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Radiation-induced cancer after radiotherapy for non-Hodgkin's lymphoma of the head and neck: a retrospective study

Radiation-induced cancer after radiotherapy for non-Hodgkin's lymphoma of the head and neck: a... Background: survivors of non-Hodgkin's lymphoma (NHL) are well known to be at an increased risk of second malignancies. In this study, we evaluated the incidence and clinical features of head and neck cancer (HNC) occurring after radiotherapy (RT) for NHL. Materials and methods: We investigated the clinical records of 322 patients who had received RT for early-stage NHL of the head and neck at our institute between 1952 and 2000. Results: There were 4 patients with a second HNC developing in the irradiated field, consisting of 2 patients with gum cancer, 1 case with tongue cancer and 1 case with maxillary sinus cancer. The pathological diagnosis in all the 4 patients was squamous cell carcinoma (SCC). Two of the patients (one with gum cancer and one with maxillary sinus cancer) died of the second HNC, while the remaining 2 patients are still living at the time of writing after therapy for the second HNC, with neither recurrence of the second tumor nor relapse of the primary tumor. The ratio of the observed to the expected number (O/E ratio) of a second HNC was calculated to be 12.7 (95%CI, 4.07–35.0), and the absolute excess risk (AER) per 10,000 person-years was 13.3. The median interval between the RT and the diagnosis of the second HNC was 17.0 years (range, 8.7 to 22.7 years). Conlusion: The risk of HNC significantly increased after RT for early-stage NHL. These results suggest that second HNC can be regarded as one of the late complications of RT for NHL of the head and neck. as that associated with diagnostic X-ray examinations, is Background Carcinogenesis associated with exposure to radiation is debatable [1,2]. Exposure to therapeutic doses of radia- widely known, first reported in the early 20th century, tion has also been shown to be associated with an when skin cancer was noted in radiation workers. The risk increased risk of a second cancer, although the precise risk of carcinogenesis following low-dose radiation exposure remains unknown. For selected cancers with a high cure was estimated to be 0.05–0.1 Sv based on the results of rate, the benefits of treatment need to be weighed against follow-up of atomic bomb survivors in Japan, however, the potential risk of treatment-related second malignancy. that associated with exposure to much lower doses, such Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 Progress of therapeutic modalities in recent decades have Results considerably improved the prognosis of malignant lym- The patient characteristics are listed in Table 1. In all, 96 phoma, on the other hand, development of therapy- patients had NHL lesions in the Waldeyer's ring. Extran- related second cancer as a late complication of treatment odal lesions were seen in 124 patients. The most frequent has became obvious [3-6]. As compared with the case in site of NHL was the oral cavity (n = 48). Neoadjuvant and/ HL, RT still occupies a more important position in the or adjuvant chemotherapy was administered in 144 treatment of NHL, especially early-stage NHL. Although patients (44.7%), and the most frequently administered the head and neck area is one of the most frequent sites of regimen was cyclophosphamide, doxorubicin, vincris- NHL, the risk of a second HNC after RT for NHL still tine+ prednisolone (CHOP) or a CHOP-like regimen (n = remains unclear. We investigated the incidence and clini- 88). cal features of a second HNC occurring after RT for early- stage NHL. RT was administered with high-voltage X-rays from a lin- ear accelerator in 150 patients, with γ-rays from Co-60 in Materials and methods 89 patients, with orthovoltage X-rays in 55 patients, with We conducted a retrospective review of a total of 322 either high-voltage X-rays or γ-rays plus electrons in 15 patients who received RT with/without chemotherapy as patients, with electrons alone in 9 patients, with high- initial therapy for early-stage NHL (stage I or stage II) of voltage X-rays plus γ-rays in 2 patients, with γ-rays plus the head and neck at our institute between 1952 and 2000 orthovoltage X-rays in 1 patient, and orthovoltage X-rays [7]. The patient parameters investigated were the sex, age plus brachytherapy in 1 patient. RT was administered with at the time of RT, the chemotherapy regimen employed, conventional RT techniques, therefore 1 field, 2 opposed the clinical stage and location of the lymphoma, the irra- fields and a combination of them were mostly used. diated field, the dose and type of RT, and the cause of death. The median total dose of RT was 40.8 Gy (range, 5.5–78 Gy), and the dose per fraction was 1.5–3 Gy (2 Gy in most For the patients in whom a second HNC developed in the cases). The total radiation dose was unknown in the irradiated field after RT, we investigated the site and path- patient who received low-dose-rate intracavitary brachy- ological diagnosis, the interval from the time of RT to the therapy in addition to orthovoltage X-rays for NHL of the diagnosis of the second HNC, and the clinical course of tonsil. The total dose employed was 5.5–19.8 Gy in 9 the second cancer. We calculated the expected numbers of patients (2.8%), 21–30 Gy in 64 patients (19.9%), 30.8– second cancers by using the person-years method [8,9]. 