cell lung cancer. A randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders;

and with wideﬁ eld versus reduced volume radiation in partial responders: a Southwest Oncology Group study. J Clin Oncol 5:592-600

Komaki R, Swann S, Ettinger D (2003) Phase I dose-escalation study of thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC).

Radiation Therapy Oncology Group (RTOG) protocol 9712.

Proc Am Soc Clin Oncol 21:2003 (abstract 2539)

Kosmidis P, Samantas E, Fountzilas G, Pavlidis N, Apostolopoulou F, Skarlos D (1994) Cisplatin/etoposide vs carboplatin/etoposide and irradiation in small-cell lung cancer: a randomized phase III study. Semin Oncol 21 [Suppl 6]:23-30

Lebeau B, Chastang CL, Allard P, Migueres J, Boita F, Fichet D (1992) Six vs. twelve cycles for complete responders to chemotherapy in small cell lung cancer: deﬁ nitive results of a randomised clinical trial. Eur Respir J 5:286-290 Levitan N, Dowlati A, Shina D, Craffey M, Mackay W, DeVore R,

Jett J, Remick SC, Chang A, Johnson D (2000) Multi-institu- tional phase I/II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung carcinoma. J Clin Oncol 18:1102-1109

Maurer LH, Tulloh M, Weiss R, Blom J, Leone L, Glidewell O, Pajak TF (1980) A randomized combined modality trial on small cell carcinoma of the lung. Cancer 45:30-39 Mavroudis D, Papadakis E, Veslemes M, Tsiafaki X, Stavrakakis

J, Kouroussis C, Kakolyris S, Bania E, Jordanoglou J, Agelidou M, Vlachonicolis J, Georgoulias V(2001)A multicenter randomized clinical trial comparing paclitaxel- cisplatin-etoposide versus cisplatin-etoposide as ﬁ rst-line treatment in patients with small-cell lung cancer. Ann Oncol 12:463-470

(9)

Mehta C, Vogl SE, Farber S (1982) High-dose cyclophosphamide (c) in the induction (ind) chemotherapy (ct) of small cell lung cancer (sclc) – minor improvements in rate of remission and survival. Proc Am Assoc Cancer Res 23:165 Mennecier B, Jacoulet P, Dubiez A, Westeel V, Bosset JF, Magnin

V, Depierre A. (2000) Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: a phase II study. Lung Cancer 27:137-143

Miller KL, Marks LB, Sibley GS, Clough RW, Garst JL, Crawford J, Shafman TD (2003) Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited- stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 56:355-359

Mulshine JL, Treston AM, Brown HP, Birer MJ, Shaw GL (1993) Initiators and promoters of lung cancer. Chest 103 [Suppl 1]:4S-11S

Murray N, Coy, Pater J, Hodson I, Arnold A, Zee BC, Payne D, Kostashuk EC, Evans WK, Dixon P (1993) Importance of timing for thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. J Clin Oncol 11:336-344

Niell HB, Herndon JE, Miller AA (2002) Randomized phase III intergroup trial (CALGB 9732) of etoposide and cisplatin with or without paclitaxel and G-CSF in patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 21:293a

Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N; The Japan Clinical Oncology Group (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91

Papac RJ, Son Y, Bien R, Tiedemann D, Keohane M, Yesner R (1987) Improved local control of thoracic disease in small- cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy. Int J Radiat Oncol Biol Phys 13:993- 998

Perez CA, Krauss S, Bartolucci AA, Durant JR, Lowenbraun S, Salter MM, Storaalsi J, Kellermeyer R, Comas F (1981) Thoracic and elective brain irradiation with concomitant or delayed multiagent chemotherapy in the treatment of localized small cell carcinoma of the lung: a randomized prospective study by the Southeastern cancer Study Group.

Cancer 47:2407-2413

Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP, Skarin A, Carey RW, Kreisman H, Faulkner C (1987) Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316:912-918

Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, Brodin O, Joss RA, Kies MS, Lebeau B (1992) A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1627

Reck M, von Pawel J, Macha HN (2003) Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 95:1118-1127

Roof KS, Fidias P, Lynch TJ, Ancukiewicz M, Choi NC. (2003) Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Onmcol Biol Phys 57:701-708

Sandler A (2003) Chemotherapy for small cell lung cancer.

