Strahlentherapie und Onkologie

Original Article

Three-Times-Daily Radiotherapy with Induction Chemotherapy in Locally Advanced Non-Small Cell Lung Cancer Feasibility and Toxicity Study Gianpiero Catalano1, Barbara Alicija Jereczek-Fossa1, Tommaso De Pas1, Maria Elena Leon3, Frederica Cattani4, Lorenzo Spaggiari5, Giulia Veronesi5, Filippo de Braud2, Roberto Orecchia1, 6

Purpose: To evaluate the feasibility and toxicity of three-times-daily radiotherapy (3tdRT), preceded by induction chemotherapy (iCT), in stage IIIA–IIIB non-small cell lung cancer (NSCLC). Patients and Methods: iCT consisted of three cycles of cisplatin and gemcitabine. Surgery was considered for stage IIIA patients responsive to iCT; definitive or postoperative 3tdRT was planned. Doses of 54.4 Gy and 64.6 Gy in postoperative and definitive treatments, respectively, were delivered in three daily fractions. Results: From February 1998 to October 2000, 37 patients received 3tdRT as definitive (n = 18) or postoperative treatment (n = 19). Toxicity was limited to RTOG grade 2 (25 patients, 67.6%) and grade 3 (four patients, 10.8%) acute esophagitis; no grade 3 late esophagitis occurred. Late lung toxicity was represented by one grade 3 pneumonitis. No correlation emerged between acute esophageal toxicity and irradiated esophageal volume or disease- and treatment-related factors. A significant correlation was found for stage (IIIA vs. IIIB; p = 0.03) and a trend for the N-class (N2 vs. N3; p = 0.08). Conclusion: In this experience of 3tdRT preceded by iCT, the low toxicity profile confirmed the feasibility of this combination. The limited statistical power does not permit a definition of predictors for radiation-induced esophagitis incidence and severity; additional studies are required to clarify the impact of volumetric and dosimetric parameters. Failure patterns and survival results are warranted to confirm the efficacy of this approach in locally advanced NSCLC. Key Words: Lung cancer · Hyperfractionated radiotherapy · Three-times-daily radiotherapy · Induction chemotherapy · Acute toxicity · Esophagitis Strahlenther Onkol 2005;181:363–71 DOI 10.1007/s00066-005-1332-8 Dreimal tägliche Strahlentherapie mit Induktionschemotherapie bei lokal fortgeschrittenem nichtkleinzelligen Bronchialkarzinom. Machbarkeits- und Toxizitätsstudie Ziel: Untersuchung der Durchführbarkeit und Toxizität einer dreimal täglichen Strahlentherapie (3tdRT) nach Induktionschemotherapie (iCT) bei nichtkleinzelligem Bronchialkarzinom (NSCLC) im Stadium IIIA–IIIB. Patienten und Methodik: Die iCT umfasste drei Zyklen Cisplatin und Gemcitabin. Bei Patienten, die auf die iCT ansprachen, wurde eine operative Therapie erwogen. Nach Planung der definitiven bzw. postoperativen 3tdRT wurden Gesamtdosen von 54,4 bzw. 64,6 Gy in drei Fraktionen pro Tag verabreicht. Ergebnisse: Zwischen Februar 1998 und Oktober 2000 erhielten 37 Patienten eine radikale (n = 18) oder postoperative 3tdRT (n = 19). Die Toxizität beschränkte sich auf eine akute Ösophagitis RTOG-Grad 2 (25 Patienten, 67,6%) und 3 (vier Patienten, 10,8%); eine späte Ösophagitis Grad 3 wurde nicht beobachtet. Bei einem Patienten zeigte sich eine späte Lungentoxizität in Form einer Grad-3-Pneumonie. Zwischen akuter Ösophagustoxizität und bestrahltem Ösophagusvolumen oder krankheits- und therapiebezogenen Faktoren ergab sich keine Korrelation. Dagegen fanden sich eine signifikante Korrelation für das Tumorstadium (IIIA vs. IIIB; p = 0,03) und eine Tendenz für den Lymphknotenbefall (N2 vs. N3; p = 0,08).