40 Gy in 87 patients (27.1%), 40.8–50 Gy in 143 patients We used the age-, sex-, and calendar year-specific cancer (44.5%), 50.6–60 Gy in 16 patients (5.0%), and over 60 incidence rates in the general population of Japan [10]. O/ Gy in 2 patients (0.6%). E ratio was then calculated with the 95%CI from the Pois- son distribution. These results were statistically analyzed The overall 2-, 5- and 10-year survival rates of the patients by the SPSS for Windows (SPSS Inc. Chicago, Illinois). calculated by the Kaplan-Meier method were 77.6%, Table 1: Characteristics of all the patients (n = 322) n% Sex Male 191 59.3 Female 131 40.7 Age at the time of RT (median, 53 years{range,4 – 91}) <60 years 200 62.1 60 years 122 37.9 Stage I 200 62.1 II 122 37.9 Chemotherapy + 144 44.7 - 178 55.3 Follow-up duration after RT Average(range) 8.6 years(0 – 35.1) Abbreviations RT: radiotherapy Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 65.5% and 54.7%, respectively. The median survival time second HNC per 10,000 PYs was 13.3. When the analysis was 14.9 years (95%CI, 8.2–21.5 years). The lymphoma- was limited to the 192 patients who could be followed up related 2-, 5- and 10-year survival rates were 80.1%, for over 5 years, the expected number was 0.28 during 70.4% and 63.7%, respectively. There was a significant 2544 PYs, the O/E ratio was 14.1 (95%CI, 4.5–38.7, p < difference in the overall survival rate between NHL 0.01), and the AER was 14.6. Furthermore, the O/E ratio patients with clinical stage I and those with clinical stage was 12.0 (95%CI, 2.1–48.4, p < 0.01) during 1600 PYs in II (p < 0.05) (Fig. 1). the 178 patients who did not receive chemotherapy, and 13.5 (95%CI, 2.3–54.5, p < 0.01) during 1176 PYs in Of the patients, 19 (5.9%) developed a second malig- the144 patients who received chemotherapy. nancy, which was metachronous in 16 cases and synchro- nous in 3 cases (table 2). In 4 patients, the second HNC Of the 19 patients with a second cancer, 2 cases of second occurred in the irradiated field. The clinical outlines of cancer arose near the previous radiation field: one of these 4 patients are shown in [table S1; Additional file 1]. laryngeal cancer developing 14 years after RT for NHL of Two of the 4 patients had also received chemotherapy (3 the nasal cavity, and one of esophageal cancer developing cycles of CHOP). The pathological diagnosis of the sec- 16 years after RT and chemotherapy for NHL of the oral ond HNC in all the 4 cases (2 cases of cancer of the gum, cavity and neck. 1 case of tongue cancer, and 1 case of maxillary sinus can- cer) was SCC (fig. 2). The median interval after the RT to Discussion the development of the second cancer was 13.9 years Some definitions of radiation-induced malignancy have (range, 8.7 to 22.7 years). Two of the patients (1 with gum been proposed. We removed the 2 second cancers (one cancer and 1 with maxillary sinus cancer) died of the sec- each of laryngeal cancer and esophageal cancer) which ond cancer. The remaining 2 patients are still living at the arose near the radiation field from the analysis of radia- time of writing, with neither recurrence of the second tion-induced cancer according to the criteria that Sakai et HNC nor relapse of the primary NHL, or indeed any al. proposed, even though these cases might well have had severe complications during the follow-up. The patient a relation to scattered radiation [11]. Cahan et al. reported with gum cancer is still living, 3.3 years after surgery for their criteria for the diagnosis of radiation-induced oste- SCC of the right upper gum, and the patient with tongue osarcoma in the middle of last century [12]. According to cancer is also still living, 8.9 years after RT for SCC of the their criteria, the primary lesion for which RT was admin- tongue. The latter case received 90.5 Gy as brachytherapy istered must be a benign disease. In the early part of the for tongue cancer by Au-198 grain implantation. last century, RT was widely used for benign diseases such as tuberculous lymphadenitis, skin diseases, thyroid dis- During the 2776 person-years (PYs) of observation, the eases and spondylitis, however, at present, RT is mainly expected number of a second HNC in the general popula- used to treat malignancies. The limitation of the prior dis- tion was 0.31, so that the O/E ratio was 12.7 (95%CI, ease treated by RT to a benign disease might thus be 4.07–35.0, p < 0.01). The absolute excess risk (AER) of a impractical. Sakai et al. argued the criteria for the diagno- (a Figure 1 ) Overall survival and lymphoma-specific survival rates in NHL patients (a) Overall survival and lymphoma-specific survival rates in NHL patients. (b) Overall survival of NHL patients by stage. Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 Table 2: Characteristics of the second tumor(n = 19) cancer, bladder cancer and colorectal cancer [4]. No cases of second leukemia and second lung cancer were observed Type of second tumor n O/Eratio 95%CI AER* in this study. The lack may be affected by a strong relation- ship between these second malignancies and chemother- Synchronous 3 apy. Chemotherapy occupied a relatively lower place in Esophagus 1 the therapy for NHL than in that for HL, at least especially Stomach 1 Cervix 1 in the earlier decades. For example, only about 27% of all the patients received CHOP that is now standard regimen Metachronous 16 0.8 0.47–1.33 -14.6 for B-cell NHL in combination with rituximab and Head and neck CHOP-like regimens in this study. The increased risk of In irradiated field 4 12.7 4.07–35.0 13.3 second malignancies in the synergy of radiation and Out of irradiated field 1 chemotherapy is also known, although how the synergy Esophagus 2 3.24 0.56–13.1 4.95 affected induction of second HNC was unknown. Stomach 2 0.39 0.07–1.55 -11.4 Colon 3 1.55 0.40–4.93 3.80 Breast 1 The risk of certain malignancies is significantly associated Gallbladder 1 with smoking, habitual alcohol consumption, immuno- Soft-tissue sarcoma(buttocks) 1 suppressive conditions, and some genetic disorders. It Myeloma(thoracic vertebra) 1 would appear that the higher risk of a second cancer in patients with HNC remains even after they stop smoking * Absolute excess risk per 10,000 person-years [15]. Moertel et al. described multicentric cancer develop- sis of radiation-induced cancer, except leukemia, and their ment associated with carcinogenic stimulation of large results suggested that the reliability of the diagnosis of areas of tissues [16,17]. Slaughter et al. proposed "field radiation-induced cancer depends on the pathological cancerization" in oral SCC [18]. These reports underscore diagnosis, the organ of origin, the follow-up duration the difficulty of distinguishing radiation-induced malig- after RT (over 5 years) and on whether the lesion is located nancy from not only recurrence of the first malignancy, in the irradiated field [11]. These criteria were based on but also from multicentric primary tumors in the head the criteria of double primary cancer proposed by Warren and neck area [19]. We did not have sufficient data about et al. [13]. the smoking, alcohol drinking habit, and genetic disor- ders of all the patients. We do know, though, that only 1 A limitation of our study is that our study population was of the 4 patients with a second HNC had a smoking his- small. A long latency period of radiation-induced malig- tory, and that none of them engaged in habitual alcohol nancies except leukemia would make it difficult to ana- consumption. lyze these malignancies [11,12,14]. Therefore, a large number of patients who have been under observation for A dose-response relationship is known in the develop- a long time after RT would be necessary to correctly assess ment of leukemia in experimental animals. The incidence a radiation-induced cancer. Tward et al reported that the of leukemia was reported to increase with the radiation O/Eratio of a second HNC among 77823 NHL patients dose in the dose range between 3 and 10 Gy [20]. The was 1.28 (95%CI, 1.12–1.46) [5]. British group reported explanation for the decrease in the incidence at higher that the O/Eratio of a second HNC among 5519 HL doses is that the number of surviving cells decreases at patients was 2.8(95%CI, 1.1–5.8) and that among 2456 these doses. A similar relationship was suggested between NHL patients was 2.6(95%CI, 0.8–6.0) [4,6]. These stud- sarcoma induction and the radiation dose employed, with ies showed that RT alone did not significantly relate to a the maximum dose levels for malignant transformation second HNC, although the relationship between the and decreased cell survival being higher than those for details of RT and a site of second malignancies was not leukemia [21]. This is held to be one of the reasons why considered. In this study, O/Eratio of a second HNC was sarcomas are likely to be induced in heavily irradiated tis- higher than those previously reported and significantly sues. A relationship between initial RT doses and second increased even among the patients who received RT alone. head and neck malignancies was unknown in this study. The possibility that those large-scale studies underesti- The RT doses employed in our study were relatively lower mated carcinogenicity of RT because of the lack of consid- than those used for other solid tumors, and likely to be eration for the details of RT could not be ruled out, higher than those used for NHL in today. To be concrete, although our study population was smaller than that in about half of all the patients including 4 second HNC previous studies. patients received 40 Gy and over. No other pathological diagnosis than SCC was seen in second head and neck Chemotherapy for NHL is held to be associated with a cer- malignancies and this result was similar to previous stud- tain risk of carcinogenesis, especially of leukemia, lung ies [22,23]. In