Semin Oncol 30:9-25

Sandler A, Declerck L, Wagner H (2000) A phase II study of cisplatin plus etoposide plus paclitaxel and concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): an Eastern Cooperative Oncology Group trial. Proc Am Soc Clin Oncol 19:491a (abstract 1920)

Schild S, Brindle JS, Geyer SM (2003) Long-term results of a phase III trial comparing once a day radiotherapy (QD RT) or twice a day radiotherapy (BID RT) in limited stage small cell lung cancer (LSCLC). Proc Am Soc Clin Oncol 21 (abstract 2536)

Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH. (2001) Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19:2114-2122

Schultz HP, Nielsen OS, Sell A (1988) Timing of chest radiation with respect to combination chemotherapy in small cell lung cancer, limited disease. Lung Cancer 4:153 (abstract)

Sculier JP, Paesmans M, Bureau G, Giner V, Lecomte J, Michel J, Berchier MC, van Cutsem O, Kustner U, Kroll F, Sergysels R, Mommen P, Klastersky J (1996) Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. J Clin Oncol 14:2337-2344

Segawa Y, Uoeka H, Kiura K, Tabata M, takigawa N, Hiraki Y, Watanabe Y, Yonei T, Moritaka T, Hiyama J, Hiraki S, Tanim- oto M, Harada M. (2003) Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer. Lung Cancer 41:13-20 Sloan JA, Bonner JA, Hillman SL, Allmer C, Shanahan TG,

Brooks BJ, Marks RS, Vargas-Chanes D, Jett JR (2002) A quality-adjusted reanalysis of a phase III trial comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with limited-stage small-cell lung cancer.

Int J Radiat Oncol Biol Phys 52:371-381

Spiro SG, Souhami RL, Geddes DM, Ash CM, Quinn H, Harper PG, Tobias JS, Partridge M, Eraut D (1989) Duration of chemotherapy in small cell lung caner: A Cancer Research Campaign trial. Br J Cancer 59:578-583

Stahel RA, Ginsberg R, Havemann K (1989) Staging and prog- nostic factors in small cell lung cancer: a consensus report.

Lung Cancer 5:119-126

Steward WP, von Pawel J, Gatzemaier U, Woll P, Thatcher N, Koschel G, Clancy L, Verweij J, de Wit R, Pfeifer W, Fen- nelly J, von Eiff M, Frisch J (1998) Effects of granulocyte colony-stimulating factor and dose-intensiﬁ cation of V- ICE chemotherapy in small-cell lung cancer: a prospective randomised study of 300 patients. J Clin Oncol 16:642-650 Takada M, Fukuoka M, Kawahara M, Sugiiura T, Yokoyama

A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N (2002) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group study 9104. J Clin Oncol 20:3054-3060

Thatcher N, Girling DJ, Howood P, Sambrook RJ, Qian W, Stephens RJ (2000) Improving survival without reducing quality of life in small-cell lung cancer patients by increas- ing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Med-

(10)

ical Research Council multicenter randomised trial. J Clin Oncol 18:395-404

Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:264-271

Videtic GMM, Truong PT, Dar AR, Yu EW, Stitt LW (2003) Shift- ing from hypofractionated to “conventionally” fractionated thoracic radiotherapy: a single institution’s 10-year experience in the management of limited-stage small-cell lung cancer using concurrent chemoradiation. Int J Radiat Oncol Biol Phys 57:709-716

Videtic GMM, Fung K, Tomiak AT, Stitt LW, Dar AR, Truong PT, Yu EW, Vincent MD, Kocha WI. (2001) Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control. Lung Cancer 33:249-258 Warde P, Payne D (1992) Does thoracic radiation improve

survival and local control in limited-stage small cell carcinoma of the lung? J Clin Oncol 10:890-895

White JE, Chen T, McCracken J, Kennedy P, Seydel HG, Hart-

man G, Mira J, Khan M, Durrance FY, Skinner O (1982) The inﬂ uence of radiation therapy quality control on survival, response, and sites in oat cell carcinoma of the lung.

Preliminary report of a Southwest Oncology Group study.

Cancer 50:1084-1090

Work E, Nielsen O, Bentzen S, Fode K, Palshof T (1997) Ran- domized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small cell lung cancer. J Clin Oncol 15:3030-3037

Woo IS, Park YS, Kwon SH, Park YL, Lee JA, Park MJ, Hyun IG, Jung KS, Bae HS, Oh DH, Kim WS, Park K, Park CH, Kim HJ, Ahn YC (2000) A phase II study of VP-16-Ifosfamide-Cis- platin combination chemotherapy plus early concurrent thoracic irradiation for previously untreated limited small cell lung cancer. Jpn J Clin Oncol 30:542-546

Woods RL, Levi JA (1984) Chemotherapy for small cell lung cancer (SCLC): a randomised study of maintenance therapy with cyclophosphamide, adriamycin and vincristine (CAV) after remission induction with cis-platinum (CIS-DDP), VP 16-213 and radiotherapy. Proc Am Soc Clin Oncol 3:214 Zakowski MF (2003) Pathology of small cell carcinoma of the

lung. Semin Oncol 30:3-8