- Email: [email protected]
Probiotics for Rectal Volume Variation During Radiation Therapy for Prostate Cancer
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Probiotics for Rectal Volume Variation During Radiation Therapy for Prostate Cancer Yongkan Ki, MD,* Wontaek Kim, MD,* Jiho Nam, MD,* Donghyun Kim, MD,* Juhye Lee, MD,* Dahl Park, PhD,* Hosang Jeon, PhD,* Honggu Ha, MD,y Taenam Kim, MD,y and Dongwon Kim, MD* Departments of *Radiation Oncology and yUrology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea Received Apr 29, 2013, and in revised form Jul 2, 2013. Accepted for publication Jul 30, 2013.
Summary The aim of this study was to evaluate the effect of the probiotic Lactobacillus acidophilus on the percentage volume change of the rectum (PVCR) during radiation therapy for prostate cancer. A significantly lower rectal volume variance was observed in the probiotics group. Therefore, L acidophilus was useful in reducing the PVCR during radiation therapy for prostate cancer.
Purpose: To investigate the effect of the probiotic Lactobacillus acidophilus on the percentage volume change of the rectum (PVCR), a crucial factor of prostate movement. Methods and Materials: Prostate cancer patients managed with tomotherapy as a radical treatment were enrolled in the study to take a probiotic capsule containing 1.0 108 colony-forming units of L acidophilus or a placebo capsule twice daily. Radiation therapy was performed at a dose of 78 Gy in 39 fractions. The PVCR, defined as the difference in rectal volume between the planning computed tomographic (CT) and daily megavoltage CT images, was analyzed. Results: Forty patients were randomized into 2 groups. The L acidophilus group showed significantly lower median rectal volume and median PVCR values than the placebo group. L acidophilus showed a significant reduction effect on the PVCR (P<.001). However, the radiation therapy fraction number did not significantly influence the PVCR. Conclusions: L acidophilus was useful in reducing the PVCR, which is the most important determining factor of prostate position, during radiation therapy for prostate cancer. Ó 2013 Elsevier Inc.
Introduction Highly conformal irradiation techniques such as intensity modulated radiation therapy and image guided radiation therapy (IGRT) may allow a smaller margin and a higher dose in radiation therapy for prostate cancer. These precise technologies can improve cure rate and decrease toxicity. However, inter- and intrafraction organ motion emerge as important issues. The position error or Reprint requests to: Wontaek Kim, MD, Department of Radiation Oncology, School of Medicine, Pusan National University, 1-10 Ami-dong,
Int J Radiation Oncol Biol Phys, Vol. 87, No. 4, pp. 646e650, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.07.038
movement of an internal organ can be corrected using an IGRT system such as megavoltage computed tomography (MVCT) or cone-beam computed tomography. However, they are limited with regard to adjusting for a change in volume or the shape of internal organs. The prostate is known to move in response to bladder or rectal filling, leg rotation, and respiration (1-3). It is generally accepted that rectal volume is among the most significant factors influencing the location of the prostate (4, 5). Rectal volume is Seo-gu, Busan, Republic of Korea. Tel: (þ82) 51-2407383; E-mail: rokwt@ hanmail.net Conflict of interest: none.
Volume 87 Number 4 2013 affected primarily by the amount of rectal gas, which makes estimation or control of rectal volume difficult (6, 7). Minimizing rectal gas is important to reduce the prostate movement in radiation therapy for prostate cancer. Many institutes ask patients with prostate cancer to evacuate their rectums to decrease rectal volume. However, if the patients have an excessive production of bowel gas, the gas can accumulate in the rectum even after emptying. Furthermore, patients with chronic constipation or evacuation disorder have difficulty emptying their rectums. Therefore, inhibiting intestinal gas formation and relieving an evacuation disorder are no less important than emptying the rectum. Intestinal microflora imbalance may induce the production of excessive gas and exacerbate bloating or distension (8). Probiotics are defined as live microorganisms such as Lactobacillus acidophilus that exert specific favorable effects on the host (9). They have been reported to modify gut microbial balance and thereby reduce gas accumulation within the bowel (10). In this study, we aimed to develop a method to reduce rectal gas formation using probiotics. In addition, we evaluated the effect of L acidophilus to stabilize rectal volume during radiation therapy for prostate cancer.
Methods and Materials Patients In the present study, prostate cancer patients managed with tomotherapy as a radical treatment between May 2011 and September 2012 were enrolled. The exclusion criteria were as follows: pelvic lymph node or distant metastasis on computed tomography (CT) scan, magnetic resonance imaging, or bone scan; another primary tumor; inflammatory bowel disease; history of abdominal surgery; and taking antibiotics or laxatives for other diseases. Informed consent was obtained from all the patients. The trial protocol was approved by the institutional review board of our hospital.