1

Division of Radiotherapy, European Institute of Oncology, Milan, Italy, Division of Medical Oncology, European Institute of Oncology, Milan, Italy, 3 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy, 4 Division of Medical Physics, European Institute of Oncology, Milan, Italy, 5 Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy, 6 Radiotherapy, University of Milan, Milan, Italy. 2

Received: June 16, 2004; accepted: February 2, 2005

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Catalano G, et al. Feasibility of Three-Times-Daily Radiotherapy in Lung Cancer

Schlussfolgerung: In dieser Studie zur 3tdRT nach iCT erwies sich die Kombinationstherapie aufgrund ihrer geringen Toxizität als geeignet. Die eingeschränkte statistische Aussagekraft lässt keine Bestimmung prädiktiver Faktoren für Häufigkeit und Schwere einer strahlenbedingten Ösophagitis zu; weitere Studien sind erforderlich, um den Einfluss von Volumen- und Dosisparametern zu klären. Analysen von Rezidivierungsverhalten und Überleben könnten die Wirksamkeit dieses Verfahrens bei lokal fortgeschrittenem NSCLC bestätigen. Schlüsselwörter: Lungenkarzinom · Hyperfraktionierte Strahlentherapie · Dreimal tägliche Strahlentherapie · Induktionschemotherapie · Akuttoxizität · Ösophagitis

Introduction There is no consensus on what is the most appropriate treatment of locally advanced non-small cell lung cancer (NSCLC). Although the great majority of patients develop distant metastases, a significant number die with active thoracic disease [19]. Actual strategies are directed toward the reduction of metastatic disease by adding chemotherapy (CT) to local treatments and the improvement of local control through more aggressive radiotherapy (RT), since it is well known that a direct dose-survival relationship exists [3, 14]. Recent studies revealed a significant survival improvement when adding a systemic treatment, such as induction chemotherapy (iCT), to RT [2, 11, 12, 18, 21, 25, 26, 31, 32]. Unconventional RT is based on rich radiobiological background mainly characterized by the reduction of the dose per fraction and/or the overall treatment time. In particular, it is well accepted that the fraction dose reduction leads to the possibility of delivering higher total doses, sparing late-responding tissues. On the other hand, a reduction of treatment time balances the tumor cell repopulation occurring during treatment, and consequently, accelerated fractionation schedules should improve tumor control. The hybrid hyperfractionated accelerated schedule combines the features of both previous schedules and, thus, their theoretical biological advantages. Unconventional RT showed to be more effective than conventional treatment in improving local control and overall survival, as reported in phase II–III studies [7, 16, 17, 21]; dose escalation trials have also been performed, confirming a dose-effect relationship for locally advanced NSCLC, with a significant survival advantage in selected patients [8]. A major randomized trial investigated a more aggressive schedule of continuous hyperfractionated accelerated radiotherapy (CHART), given as definitive treatment by means of three daily fractions of 1.5 Gy up to a total dose of 54 Gy. CHART evidenced a significant survival improvement associated with an acceptable toxicity profile [28, 29]. To our knowledge, few data are available in the literature on the association of iCT followed by hyperfractionated accelerated RT and specifically, on the integration of iCT and three-times-daily RT (3tdRT). In this context, toxicity and feasibility of the said treatment are reported in a prospective study administering three cycles of cisplatin (CDDP) and gemcitabine (GCB), followed by 3tdRT, in stage IIIA (N2) and IIIB NSCLC patients.

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Patients and Methods Patients Mediastinoscopically proven stage IIIA (N2) to IIIB NSCLC patients were eligible for inclusion in the study. Criteria included: age 18–75 years, performance status (Karnofsky index) ≥ 80, adequate bone marrow, hepatic and renal functions, life expectancy ≥ 3 months. Previous RT or CT, concurrent malignancies, uncontrolled infections, and pregnancy constituted exclusion criteria. All patients gave written informed consent to participate in the trial. The hospital’s ethics committee approved the study protocol. Medical Work-up Pretreatment evaluation included a complete history and physical examination, full chemistry profile, whole-body computed tomography scan, and bone scan. Pulmonary function, with spirometry and perfusion scan, was evaluated before CT and eventual surgery. During iCT, complete blood cell count and renal function assessments were performed weekly. Treatment Cisplatin (CDDP) 80 mg/m2 as 1-h intravenous infusion on day 1 and gemcitabine (GCB) 1,250 mg/m2 administered as a 30-min infusion on days 1 and 8, repeated every 3 weeks, were planned. Three courses of iCT were administered unless clinical progression or excessive toxicity occurred. All patients with measurable disease underwent complete tumor response assessment after two cycles. The World Health Organization’s (WHO) response-to-treatment criteria were used [39]. Patients with resectable stage IIIA (N2), showing no disease progression (PD), underwent surgery followed by postoperative RT. For stage IIIB patients or stage IIIA not suitable for surgery, definitive RT was planned 4–6 weeks after the completion of iCT. Patients were considered eligible for surgery with acceptable risk, if postoperative predictive FEV1 (forced expiratory volume in 1 s) at spirometry was > 33% of the theoretical value (based on weight, height, and sex). The rules used to evaluate this parameter were the following: • for lobectomy, predictive postoperative FEV1 was equal to preoperative FEV1 × 1–(0.053 × number of resected segments), where 0.053 is 1/19;

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Catalano G, et al. Feasibility of Three-Times-Daily Radiotherapy in Lung Cancer

