Lung cancer is occasionally detected as small centrally located tumors such as carcinoma in situ (CIS) or early invasive cancer. When lymph node and distant metastasis are not present, good clinical outcome including cure can be expected. Surgical resection, photodynamic therapy (PDT), and endobronchial brachytherapy are the modalities of treatment of choice. Although surgical resection is the standard treatment for early invasive central airways lung cancer, elderly patients or those with severe comorbidities are frequently determined medically inoperable. Additionally, as most of CIS or early invasive central airways lung cancers are smoking-related and have a tendency to be multifocal, conservative treatment is often sought. PDT is less invasive and effective for CIS or early invasive cancer, but complete remission is unlikely with large lesions and those deeper than bronchial cartilage.1 In endobronchial brachytherapy, control of radiation dose is difficult and could lead to massive hemoptysis and exsanguination.2
Although external beam radiation remains an option for these patients, conventional one is associated with poor outcomes with 5-year survival rates of 25% to 30%.3–17 Dose escalation of radiation using conventional fractionation and techniques would likely cause prohibitive toxicity. Three-dimensional conformal radiotherapy (3D-CRT) is intended to deliver higher doses of radiation, while minimizing damage to surrounding normal tissues. Because good results are reported in 3D-CRT for stage I peripheral lung cancer, 3D-CRT may have a potential to be curative for central-type lung cancers.18 However, high-dose irradiation to hilar regions is still considered to be unsafe.19 However, high but acceptable dose of irradiation seems to be necessary for centrally located small lung cancers.
Since 2001, we have been treating CIS and early invasive central airways lung cancer using 3D-CRT, when the lesions were inoperable or too invasive to treat with PDT. In this manuscript, we report the safety and efficacy of 3D-CRT for small centrally located lung cancers.
MATERIALS AND METHODS
Between November 2001 and December 2004, 8 centrally located lung cancers without nodal (N0) and distant metastasis (M0) in 8 patients were treated with 3D-CRT with curative intent. Central lung cancer is defined as that originated from airways including and proximal to subsegmental bronchi.20,21 All lesions were cytologically or histologically proved as squamous cell carcinoma and located from carina up to the segmental bronchus. No tumors could be detected by conventional chest computed tomography (CT). The local spread of the lesions was determined by conventional and autofluorescence bronchoscopy, together with endobronchial ultrasonography. Routine staging of the disease included chest x-rays and CT scans of thorax and abdomen. Brain CT/magnetic resonance imaging and bone scintigraphy/positron emission tomography were not mandatory in the cases of CIS.
Pretreatment characteristics of all 8 patients are shown in Table 1. They were all males and smokers/exsmokers, whose Brinkman smoking indices were ranged between 800 and 1320. The median age was 71 (range: 56 to 80) years. Eastern Cooperative Oncology Group performance status was 0 in all patients. Most patients were considered to be inoperable, mostly as a result of comorbidities and poor pulmonary function owing to previous surgery, higher age, or chronic obstructive pulmonary disease. Two patients (nos. 1 and 8) experienced stump recurrences at the bronchial resection margins. In 1 patient (no. 7), a new primary lesion appeared away from the stump region. Another one (no. 2) was treated by PDT twice, surgery and endobronchial brachytherapy for the left lower lobe endobronchial cancer, yet developed recurrence. Another one (no. 4) had CIS and received prior PDT for the lesion, but complete regression could not be attained. The remaining 3 patients (nos. 3, 5, and 6) were considered to be inoperable mostly as a result of comorbidities and endobronchial therapy, such as PDT or brachytherapy, was not indicated owing to the extent of the lesions. Patient nos. 3 and 5 had CIS. As conformal radiotherapy (CRT) is considered to be the only available curative treatment, the modality was used after obtaining informed consent.
