Interferon Therapy

Radiocurable Tumors and Non-Radiocurable Tumors

JMAJ 47(2): 79–83, 2004

Naofumi HAYABUCHI

Professor and Chairman, Department of Radiology, Kurume University School of Medicine

Abstract: In Japan, the main technique for curing patients with malignant tumors has been surgery. However, the rapid aging of the population has necessitated a change in treatment strategy, and radiotherapy has become a powerful option. The main concern with radiation therapy is its reliability, since some tumors are radiocurable whereas others are not. Although radiosensitivity was first reported in 1906 by Bergonie and Tribondeau, clinical radiocurability is somewhat different. Leukemias and lymphomas, while exceedingly radiosensitive, are not readily radiocurable. This article discusses recent progress in radiotherapy and other complementary treatments, including malignant lymphomas of the stomach, head and neck cancer, and lung cancer, with special emphasis on treatment success and QOL. Key words: Radiocurable tumor; Radiosensitivity; Radiotherapy,; Malignant lymphoma; Head and neck cancer

Introduction to the patient’s quality of life, simply saving a patient’s life is not necessarily the best option Japan currently is facing the effects of a rap- if severe limitations in subsequent daily living idly aging population. Although it is fortunate are apt to occur. Because of this, radiotherapy that more and more people are living longer, has been attracting increased attention. Radio- this demographic change has created a number therapy, however, cannot be used as an alterna- of problems as well. One problem specific to tive to surgical resection in every case because cancer treatment is that it has become more whereas some tumors are highly radiosensitive difficult to employ surgical resection as the pri- and thus responsive to radiotherapy, others are mary treatment for malignant tumors. In addi- not. tion, since more importance is being attached

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 128, No. 7, 2002, pages 1080–1083). The Japanese text is a transcript of a lecture originally aired on July 5, 2002, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

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Radiosensitivity Table 1 Factors Affecting Tumor Radiosensitivity 1. Histologic type Determination of the conditions for which • High sensitivity: Malignant lymphoma, Seminoma, etc. radiotherapy is effective has been a major • Moderate sensitivity: Epithelial tumor (Carcinoma) focus of attention almost since radiant rays • Low sensitivity: Osteosarcoma, Malignant melanoma, etc. 2. Oxygen concentration in tumor tissue: Radiosensitivity were discovered. In 1906, only 11 years after is low in the hypoxic state. the discovery of radiation, Bergonie and 3. Cell cycle: Radiosensitivity is high in M phase and low Tribondeau carried out an experiment in which in S phase. 4. Cancer-related genes: p53, Bel-2, Fas, VEGF, etc. irradiation to the testis of mice was used to determine the sensitivity of tissue. They found M phase: Mitotic phase, S phase: DNA synthetic phase. that the sensitivity of cells to radiation is pro- portional to the degree of proliferative activity and inversely proportional to the degree of dif- nomas of the esophagus, some are highly radio- ferentiation. In other words, undifferentiated sensitive but others are not. As this indicates, cells with high mitotic capability are more radiosensitivity depends not only on the histo- radiosensitive. According to this principle, tis- logic type of the tumor but also on other fac- sues rich in actively dividing cells generally tors. The oxygen concentration in the tumor show high sensitivity to radiation, whereas and the mitotic cycle of tumor cells are two those with few such cells have low radio- such factors. For example, in tumors accom- sensitivity. panied with ulcers or inflammation, tumor cells More specifically, genital glands such as the are in a hypoxic state, and thus respond poorly testis and ovary, lymphatic tissue, fetal tissue, to radiation. Therefore, attempts to raise the and fetus-like blast cell tissue are highly radio- oxygen concentration in tumor tissue, to de- sensitive. Tissues with low radiosensitivity velop drugs that increase the radiosensitivity of include adult bone, fatty tissue, muscle, and hypoxic tumor tissue alone, and to synchronize large vessels. Because the radiosensitivity of a the cell cycle have been attempted, although tumor reflects the sensitivity of the tissue from the results so far have been unsatisfactory. which it has arisen, malignant lymphomas, On the other hand, recent studies have which originate in lymphatic tissue, and semi- clarified the DNA repair process and regula- nomas, which originate in the testis, have high tory mechanism of cell death in radiation- sensitivity to radiation. In contrast, osteogenic injured cells. From these studies, the presence sarcomas and liposarcomas demonstrate low of cancer-related genes affecting the radiosen- radiosensitivity. sitivity of cells has become apparent. p53 is a Epithelial tumors, or cancers in the narrow well-known cancer-related gene, as are Bel-2 sense, are considered to have moderate radio- and Fas. In addition, other genes, including sensitivity. Among these tumors, undifferen- hepatoma-derived growth factor (HDGF),1) tiated carcinoma and small cell carcinoma have have been found as a result of differences in relatively high radiosensitivity, followed by squa- radiosensitivity among esophageal cancers. In mous cell carcinoma. The radiosensitivity of recent years, angiogenetic factors such as vas- adenocarcinoma is generally lower than that of cular endothelial growth factor (VEGF) have other types of epithelial tumors. In light of this, been attracting attention in conjunction with head and neck cancer, esophageal cancer, uter- radiosensitivity. The involvement of many ine cervical cancer, and skin cancer, among other genes has been suggested, and the micro- which squamous cell carcinoma is common, array technique, which allows simultaneous seem to be good indications for radiotherapy. examination of these genes, has been an aid to However, even among squamous cell carci- research. Table 1 lists the factors involved in