• for pneumonectomy, predictive postoperative FEV1 was equal to (preoperative FEV1 × percentage of perfusion of the healthy lung)/100. RT was intended to be delivered on an outpatient basis; total doses of 54.4 Gy and 64.6 Gy were planned in postoperative and definitive patients, respectively. In both cases, total doses were delivered in three daily fractions of 1.2 Gy, 1 Gy and 1.2 Gy, 5 days a week, with an interfraction interval of at least 4 h. Conscious that a 4-h interval may not be as safe as a longer one to guarantee a partial recovery from radiation sublethal damage, especially for cord tolerance, a “concomitant-boost” technique was used for delivery of the planned dose. In short, a “large” volume was irradiated via two opposed, anterior-posterior and posterior-anterior (AP-PA) fields, in the first and third daily fractions, up to the dose of 38.4 Gy. This volume consisted of pre-CT gross tumor disease, mediastinal-ipsilateral hilar lymph nodes (with a safety margin of 2 cm), plus ipsilateral supraclavicular lymph nodes in case of upper lobe tumors. This field assessment for the first part of treatment was chosen in order to standardize irradiation technique, if possible. In the second daily fraction, a “boost” volume, limited to gross tumor volume (plus a 1.5-cm margin), was irradiated via isocentric multiportal fields, assessed depending on volume site and extension, up to the additional dose of 16 Gy. In case of definitive irradiation, after 54.4 Gy the treatment was carried on to irradiate the boost volume only, three times a day, up to the total prescribed dose of 64.6 Gy. With this approach in the second daily fraction the irradiation was delivered “off-cord”, thus reducing cord irradiation by means of a longer interval (8 h) between the first and third fraction in which spinal cord was irradiated. Lungs, spinal cord and esophagus were defined as organs at risk (OARs); in particular, lungs were automatically contoured by the treatment planning software, while spinal cord and esophagus were manually drawn, starting from the upper thoracic inlet to the diaphragm. All patients were treated in a supine position, with arms above head and α-cradle immobilization devices with skin marks ensuring the reproducibility of treatment. Dedicated 5-mm thickened and spaced computed tomography scan was used for treatment planning; manual contouring of target volumes and OARs was performed. Dose prescription followed the ICRU (International Committee of Radiation Units) Report No. 50 recommendations [15]. High-energy (6–15 MV) photon beams from a linear accelerator were used for treatment, and beam shaping was performed via beam’s eye view. Inhomogeneity corrections, like lung correction, were used in the treatment planning. “In vivo” dosimetry and electronic portal verification were also performed, ensuring the requested quality assurance program. Dose-volume histograms (DVHs) completed the assessment of treatment, comparing different plans. Since the absolute dose differed in relation to the aim of treatment, DVHs

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were expressed in terms of percent of total dose, allowing comparison of definitive and postoperative 3tdRT. Furthermore, since treatment technique for the first 38.4 Gy was standard, AP-PA DVHs were referred to the first phase, boost DVHs were referred to the latter part of treatment, and DVH calculations were made separately. This choice was made because of the fact that the treatment planning system did not allow to calculate DVHs for summed plans. The percentages of either the target or OAR volumes exposed to a dose ≥ 100%, 95%, 80%, and 50% of the prescribed dose were recorded for AP-PA and boost DVHs, respectively. Follow-up First follow-up started 4 weeks after RT with clinical and radiologic evaluation of medical conditions, toxicity and disease status every 4 months, for the first 2 years, and subsequently every 6 months. When high toxicity or progressive disease was identified, a closer monitoring was contemplated. After treatment patients were also instructed to refer to the physician in case of any symptom, if occurring before the scheduled follow-up control. RT acute toxicity (from the beginning up to 3 months after 3tdRT) was evaluated according to the RTOG (Radiation Therapy Oncology Group) scoring system; similarly, late toxicity (> 3 months after 3tdRT) was scored according to the RTOG/EORTC (European Organization for Research and Treatment of Cancer) system. Statistical Analysis In order to identify factors possibly associated with esophagitis, patients were grouped according to two different toxicity classifications: grades 0/1 versus 2/3, and grades 0/1, 2 and 3 separately. The small number of patients registering either very low (grade 0) or high (grade 3) toxicity imposed grouping with adjacent toxicity categories. Mean percentage of irradiated esophageal volume, as derived from DVH calculation, was compared to the toxicity level developed for each percentage of intended dose separately, using simple linear regression. Models were run twice, for AP-PA and boost. Furthermore, the distribution of patients developing toxicity was compared across demographic, clinical and treatment-specific variables using Fisher’s exact test, assuming a p-value < 0.05 to be significant. Results From February 1998 to October 2000, 52 eligible patients (39 IIIA, 13 IIIB) were enrolled (Table 1); iCT was completed in 46 patients, with one interruption due to PD, four caused by toxicity, and one for unknown reasons. iCT resulted in 38 partial responses (PRs), eight cases with stable disease (SD) and six with PD. Surgery was performed in 28/39 stage IIIA patients, with 25 radical resections and no perioperative mortality; in eleven IIIA patients surgery was not performed because of PD (five patients), extension of disease (three patients), or

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Table 1. Description of the whole study population and number of patients treated with three-times-daily radiotherapy (3tdRT). iCT: induction chemotherapy; PD: disease progression.

