Abstract
Background/Aim: Palliative radiotherapy is one of the effective treatments for pelvic tumors with bleeding or pain. In this study, we evaluated the safety and efficacy of palliative radiotherapy (RT) for symptomatic pelvic tumors when delivered as 25 Gy in 5 fractions. Patients and Methods: We retrospectively analyzed 34 patients (gynecological cancer: n=14, rectal cancer: n=5, metastatic pelvic bone tumor: n=7, metastatic pelvic lymph node tumor: n=5, synovial sarcoma of the pelvis: n=1, prostate cancer: n=1, and urothelial cancer: n=1), who were treated between July 2016 and July 2021. The symptoms were bleeding in 16 patients, pain in 17 patients, and both bleeding and pain in 1 patient. The hemostatic effect of RT was evaluated with pre- and post-treatment hemoglobin (Hb) values. If the Hb levels reached a nadir and increased thereafter, we considered that there is a hemostatic response. The pain was evaluated with a numerical rating scale (NRS) and treatment response was defined as a decrease in NRS. Results: Their median follow-up period was 4 months. A hemostatic response was observed in 82% of patients (14 of 17 patients). A pain relief response was observed in 78% of patients (14 of 18 patients). Acute adverse effects (AEs) included grade 1 diarrhea (n=3), grade 1 dermatitis (n=1) and grade 1 urinary frequency (n=1); late AEs have not been observed so far. Conclusion: 25 Gy of palliative RT in 5 fractions seems to be safe and effective for symptomatic pelvic tumors, similar to conventional palliative RT schedules.
Radiotherapy (RT) has an established role in palliative care for various cancers (1, 2). It has also been applied for advanced pelvic tumors, such as rectal cancer and uterine cervical cancer which often present complicated symptoms including bleeding and pain (3, 4). There are various patterns of dose-fractionation schedules for palliative RT for pelvic tumors from single fraction to 30 fractions (3-9), which could be determined individually by considering each patient’s condition, tumor characteristics, and resources of each hospital (5). A 20 Gy in 5 fractions or 30 Gy in 10 fractions of palliative RT are conventionally used dose-fractionation schedules for various types of tumor and tumor-related symptoms (1, 3). Recently, a 25 Gy in 5 fractions of palliative RT has been proposed by some facilities as a slightly modified dose-fractionation schedule of this conventional schedule (7, 8). A palliative RT regimen of 25 Gy/5 fractions has a greater biologically effective dose (BED) than 8 Gy/1 fraction or 20 Gy/5 fractions; and has almost the same BED as 30 Gy/10 fractions, with a shorter treatment period. Kim et al. reported the efficacy of 25 Gy in 5 fractions of palliative RT for symptomatic uterine cervical cancer (7). Similarly, Picardi et al. reported that 25 Gy in 5 fractions of palliative RT was effective and tolerable for patients with advanced rectal cancer (8). We applied 25 Gy/5 fractions of palliative RT for various tumors in the pelvis utilizing the advantage of a shorter treatment period compared to 30 Gy/10 fractions with almost the same biological effect. However, the increase of acute adverse events is a concern with high-dose (>5 Gy/fraction) therapy, and the efficacy of 25 Gy in 5 fractions of palliative RT for various pelvic conditions and various tumors is also unknown. Therefore, in this study, we assessed the safety and efficacy of 25 Gy/5 fractions of palliative RT for symptomatic pelvic tumors.
Patients and Methods
Patients. We retrospectively analyzed patients who were treated with 25 Gy in 5 fractions of palliative RT for symptomatic pelvic tumors between July 2016 and August 2021, under the approval of the Institutional Review Board of the International Medical Center, Saitama Medical University, Saitama, Japan (reference number: 20-091). Pelvic tumors in this study were included as both primary tumors at the pelvis and metastatic tumors at the pelvic bone and lymph node.
Radiotherapy. Treatment was delivered by a linear accelerator with a 3-dimensional conformal RT technique. Gross tumor volume (GTV) was defined on computed tomography images with 2.5-mm thickness. A 5 mm of the clinical target volume (CTV) margin was added to GTV and a 5 mm of planning target volume (PTV) margin was added to CTV. Generally, beams from 4-5 directions were used and doses were prescribed at the isocenter of the beam. Commercially available software (XiO) was used for treatment planning and dose calculation. The dose-calculation algorithm used was superposition (10). The maximum dose of cauda equina should be less than 25 Gy.
