Lung cancer

Background: It is well known that central-type early stage lung cancer < 1.0 cm in diameter shows almost 100% complete response (CR) to photodynamic therapy (PDT). However, we have encountered cases of local recurrence after CR of tumors with a surface diameter < 1.0 cm.

Patients and methods: Ninety-three patients with 114 lesions were followed up, and eases of recurrence after CR has been obtained with initial tumors that had a diameter < 1.0 cm were examined. We compared the cytologic findings of local recurrence after CR to the cytologic findings before PDT. The relationship between the cell features and the depth of bronchial tumor invasion before PDT and on recurrence was evaluated.

Results: The CR and 5-year survival rates of patients with lesions < 1.0 cm were 92.8% (77 of 83 patients) and 57.9%, respectively; meanwhile, in the group of patients with lesions [greater than or equL to 1.0 cm, CR and 5-year survival rates were 58.1% (18 of 31 patients) and 59.3%. There was a significant difference in efficacy between the two groups (p < 0.001). Recurrences after CR were recognized in 9 of 77 lesions (11.7%) < 1.0 era. When the recurrent tumor cells showed type I-II (low-to-moderate atypia) at the same site initially treated, CR could be obtained by a second PDT. Type III cells (high-grade atypia) showed the characteristics of tumor cells from deeper layers of the bronchial wall. Local recurrence at the same site may be caused by residual tumor cells from deep layers because of inadequate laser irradiation and penetration.

Conclusions: To reduce the recurrence rate, it is essential to accurately grasp the tumor extent and the depth of the bronchogenic carcinoma before performing PDT. Analysis of cell features of recurrent lesions after CR appears to be a useful source of information as to the depth of cancer invasion in the bronchial wall.

Key words: early stage lung cancer; occult lung cancer; photodynamic therapy; porfimer sodium

Abbreviations: AFB = autofluorescence bronchoscopy; CIS = carcinoma in situ; CR = complete remission; EBUS = endobronchial ultrasonography; ESLC = early stage lung cancer; PDT = photodynamic therapy; PR = partial remission

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Lung cancer has a tendency to develop in older people, with a very poor prognosis A total of 55,000 Japanese died from lung cancer in 2003, which made it the number-one cause of cancer death. Although diagnostic techniques such as highresolution CT scan, video bronchoscopy, fluorescence bronchoscopy, and endobronchial ultrasonography (EBUS) have been developed recently, many patients with newly detected lung cancer still have inoperable advanced cancer. Therefore, the detection of early stage lung cancer (ESLC) is considered essential to reduce the mortality rate. Meanwhile, even when ESLC is detected, some eases are inoperable because of cardiopulmonary dysfunction due to age. Endoscopic procedures that are minimally invasive and do not compromise pulmonary function are considered useful modalities for centrally located lung cancer. In particular, photodynamic therapy (PDT) is considered a useful and attractive modality for central-type ESLC. (1-7) Its action mechanism is considered to involve singlet oxygen, which is generated through photochemical reactions and causes degenerative necrosis of cells that have taken up the photosensitizer, it, tumor cells. (8)

PDT using red laser light and a tumor-specific photosensitizer was established as a new therapeutic modality for central-type ESLC in 1982. (1) The length of longitudinal tumor extent was the only independent predictive factor for complete remission (CR), and 100% CR in lesions < 1.0 cm in diameter treated by PDT was reported. (5) However, we have encountered local recurrences after CR of tumor even in cases with a surface diameter < 1.0 cm. Therefore, we investigated the characteristics and cytomorphologic features of primary lesions and recurrences after CR in patients with lesions < 1.0 cm in diameter.

MATERIALS AND METHODS

Patient Selection

A total number of 145 patients with 191 lesions of endoscopic ESLC uuderwent PDT from February 1980 to April 2001 in the Department of Tokyo Medical University. Of the 145 patients with 191 lesions, 93 patients with 114 lesions were followed up, and cases of recurrence after CR was obtained with initial tumors with a diameter < 1.0 cm were examined.

