Patients treated with radiotherapy are under increased long-term risk of developing radiation-induced tumors. In this report we present an exceptionally rare case of a patient who, following radiotherapy for cervical cancer, developed 3 radiation-induced metachronous pelvic tumors.
In 1997, a 37-year-old patient with cervical adenocarcinoma (FIGO stage IB2) was subjected to adjuvant conventionally fractionated external-beam radiation therapy and brachytherapy following surgical treatment. Eleven, 14 and 15 years later, 3 radiation-induced malignant tumors developed: a leiomyosarcoma of the gluteus and 2 separate carcinomas of the rectum.
Radiotherapy for cervical carcinoma increases the standardized incidence ratios for rectal cancer and soft tissue sarcoma. Unfortunately, the current guidelines on contraindications to radiotherapy appear insufficient as they take into account a very limited number of clinical states and associated conditions, which is in disproportion to the rather high risk of radiation-induced malignancies of 0.45%. Information on the molecular characteristics of human radiation-induced tumors is still of no relevance for everyday clinical practice. Although radiotherapy is one of the most important modalities of oncological treatment, it should be judiciously used in cases where the benefits clearly outweigh the risk of serious untoward effects. In the case of patients undergoing pelvic irradiation, careful follow-up is needed for years.
Tumori 2016; 102(Suppl. 2): e93 - e95
Article Type: CASE REPORT
AuthorsMarijo Boban, Snjezana Tomic, Marija Sulic, Eduard Vrdoljak
- • Accepted on 06/04/2016
- • Available online on 27/04/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
The association between radiation therapy (RT) and the occurrence of new malignancies within the radiation field is well established (1). There are several criteria to be met before declaring a neoplasm to be radiation induced: a prior history of RT, a proper latency period between exposure to RT and tumor onset, and development of a neoplasm within a previously irradiated field (2).
The study by Maddams et al (3) showed that out of 298,000 newly diagnosed malignancies during 2007 in the United Kingdom, 1,346 (0.45%) were related to previous RT to malignant tumors. The highest incidence of second malignancies associated with RT was observed in patients who were treated for Hodgkin’s disease, tumors of the mouth and pharynx, and cervical cancer (3). Among survivors of cervical cancer who were treated with RT there is an increased long-term risk of developing cancers of the rectum/anus, colon, bladder, ovaries, and female genitourinary system in general (4).
In this paper we present an exceptionally rare case of a patient who, following RT for cervical cancer, developed 3 radiation-induced malignant tumors.
A 37-year-old patient with cervical adenocarcinoma (FIGO stage IB2, (pT1b2N0M0) underwent surgical treatment (Wertheim) in 1997. Following surgery, adjuvant conventionally fractionated external-beam RT and low-dose brachytherapy were applied. External RT was delivered by the 2-opposite-radiotherapy-fields technique with a tumor dose of 45 Gy without central block, and brachytherapy was delivered in a single insertion at a dose of 32 Gy calculated at point A.
In 2008, 11 years after RT for cervical cancer, the patient was diagnosed with rectal adenocarcinoma (pT3N0M0). After surgical treatment, 8 cycles of adjuvant chemotherapy with capecitabine were administered.
In 2011, 14 years after RT for cervical cancer, the patient was diagnosed with a new 35-mm tumor in the right gluteal area, within the applied external radiotherapy field, with no other abnormalities detected by PET/CT scan. The tumor was surgically removed and histopathological examination revealed a grade 2 leiomyosarcoma (FNCLCC score 5). Immunohistochemically the tumor was positive for vimentin, CD10, actin, h-caldesmon, p16 and p53, and the Ki67 proliferation index was 42.4%. Due to the positive resection margins, radical reexcision was performed with no adjuvant treatment being indicated.
Finally, in 2012, 15 years after RT for cervical cancer, during a control colonoscopy, a new tumor was detected in the rectum. The tumor was surgically removed and the histopathological diagnosis was adenocarcinoma (T1N0M0). Soon after surgery of the rectum, a relapse of the leiomyosarcoma occurred. MRI detected 3 tumor lesions in the right gluteal area. After repeat surgery, histopathological examination confirmed leiomyosarcoma (grade 3, FNCLCC score 6). Unfortunately, soon after, a control MRI showed multiple disease residues across the gluteus that were considered inoperable at the time. Seven cycles of chemotherapy with doxorubicin were given, and a partial response was achieved according to the RECIST criteria. Once again, due to significant regression of the tumor and based on the surgeon’s positive opinion on the possibility of radical resection, a surgical intervention was performed. Histopathology again showed grade 3 leiomyosarcoma, FNCLCC score 6, with positive resection margins. Postsurgical diagnostics revealed residual disease in the pelvis and metastases in the right lung. The patient was given second-line chemotherapy with ifosfamide. After 2 cycles disease progression occurred and the patient was switched to third-line chemotherapy with dacarbazine. There was further progression after 1 cycle and further oncological treatment was therefore not indicated. In March 2014 the patient died because of extensive locoregional disease progression and associated exhaustion.