Plain CT images of 0.5-mm thickness were obtained over whole lungs. The images were transferred to radiation planning computer (CADPLAN, Varian Medical Systems, Palo Alto, CA) to make 3D-CRT plans. As the tumor could not be depicted on CT images, clinical target volumes (CTVs) were defined as possible tumor length along the bronchial tree and tumor depth into the bronchial wall on the basis of bronchoscopical findings. Hilar, mediastinal, and supraclavicular nodal regions were not included in CTV. The planning target volume (PTV) was designed by enlarging CTV in all directions by 8 to 10 mm, taking both setup uncertainty and respiratory movement into considerations. Radiation fields were formed with multileaf collimator to achieve conformity with leaf margin of 5 mm and coplanner 5-beams arrangement. Beam energy was 6 or 10 MV x-ray. Figure 1 shows an example of 3D-CRT planning for a central-type lung cancer.
Total 60 Gy, prescribed at the isocenter, was administered by 3-Gy fraction, once a day for 4 weeks. V20 of the lungs was defined as the percentage of lung volume that received ≥20 Gy radiations in the treatment plan. The biologic effective dose (BED) was calculated using the following formula: BED=nd [1+d/(α/β)] where n=number of fractions, d=fraction dose, and α/β is assumed to be 10 for tumor cells or acute responding tissues.
Tumor response was evaluated by bronchoscopy and chest CT. Chest x-ray and CT were examined regularly. Radiation-induced toxicities were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) Late Radiation Morbidity Scoring Scheme. Pulmonary function tests including percent vital capacity and percent forced expiratory volume in 1 second and arterial blood gas analysis were obtained before and after the treatment to identify the risk factors for lung toxicity by 3D-CRT. Paired t test was used to compare respiratory function and PaO2 values.
The planned treatment was safely performed in all 8 patients with no or minimal acute adverse events. No acute esophageal toxicity was observed. Grade 1 acute radiation pneumonitis (RTOG) was observed in 1 patient. Local response was evaluated by both bronchoscopy and chest CT in 6 patients, but the other 2 patients were considered unsuitable for bronchoscopy and their response was evaluated by sputum cytology and chest CT.
The median follow-up period was 36.8 months (range: 30 to 50 mo). Median survival time was 36.8 months (range: 30 to 50 mo). The 2-year locoregional control rate was 100%. Six patients were alive and 2 died of intercurrent disease without recurrence of centrally located lung cancer. Local failure did not occur in any patient. During follow-up period, secondary lung cancer (adenocarcinoma in both patients) was developed in 2 of 8 patients and they underwent additional 3D-CRT. One of them died of secondary lung cancer due to primary failure at 31 and 10 months after the first and second CRT, respectively. The other patient is alive in the presence of metastasis to the bone and brain, whereas 2 primary sites were maintained to be well controlled in all examinations, including positron emission tomography.
No patient experienced late toxicities at 90 days from the first day of radiation therapy. Table 2 depicts the PTV and the V20 values. The median PTV was 45.5 mL (range: 27.6 to 61.8mL) and the median V20 value was 10.7% (range: 8.3 to 17.0). We did not encounter interstitial changes in the irradiated lung field with this focal radiation therapy in any of our patients (Figs. 2A, B). Bronchoscopically, the irradiated bronchus was slightly stenotic and scarred (Figs. 3A, B). Respiratory functions and arterial blood gas analysis were unaffected in all patients who underwent the evaluation (Figs. 4A–C). Some patients did experience acute radiation esophagitis, yet it was in grade 2 or less at each occasion.
Natural history of CIS and severe dysplasia in the respiratory tract is not clarified completely, and therefore, their treatment strategy is still controversial. Although all of these lesions do not necessarily progress to clinically relevant lung cancers,22 appreciable proportions of them have high risk of becoming invasive carcinoma. Their risk to progress to a clinical lung cancer was reported to be 33% at 1 year and 54% at 2 years.23 Therefore, these lesions should be treated in their early stages.