Table 2. Acute toxicity patterns in 37 patients with non-small cell lung cancer stage IIIA/B receiving definitive or postoperative three-timesdaily radiotherapy. RTOG: Radiation Therapy Oncology Group.

Tabelle 1. Darstellung der gesamten Studienpopulation und der Anzahl der mit dreimal täglicher Radiotherapie (3tdRT) behandelten Patienten. iCT: Induktionschemotherapie; PD: Krankheitsprogression.

Tabelle 2. Akuttoxizität bei 37 Patienten mit nichtkleinzelligem Bronchialkarzinom im Stadium IIIA/B, die eine definitive oder postoperative dreimal tägliche Strahlentherapie erhielten. RTOG: Radiation Therapy Oncology Group.

IIIA

IIIB

Total

39

13

52

34 5 (toxicity 3; PD 1; unknown 1)

12 1 (toxicity)

46

27 6 6

11 2 –

38 8 6

RTOG score Patients enrolled iCT • Completed • Not completed

Response to iCT • Partial • Stable disease • Progressive disease Surgery (only stage IIIA) • Performed • Not performed

Radical surgery 3tdRT • Performed

• Not performed

3tdRT purpose • Definitive • Postoperative

28 11 (PD 5; disease extension 3; respiratory condition 3) 25

28

25 12 (after surgery 20; without surgery 5) 14 1 (after surgery 8; (PD after iCT) without surgery 6)

37

6 19

18 19

25

12 –

medical and functional respiratory limitations (three patients). 3tdRT was performed in 20/28 operated IIIA patients, 5/11 nonoperated IIIA patients, and 12/13 IIIB patients. One IIIA patient, although operated, did not undergo radical surgery and was therefore enrolled in the definitive RT group. In 15 cases 3tdRT was not performed because of PD (five patients with systemic PD after iCT, two with systemic PD after surgery, two with locoregional PD after iCT, one with locoregional PD at surgical exploration), protocol violation (four patients), and postoperative complications (one patient). Thus, 37 patients underwent 3tdRT. Definitive RT was performed in 18 patients, while postoperative treatment was applied in 19. The majority of patients receiving 3tdRT were male (32 of 37); median age was 58 years (range, 40–75 years) with a good performance status (median Karnofsky index of 90). Overall, patient compliance was satisfactory, and no 3tdRT delays due to treatment-related toxicity occurred. All patients received the planned definitive dose of 64.6 Gy; all but one patient reached 54.4 Gy for postoperative treatment. Median duration of 3tdRT for definitive and postoperative treatment was 27.6 days (range, 25–30 days) and 23.3 days

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Acute toxicity • Grade 0 • Grade 1 • Grade 2 • Grade 3 • Grade 4 Late toxicity • Grade 0 • Grade 1 • Grade 2 • Grade 3 • Grade 4

Number of events (%) Esophagus Lung 1 (2.7) 7 (18.9) 25 (67.6) 4 (10.8) 0 35 (94.6) 1 (2.7) 1 (2.7) 0 0

10 (27) 23 (62.2) 3 (8.1) 1 (2.7) 0 22 (59.5) 8 (21.6) 6 (16.2) 1 (2.7) 0

(range, 23–25 days), respectively. Any delay in 3tdRT treatment time in relation to planned duration was essentially due to technical malfunctions at the treatment unit. At present, median follow-up period, for patients completing the whole course of treatments, is 25 months (range, 5–68 months). After 3tdRT, acute toxicity was mainly represented by esophagitis (Table 2), which appeared as moderate (RTOG grade 2) dysphagia for solids and liquids in 25 patients (67.6%). Severe esophagitis, with a weight loss > 15% or enteral/parenteral feeding (grade 3), occurred in four patients (10.8%); in one case only 3tdRT was interrupted (after 51 Gy). Supportive therapy was started at the time of onset of esophagitis and included nonsteroidal anti-inflammatory drugs, as well prophylactic treatment with fluconazole. Mucositis usually began during the last 2 weeks of radiotherapy, often reaching the highest level after completion of 3tdRT. Even though endoscopic control was not considered a routine procedure during follow-up, it was performed in two patients, due to the long-lasting dysphagia after 3tdRT, and revealed a pattern of mucosal erythema without any sign of ulceration. No severe late toxicity occurred during follow-up. Lung acute toxicity was confined, in the majority of irradiated patients, to mild symptoms of cough and dyspnea with minimal effort (Table 2); one episode of septic pneumonitis completely recovered after administration of antibiotics, occurred few days after the end of 3tdRT. The usual treatment of mild pulmonary symptoms consisted of topic or systemic bronchodilators and expectorants-mucolytics. Topic or systemic steroids, although discouraged, were considered in case of symptom persistence. Concerning late toxicity, no grade 3 esophagitis occurred; by contrast, one grade 3 lung toxicity was seen during fol-