Evaluation of treatment response. All patients were assessed for pain using the Numerical Rating Scale (NRS) prior to the start of radiation therapy. Also, pain relief was evaluated by a numerical rating scale (NRS) before and after RT. Radiotherapy pain relief is considered to require 2-4 weeks after irradiation, so the patients were reevaluated as needed during radiotherapy, and analgesics were readjusted aggressively. Pain relief was evaluated by a numerical rating scale (NRS) before and after RT. If post-treatment NRS was decreased compared with pre-treatment NRS, we determined that there is a treatment response for pain relief. The hemostatic effect of RT was evaluated with pre- and post-treatment hemoglobin (Hb) values. If the Hb level reached a nadir and increased thereafter, we considered that there is a hemostatic response. Additional endpoints for hemostatic effect were also examined for the presence or absence of blood transfusion within 4 months of radiotherapy. We evaluated adverse events at every patient’s visit to the hospital after palliative RT. Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events, version 5. Diarrhea or nausea was classified as gastrointestinal toxicity (GI toxicity) and urinary frequency was classified as genitourinary toxicity (GU toxicity).
Statistical analysis. The median value of the 2 groups was compared with Mann-Whitney’s U-test and relationships between categorical characteristics and treatment responses were examined using the Chi-square test. Statistical analyses were performed with SPSS, version 26 (IBM, Armonk, NY, USA). p<0.05 was considered significant and all tests were two-sided.
Results
Patient and tumor characteristics. We identified and analyzed 34 patients (gynecological cancer: n=14, rectal cancer: n=5, metastatic pelvic bone tumor: n=7, metastatic pelvic lymph node tumor: n=5, synovial sarcoma of the pelvis: n=1, prostate cancer: n=1, and urothelial cancer: n=1) who were treated between July 2016 and July 2021. A representative patient is shown in Figure 1. The histological type of the tumors was adenocarcinoma in 19 patients, squamous cell carcinoma in 6 patients, sarcoma in 5 patients, neuroendocrine carcinoma in 2 patients, urothelial carcinoma in 1 patient, and undifferentiated carcinoma in 1 patient. Primary tumors of metastatic bone tumors were lung cancer in 3 patients, breast cancer in 2 patients, and renal cell carcinoma in 2 patients. Primary tumors of metastatic lymph node tumors were lung cancer in 2 patients, uterine carcinosarcoma in 1 patient, ovarian cancer in 1 patient, and pelvic solitary fibrous tumor in 1 patient. Their symptoms were bleeding in 16 patients, pain in 17 patients, and both bleeding and pain in 1 patient. The median PTV volume was 253.3 cc (range=20.8-1049.0). These characteristics are summarized in Table I.
The treatment plan of a representative patient is shown. The patient had a recurrence of ovarian cancer at the vaginal stump which caused bleeding. The light blue line shows the tumor in the figure on the left. Beams were created from 5 directions to ensure coverage of the tumor while avoiding high doses to the rectum. The dose distribution is shown in color wash, and the red thin line indicates 95% of the prescribed dose (25 Gy in 5 fractions). Diagnostic computed tomography image with contrast media of the same patient taken 6 months after treatment is shown on the right figure. The tumor shrunk well, and bleeding was controlled.
Patient and tumor characteristics (n=34).
Treatment response and toxicity. The median follow-up period was 4 months. At the last follow-up, 8 patients died with a median survival period of 4 months. Among 17 patients with bleeding, the median pre-treatment Hb level was 10.1 g/dL while the post-treatment Hb level was 10.3 g/dl (p=0.812). 14 out of 17 patients (82%) showed a hemostatic response. 10 patients had blood transfusions prior to the start of radiotherapy, and only one patient with uterine sarcoma required continued blood transfusions after radiotherapy. All patients were on oral analgesics for pain control prior to the initiation of radiotherapy. Of the 18 patients with pain, 11 were on opioids and 7 were on non-opioid analgesics. One patient experienced worsening pain during radiotherapy, which was thought to be a flare phenomenon, and was controllable with increased doses of analgesics. Among 18 patients with pain, the median pre-treatment NRS was 5 while the median post-treatment NRS was 2.5 (p=0.001). Among 18 patients with pain, 4 patients (22%) did not show pain relief response after treatment. The histological types of these 4 patients were sarcoma (3 patients, 16%) and renal cell carcinoma (1 patient, 5%). As a result, the pain relief response rate was 78% (14 out of 18 patients). However, there were no cases in which analgesics could be reduced within 4 months after radiotherapy. Acute adverse effects (AEs) included grade 1 diarrhea (n=3), grade 1 dermatitis (n=1), and grade 1 urinary frequency (n=1); grade 2 or greater acute toxicity has not been observed so far.
Factors related to treatment response. We found that sarcoma significantly correlated with refractoriness to palliative RT for pain relief response (p=0.004). Other factors, such as age, performance status, primary tumors, or metastatic tumors did not correlate with pain relief response. These results are summarized in Table II. The hemostatic response, histological type, age, performance status and presence of primary or metastatic tumors did not correlate with treatment response.
Factors related to pain relief response (n=18).