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the radiosensitivity of tumors. better results and was associated with fewer In the clinical setting, however, gene diag- drug-related complications. The optimal com- nosis and the diagnosis of factors other than bination of chemotherapy and radiotherapy to histologic type are not always feasible, and ini- yield the best outcome is an important issue for tiation of treatment may be necessary before the future. the results of such diagnoses are available. Malignant lymphomas occurring in the stom- Therefore, radiotherapy currently tends to be ach will be described briefly. The incidence of indicated for tumors of a highly radiosensitive malignant lymphomas of the stomach is re- histologic type, while attempts to increase the ported to be only about 1%, in contrast to gas- radiosensitivity of the tumor and concurrent tric carcinomas. These lymphomas are divided treatment may be necessary for epithelial tumors into two types: mucosal-associated lymphoid of moderate radiosensitivity. tissue (MALT) lymphoma, which has lower Some clinical examples of radiotherapy of malignancy, and usual diffuse B-cell lympho- tumors are described below. mas. Since MALT lymphoma is considered Heavy particle therapy, which is not influ- closely associated with Helicobacter pylori, enced by factors that affect radiosensitivity patients with this disease are first treated by (e.g., hypoxic cells), and photon beam therapy, bacterial eradication using antibiotics. How- which affords minimal injury to normal tissue, ever, bacterial eradication is reported to be have recently become available in Japan. How- ineffective in 30% of patients with MALT ever, these treatments are not common, and lymphoma. therefore will not be discussed here. For cases of MALT lymphoma not amenable to bacterial eradication and those of diffuse Malignant Lymphomas lymphomas, gastrectomy was formerly the stan- dard treatment, as in cases of gastric cancer. Because malignant lymphomas are highly However, gastrectomy was associated with de- radiosensitive, radiotherapy was commonly creased quality of life mainly owing to post- employed for them in the past. However, operative dumping syndrome. To eliminate this non-Hodgkin lymphomas, which predominate drawback, treatment of malignant lymphomas in Japan, are likely to spread throughout of the stomach without gastrectomy was at- the entire body, and, therefore, radiotherapy tempted through the cooperation of radiation alone did not yield favorable therapeutic re- oncologists from various institutions in Japan. sults because of frequent recurrence in non- More specifically, patients with MALT lym- irradiated areas. Effective anticancer drugs for phoma were treated with radiotherapy alone malignant lymphomas, such as Adriamycin, when bacterial eradication was ineffective, while were developed, and combination chemo- those with diffuse lymphomas were treated therapy regimens were improved. In addition, with a combination of chemotherapy and radio- adjuvant agents such as G-CSF began to be therapy from the beginning, without eradica- used, resulting in considerable improvement tion. Good therapeutic results were obtained in the therapeutic results of malignant lym- in all 47 patients with gastric malignant lym- phomas. Subsequently, malignant lymphomas, phoma (22 with MALT lymphoma and 25 with particularly non-Hodgkin lymphomas, were diffuse lymphoma) without gastrectomy.3) treated for a time by chemotherapy alone. However, in the latter half of the 1990s, ran- Head and Neck Cancers domized controlled studies2) showed that short- term chemotherapy plus radiotherapy, rather Most cancers occurring in the head and neck than prolonged chemotherapy alone, achieved region are squamous cell carcinomas, which