contrast, Sale et al. reported 13 second Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 (a) Dose distribution of RT for NHL of the max Figure 2 illary sinus (a) Dose distribution of RT for NHL of the maxillary sinus. (b) and (c) PET-CT showing second SCC infiltrating the bone. malignancies of the head and neck after RT, with the most patients were treated with conventional RT techniques. frequent histological diagnosis being sarcoma, followed However, how advance of radiation techniques affects sec- in frequency by SCC [24]. And Patel et al. reported 10 ond malignancies is held to be debatable. Intensity mod- patients of radiation-induced sarcoma of the head and ulated radiation therapy (IMRT) which is one of the neck, and malignant fibrous histiocytoma was the com- advanced RT techniques is concerned to increase the risk monest pathological diagnosis (4 patients) in their of a second cancer compared with three-dimensional con- patient series [25]. The difference of the pathological diag- formal radiotherapy (3D-CRT) [26,27]. The change from nosis among these studies might be related to the differ- 3D-CRT to IMRT involves a bigger volume of normal tis- ence of RT doses, nevertheless a correct relationship sue irradiated by lower doses as a result of the increase of between initial RT doses and second head and neck malig- fields, of monitor units and of scattered radiation. In con- nancies is unclear because of a small number of these trast, Ruben at al. argued that the risk of radiation-induced malignancies. cancer did not significantly differ between IMRT and 3D- CRT concerning the body in totality, and the risk of sec- Equipment and techniques mainly used for RT in today ond cancer was regarded to be influenced by RT equip- are likely to differ from those used for our patients. About ment [28]. At least, it must be inappropriate to simply half of our patients were treated with a linear accelerator apply our results to NHL patients treated with modern RT which is now standard RT equipment, and almost all the equipment and techniques. Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 It is debatable whether the prognosis of radiation-induced Authors' contributions malignancy might differ from that of spontaneously KT and HS designed/conducted analysis and wrote the occurring tumors. Previous studies on radiation-induced manuscript. KH and FA assisted in the acquisition and sarcoma suggested a poor prognosis of these patients and analysis of data. All authors have read and approved the also the beneficial effects of surgery for these tumors final manuscript. [21,25,29-33]. In addition, the poor prognosis of radia- tion-induced sarcoma of the head and neck might be Additional material related to the difficulty in complete resection of these tumors due to post-radiation changes [25]. It was held Additional file 1 that surgery should be conducted prior to RT in the treat- Table S1. Characteristics of the radiation-induced head and neck cancer ment of radiation-induced cancer, because of the lowered patients (n = 4). tolerance of the tissues to re-radiation and the oxygen Click here for file effect of the second tumor [19]. McHugh et al. compared [http://www.biomedcentral.com/content/supplementary/1748- 717X-4-21-S1.doc] the characteristics of radiation-induced craniofacial oste- osarcoma with those of the corresponding primary tumors, and proposed that the poorer prognosis of radia- tion-induced osteosarcoma was related to the higher References expression of adverse prognostic markers, such as p53, 1. Pierce DA, Preston DL: Radiation-related cancer risks at low TP53 mutations, ezrin expression, and the higher prolifer- doses among atomic bomb survivors. Radiat Res 2000, ative activity [34]. In contrast, there are some reports of 154:178-186. 2. 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Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M: Report of a commit- those for solid tumors would lead to a lower extent of tee convened to discuss the evaluation and staging of damage of the surrounding tissue, patients with a second patients with Hodgkin's disease; Cotswolds meeting. J Clin cancer after RT for NHL might show better tolerance to Oncol 1989, 7:1630-1636. 8. Schoenberg BS, Myers MH: Statistical methods for studying treatment for the second tumor. Therefore, an early detec- multiple primary malignant neoplasms. Cancer 1977, tion of second HNC may aid in a better choice of a thera- 40:1892-1898. peutic modality. Of course, an irradiated area is ought to 9. Breslow NE, Day NE: Statistical methods in cancer research. The design and analysis of cohort studies Volume II. Lyon, France: International be under careful observation. In addition, observations of Agency for Research on cancer; 1987. IARC Sci Publ 82 NHL patients ordinarily include systemic follow-up that 10. Oshima A, Kuroishi T, Tajima K, Eds: Gan toukeihakusho rikan/sibou/ yogo 2004 (statistical white paper of cancer. Incidence/death/prognosis) may encourage a detection of second primary cancer even Tokyo, Japan: Shinoharashinsha Inc; 2004. distant from an irradiated area. 11. Sakai K, Kitamura T, Hinata H, Yamashita H: Second cancers fol- lowing RT for malignant tumors. the second mail study in japan. Nippon Igaku Hoshasen Gakkai Zasshi 1986, 46(6):811-818. Conclusion 12. Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: The risk of HNC significantly increased after RT for early- Sarcoma arising in irradiated bone: Report of 11 cases. Can- cer 1948, 1:3-29. stage NHL, although a precise relationship between RT 13. Warren S, Gates O: Multiple primary malignant tumors: a sur- and second head and neck malignancies remains unclear vey of the literature and a statistical study. 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Goolden AW, Morgan RL: Radiation cancer of the pharynx. Acta Radiol Ther Phys Biol 1965, 3:353-360. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Radiation-induced cancer after radiotherapy for non-Hodgkin's lymphoma of the head and neck: a retrospective study

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Copyright © 2009 by Toda et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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19591686
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Abstract

Background: survivors of non-Hodgkin's lymphoma (NHL) are well known to be at an increased risk of second malignancies. In this study, we evaluated the incidence and clinical features of head and neck cancer (HNC) occurring after radiotherapy (RT) for NHL. Materials and methods: We investigated the clinical records of 322 patients who had received RT for early-stage NHL of the head and neck at our institute between 1952 and 2000. Results: There were 4 patients with a second HNC developing in the irradiated field, consisting of 2 patients with gum cancer, 1 case with tongue cancer and 1 case with maxillary sinus cancer. The pathological diagnosis in all the 4 patients was squamous cell carcinoma (SCC). Two of the patients (one with gum cancer and one with maxillary sinus cancer) died of the second HNC, while the remaining 2 patients are still living at the time of writing after therapy for the second HNC, with neither recurrence of the second tumor nor relapse of the primary tumor. The ratio of the observed to the expected number (O/E ratio) of a second HNC was calculated to be 12.7 (95%CI, 4.07–35.0), and the absolute excess risk (AER) per 10,000 person-years was 13.3. The median interval between the RT and the diagnosis of the second HNC was 17.0 years (range, 8.7 to 22.7 years). Conlusion: The risk of HNC significantly increased after RT for early-stage NHL. These results suggest that second HNC can be regarded as one of the late complications of RT for NHL of the head and neck. as that associated with diagnostic X-ray examinations, is Background Carcinogenesis associated with exposure to radiation is debatable [1,2]. Exposure to therapeutic doses of radia- widely known, first reported in the early 20th century, tion has also been shown to be associated with an when skin cancer was noted in radiation workers. The risk increased risk of a second cancer, although the precise risk of carcinogenesis following low-dose radiation exposure remains unknown. For selected cancers with a high cure was estimated to be 0.05–0.1 Sv based on the results of rate, the benefits of treatment need to be weighed against follow-up of atomic bomb survivors in Japan, however, the potential risk of treatment-related second malignancy. that associated with exposure to much lower doses, such Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 Progress of therapeutic modalities in recent decades have Results considerably improved the prognosis of malignant lym- The patient characteristics are listed in Table 1. In all, 96 phoma, on the other hand, development of therapy- patients had NHL lesions in the Waldeyer's ring. Extran- related second cancer as a late complication of treatment odal lesions were seen in 124 patients. The most frequent has became obvious [3-6]. As compared with the case in site of NHL was the oral cavity (n = 48). Neoadjuvant and/ HL, RT still occupies a more important position in the or adjuvant chemotherapy was administered in 144 treatment of NHL, especially early-stage NHL. Although patients (44.7%), and the most frequently administered the head and neck area is one of the most frequent sites of regimen was cyclophosphamide, doxorubicin, vincris- NHL, the risk of a second HNC after RT for NHL still tine+ prednisolone (CHOP) or a CHOP-like regimen (n = remains unclear. We investigated the incidence and clini- 88). cal features of a second HNC occurring after RT for early- stage NHL. RT was administered with high-voltage X-rays from a lin- ear accelerator in 150 patients, with γ-rays from Co-60 in Materials and methods 89 patients, with orthovoltage X-rays in 55 patients, with We conducted a retrospective review of a total of 322 either high-voltage X-rays or γ-rays plus electrons in 15 patients who received RT with/without chemotherapy as patients, with electrons alone in 9 patients, with high- initial therapy for early-stage NHL (stage I or stage II) of voltage X-rays plus γ-rays in 2 