Photodynamic Therapy for Early Stage Central Type of Lung Cancer

Abstract

Overall, results of treatment of lung cancer are unsatisfactory, and only marginally satisfactory results have been obtained with stage I lesions (Fig. 1), especially the early stage central type. Therefore, in order to cure lung cancer, detection and treatment of early stage lung cancer are essential. Some problems have been encountered in the early treatment of the central type of lung cancer. Recently available surgical procedures include bronchial plastic surgery and sleeve lobectomy in an effort to minimize reduction in lung volume. Because the indications for these procedures are limited, most patients still undergo extensive surgical resection even if the volume of the central type of early stage carcinoma is extremely small, such as in carcinoma in situ. Surgical treatment often is associated with postoperative complications, especially in elderly patients and patients with pulmonary dysfunction. Additionally, surgical intervention is a limited option for the multiple occurrences of lung cancer, which have recently increased: in our department, the detection rate was 2.17% (15 of 690 cases of lung cancer) from 1981 to 1985 but 4.55% (41 of 901 cases) from 1991 to 1995. Because the lung is a vital organ, maximal preservation of pulmonary function is important, regardless of therapeutic modality. From this standpoint, new minimally invasive therapeutic options are needed. Development of Photodynamic Diagnosis and Therapy.—Photodynamic therapy (PDT) is achieved by a photodynamic reaction that is induced by excitation of a tumor-specific photosensitizer exposed to light. Because this treatment makes it possible to manage malignant lesions selectively, it is an attractive strategy for small superficial malignant tumors. The phenomenon of photosensitization was already known at the beginning of this century.1Raab O Ueber die Wirkung fluorescirender Stoffe auf Infusorien.Z Biol. 1900; 39: 524-546Google Scholar Only since the 1960s, however, have developments in photobiol-ogy, bronchoscopy, endoscopy, and ancillary medical equipment resulted in the firm establishment of photodynamic diagnosis and PDT. In 1960, Lipson and Baldes,2Lipson RL Baldes EJ The photodynamic properties of a particular hematoporphyrin derivative.Arch Dermatol. 1960; 82: 508-516Crossref PubMed Scopus (281) Google Scholar at the Mayo Clinic, reported the development of hematoporphyrin derivative (HpD), which did not have the adverse effects of hematoporphyrin. After this development, these two investigators in conjunction with Olsen3Lipson RL Baldes EJ Olsen AM Hematoporphyrin derivative: a new aid for endoscopic detection of malignant disease.J Thorac Cardiovasc Surg. 1961; 42: 623-629PubMed Google Scholar and with Sanderson and Fontana4Sanderson DR Fontana RS Lipson RL Baldes EJ Hematoporphyrin as a diagnostic tool: a preliminary report of new techniques.Cancer. 1972; 30: 1368-1372Crossref PubMed Scopus (76) Google Scholar studied the localization of bronchogenic carcinoma by using a mercury arc lamp bronchoscopically for the first time in the world. These pioneers were later joined by Cortese, Edell, and Kinsey,5Cortese DA Kinsey JH Woolner LB Payne WS Sanderson DR Fontana RS Clinical application of a new endoscopic technique for detection of in situ bronchial carcinoma.Mayo Clin Proc. 1979; 54: 635-641PubMed Google Scholar, 6Edell ES Cortese DA Bronchoscopic phototherapy with hematoporphyrin derivative for treatment of localized bronchogenic carcinoma: a 5-year experience.Mayo Clin Proc. 1987; 62: 8-14Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar who are the authors of the current article in this issue of the Mayo Clinic Proceedings (pages 595 to 602). The development of HpD and the initial clinical studies by the investigators at the Mayo Clinic established the foundations of today's PDT. In 1975, Dougherty and associates,7Dougherty TJ Grindey GB Fiel R Weishaupt KR Boyle DG Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light.J Natl Cancer Inst. 1975; 55: 115-121PubMed Google Scholar at Roswell Park Memorial Institute, successfully treated tumors in animals by PDT with use of a xenon arc lamp. The subsequent introduction of laser equipment and medical electronics resulted in rapid progress in PDT. Since 1980, PDT has been used to treat patients with lung cancer, especially early stage central-type squamous cell carcinoma. When successful results were reported in 1982,8Hayata Y Kato H Konaka C Ono J Takizawa N Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer.Chest. 1982; 81: 269-277Crossref PubMed Scopus (403) Google Scholar PDT began to attract attention. The tumor-specific photosensitizer and laser with suitable wavelength are the key elements in PDT. Although HpD had been initially used as a photosensitizer for many years, Photofrin (porfimer sodium, a refined form of HpD) has recently been approved by several governments for clinical use. Various kinds of lasers such as the argon dye laser, gold vapor laser, copper dye laser, excimer dye laser, diode laser, and yttrium-aluminum-garnet (YAG) laser with a potassium titanyl phosphate crystal or an optical parametric oscillator have been used thus far. Although PDT may be viewed as a recent development, more than 3,000 malignant tumors in various organs have been treated by this technique thus far in 32 countries. Results With Use of PDT.—In the Department of Surgery at Tokyo Medical College, 251 patients with 297 lung cancers received PDT. Since 1980, PDT has been used in 95 patients with 116 early stage central-type squamous cell carcinomas. Complete remission was obtained in 77 patients (81%) and partial remission in 18 cases. Among the 77 patients with complete remission, recurrence was detected in 12 (16%). Currently, 72 patients are apparently free of disease after 2 to 195 months of follow-up. In patients with superficial lesions (less than 2 cm in longest dimension), almost 100% complete remission was obtained.9Furuse K Fukuoka M Kato H Horai T Kubota K Kodama N A prospective phase II study on photodynamic therapy with Photofrin II for centrally located early-stage lung cancer.J Clin Oncol. 