We are not currently aware of any established standard therapeutic approach for the treatment of advanced cancer patients with clinically significant bleeding as a result of their cancer. At the moment, treatment decisions are primarily based on the underlying causes and overall patient PS. The therapeutic approach varies from comfort measurement to invasive surgical procedures.
Hemostatic RT is generally believed to be an effective treatment for patients with bleeding due to cancer. Although bleeding occurs in 6-10% of patients with advanced cancer , relatively little published literature is available which focuses on bleeding control of hemostatic RT; even less is known about the optimal RT total dose and fractionation.
In our retrospective study containing 62 patients with different primary tumors with significant bleeding (including 1 patient whose benign cause of bleeding was pseudomyxoma pertinonei), it was demonstrated that hemostatic RT reduced the incidence and grading of bleeding significantly. This effect seemed to be durable in the majority of patients. Furthermore, our data suggests an association between a total RT dose > 30 Gy and increased OS. Male patients and those with a bleeding grade ≥ 2 at the end of RT were shown to have a greater risk of dying. Although RT dose remained significantly associated with OS in the multivariate analysis, we are aware that this association may be biased due to possible confounding factors, such as increased dose given to patients with a higher PS and/or better prognosis.
Bleehen et al. reported almost 20 years ago results from a phase III trial which compared 2 different fractionation schedules (1 x 10 Gy vs. 2 x 8.5 Gy) as palliative treatment in 235 patients with incurable locally advanced NSCLC. One of the symptoms of interest was hemoptysis which was present in some form in 47% of all patients. After thoracic RT, hemoptysis improved in 72-75% of patients and completely disappeared in 54-64% of patients. Median duration of this palliative effect was 64–73 days; no significant difference was observed between the 2 arms . Similarly, Langendijk et al. prospectively assessed the influence of palliative thoracic RT using 10 x 3 Gy in 65 patients with incurable NSCLC on QoL. There was a 79% response rate of hemoptysis after RT . Comparably, the symptoms of all 10 patients where lung was the treated site in our retrospective study improved during RT. There was a 80% CR rate for bleeding. Furthermore, bleeding remained improved in 80% of patients until the end of follow-up.
Biswal et al. reported a bleeding control of 100% 12-48 hours after EBRT with 5–20 Gy with/or low-dose rate brachytherapy with 30 Gy for severe refractory bleeding caused by cervical cancer. However, in 85% bleeding was observed again within the following two years. GI toxicities ≥ grade 2 were observed in 3 patients . Of the 19 patients who received RT to the uterovaginal region in our study, improvement of bleeding during RT occurred in 95%, 68% had a CR and bleeding remained improved until the end of follow-up for 79%. Srinivasan et al. treated in total 41 cT3-4 patients, with bladder cancer who had hematuria, with 2 x 8.5 Gy = 17 Gy (EQD3 = 24 Gy) as compared to 12 x 3.75 Gy = 45 Gy. Interestingly, the effect on hematuria was larger in the 17 Gy hypofractionated patients with a 59% clearing probability as compared to 16% in the other group, while toxicity did not differ between the groups . Others have reported that 6 weeks after palliative RT using 20 Gy in 5 fractions, the bleeding response rate was 81% in 31 patients with castrant resistant prostate cancer, however the response rate appeared to drop to 42% and 29% after 4 months and 7 months, respectively . Seventeen patients in our study received RT to the bladder region (for different primary tumors and histologies, respectively); 65% showed an improvement in their bleeding during RT, 47% had a CR and 59% remained with improved symptoms until the end of follow-up.
Hoskin et al. described the outcome after intraluminal HDR-B for 50 patients with inoperable cancer of the rectum or anal canal. Treatment was either performed in curative intent with 6 x 6 Gy = 36 Gy HDR-B monotherapy, 12 Gy HDR-B boost after 45 Gy EBRT (n = 22), or 1 x 10 Gy HDR-B as palliative treatment (n = 28). Twenty-eight patients had initial bleeding; a 57% CR rate was obtained in these patients, with a 10-month median response duration . In our study only 4 patients with tumors of the lower GI tract were available, all of whom experienced CR for bleeding which remained until the end of follow-up.
Hemostatic RT was also used to treat locally advanced or recurrent gastric cancer. Tey et al.’s study contained 33 patients; 24 of whom had initial bleeding. After RT where 10 x 3 Gy was applied in the majority of cases, 54% showed a reduction in bleeding with median response duration of 140 days. No dose–response relationship was observed. One patient experienced grade 3 toxicity . In our study, 10 patients received RT to the upper GI tract; 5 of whom was to the stomach. A reduction in bleeding was observed in 90%, CR in 50% and durable response in 60%. Notably in 30% of these patients bleeding worsened during the end of follow-up.
We are aware of the limitations within our retrospective non-randomized study; no firm conclusions can be made in regard to the optimal radiation dose. The possible advantages of using a higher RT dose should be balanced against potentially higher toxicity in addition to patient discomfort due to the prolonged treatment time. Hypofractionation with large single doses may be useful in case of life-threatening bleeding to induce rapid hemostypsis, but the risks of severe toxicities (Grade 3–5) have to be taken into account even in this palliative end-of-life setting .
We also acknowledge the heterogeneity of our patient population; several different primary tumors were involved and ultimately different treatment sites were targeted by hemostatic RT. While, the total response rate compares well with the current literature for different individual disease types, the bleeding control seemed to be lower in lesions involving the bladder as compared to the other treated sites. This finding, however, is again subject to several potential confounding factors such as use of different total doses and therefore needs further confirmation by other studies.