patients, with γ-rays plus the head and neck at our institute between 1952 and 2000 orthovoltage X-rays in 1 patient, and orthovoltage X-rays [7]. The patient parameters investigated were the sex, age plus brachytherapy in 1 patient. RT was administered with at the time of RT, the chemotherapy regimen employed, conventional RT techniques, therefore 1 field, 2 opposed the clinical stage and location of the lymphoma, the irra- fields and a combination of them were mostly used. diated field, the dose and type of RT, and the cause of death. The median total dose of RT was 40.8 Gy (range, 5.5–78 Gy), and the dose per fraction was 1.5–3 Gy (2 Gy in most For the patients in whom a second HNC developed in the cases). The total radiation dose was unknown in the irradiated field after RT, we investigated the site and path- patient who received low-dose-rate intracavitary brachy- ological diagnosis, the interval from the time of RT to the therapy in addition to orthovoltage X-rays for NHL of the diagnosis of the second HNC, and the clinical course of tonsil. The total dose employed was 5.5–19.8 Gy in 9 the second cancer. We calculated the expected numbers of patients (2.8%), 21–30 Gy in 64 patients (19.9%), 30.8– second cancers by using the person-years method [8,9]. 40 Gy in 87 patients (27.1%), 40.8–50 Gy in 143 patients We used the age-, sex-, and calendar year-specific cancer (44.5%), 50.6–60 Gy in 16 patients (5.0%), and over 60 incidence rates in the general population of Japan [10]. O/ Gy in 2 patients (0.6%). E ratio was then calculated with the 95%CI from the Pois- son distribution. These results were statistically analyzed The overall 2-, 5- and 10-year survival rates of the patients by the SPSS for Windows (SPSS Inc. Chicago, Illinois). calculated by the Kaplan-Meier method were 77.6%, Table 1: Characteristics of all the patients (n = 322) n% Sex Male 191 59.3 Female 131 40.7 Age at the time of RT (median, 53 years{range,4 – 91}) <60 years 200 62.1 60 years 122 37.9 Stage I 200 62.1 II 122 37.9 Chemotherapy + 144 44.7 - 178 55.3 Follow-up duration after RT Average(range) 8.6 years(0 – 35.1) Abbreviations RT: radiotherapy Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 65.5% and 54.7%, respectively. The median survival time second HNC per 10,000 PYs was 13.3. When the analysis was 14.9 years (95%CI, 8.2–21.5 years). The lymphoma- was limited to the 192 patients who could be followed up related 2-, 5- and 10-year survival rates were 80.1%, for over 5 years, the expected number was 0.28 during 70.4% and 63.7%, respectively. There was a significant 2544 PYs, the O/E ratio was 14.1 (95%CI, 4.5–38.7, p < difference in the overall survival rate between NHL 0.01), and the AER was 14.6. Furthermore, the O/E ratio patients with clinical stage I and those with clinical stage was 12.0 (95%CI, 2.1–48.4, p < 0.01) during 1600 PYs in II (p < 0.05) (Fig. 1). the 178 patients who did not receive chemotherapy, and 13.5 (95%CI, 2.3–54.5, p < 0.01) during 1176 PYs in Of the patients, 19 (5.9%) developed a second malig- the144 patients who received chemotherapy. nancy, which was metachronous in 16 cases and synchro- nous in 3 cases (table 2). In 4 patients, the second HNC Of the 19 patients with a second cancer, 2 cases of second occurred in the irradiated field. The clinical outlines of cancer arose near the previous radiation field: one of these 4 patients are shown in [table S1; Additional file 1]. laryngeal cancer developing 14 years after RT for NHL of Two of the 4 patients had also received chemotherapy (3 the nasal cavity, and one of esophageal cancer developing cycles of CHOP). The pathological diagnosis of the sec- 16 years after RT and chemotherapy for NHL of the oral ond HNC in all the 4 cases (2 cases of cancer of the gum, cavity and neck. 1 case of tongue cancer, and 1 case of maxillary sinus can- cer) was SCC (fig. 2). The median interval after the RT to Discussion the development of the second cancer was 13.9 years Some definitions of radiation-induced malignancy have (range, 8.7 to 22.7 years). Two of the patients (1 with gum been proposed. We removed the 2 second cancers (one cancer and 1 with maxillary sinus cancer) died of the sec- each of laryngeal cancer and esophageal cancer) which ond cancer. The remaining 2 patients are still living at the arose near the radiation field from the analysis of radia- time of writing, with neither recurrence of the second tion-induced cancer according to the criteria that Sakai et HNC nor relapse of the primary NHL, or indeed any al. proposed, even though these cases might well have had severe complications during the follow-up. The patient a relation to scattered radiation [11]. Cahan et al. reported with gum cancer is still living, 3.3 years after surgery for their criteria for the diagnosis of radiation-induced oste- SCC of the right upper gum, and the patient with tongue osarcoma in the middle of last century [12]. According to cancer is also still living, 8.9 years after RT for SCC of the their criteria, the primary lesion for which RT was admin- tongue. The latter case received 90.5 Gy as brachytherapy istered must be