Surgery is the standard treatment for early invasive central airways lung cancer in the patients with good performance status. In Japan, 5-year survival rates of the patients with lung cancer treated surgically are 72% for cIA and 49.9% for cIB and 79.5% for pIA and 60.1% for pIB.24 On the other hand, Kato et al1 reported that PDT yielded an initial complete response rate of 84.8% for centrally located early-stage lung cancer. PDT is considered as an effective alternative for surgery for centrally located stage 0 (TisN0M0) and stage I (T1N0M0) early invasive lung cancer, when surgical intervention is difficult or the patients refuse surgery. PDT is especially attractive for elderly patients or those in poor physical condition. Whereas PDT is reported to be effective only for the superficial tumors of <1 cm in diameter with visible peripheral margin and which is located no more peripherally than subsegmental bronchi, another modality is necessary for the tumors that do not fulfill at least 1 of these conditions.
For many years, the mainstay of treatment for inoperable lung cancer was radiation of nearly 60 Gy of total dose with 2 Gy/fraction over 6 weeks. Conventional external beam radiation of 60 to 70 Gy alone is reported to result in 15% of 5-year overall survival rate, 25% intercurrent death rate, and 50% of treatment failures in local site alone, in the expense of grade 3 to 5 complications of <5%.25 These results are not satisfactory for stage I lung cancer. On the basis of dose-response data, Mehta et al26 estimated that it would take a dose of approximately 85 Gy to achieve 50% long-term control rate using standard 2-Gy daily fractions. It seems that higher doses and shorter treatment times are required to achieve better disease control. However, radiation dose escalation using conventional fractionation and techniques would likely cause prohibitive toxicity. 3D-CRT is intended to deliver higher dose of radiation while minimizing damage to surrounding normal tissues. We treated the patients by CRT with 20 fractions of 3 Gy. The biologically effective dose (BED) of this radiation is calculated to be almost equal to 78 Gy in conventional fractionation (assuming α/β of 10). Almost no, at most minimal, interstitial changes were observed in the irradiated lung fields (Figs. 2A, B). This observation was further supported by the fact that respiratory functions were unaffected by the treatment in all patients. These are ascribed to very limited PTV with a median of 45.5 mL. Lagerwaard et al27 showed that central location of tumors (endobronchial tumor extension) was the only factor that significantly reduced local progression-free survival in 3D-CRT for lung cancer. Our good results can be ascribed to small size of the tumors, which do not require large dose of radiation compared with established invasive cancer. Recently, stereotactic radiotherapy (SRT) is showing favorable results in the treatment of peripherally located stage I lung cancer. Timmerman et al19 reported a phase 2 trial of SRT with 60 to 66 Gy in 3 fractions during 1 to 2 weeks in 70 patients with medically inoperable early-stage lung cancer. Grade 3 to 5 toxicity occurred in 14 patients (20%). In 2-year follow-up after SRT, 83% of the patients with peripherally located lung cancer experienced no severe complications, whereas 54% of those with centrally located cancer did. The patients with centrally located tumors have 11-fold increased risk of experiencing severe complications compared with those with lung cancer located more peripherally. Their conclusion was that SRT of this regimen should not be used for the patients with tumors located near the central airways because of excessive complications. Similarly, Le et al28 reported the results of dose-escalation study using single-fraction SRT of 15 to 30 Gy for lung tumors. Majority of the patients who showed grade 2 or greater complications had either centrally located tumors and/or the tumors with treatment volumes greater than 50 mL. The toxicities observed included pneumonitis, pleural effusion, pulmonary embolism, and tracheoesophageal fistula. These results indicate that high-dose radiation by limited fractions is dangerous for perihilar structure of the lung. As small lung cancer, such as CIS and early invasive cancer, is curative by radiation with sufficient dose, determination of total dose and fractionation is critical to treat small lung cancer located in the central airways. Although the number of the patients entered into this study is small, our method may afford a good clue.
As small lung cancer, such as CIS and early invasive cancer, is curative by radiation with sufficient dose, determination of total dose and fractionation is critical to treat small lung cancer located in the central airway. 3D-CRT given by 20 fractions of 3 Gy is a safe and effective treatment for inoperable CIS or early invasive central airways lung cancer.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
conformal radiotherapy; in situ or early invasive central airways lung cancer; local control; radical radiotherapy