Discussion
In this study, 14 of 17 patients (82%) showed a hemostatic response. Although 3 patients showed no hemostatic response by our definition, a decrease in Hb level in these 3 patients became slow and they could be discharged from the hospital without the necessity of a blood transfusion. In a previous study, Kim et al. reported that 94% of patients (15 out of 16 patients) with bleeding showed a hemostatic response after 20-25 Gy in 5 fractions of palliative RT for uterine cervical cancer (6). Picardi et al. reported that 25 Gy in 5 fractions of palliative RT for advanced rectal cancer achieved a 100% (9 out of 9 patients) hemostatic response rate (7). The present study similarly showed an adequate hemostatic purpose, as Kim et al. and Picardi et al., although our study included various cancers, beyond uterine cervical cancer and rectal cancer. Although a few reports mention hemostasis-dose-response relationships, a meta-analysis has suggested that a minimum of 30 GyEQD2 is necessary for hemostatic radiation therapy for gastric cancer (11). EQD2 means that radiation doses were biologically converted to equivalent doses in 2 Gy (EQD2) by a linear quadratic model using an alpha/beta ratio of 10 Gy for GTV and 3 Gy for OARs. A 25 Gy in 5 fractions deserves 31.25 GyEQD2, which was higher than this cut-off value. We think that 25 Gy in 5 fractions of palliative radiotherapy has an adequate hemostatic effect for pelvic tumors.
In this study, the pain relief response rate was 78% (14 out of 18 patients). Picardi et al. reported that the pain relief response rate was 87% with 25 Gy in 5 fractions of palliative RT for rectal cancer (7). Our study showed the same tendency; pain relief response rates were relatively lower compared to hemostatic response rates. However, the pain relief response rate was still adequate, given the reported pain relief response rate (61-70%) of palliative RT for various cancers (12, 13). In this study, 4 of 18 patients showed no pain relief response. The histological types of these 4 patients were sarcoma (3 patients) and renal cell carcinoma (1 patient). When the histopathology of the primary lesion results in sarcoma, there is a significant correlation with refractoriness to palliative RT for pain relief (p=0.004). Nevertheless, sex, age, PS, and the primary or metastatic tumor did not show a significant difference. The same tendency was observed in patients with bleeding. Among 17 patients with bleeding, 1 patient with uterine sarcoma could not avoid a blood transfusion. Generally, sarcoma showed refractoriness to RT (14, 15). Further studies with a larger number of patients are needed to clarify the optimal dose-fractionation schedule of palliative RT for sarcoma.
Another concern of palliative RT for pelvic tumors is acute GI and GU toxicity. Picardi et al. reported that Grade 1-2 GI and GU toxicity was observed in 39% of patients after palliative RT of 25 Gy in 5 fractions for advanced rectal cancer (7). The incidence of grade 1 GI and GU toxicity in the present study was 12% (4 of 34 patients), which seems to be adequately low. In this study, 71% of patients (24 out of 34 patients) had primary pelvic tumors. To avoid unnecessary doses to the surrounding GI tract when the tumor is located in the central area of the pelvis, we used beams from multiple directions rather than anterior-posterior opposite beams. The median number of beams of RT was 5 for the patients with primary pelvic tumors. We think that one of the reasons for the low incidence of low GI toxicity is the delivery of beams from multiple directions, so as to spare the surrounding GI tract. Our findings suggest that 25 Gy in 5 fractions of palliative RT with careful attention to reducing unnecessary doses to the surrounding GI tract is a tolerable option for pelvic tumors.
Limitations of this study should be noted. This was a retrospective study with a relatively small patient cohort, which may have led to sample bias with respect to tumor types and other patient characteristics. Toxicity and treatment responses were not evaluated with fixed schedules, which may have produced uncertainty in the results. Also, the unfixed evaluation method and patients’ short follow-up period made it difficult to evaluate the duration of the effects. Therefore, AEs and treatment responses should be evaluated with stricter criteria in a future prospective trial. We did not apply intensity modulated radiation therapy (IMRT) or stereotactic body radio therapy (SBRT) in this study due to the lack of machine and human resources to perform these high-precision RT for palliative purposes. The dose to the surrounding normal tissue could be reduced or the dose to the tumor could be increased with these techniques. Further study is needed to clarify the effect and safety of these advanced RT techniques for palliation of pelvic tumors.
Conclusion
In this study, 25 Gy in 5 fractions had good hemostatic and analgesic effects, and no serious adverse events occurred. We think that 25 Gy of palliative RT in 5 fractions seems to be safe and effective for symptomatic pelvic tumors, similar to conventional palliative RT schedules.
Acknowledgements
The institutional review board of the Saitama Medical University International Medical Center approved this study (20-091). We thank Marla Brunker from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
TA and TA designed the study. MI, SS, TA, YR, TO, MI, RH, YK, SN and SK contributed to the acquisition and analysis of data. TA performed the statistical analysis. TA, TA and SK created the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received October 27, 2022.
- Revision received November 4, 2022.
- Accepted November 8, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