Procedures of PDT and Follow-up

The depth of tumor invasion was judged by biopsy specimen and CT scan, and was also evaluated by bronchoscopic findings based on the diagnostic criteria of ESLC defined by the Japan Lung Cancer Society. (9) To determine tumor size, bronchoscopic biopsies of the proximal and distal sites of the lesion and bronchoscopic measurements using forceps were performed. PDT procedures were performed with the combination of Fortimer sodium (Photofrin; Wyeth Japan K.K.; Tokyo, Japan) that is taken up selectively in tumor, and an argon gas laser system (model 770; Spectra-Physics; Mountain View, CA) or excimer dye laser (EDL-1; Hamamatsu Photonics; Hamamatsu, Japan). Laser irradiation was performed via a quartz fiber inserted through the biopsy channel of the endoscope at 48 h alter the IV administration of 2.0 mg/kg of porfimer sodium. The total energy of the laser irradiation was 100 J/[cm.sup.2], and energy levels in this range do not cause any heat degeneration or other adverse effects. The duration of irradiation required usually 10 to 20 min. Clean-up bronchoseopies to remove necrotic tissue produced by the PDT reaction were performed at 1, 3, and 7 days after PDT. Both cylologic and histologic examinations via fiberoptic bronchoscopy were performed at 1, 2, and 3 months, and thereafter at 3-month intervals in the first year and 6-month intervals after the second year until 5 years after PDT.

Efficacy Evaluation

The antitumor effect of initial treatment was rated based on endoscopic measurement of tumor size using forceps, morpho logic observations, and histopathologic examination by biopsy, according to the general rules of the Japan Lung Cancer Society9 and the Japan Society of Clinical Oneology. (10) The antitumor effect was rated at 1 month and 2 months after PDT. Antitumor effect was rated as CR (no demonstrable tumor microscopically by brushing and/or biopsy for a period of 4 weeks), partial rernission (PR) [[greater than or equal to] 50% reduction in tumor size], no change (< 50% reduction or < 25% increase in tumor size), progressive disease (> 25% increase in tumor size), or not evaluable.

Evaluation of Cytomorphologic Features of Local Recurrences

In the central-type ESLC < 1.0 cm in greatest dimension, we have compared the cytologic findings of local recurrence after CR to the cytologic findings before PDT using bronchial brushing specimen. Cytologic findings were classified into three cytologic morphotypes using the classification of cell features proposed by Konaka and coworkers, (11) which appears to yield information as to the depth of cancer invasion in the bronchial wall. The classification was described as follows: type I cell, low-grade atypia (resembling atypical squamous cell metaplasia); type II cell, moderate-grade atypia (resembling early stage squamous cell carcinoma); and type III cell, high-grade atypia (resembling invasive squamons cell carcinoma). The biopsy specimens before PDT and on recurrence, or resected materials, in cases of resection after recurrence, were examined histopathologically, and the depth of bronchial wall invasion was classified into three groups: grade 1, carcinoma in situ (CIS) or microinvasion; grade 2, extramuscular bronchial wall invasion; and grade 3, intracartilaginous to extracartilaginous invasion. The relationship between the cell features and the depth of bronchial tumor invasion before and after PDT was evaluated.

Statistical Analysis

Statistical analysis were done using statistical software (Stat Flex for Windows, version 5.0; Artec; Osaka, Japan). The [chi square] test was used to compare the efficacy of PDT between lesions < 1.0 cm and > 1.9 cm in diameter. Differences between the survival rates of two groups in the Kaplan-Meier survival curves were analyzed using the log-rank test; p < 0.05 was considered to indicate a statistically significant difference.