Probiotics The patients were randomly assigned to the L acidophilus and placebo groups on the basis of a computer-generated random allocation sequence by simple randomization. The L acidophilus group was prescribed a probiotic capsule (300 mg, 2 times a day) that contained 1.0 108 colony-forming units of L acidophilus. Meanwhile, the placebo group was prescribed a placebo capsule (300 mg, twice daily). All patients were instructed to start taking the capsules from the day of simulation, 5 to 7 days before a first radiation therapy session, and to keep taking them continuously until the last session. No prohibitions were imposed with regard to the intake of fermented foods or drinks except for probiotic drugs.
Radiation therapy Radiation therapy was performed using the TomoTherapy Hi-Art Treatment System (TomoTherapy Inc, Madison, WI) at a dose of up to 78 Gy at 2 Gy per fraction. The prescribed dose was 54 Gy in 27 fractions for the prostate and the entire or proximal seminal vesicles and then a 24-Gy boost in 12 fractions for the prostate and proximal seminal vesicles. The patients were treated in the supine
Probiotics for rectal volume variation
647
position on a whole-body vacuum cushion. All the patients were ordered to empty their rectum and bladder and to drink 500 mL of water to fill their bladders 1 hour before the planning CT scan and each radiation therapy session. An enema was used routinely to empty the rectum properly regardless of the group assignment only before the planning CT scan. MVCT images were obtained without daily enema before every treatment session to identify the patient alignment and position of the prostate and seminal vesicles. If dilated with feces or gas, the rectum was then emptied using enema and rescanned. In this case, the first MVCT image before enema in each treatment session was used in this study.
Rectal volume measurement The particular part of the rectum that lies between the upper (proximal) and lower (distal) margins of the femoral heads was delineated on planning CT and MVCT images by 2 blinded observers independently using Pinnacle (Philips Radiation Oncology System, Milpitas, CA), and the larger of the 2 volumes was selected. The reason for the selection of this particular level of the rectum was because rectal gas usually accumulates and has the greatest influence on prostate dislocation in that level. Furthermore, that level was delineated more accurately, even on the MVCT images because it was distinct from the levator ani muscle. An analysis was performed for the percentage volume change of the rectum (PVCR), which was defined as the difference between the rectal volume of the planning CT images (VP) and that of the daily MVCT images (VMV). The PVCR was calculated using the equation (VMV VP)/Vp 100. The effect of L acidophilus on prostate movement was not evaluated because the objective movement was difficult to measure without fiducial markers, and the prostate position could be corrected by the MVCT images.
Statistical analysis The rectal volume on planning CT and MVCT and PVCR were compared between the 2 groups with Mann-Whitney U test. The t test for independent samples and c2 test were used to compare the other variables of the groups. The change of PVCR according to fraction number was analyzed by repeated-measures analysis of variance. A statistical analysis was performed using SPSS, version 19.0 (IBM, Somers, NY).
Results Forty-two patients were initially included in this study. However, 1 patient in each group discontinued their regular intake of the capsules and skipped taking the capsules for >2 days for nonmedical reasons. All the remaining 40 patients completed the radiation therapy without suspension of the treatment. The patients were randomized into the L acidophilus and placebo groups, with 20 patients in each group. The characteristics of the patients are summarized in Table 1. The median treatment period was 54 days (range, 53-61 days). Ultimately, 1600 images, including 40 planning CT images and 1560 MVCT images, were obtained from the 40 patients and analyzed. The overall median rectal volumes on the planning CT and MVCT images were 25.0 cm3 (17.5-38.0 cm3) and 28.1 cm3 (15.4-101.1 cm3), respectively. On the MVCT images, the L acidophilus group showed a median rectal volume of 27.9 cm3 (15.6-78.6 cm3), indicating
International Journal of Radiation Oncology Biology Physics
Ki et al.
Table 1
100
Patients’ characteristics Placebo group
Age Median Range Tumor stage T1-2 T3 Gleason score 4-6 7 8-10 Pretreatment PSA (ng/mL) Mean Range Androgen deprivation
Lactobacillus acidophilus group
P value .612
69 58-79
70 54-80
7 13
9 11
3 5 12
5 5 10
.456
.711
95% CI Rectal volume change (%)
648
50
0
-50
22.4 5.8-52.0 12
.507
a significantly smaller rectal volume than the 28.5 cm3 (15.4101.1 cm3) of the placebo group (PZ.018). Table 2 and Figure 1 present a significant difference in median PVCR between the L acidophilus (8.0%) and placebo groups (18.5%). Each patient showed varied PVCR distributions (Fig. 2). However, most of the patients in the L acidophilus group were localized in a lower distribution than that of the placebo group. The mean PVCR of each group according to the radiation therapy fraction is shown in Figure 3, which indicates that the L acidophilus group had a significantly smaller PVCR than that of the placebo group. In addition, we evaluated the frequency of emptying the rectum with enema and repeating MVCT because of rectal dilatation. The average numbers of rescanning during the 39 fractions were 2.1 times in L acidophilus group and 2.8 times in placebo group (PZ.054). The change in PVCR according to fraction number demonstrated no significant variation (PZ.202).