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low-up, and 14 patients developed grade 1–2 lung toxicity, in the majority of cases characterized by radiologic signs of lung fibrosis without clinical symptoms. DVH calculation evidenced that the esophagus, due to its central position in the mediastinum, was heavily irradiated in the AP-PA fields, receiving a mean of > 95% of the prescribed dose to almost two thirds (61%) of its volume. Similarly, in the boost phase a wide volume of the organ (63%) underwent significant irradiation, being exposed to > 80% of the prescribed dose. Regarding lungs, preservation of the uninvolved lung was achieved (16% and 21% of volume irradiated to ≥ 50% of prescribed dose, in the two phases of treatment, respectively). On the other hand, a relevant irradiation of the ipsilateral lung (35–40% of volume exposed to ≥ 80% of prescribed dose) was observed. The absolute dose to the spinal cord never exceeded 42 Gy (Table 3). There was no association between irradiated esophageal volume, as measured by means of DVHs, and the observed toxicity grade (Table 4). In other words, the extent of esophageal exposure to irradiation was similar across patients developing toxicity grades 0/1, 2, or 3. Demographic, clinical and treatment variables did not differ by toxicity level, indicating a lack of association (Table 5). Particularly, no correlation was found between esophageal toxicity and gender, age, or performance status; furthermore, no statistical significance emerged when considering disease-specific (histology, lobe, number of involved mediastinal stations) and treatment-related parameters, like iCT grade 3 toxicity, iCT dose reduction, 3tdRT dose, and AP-PA target volume. All patients with stage IIIB developed grade 2/3 toxicity, whereas only 17 out of 25 stage IIIA patients (68%) developed similar toxicity (p = 0.03). Likewise, although not statistically significant, all patients with N3 disease registered grade 2/3 toxicity as compared to N2 disease (19 patients, 70%; p = 0.08). The boost volume was not associated with toxicity (p = 0.23). Discussion The esophagus, due to its position, represents a critical structure in thoracic irradiation especially in the case of centrally located tumors and mediastinal node involvement. Acute esophagitis is a common side effect of high-dose treatment in lung cancer. In the literature, severe esophagitis rate commonly ranges from 10% to > 40% and is mainly related to the applied radiation dose, RT fractionation, and concomitant CT administration. Specifically, the incidence of severe acute esophageal toxicity results to be higher in case of unconventional fractionation schedules and/or concomitant chemoradiation [4, 6, 33, 37]. A retrospective analysis of 461 locally advanced NSCLC patients revealed a significant increase of severe acute esophagitis rate in case of unconventional RT and concomitant CT up to 34% [4]. Similar conclusions have been reached in another report in which the overall grade 3, or greater, dysphagia rate was 13%, with higher values occurring in case of chemo-

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Table 3. Dose-volume histograms relative to organs at risk in AP-PA (anterior-posterior and posterior-anterior) and boost phase of treatment: mean values. Tabelle 3. Dosis-Volumen-Histogramme hinsichtlich Risikoorganen in der AP-PA- (anterior-posterior und posterior-anterior) und Boost-Phase der Strahlentherapie: Mittelwerte. Dose (%)a

AP-PA fields • ≥ 100 • ≥ 95 • ≥ 80 • ≥ 50 Boost fields • ≥ 100 • ≥ 95 • ≥ 80 • ≥ 50 a

Volume (%) Ipsilateral Contralateral lung lung

Esophagus

Spinal cord

28 36 41 46

7 10 12 16

20 61 83 86

33 67 77 80

17 24 35 49

6 8 13 21

15 42 63 69

0 0 0 0

values referred to the percentage of prescribed dose for each part of the treatment, depending on radiotherapy purpose (AP-PA fields: 38.4 Gy; boost: 16 Gy and 26.2 Gy for postoperative and definitive radiotherapy, respectively)

therapy concurrent to standard or hyperfractionated RT (18% and 43%, respectively) [37]. We report on our experience with a sequential combination of platinum-based CT followed by 3tdRT, and particularly, on the clinical feasibility of this intensive RT schedule, focusing our attention on acute esophagitis, since it emerged as the major pattern of toxicity experienced by our patients. Table 4. Mean percentage of irradiated esophageal volume compared to toxicity level (grade 0–1 vs. grade 2 vs. grade 3) developed for each percentage of intended dose, using simple linear regression. AP-PA: anterior-posterior and posterior-anterior; SD: standard deviation. Tabelle 4. Mittlerer prozentualer Anteil des bestrahlten Ösophagusvolumens im Vergleich zum Toxizitätsniveau (Grad 0–1 vs. Grad 2 vs. Grad 3), für jede geplante prozentuale Dosis mittels einfacher linearer Regression ermittelt. AP-PA: anterior-posterior und posterior-anterior; SD: Standardabweichung. Dose (%)a