1993; 10: 1844-1845Google Scholar A multicenter phase II clinical trial of PDT for early stage cancer was performed from 1989 to 1992 in an effort to obtain government approval in Japan.10Kato H Horai T Furuse K Fukuoka M Suzuki S Hiki Y Photodynamic therapy for cancers: a clinical trial of porfimer sodium in Japan.Jpn J Cancer Res. 1993; 84: 1209-1214Crossref PubMed Scopus (61) Google Scholar Photofrin and the excimer dye laser for PDT were given government approval in 1994 and national insurance reimbursement status in 1996. Balchum and coworkers11Balchum OJ Doiron DR Huth GC HPD photodynamic therapy for obstructing lung cancer.Prog Clin Biol Res. 1984; 170: 727-745PubMed Google Scholar reported the palliative effectiveness of PDT in advanced obstructive bronchial lesions. PDT resulted in a decrease in symptoms attributable to bulky tumors and maintenance of the quality of life for patients. Numerous investigators, including Hayata, Cortese, Edell, and Furuse, have described the effectiveness of PDT in early stage central-type lung cancer.6Edell ES Cortese DA Bronchoscopic phototherapy with hematoporphyrin derivative for treatment of localized bronchogenic carcinoma: a 5-year experience.Mayo Clin Proc. 1987; 62: 8-14Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 8Hayata Y Kato H Konaka C Ono J Takizawa N Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer.Chest. 1982; 81: 269-277Crossref PubMed Scopus (403) Google Scholar, 10Kato H Horai T Furuse K Fukuoka M Suzuki S Hiki Y Photodynamic therapy for cancers: a clinical trial of porfimer sodium in Japan.Jpn J Cancer Res. 1993; 84: 1209-1214Crossref PubMed Scopus (61) Google Scholar Thus, PDT has become recognized as one of the curative therapies for early stage lung cancer. New photosensitizers that can be excited effectively at longer wavelengths are being developed. Therefore, PDT with use of such photosensitizers could expand the indications for the procedure in the future. A study on the effectiveness of PDT as an alternative to lobectomy in the early stage central type of lung cancer, similar to the investigation by Cortese, Edell, and Kinsey, is also being conducted in Japan. Interim analysis revealed an almost 90% cumulative survival rate at 2.5 years. This finding lends further support to the concept that PDT is an effective alternative to surgical resection. Cost-Effectiveness of PDT.—Because the cost of health care is one of the most important problems in medicine today, especially with the explosive increase in the percentage of the population older than 60 years of age, we12Kato H Okunaka T Fujino S Ogawa I Cost-effective analysis of photodynamic therapy in early stage lung cancer. [In Japanese.].Shinryo to Shinyaku. 1994; 31: 103-129Google Scholar evaluated the cost-effectiveness of PDT in relationship to lobectomy for early stage lung cancer. Effectiveness was determined by using quality adjusted life years saved, which is the 5-year survival rate adjusted in terms of the quality of life of the patient. We determined the cost-effectiveness rates based on the costs of treatment during hospitalization. Health-care costs, including drugs, were calculated on the basis of the Japanese 1993 National Health Insurance list. The total cost in the surgically treated group was $14,948 and in the PDT group was $8,475. The cost-effectiveness rate for the surgical group—that is, the mean cost of treatment per postoperative living month—was $313, whereas that for the PDT group was $250. This finding indicates that the overall cost was approximately 1.3 times higher in the surgically treated group than in the PDT group. The monthly cost-effectiveness rate for patients in the PDT group who had superficial lesions (smaller than 2 cm) was $213. PDT Versus Surgical Resection.—The current important study by Cortese, Edell, and Kinsey elegantly solved the ethical problem of a clinical study of an alternative to surgical treatment and statistically clarified the role of PDT for early stage squamous cell carcinoma. Although the ideal study should be randomized, huge numbers of patients would be required. Therefore, this study focused on the endpoint of the need for subsequent surgical treatment in patients who had received PDT; thorough follow-up was an integral part of the assessment. These investigators concluded that at least 22% of patients with early stage squamous cell carcinoma of the lung who are candidates for PDT can be spared surgical resection. Because our Japanese study for evaluation of PDT as an alternative to surgical treatment showed similar results, I would like to emphasize the importance of these findings. Many members of the staff of the Mayo Clinic, such as Drs. Lipson, Baldes, Fontana, Sanderson, Cortese, Kinsey, and Edell, have enthusiastically studied photodynamic diagnosis and treatment for many years, and their contributions to the field are recognized throughout the world—and especially in Japan. PDT obtains a high rate of complete response in early stage central-type lung cancer and can eliminate the need for surgical intervention in certain patients. Better quality of life can be provided by PDT—especially in elderly patients and in patients with multiple lung cancers. Moreover, PDT is a cost-effective option in comparison with other treatments. Conclusion.—Studies of PDT began just 25 years ago. Therefore, many unresolved problems remain. Clearly, however, PDT is now one of the new therapeutic strategies for early stage central-type lung cancer. I am certain that future literature on the subject of PDT will repeatedly refer to this seminal work by Cortese and associates on the role of PDT versus surgical treatment of early stage squamous cell lung cancer.