RESULTS

Results of PDT for Central-Type ESLC

A total of 93 patients with 114 lesions of centraltype ESLC who underwent PDT were examined. Thirteen synchronous lesions in six cases, 15 metachronous lesions in six cases, and 5 synchronous/ metachronous lesions in one ease were observed. The evaluation of the efficacy of PDT is shown in Table 1. CRs and PRs were obtained in 75 patients with 95 lesions (83.3%) and in 18 patients with 19 lesions (16.7%) out of 93 patients with 114 lesions. Each lesion with PR was subsequently treated with other modalities, including surgery in 13 eases, chemotherapy in 5 eases, or radiotherapy in 1 case, and finally achieved 100% CR. Recurrences after CR were recognized in 12 of 95 lesions (12.6%). The 114 lesions were classified in two groups according to the maximum longitudinal tumor extent. Of these, 83 lesions (72.8%) were < 1.0 cm and 31 lesions (27.2%) were [greater than or equal to] 1.0 cm in diameter. The CR and PR rates in the group of patients with lesions < 1.0 cm in maximum diameter were 92.8% (77 of 83 patients) and 7.2% (6 of 83 patients), respectively. Meanwhile, in the group of patients with lesions [greater than or equal to] 1.0 cm in diameter, the CR and PR rates were 58.1% (18 of 31 patients) and 41.9% (13 of 31 patients), respectively. Neither no change nor partial disease were observed in these groups. There was a significant difference in efficacy between the two groups using the [chi square] test (p < 0.001). Recurrences after CR were recognized in 9 of 77 lesions (11.7%) in the group < 1.0 cm and 3 of 18 lesions (16.7%) in the group [greater than or equal to] 1.0 cm in diameter. The overall S-year survival rates of the two groups were 57.9% and 59.3%, respectively (Fig. 1). There was no significant difference between the two groups on the basis of the log-rank test (p = 0.207).

[FIGURE 1 OMITTED]

Characteristics of Local Recurrence < 1.0 cm in Diameter After CR

The information on nine patients with nine lesions in the group of patients with lesions < 1.0 cm in diameter who had recurrence after CR had been achieved by initial PDT are presented in Table 2. All patients with recurrence were male, and the age distribution ranged from 64 to 71 years (average age, 67.6 years at the time of initial diagnosis). Evidences of local recurrence were found in nine patients with nine lesions at the site of the primary lesion. The recurrent lesions were located on the trachea in one patient, lobar bronchus in one patient, segmental bronchi in five patients, and subsegmental bronchi in two patients. The average diameter of the nine recurrent lesions was 0.46 cm. All lesions were squamous cell carcinoma, and endoscopic findings showed nodular type in two lesions and superficial type in seven lesions. The disease-free interval of these nine patients ranged from 3 to 18 months (average, 10 months).

Local recurrence at site corresponding to the peripheral margin of the lesion initially treated by PDT was observed in three patients (cases 1 to 3), while local recurrence at the same site as the initial tumor initially treated was observed in six patients (cases 4 to 9). The local recurrences at the site corresponding to the peripheral lesion were initially located in the subsegmental bronchus in two of three primary lesions. The patients with three local recurrences at the site corresponding to the peripheral margin underwent a second PDT session; however, CR was not obtained in any of these patients. Therefore, additional conventional surgery was performed in two patients and brachytherapy in one patient. The pathologic examinations of two operated patients showed residual tumor at the peripheral site. Right upper lobectomy was performed for case 1, and the resected material revealed superficial tumor invasion peripheral to the right [B.sup.3]b. Left pneumonectomy was selected for case 2 (ipsilateral double cancer) because an ESLC was located at the bifurcation of left [B.sup.3]a-b and a malignant lymphoma was in left [B.sup.3]. This patient died due to malignant lymphoma at 56 months after the initial PDT session. Four patients (cases 4 to 7) with six local recurrences at the same site as the initial tumor local showed superficial tumor invasion (CIS), and a second PDT session was performed in three of four patients. CRs were again obtained in all three patients, who are presently disease free. One double cancer patient who had advanced stomach cancer underwent systemic chemotherapy without a second PDT but died 5 months after the initial PDT session. The pathologic examinations of the two other surgically treated patients (cases 8 and 9) revealed intracartilagious invasion of the bronchial wall. One multiple lung cancer patient (case 8) who received right middle and lower lobectomy after local recurrence died of hemoptysis due to another advanced lung cancer at 56 months after the initial PDT session. At the last follow-up of the nine patients who had local recurrence after CR had been obtained by initial PDT in whom the original primary lesion had been < 1.0 cm in diameter, three patients had died of other diseases and six patients were alive, and there were no deaths from the primary lesion.