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often respond well to radiotherapy. However, nable to systemic chemotherapy because of its radiotherapy in these cases may be less certain adverse effects. For example, this technique has than surgical treatment. achieved favorable results in elderly patients Among laryngeal cancers, glottic cancer is with unresectable cancer in the sphenoidal clinically characterized by hoarse voice and, sinus involving the cranial base and in those therefore, is often detected in stage I with advanced lingual cancer for which surgical (T1N0M0) or II (T2N0M0). Radiotherapy has treatment was denied. These patients have commonly been used for these cases with the been followed to date without recurrence.5) aim of preserving the patient’s voice. Formerly, In Kurume University Hospital, selective local control of glottic laryngeal cancer in the rapid intra-arterial infusion via the femoral T2 stage involving the laryngeal ventricle was artery in combination with radiotherapy is not necessarily satisfactory after radiotherapy employed for the treatment of maxillary sinus alone, with local control obtained in 70–80% of cancer, instead of continuous intra-arterial patients. In Kurume University Hospital, coop- infusion from the superficial temporal artery. eration between head and neck surgeons and Selective rapid intra-arterial procedure has radiation oncologists resulted in a combination yielded excellent results, with fewer compli- treatment by which part of the tumor is cations in comparison with infusion of anti- resected to allow greater preservation of voice cancer drugs from the superficial temporal quality, followed by irradiation to the reduced artery. Recently, some patients with maxillary tumor. As a result, tumor control was achieved sinus cancer have been admitted to a radiology in more than 90% of patients without loss of clinic rather than a otorhinolaryngology clinic. voice quality.4) Thus, a combination of radiotherapy and ad- Radiotherapy has been indicated for other ministration of anticancer drugs tailored to the cancers in the head and neck region that previ- specific patient can achieve tumor control even ously might have been subject to extensive sur- in cases not responding adequately to radio- gical resection, owing to consideration of pos- therapy alone. sible postoperative decreases in quality of life, Not only anticancer drugs, but also hyper- including functional disturbances in swallow- thermia may improve efficacy when combined ing and phonation as well as esthetic problems. with radiotherapy. Therefore, hyperthermia is Anticancer drugs were combined with radio- also an option for combined treatment in suit- therapy to ensure efficacy of treatment. able cases in Kurume University Hospital. Although concomitant anticancer drug ther- apy has been employed in various ways, we Lung Cancer used direct periodic administration of anti- cancer drugs into the tumor via catheter from Lung cancer (specifically cancer of broncho- the femoral artery, applying an angiographic alveolar origin as used in this paper) ranks first technique. Bolus intra-arterial administration as the cause of death among Japanese men. of anticancer drugs into the tumor once weekly This type of cancer is often advanced when during radiotherapy is highly effective and is detected and therefore associated with very associated with minimal adverse effects and poor therapeutic results. Radiotherapy of lung complications of anticancer therapy, since cancer is usually inferior to surgical treatment simultaneous systemic administration of anti- in terms of certainty, and lung tissue is suscep- dotes to the anticancer drugs is possible tible to radiation. Therefore, radiotherapy for through the venous route. Therefore, this rapid this disease is used predominantly in patients in intra-arterial infusion of anticancer drugs is whom radical surgery is impossible or in whom feasible for aged patients who are not ame- control of symptoms caused by metastasis is

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attempted. However, progress in diagnostic relatively low radiosensitivity and responds imaging, including computed tomography (CT), poorly to radiotherapy, provided that the mode magnetic resonance imaging (MRI), and posi- of radiotherapy and type of combination ther- tron emission tomography (PET), have enabled apy are carefully considered. Radiotherapy is accurate diagnosis of the properties and extent expected to play an increasingly important role of the tumor even when it is still small. There in the treatment of malignant tumors as Japan’s have also been advances in technology for population continues to age. concentrating radiation on the tumor, such as stereotactic radiation therapy and intensity- REFERENCES modulated radiation therapy (IMRT), focusing 1) Matsuyama, A. et al.: Hepatoma-derived growth high-dose concentrated radiation on the tumor factor is associated with reduced sensitivity to alone, with minimal injury to the lung. irradiation in esophageal cancer. Cancer Res The use of these latest techniques in diag- 2001; 61: 5714–5717. nosis and treatment can achieve therapeutic 2) Miller, T.P. et al.: Chemotherapy alone com- efficacy equal to or better than that of surgical pared with chemotherapy plus radiotherapy resection, even in patients with adenocarci- for localized intermediate- and high-grade noma, which is known to have relatively low non-Hodgkin’s lymphoma. N Engl J Med 1998; sensitivity to radiation.6) In the near future, the 339: 21–26. extension of these techniques is likely to offer 3) Hayabuchi, N. et al.: Radical radiotherapy of primary non-Hodgkin’s lymphoma of the stom- treatment for lung cancer that maintains qual- ach. J Jpn Soc Ther Radiol Oncol 2002; 14: 61– ity of life and eliminates the need for surgical 67. (in Japanese) resection. 4) Suzuki, G. et al.: Laser-radiation therapy for Y2N0M0 laryngeal-glottic cancer. Nippon Acta Conclusion Radiologica 2002; 62: 151–155. (in Japanese) 5) Tanaka, H. et al.: Ultraselective intra-arterial Although various factors affect the radio- infusion chemotherapy for advanced head and sensitivity of tumors, histologic type is still an neck cancer: Efficacy of treatment by rapid intra-arterial infusion. Head and Neck Cancer important indicator in clinical practice. In addi- 2002; 28(2): 377. (in Japanese) tion to tumors with a histologic type that is 6) Uematsu, M. et al.: Computed tomography- highly sensitive to radiation and thus responds guided frameless stereotactic radiotherapy for well to radiation therapy, radiotherapy can be stage I non-small cell lung cancer. Int J Radiat effective for tumors of a histologic type that has Oncol Biol Phys 2001; 51: 666–670.

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