AP-PA fields • ≥ 100 • ≥ 95 • ≥ 80 • ≥ 50 Boost • ≥ 100 • ≥ 95 • ≥ 80 • ≥ 50 a

Esophageal volume [% (SD)] Grade 0–1 Grade 2 Grade 3 (n = 8) (n = 25) (n = 4)

p-value

22.8 (26.2) 68.8 (23.3) 83.4 (19.4) 86.8 (18.6)

18.9 (18.6) 60.2 (22.5) 82.4 (13.6) 85.5 (13.5)

21.8 (25.6) 52.6 (22.6) 83.8 (8.6) 87.5 (6.0)

0.89 0.5 0.97 0.95

8 (14.9) 38.9 (23.7) 64.2 (33.3) 71.5 (29.1)

19 (20.1) 46.3 (22.8) 63.1 (27.4) 68.7 (27.1)

10.3 (19.6) 26.6 (23.8) 59.2 (16.3) 66.5 (19.4)

0.33 0.27 0.96 0.95

values referred to the percentage of prescribed dose for each part of the treatment, depending on radiotherapy purpose (AP-PA fields: 38.4 Gy; boost: 16 Gy and 26.2 Gy for postoperative and definitive radiotherapy, respectively)

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Table 5. Distribution of patients developing toxicity compared across demographic, clinical and treatment-specific variables using Fisher’s exact test. AP-PA: anterior-posterior and posterior-anterior fields; iCT: induction chemotherapy; PS: performance status (Karnofsky index); 3tdRT: three-times-daily radiotherapy. Tabelle 5. Verteilung der Patienten, bei denen toxische Wirkungen auftraten: Vergleich der demographischen, klinischen und behandlungsspezifischen Variablen mit dem Fisher-Exakt-Test. AP-PA: anterior-posteriore und posterior-anteriore Felder; iCT: Induktionschemotherapie; PS: Performance-Status (Karnofsky-Index); 3tdRT: dreimal tägliche Strahlentherapie. Patient distribution Grade 0–1 Grade 2–3 (n = 8) (n = 29) p

Variable Sex Age (years) Histologyb

PS T-class

N-class Stage Lobeb

Positive node stations (n)b iCT G3 toxicityb iCT dose reductionb 3tdRT dose (Gy) AP-PA target volume (cm3)a Boost target volume (cm3) a b

M F < 58a ≥ 58 Squamous cell carcinoma Adenocarcinoma < 90a ≥ 90 1 2 3 4 2 3 IIIA IIIB Upper Medium Lower 1 2 ≥3 Yes No Yes No 64.6 54.4 < 239a ≥ 239 < 206a ≥ 206

7 1 4 4 3

25 4 13 10 13

4 3 5 0 5 3 0 8 0 8 0 6 1 1 3 2 2 2 5 1 7 6 2 5 3 6 2

12 4 25 1 20 6 2 19 10 17 12 2 0 7 7 7 6 11 15 9 19 12 17 14 15 13 16

1.0 1.0 1.0

0.16 0.66

0.08 0.03 0.13

0.92

0.67 0.39 0.23 0.70 0.23

median values parameters containing missing frequencies due to unknown data

The iCT regimen has already shown its good tolerance and proven efficacy in this kind of disease [5, 9, 27, 36]. At the same time, the possibility of radical surgery for IIIA patients who experienced a response to iCT was also considered, as recommended in a previous report [1]. RT total dose and fractionation were chosen keeping the linear-quadratic formula in mind [13]. For a radical treatment, calculated biological effec-