Table 2 Comparison of the rectal volume and percentage volume change of the rectum between the groups Lactobacillus acidophilus group
Lactobacillus acidophilus
Fig. 1. Comparison of the percentage volume change of the rectum between groups. CI Z confidence interval.
Abbreviation: PSA Z prostate-specific antigen.
Placebo group
Placebo
Groups
.414 21.8 2.3-65.1 14
p<.001
P value
Rectal volume on .478 planning CT scan (cm3) Median value 24.6 25.9 Range 17.5-35.8 18.4-38.0 Rectal volume on .018 MVCT (cm3) Median value 28.5 27.9 Range 15.4-101.1 15.6-78.6 PVCR (%) <.001 Median value 18.5 8.0 Range 29.2 to 264.5 33.9 to 147.5 Abbreviations: CT Z computed tomography; MVCT Z megavoltage computed tomography; PVCR Z percentage volume change of the rectum.
Only 1 patient (5%) in the L acidophilus group complained of mild bloating 3 weeks after taking the L Acidophilus-containing probiotic capsule; however, the symptom was relieved within several days without discontinuing the medication during radiation therapy. No other L acidophilus-related adverse effect was encountered.
Discussion The results of this trial show the significant benefit of L acidophilus for reducing the change in rectal volume. Although individual differences in effect were observed, L acidophilus generally reduced the production of rectal gas and stabilized the rectal volume. Rectal volume is an important determining factor of the position of the prostate and seminal vesicles during radiation therapy for prostate cancer (7). In particular, excessive rectal gas is the main factor related to variation in rectal volume and prostate displacement and can be a major obstacle in IGRT for prostate cancer because of its unpredictability (11). Although many institutes request that patients empty their rectum before each treatment fraction to reduce rectal volume, a consistent rectal evacuation is difficult to achieve. Recently, cone-beam CT or MVCT have been widely used in IGRT to overcome certain variations in target position. However, an immoderate target displacement may be uncorrectable by couch movement or rotation in most cases. Some efforts to reduce rectal gas production and manage the prostate position are laxatives, diet protocol, and direct removal of gas by finger or tube. Laxatives have been used to reduce interfractional or intrafractional setup errors due to rectal gas (12-14). Increased bowel movements from laxative use make it difficult for the colon to absorb water, causing loose stool or diarrhea, which in turn facilitates easy rectal evacuation. However, active fecal movement may cause rectal distension during irradiation and influence intrafractional prostate movement (12). Long-term use of laxatives is also associated with adverse gastrointestinal effects such as severe diarrhea, which is also a common toxicity in pelvic irradiation. The effects of a dietary protocol to decrease rectal gas formation were reported. The protocol included increasing physical activity, drinking enough water, taking magnesium oxide
Volume 87 Number 4 2013
Probiotics for rectal volume variation
649
95% CI Rectal volume change (%)
200
150
100
50
0
Pl a Pl ce a b Pl ce o 1 a b Pl ce o 2 a b Pl ce o 3 a b Pl ce o 4 a b Pl ce o 5 a b Pl ce o 6 a b P ce o 7 Pl lac bo ac eb 8 Pl e o a b 9 Pl ce o 1 a b 0 Pl ce o 1 a b 1 Pl ce o 1 a b 2 Pl ce o 1 a b 3 Pl ce o 1 a b 4 Pl ce o 1 a b 5 Pl ce o 1 a b 6 Pl ce o 1 a b 7 Pl ce o 1 ac bo 8 eb 1 o 9 LB 20 LBA 1 LBA 2 LBA 3 LBA 4 LBA 5 LBA 6 LBA 7 L A8 LBBA 9 LBA 1 0 LBA 1 1 LBA 1 2 LBA 1 3 LBA 1 4 LBA 1 5 LBA 1 6 LBA 1 7 LBA 1 8 LBA 1 A 9 20
-50
Patients
Fig. 2. Percentage volume change of the rectum in each patient. CI Z confidence interval; LBA Z Lactobacillus acidophilus.