Evaluation of Cytomorphologic Features of Local Recurrences

As mentioned above, local recurrence of the carcinoma at the same site as lesions < 1.0 cm in diameter initially treated successfully by PDT was observed in six out of nine locally recurrent patients (cases 4 to 9). A summary of the cell features and depth of bronchial wall invasion before PDT and after recurrence are shown in Table 3. The brushing cytology specimens before PDT mainly showed type I or II, and biopsy revealed grade 1 in all six cases. The majority of cell features in cases 4 to 7 showed type I or II, and the biopsy specimens showed grade 1 on recurrences. The cytopathologic and bronchoscopic findings of case 7 are shown Figure 2. Populations of type I and II cells were predominant in the recurrent lesions in these cases, which implied that the recurrent tumor was located in a superficial layer of bronchial wall. When the recurrent tumor cells showed type I-II (low-to-moderate atypia) local recurrence at the same site as the initial tumor initially treated, CR could be obtained by a second PDT. In cases 8 and 9, mainly type III cell features were observed in brushing cytology on recurrence (Fig 3). These two cases underwent resection, and the resected specimens revealed intracartilagious tumor invasion of bronchial wall (grade 3), which implied the residual tumor located in a deep layer of bronchial wall.

[FIGURES 2-3 OMITTED]

DISCUSSION

PDT for cancer using a combination of low-power laser irradiation and tumor specific photosensitizer was first applied clinically by Dougherty et al (12) in 1978 to the skin metastasis of breast cancer. Since then, we performed the first reported endoscopic clinical application of PDT in cooperation with Dougherty and coworkers. (12) In Japan, PDT using porfimer sodium, a tumor-specific photosensitizer and excimer dye laser, was recognized by the government; and from April 1996, hospitals could receive reimbursement for PDT of early stage carcinomas of the lung, esophagus, stomach, and cervix from the national health insurance system.

The best PDT candidates in lung cancer are cases with central-type ESLC because of their endoscopic accessibility; therefore, selection of patient is important to achieve CR. Nagamoto et al (13) demonstrated that no lymph node involvement was found in 59 cancers with a longitudinal extent of < 20 mm; in another study, (14) histology by serial block sectioning showed that there was no nodal involvement in any CIS cases. Nakamura et al (15) retrospectively analyzed resected cases of central-type ESLC to clarify the relation between the endoscopic findings and the histologic extent of tumor. They demonstrated a significant difference is the maximum dimension according to the depth of bronchial invasion between CIS and extramuscular invasion and CIS and invasion into or beyond the cartilaginous layer. Lesions with a maximum diameter < 1.0 cm have a high possibility of being CIS. Their preoperative bronchoscopic diagnosis of centrally located ESLC was correct in 74.0%. In another study, Akaogi et al (16) demonstrated that polypoid or nodular lesions < 1.0 cm and flatly spreading lesions < 1.5 cm in greatest dimension were limited to within the cartilaginous layer without regional lymph node involvement. Also, Furuse et al (5) demonstrated that the length of longitudinal tumor extent was the only independent predictive factor for CR by PDT, and that lesions < 1.0 cm in diameter showed 100% CR. According to these data, therapy for CR requires satisfaction of the following endoscopic conditions: (1) no evidence of lymph node metastasis; (2) the lesion is superficial with a maximum diameter of < 1.0 cm; (3) no invasion into or beyond the cartilaginous layer; (4) the histologic type is squamous cell carcinoma; and (5) the lesion is located in a position that can be easily irradiated with the laser.

In this study, excellent efficacy with a significant difference of CR rate was seen in patients with lesions < 1.0 cm (92.8%) compared to [greater than or equal to] 1.0 cm (58.1%) in diameter; however, the overall 5-year survival rate of the two groups showed no significant difference (57.9% vs 59.3%). This may be because it was possible to perform additional alternative modalities such as surgery, second PDT, and brachytherapy to achieve CR after failure of initial PDT or recurrence after PDT. Considering that the 5-year survival rate of pathologic stage Ia (T1N0M0) patients who underwent surgery is approximately 67.0%, (17) our data are favorable because the majority of the PDT group consisted of patients with advanced age and poor cardiopulmonary function. Therefore, we consider that PDT may be used as first-line therapy for central-type ESLC prior to surgery, especially in cases with poor cardiopulmonary function. Also, Edell et al (18) and Cortese et al (19) demonstrated that PDT is an alternative to surgical resection in the management of early superficial squamous cell carcinoma.