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tive dose (BED) for early- and late-reacting tissues was 72 Gy10 (calculated assuming an α/β ratio of 10) and 89 Gy3 (α/β ratio of 3), respectively, with a theoretical similar impact on tumor and acute toxicity of a conventional RT and a potential advantage in terms of late toxicity reduction. Postoperative mediastinal irradiation was planned using the same unconventional fractionation yet with a lower total dose. The inclusion of postoperative patients was performed to guarantee a better theoretical local treatment even on good-prognosis patients with subclinical disease only, even if we were conscious that such a decision could increase the heterogeneity of the population and reduce the statistical power of any conclusion. Concerning technical details of irradiation, a “concomitant-boost” approach was chosen, improving the spinal cord tolerance by means of an adequate interval between the larger treatment fields. This approach is similar to another study of 3tdRT reported in the literature (Eastern Cooperative Oncology Group, ECOG 4593) in which 30 stage IIIA–B patients were treated with exclusive RT up to 57.6 Gy, delivered in two daily fractions of 1.5 Gy to a larger volume, and a concomitant boost of 1.8 Gy in the central daily fraction. Reported toxicity was represented by early dysphagia (ECOG ≥ 3 grade esophagitis) in 22% of cases, without RT interruptions [24]. Similar results have also been reported in the well-known CHART trial where acceptable toxicity occurred, with dysphagia as the prevalent early-morbidity event. Severe difficulty in swallowing and alimentation limited to fluids were only experienced by 19% of patients, while a soft diet was tolerated by 46% of patients and some discomfort was observed in 28% [28]. The moderate dysphagia observed in two thirds of our patients was expected, due to the irradiation technique and the intensive fractionation used. Nevertheless, the very low rate of severe esophagitis (10% grade 3), the satisfactory compliance with the treatment schedule (only one interruption of 3tdRT), and the absence of severe lung toxicity or late effects were surprising [38] and confirmed the feasibility of the regimen. A comparison between our observation and previously reported experiences is somewhat difficult, due to differences in patient selection, study design, treatment characteristics, and the different criteria used to score toxicity. Focusing on “low-grade” (grade 1–2) toxicity levels, mild to moderate dysphagia occurred more often in our study than in the CHART and ECOG trials (86.5%, 74%, and 78%, respectively). This trend was, on the other hand, not confirmed for “high-grade” (≥ grade 3) toxicity where 3tdRT, compared to the other two studies, showed lower rates (10.8%, 19%, and 22%, respectively), as shown in Table 6. A relevant heterogeneity in patient populations exists in the three series and different inclusion criteria may have played a role in such composition. In this context, the impact of pretreatment dysphagia might be of particular importance, since this parameter is known to be predictive of severe esophagitis [23]. In our population any

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signs or symptoms of esophageal toxicity occurred before 3tdRT started; unfortunately, except for the 40% pretreatment weight loss reported in ECOG 4593, no data concerning this point was mentioned regarding CHART patients. In the CHART trial the population was very heterogeneous, with more than one third of patients (36%) having stage I–II disease; furthermore, a strict restriction of irradiated areas was made, limiting the “large-field” area to 240 cm2 and the “boost” area to 140 cm2. This restriction probably led to a different extent of esophageal irradiation compared to the more advanced stage III tumors included in our series. More analogies are observed between our trial and the ECOG study, in particular on patient characteristics and technical treatment approach. RT technique was, indeed, very similar overweighting the short interfraction interval, predictive of severe toxicity [34], with a “concomitant boost” approach in which esophageal irradiation tended to be theoretically minimized. Moreover, in both studies the patient population consisted of locally advanced disease cases, although in the ECOG trial the aim of treatment was only curative and postoperative option was not contemplated. Actually, the role of field extension in the genesis of acute esophageal toxicity is still a matter of controversy. As for lung toxicity, according to common opinion a direct relationship exists and the current trend is to minimize volumes of treatment, especially in the context of dose escalation [20]. Contrarily, some other analysis showed no correlation between toxicity and irradiated esophageal length, assuming that acute dysphagia is related more to the individual sensitivity [6, 23, 37]. In this context, a retrospective review on 207 consecutive NSCLC patients rejected any correlation between esophagitis and the percentage of esophageal volume exposed to a certain dose, underlining the concept of the maximal esophageal dose as being significantly associated with a major risk of ≥ grade 3 toxicity. No other patient- or treatment-related parameters were found to be predictive of severe esophagitis [35]. Our results apparently confirm the latter hypothesis of no correlation between irradiated esophageal volume and toxicity. Looking at the DVH analysis, an apparent contradiction emerges: despite the evidence of important esophageal irradiation both in AP-PA and boost phase, with > 61% of the esophagus being irradiated to > 95% and 80% of the prescribed dose, respectively (Table 3), there is no statistical correlation with toxicity (Table 4). In addition, other parameters theoretically related to the disease extension (T-class, number of positive mediastinal stations, AP-PA and boost target volume) are not correlated with the incidence and severity of esophagitis. On the other hand, N-class (N2 vs. N3) and clinical stage (IIIA vs. IIIB) evidenced a significant correlation with the toxicity level (Table 5). The interpretation of these findings is difficult, because these parameters seem to be related to the disease extension and, realistically, to the amount of esophagus irradiated, thus contradicting the absence of sig-

