Advertisement

Three radiation-induced metachronous pelvic tumors in a patient who underwent radiotherapy for cervical cancer: a case report

Abstract

Introduction

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.

Case presentation

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.

Discussion and conclusion

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

DOI:10.5301/tj.5000518

Authors

Marijo Boban, Snjezana Tomic, Marija Sulic, Eduard Vrdoljak

Article History

Disclosures

Financial support: No grants or funding have been received.
Conflict of interest: None of the authors has any financial interest related to this paper to disclose.

This article is available as full text PDF.

Download any of the following attachments:

Introduction

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.

Case presentation

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.

Discussion

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.

Disclosures

Financial support: No grants or funding have been received.
Conflict of interest: None of the authors has any financial interest related to this paper to disclose.
References
  • 1. Travis LB Ng AK Allan JM et al. Second malignant neoplasms and cardiovascular disease following radiotherapy. J Natl Cancer Inst 2012 104 5 357 370 Google Scholar
  • 2. Arlen M Higinbotham NL Huvos AG Marcove RC Miller T Shah IC Radiation-induced sarcoma of bone. Cancer 1971 28 5 1087 1099 Google Scholar
  • 3. Maddams J Parkin DM Darby SC The cancer burden in the United Kingdom in 2007 due to radiotherapy. Int J Cancer 2011 129 12 2885 2893 Google Scholar
  • 4. Chaturvedi AK Engels EA Gilbert ES et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst 2007 99 21 1634 1643 Google Scholar
  • 5. Gatzen C Vipond MN Fish DE Snell ME Three new primary pelvic carcinomas in a patient following radiotherapy for carcinoma of the cervix. Case report. Acta Chir Scand 1990 156 2 183 186 Google Scholar
  • 6. Fraumeni JF Jr Curtis RE Edwards BK Tucker MA Introduction. In: Curtis RE, Freedman DM, Ron E, et al, eds. New malignancies among cancer survivors: SEER cancer registries, 1973-2000. Bethesda, MD: National Cancer Institute, 2006;1-7. Google Scholar
  • 7. Rogers L Siu SS Luesley D Bryant A Dickinson HO Radiotherapy and chemoradiation after surgery for early cervical cancer. Cochrane Database Syst Rev 2012 5 CD007583 Google Scholar
  • 8. Gladdy RA Qin LX Moraco N et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol 2010 28 12 2064 2069 Google Scholar
  • 9. Bjerkehagen B Smastuen MC Hall KS Skjeldal S Smeland S Fossa SD Why do patients with radiation-induced sarcomas have a poor sarcoma-related survival? Br J Cancer 2012 106 2 297 306 Google Scholar
  • 10. des Guetz G Chapelier A Mosseri V Dorval T Asselain B Pouillart P Postirradiation sarcoma: clinicopathologic features and role of chemotherapy in the treatment strategy. Sarcoma 2009 2009 764379 Google Scholar
  • 11. Gonin-Laurent N Gibaud A Huygue M et al. Specific TP53 mutation pattern in radiation-induced sarcomas. Carcinogenesis 2006 27 1266 1272 Google Scholar

Authors

Affiliations

  • Department of Oncology, University Hospital Split, School of Medicine, University of Split, Split - Croatia
  • Department of Oncology, University Hospital, Mostar - Bosnia and Hercegovina

Article usage statistics

The blue line displays unique views in the time frame indicated.
The yellow line displays unique downloads.
Views and downloads are counted only once per session.

No supplementary material is available for this article.