In this study, recurrence after CR was recognized in 9 of 77 lesions (11.7%) in the group of patients with lesions < 1.0 cm in diameter. Despite the average diameter of the nine initial lesions being relatively small (0.46 cm), recurrence was recognized in eight of nine lesions (88.9%) within 12 months. Therefore, intensive follow-up studies should be performed until 1 year after PDT even for small primary lesions. The reasons why recurrences after CR were observed in the lesions < 1.0 cm in diameter could be explained by inappropriate estimation of the peripheral margin in eases of local recurrence at the site corresponding to the peripheral margin and insufficient laser irradiation or miss estimation of tumor depth in the cases of local recurrence at the same site as the initial tumor.

From our experiences, to achieve CR with PDT for central-type ESLC, it appears that not only the analysis of cell features but also the comprehension of tumor extent to the peripheral site and tumor invasion to the bronchial wall are of considerable significance. Kurimoto et al (20) demonstrated that endobronchial EBUS was useful to determine the depth of tumor invasion into the bronchial wall, and the accuracy of EBUS from the histopathologic findings was 95.8%. The EBUS image at 20 MHz shows five layers in the cartilaginous portion of bronchial wall. The third to fifth layers are images of cartilage. Therefore, it is feasible to evaluate the depth of invasion using EBUS whether or not the tumor invades into or beyond the cartilaginous layer.. In lesions with an intact third layer on EBUS, CR could be achieved with PDT. Miyazu et al (21) demonstrated that the depth of tumor invasion estimated by EBUS was accurate by histopathologic findings after surgical resection. They found 5 of 14 lesions (.35.7%) < 1.0 cm in diameter that showed extracartilaginous invasion on the EBUS image that was later confirmed histopathologically; also, 3 of 5 lesions appeared bronchoscopically superficial but were shown to be extracartilaginous by EBUS. The indications of PDT for centrally located ESLC with a longitudinal extension of < 1.0 cm are unquestionable; meanwhile, we should realize that even < 1.0 cm in diameter can have extracartilaginous invasion. To comprehend the surface extent of superficial tumor invasion iii the bronchial lumen, autofluorescence bronchoscopy (AFB) is considered useful. (22-25) The green autofluorescence of the lesion was decreased because of the lack of endogenous fluorophors, thickening of the membrane, and increased microvasculature. (26) We sometimes encountered unexpected surface invasion by AFB.

It is essential to know the extent of the tumor and the depth of bronchogenic carcinoma accurately for the selection of treatment modality. Corresponding to the previous study by Konaka et al, (11) the analysis of cell features is a useful source of information to evaluate the depth of cancer invasion in the bronchial wall. In addition, we believe that it could be beneficial information when choosing the treatment modality, such as recurrence after CR by PDT demonstrated in our study. Additionally, we now perform EBUS and AFB to determine the indications of PDT in all patients who have ESLC for the purpose of achieving 100% CR and reduction of recurrence rate. A comparative study of PDT for the treatment of ESLC before and after the adoption of EBUS and AFB will enable accurate evaluation of the benefits of these new diagnostic tools in the near future.

ACKNOWLEDGMENT: The authors are indebted to Professor J. P. Barron of the International Medical Communications Center of Tokyo Medical University for his review of this article.

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* From the Department of Chest Surgery (Dr. Furukawa), Kasumigaura Hospital, Tokyo Medical University, Ibaraki; First Department of Surgery (Drs. Kato, Konaka, Usuda, and Ebihara), Second Department of Pathology, Tokyo Medical University, Tokyo; and Center for Respiratory Diseases (Dr. Okunaka), Sanno Hospital, Tokyo, Japan.

Manuscript received February 12, 2005; revision accepted May 9, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. orgr/misc/reprints.shtml).

Correspondence to: Kinya Furukawa, MD, PhD, Department Chest Surgerry, Tokyo Medical University, Kasumigaura Hospital 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki 300-039,5, Japan; e-mail: k-furu@tokyo-med.ac.jp

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