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Table 6. Comparison of acute esophageal toxicity in the present study (3tdRT) versus CHART [28] and ECOG [24]. ECOG: Eastern Cooperative Oncology Group; RTOG: Radiation Therapy Oncology Group; 3tdRT: three-times-daily radiotherapy. Tabelle 6. Vergleich der akuten Ösophagustoxizität in der vorliegenden Studie (3tdRT) versus CHART [28] versus ECOG [24]. ECOG: Eastern Cooperative Oncology Group; RTOG: Radiation Therapy Oncology Group. 3tdRT: dreimal tägliche Strahlenherapie. 3tdRTa Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 a b

2.7% 18.9% 67.6% 10.8% 0

CHART

ECOG 4593b

None 7% Some discomfort 28% Soft diet 46% Fluids only 19% Severe 0

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

0 14% 64% 18% 4%

toxicity defined according to RTOG criteria toxicity defined according to ECOG criteria

nificance emerged from the DVH analysis. Compared to the results of the study by Singh et al. [35], our analysis was not able to calculate the maximal esophageal dose, since our treatment planning system did not allow a DVH calculation of the “summed plan”, so that the value of this factor was not investigated. Unfortunately, the small number of patients and events observed and the limited statistical power of the analysis may obscure further potential significant differences and represent a limitation to better clarify the impact of dosimetric and volumetric parameters in acute esophagitis genesis. Since the heterogeneity in treatment aim (i.e., curative vs. postoperative), with half of patients (51%) receiving a lower total dose, might explain the low rate of ≥ grade 3 esophagitis observed, we contemplated a comparison between toxicity and RT dose. Although potentially obscured by the small sample size, the lack of significance observed might support a negligible role of total prescribed dose on acute esophagitis incidence. Another parameter expected to be relevant in the toxicity occurrence is the addition of CT and particularly the timing with RT. As already mentioned, an increase of esophagitis in case of concomitant chemoradiation is well documented in the literature [3, 33, 37]. Concerning sequential association of RT to iCT, the impact of systemic treatment on severe esophageal toxicity incidence and on the duration of symptoms is less evident. Dillman et al., in CALGB 8433 trial, documented only 1% of early severe esophagitis after iCT [11, 12]; furthermore, in the RTOG 8808/ECOG 4588 trial acute complications were represented by “prevalent” pulmonary toxicity [32]. In a recent trial of continuous hyperfractionated accelerated radiotherapy week-end-less (CHARTWEL) combined with neoadjuvant CT, systemic treatment was given sequentially [30]. This approach resulted in enhancement of the incidence and the duration of acute dysphagia; nevertheless, this increase was transient, subsequent healing occurred in all cases, and no evidence of late esophageal complications was shown.

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In our study, we did not find any correlation between the iCT-related parameters and toxicity. In particular, neither the presence of iCT grade 3 toxicity nor the reduction (due to toxicity) of the planned iCT regimen were associated with more severe toxicity. As already remembered, it is difficult to make comparisons between our results and others, because of the lack of statistical power due to the small number of events, and the differences in treatment schedules. For instance, the median duration of irradiation in our study was longer (27 days for definitive 3tdRT, compared with 18 days in CHARTWEL 60 Gy treatment), and the fraction dose was lower (1.2 + 1 + 1.2 Gy vs. 1.5 Gy three times daily). With these uncertainties it is still possible that our findings may be a consequence of different study inclusion criteria, confirming the importance of patient selection, well known to be potentially related to radiation-induced esophagitis incidence [23]. The toxicity profile in our series was in agreement with other reports present in the literature. In particular, the rate of severe dysphagia was lower than initially expected on the basis of BED calculations. For definitive treatments, calculated BEDs for early-reacting tissues were 72 Gy10; so, compared with CHART schedule (BED10 of 62 Gy10) and ECOG schedule (BED10 of 67 Gy10), a higher biological effect on early toxicity could theoretically occur. As mentioned above, it was difficult to compare our toxicity results with the data obtained from the other two studies of 3tdRT because of differences in patient selections and treatment characteristics. Furthermore, apart from the theoretical radiobiological considerations, it has to be remembered that, compared to the other trials, in our schedule the fraction dose was lower and the planned and resultant treatment time were more prolonged. These factors might have positively affected treatment compliance. Last, the small number of patients and events did not allow for a definitive comparison of results among the studies. Anyway, despite these limitations, our results seem to support a negligible role of dosimetric parameters and induction CT regimen in the genesis of radiation-induced acute esophagitis. Our results also confirmed the clinical feasibility of and the good patient compliance with this intensive approach of 3tdRT, preceded by iCT, as a definitive or postoperative local treatment in locally advanced NSCLC, as already reported [10]. Analysis of pattern of failure and long-term survival is warranted to confirm the overall efficacy of this approach as an acceptable treatment option in well-selected locally advanced NSCLC.

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Address for Correspondence Gianpiero Catalano, MD Division of Radiotherapy European Institute of Oncology Via Ripamonti 435 20141 Milano Italy Phone (+39/2) 5748-9037, Fax -9036 e-mail: [email protected]

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