a benign disease. In the early part of the for tongue cancer by Au-198 grain implantation. last century, RT was widely used for benign diseases such as tuberculous lymphadenitis, skin diseases, thyroid dis- During the 2776 person-years (PYs) of observation, the eases and spondylitis, however, at present, RT is mainly expected number of a second HNC in the general popula- used to treat malignancies. The limitation of the prior dis- tion was 0.31, so that the O/E ratio was 12.7 (95%CI, ease treated by RT to a benign disease might thus be 4.07–35.0, p < 0.01). The absolute excess risk (AER) of a impractical. Sakai et al. argued the criteria for the diagno- (a Figure 1 ) Overall survival and lymphoma-specific survival rates in NHL patients (a) Overall survival and lymphoma-specific survival rates in NHL patients. (b) Overall survival of NHL patients by stage. Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 Table 2: Characteristics of the second tumor(n = 19) cancer, bladder cancer and colorectal cancer [4]. No cases of second leukemia and second lung cancer were observed Type of second tumor n O/Eratio 95%CI AER* in this study. The lack may be affected by a strong relation- ship between these second malignancies and chemother- Synchronous 3 apy. Chemotherapy occupied a relatively lower place in Esophagus 1 the therapy for NHL than in that for HL, at least especially Stomach 1 Cervix 1 in the earlier decades. For example, only about 27% of all the patients received CHOP that is now standard regimen Metachronous 16 0.8 0.47–1.33 -14.6 for B-cell NHL in combination with rituximab and Head and neck CHOP-like regimens in this study. The increased risk of In irradiated field 4 12.7 4.07–35.0 13.3 second malignancies in the synergy of radiation and Out of irradiated field 1 chemotherapy is also known, although how the synergy Esophagus 2 3.24 0.56–13.1 4.95 affected induction of second HNC was unknown. Stomach 2 0.39 0.07–1.55 -11.4 Colon 3 1.55 0.40–4.93 3.80 Breast 1 The risk of certain malignancies is significantly associated Gallbladder 1 with smoking, habitual alcohol consumption, immuno- Soft-tissue sarcoma(buttocks) 1 suppressive conditions, and some genetic disorders. It Myeloma(thoracic vertebra) 1 would appear that the higher risk of a second cancer in patients with HNC remains even after they stop smoking * Absolute excess risk per 10,000 person-years [15]. Moertel et al. described multicentric cancer develop- sis of radiation-induced cancer, except leukemia, and their ment associated with carcinogenic stimulation of large results suggested that the reliability of the diagnosis of areas of tissues [16,17]. Slaughter et al. proposed "field radiation-induced cancer depends on the pathological cancerization" in oral SCC [18]. These reports underscore diagnosis, the organ of origin, the follow-up duration the difficulty of distinguishing radiation-induced malig- after RT (over 5 years) and on whether the lesion is located nancy from not only recurrence of the first malignancy, in the irradiated field [11]. These criteria were based on but also from multicentric primary tumors in the head the criteria of double primary cancer proposed by Warren and neck area [19]. We did not have sufficient data about et al. [13]. the smoking, alcohol drinking habit, and genetic disor- ders of all the patients. We do know, though, that only 1 A limitation of our study is that our study population was of the 4 patients with a second HNC had a smoking his- small. A long latency period of radiation-induced malig- tory, and that none of them engaged in habitual alcohol nancies except leukemia would make it difficult to ana- consumption. lyze these malignancies [11,12,14]. Therefore, a large number of patients who have been under observation for A dose-response relationship is known in the develop- a long time after RT would be necessary to correctly assess ment of leukemia in experimental animals. The incidence a radiation-induced cancer. Tward et al reported that the of leukemia was reported to increase with the radiation O/Eratio of a second HNC among 77823 NHL patients dose in the dose range between 3 and 10 Gy [20]. The was 1.28 (95%CI, 1.12–1.46) [5]. British group reported explanation for the decrease in the incidence at higher that the O/Eratio of a second HNC among 5519 HL doses is that the number of surviving cells decreases at patients was 2.8(95%CI, 1.1–5.8) and that among 2456 these doses. A similar relationship was suggested between NHL patients was 2.6(95%CI, 0.8–6.0) [4,6]. These stud- sarcoma induction and the radiation dose employed, with ies showed that RT alone did not significantly relate to a the maximum dose levels for malignant transformation second HNC, although the relationship between the and decreased cell survival being higher than those for details of RT and a site of second malignancies was not leukemia [21]. This is held to be one of the reasons why considered. In this study, O/Eratio of a second HNC was sarcomas are likely to be induced in heavily irradiated tis- higher than those previously reported and significantly sues. A relationship between