One of the most deleterious consequences of exposure to RT is the emergence of radiation-induced malignancies. In the case of our patient, 3 different malignant tumors appeared after 11, 14 and 15 years within the field of adjuvant RT of the cervical carcinoma. The tumors diagnosed in our patient fulfill the criteria for being radiation induced. To our knowledge, this is the second report in the literature describing 3 new pelvic tumors in a patient submitted to RT for cervical carcinoma. It should be noted, however, that the tumors described in the first report by Gatzen et al (5) developed 40 years after exposure to RT, making the association between the effect of irradiation and the development of new tumors less clear.
Patients who survive malignant disease have a 14% higher probability of developing new malignancies with respect to the general population. That risk is influenced by lifestyle, genetic predisposition, and treatment of the previous malignancy (6). In a study examining the incidence of second cancers among more than 100,000 survivors of cervical cancer the importance of radiation was clearly confirmed (4). Only patients who were exposed to RT had a significantly higher risk of developing rectal cancer relative to the general population. The standardized incidence ratio (SIR) for rectal cancer among women who received any RT was 1.61 (95% confidence interval [CI] 1.21-2.09) versus 1.18 (95% CI 0.80-1.69) among women who received no RT (4).
The negative effect of RT in this population was even more pronounced with regard to soft tissue sarcoma, for which the SIR was 2.84 (95% CI 2.16-3.67) among women who received any RT versus 1.13 (95% CI 0.54-2.09) among women not treated with RT (4).
Taking into account these findings, the application of RT should be considered more cautiously. While there is general agreement on the validity of primary chemoradiation in patients with locally advanced cervical carcinoma, the benefit of adjuvant RT is less clear. In line with this are the results of a recent Cochrane systematic review evaluating the effectiveness of adjuvant RT versus no therapy after surgery for stage IB cervical cancer. It was concluded that RT decreases the risk of disease recurrence but with no overall survival improvement. At the same time the risk of serious adverse events was consistently higher (7).
It is generally accepted that patients with radiation-induced sarcoma (RIS) have a poor prognosis. For example, in a series of 7,649 patients with soft tissue sarcomas out of which 131 were RIS, it was found that disease-specific survival in patients with primary RIS was significantly worse in comparison with sporadic soft tissue sarcoma, independent of histological sarcoma type (8). Bjerkehagen et al (9) performed a study aiming to elucidate the reasons for the poor sarcoma-related survival in patients with RIS relative to sporadic high-grade sarcoma. They came to the conclusion that the poor prognosis of RIS patients was not due to the previous RT per se but rather to unfavorable factors, such as central tumor site and incomplete surgical remission, that were significantly more frequent among RIS patients than controls.
Surgery with widely negative margins remains the primary treatment of RIS. Unfortunately, the role of adjuvant and neoadjuvant chemotherapy remains uncertain.
Des Guetz et al (10) in their study with a small sample size (n = 25) demonstrated a good clinical partial response of RIS to chemotherapy in 47% of patients. Patients with leiomyosarcomas were good responders; 3 out of 4 patients responded to therapy. So, the authors concluded that RIS should not be managed differently from primary sarcoma (10). Although the molecular characterization of radiation-induced human tumors is limited by their rare occurrence, some specifics have been indicated. For example, in a series of 23 RISs a high prevalence of somatic mutations in the TP53 gene was found: 58%, which was significantly higher than in sporadic sarcomas (16.8%) (11).
In light of the above discussion several important points could be raised. First, the current guidelines on contraindications to RT appear insufficient as they take into account a very limited number of clinical states and associated conditions, which is in disproportion to the rather high risk of radiation-induced malignancies of 0.45% (3). Information on the molecular characteristics of radiation-induced human tumors are still of no relevance for everyday clinical practice and further investigations in this field are needed as well as in the field of interindividual differences in radiosensitivity.
An important aspect of this report is to enhance the awareness among clinicians prescribing RT of the risk of radiation-induced malignancies. Although RT is one of the most important treatment modalities in oncology, it should be judiciously used in cases where the benefits clearly outweigh the risk of serious untoward effects. Finally, we would like to highlight that in the case of patients undergoing pelvic radiation, careful follow-up is needed for years.
- Boban, Marijo [PubMed] [Google Scholar] 1, * Corresponding Author (email@example.com)
- Tomic, Snjezana [PubMed] [Google Scholar] 1
- Sulic, Marija [PubMed] [Google Scholar] 2
- Vrdoljak, Eduard [PubMed] [Google Scholar] 1
Department of Oncology, University Hospital Split, School of Medicine, University of Split, Split - Croatia
Department of Oncology, University Hospital, Mostar - Bosnia and Hercegovina