initial RT doses and second increased even among the patients who received RT alone. head and neck malignancies was unknown in this study. The possibility that those large-scale studies underesti- The RT doses employed in our study were relatively lower mated carcinogenicity of RT because of the lack of consid- than those used for other solid tumors, and likely to be eration for the details of RT could not be ruled out, higher than those used for NHL in today. To be concrete, although our study population was smaller than that in about half of all the patients including 4 second HNC previous studies. patients received 40 Gy and over. No other pathological diagnosis than SCC was seen in second head and neck Chemotherapy for NHL is held to be associated with a cer- malignancies and this result was similar to previous stud- tain risk of carcinogenesis, especially of leukemia, lung ies [22,23]. In contrast, Sale et al. reported 13 second Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 (a) Dose distribution of RT for NHL of the max Figure 2 illary sinus (a) Dose distribution of RT for NHL of the maxillary sinus. (b) and (c) PET-CT showing second SCC infiltrating the bone. malignancies of the head and neck after RT, with the most patients were treated with conventional RT techniques. frequent histological diagnosis being sarcoma, followed However, how advance of radiation techniques affects sec- in frequency by SCC [24]. And Patel et al. reported 10 ond malignancies is held to be debatable. Intensity mod- patients of radiation-induced sarcoma of the head and ulated radiation therapy (IMRT) which is one of the neck, and malignant fibrous histiocytoma was the com- advanced RT techniques is concerned to increase the risk monest pathological diagnosis (4 patients) in their of a second cancer compared with three-dimensional con- patient series [25]. The difference of the pathological diag- formal radiotherapy (3D-CRT) [26,27]. The change from nosis among these studies might be related to the differ- 3D-CRT to IMRT involves a bigger volume of normal tis- ence of RT doses, nevertheless a correct relationship sue irradiated by lower doses as a result of the increase of between initial RT doses and second head and neck malig- fields, of monitor units and of scattered radiation. In con- nancies is unclear because of a small number of these trast, Ruben at al. argued that the risk of radiation-induced malignancies. cancer did not significantly differ between IMRT and 3D- CRT concerning the body in totality, and the risk of sec- Equipment and techniques mainly used for RT in today ond cancer was regarded to be influenced by RT equip- are likely to differ from those used for our patients. About ment [28]. At least, it must be inappropriate to simply half of our patients were treated with a linear accelerator apply our results to NHL patients treated with modern RT which is now standard RT equipment, and almost all the equipment and techniques. Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:21 http://www.ro-journal.com/content/4/1/21 It is debatable whether the prognosis of radiation-induced Authors' contributions malignancy might differ from that of spontaneously KT and HS designed/conducted analysis and wrote the occurring tumors. Previous studies on radiation-induced manuscript. KH and FA assisted in the acquisition and sarcoma suggested a poor prognosis of these patients and analysis of data. All authors have read and approved the also the beneficial effects of surgery for these tumors final manuscript. [21,25,29-33]. In addition, the poor prognosis of radia- tion-induced sarcoma of the head and neck might be Additional material related to the difficulty in complete resection of these tumors due to post-radiation changes [25]. It was held Additional file 1 that surgery should be conducted prior to RT in the treat- Table S1. Characteristics of the radiation-induced head and neck cancer ment of radiation-induced cancer, because of the lowered patients (n = 4). tolerance of the tissues to re-radiation and the oxygen Click here for file effect of the second tumor [19]. McHugh et al. compared [http://www.biomedcentral.com/content/supplementary/1748- 717X-4-21-S1.doc] the characteristics of radiation-induced craniofacial oste- osarcoma with those of the corresponding primary tumors, and proposed that the poorer prognosis of radia- tion-induced osteosarcoma was related to the higher References expression of adverse prognostic markers, such as p53, 1. Pierce DA, Preston DL: Radiation-related cancer risks at low TP53 mutations, ezrin expression, and the higher prolifer- doses among atomic bomb survivors. Radiat Res 2000, ative activity [34]. In contrast, there are some reports of 154:178-186. 2. 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Goolden AW, Morgan RL: Radiation cancer of the pharynx. Acta Radiol Ther Phys Biol 1965, 3:353-360. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)

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Radiation OncologySpringer Journals

Published: Jul 10, 2009

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