daily, and avoiding certain foods (14). The authors who introduced the dietary protocol revealed that the incidence of feces and gas in the rectum were significantly decreased by using this protocol; however, the effects of the diet control alone on rectal gas accumulation were overlapped by the effects of the laxatives, which might have also caused the severe diarrhea (data not shown). Among previously reported methods, rectal emptying by mechanical rectal gas removal using a tube or index finger may be the most effective technique (15, 16). The mean difference in rectal volume decreased significantly from 24.9 to 7.8 cm3 using the rectal emptying tube (15). Nonetheless, routine daily tube insertion into the rectum before treatment is uncomfortable for patients and requires caution not to irritate the irradiated rectal mucosa. Increased intestinal gas production and bloating are consequences of lactase deficiency, functional bowel disorders, small intestinal bacterial overgrowth, and other factors (17). Probiotics are considered safe microbial supplements, and are also contained in fermented foods such as yogurt, fermented milk, and juice. Probiotics were reported to prevent radiation-induced enteritis and diarrhea in abdominal or pelvic irradiation. The patients taking probiotics (1.4%) had a significantly lower incidence of grade 3 or 4 diarrhea than the placebo group (54.4%) (9). Continuous intake
of probiotics may restore bowel microflora and reinforce the intestinal barrier capacity. Probiotics eventually stabilize normal bowel microflora and decrease excessive gas production and bloating (18). The intake of an appropriate amount of probiotics was demonstrated to be effective in relieving flatulence and hard stool in patients with evacuation disorder (19). Probiotics were also reported to reduce bloating and stool-related symptoms of irritable bowel syndrome (20). We presumed that L acidophilus could replace the excessive gas-forming bacteria and stabilize the bowel flora and consequently reduce bowel gas production, relieve constipation, and help empty the rectum. We assessed the effectiveness of L acidophilus for suppressing rectal gas accumulation. Our findings indicate that probiotics were useful in reducing the median PVCR from 18.5% to 8.0%, although it had only a marginally significant effect on the frequency of the need for enema and rescan. However, some patients in the L acidophilus group also showed unexpected excessive rectal extension. The specific characteristics of these patients need to be elucidated. Furthermore, the PVCR did not show a significant variation according to fraction number. Radiation therapy seemed to have little influence on the gas formation and rectal volume. The application of probiotics during radiation therapy had benefits such as the reduction of the radiation
95% CI Rectal volume change (%)
100 80 60 40 20 0 -20
0
5
10
15
20
25
30
35
40
Fraction number
Fig. 3. Mean percentage volume change of the rectum according to fraction number. CI Z confidence interval.
650
Ki et al.
toxicities and interfractional setup error. We used L acidophilus alone for bowel gas reduction because it is one of the most commonly prescribed probiotic species for bloating. The L acidophilus capsule (containing 1.0 108 colony-forming units of the microorganism) was prescribed 2 times a day because an excessive dose of L acidophilus may cause occasional flatulence. Further evaluation of various probiotics to determine the ideal combination and proper dose is needed.
References 1. Ten Haken RK, Forman JD, Heimburger DK, et al. Treatment planning issues related to prostate movement in response to differential filling of the rectum and bladder. Int J Radiat Oncol Biol Phys 1991; 20:1317-1324. 2. Malone S, Crook JM, Kendal WS, et al. Respiratory-induced prostate motion: Quantification and characterization. Int J Radiat Oncol Biol Phys 2000;48:105-109. 3. van Herk M, Bruce A, Kroes AP, et al. Quantification of organ motion during conformal radiotherapy of the prostate by three dimensional image registration. Int J Radiat Oncol Biol Phys 1995;33:1311-1320. 4. Antolak JA, Rosen II, Childress CH, et al. Prostate target volume variations during a course of radiotherapy. Int J Radiat Oncol Biol Phys 1998;42:661-672. 5. Kupelian PA, Langen KM, Zeidan OA, et al. Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2006;66:876-882. 6. Ogino I, Kaneko T, Suzuki R, et al. Rectal content and intrafractional prostate gland motion assessed by magnetic resonance imaging. J Radiat Res 2011;52:199-207. 7. Frank SJ, Dong L, Kudchadker RJ, et al. Quantification of prostate and seminal vesicle interfraction variation during IMRT. Int J Radiat Oncol Biol Phys 2008;71:813-820. 8. Schmulson M, Chang L. Review article: The treatment of functional abdominal bloating and distension. Aliment Pharmacol Ther 2011;33: 1071-1086. 9. Delia P, Sansotta G, Donato V, et al. Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 2007;13:912-915.
International Journal of Radiation Oncology Biology Physics 10. Gill HS, Guarner F. Probiotics and human health: A clinical perspective. Postgrad Med J 2004;80:516-526. 11. Stasi M, Munoz F, Fiorino C, et al. Emptying the rectum before treatment delivery limits the variations of rectal dose-volume parameters during 3DCRT of prostate cancer. Radiother Oncol 2006;80:363370. 12. Lips IM, van Gils CH, Kotte AN, et al. A double-blind placebocontrolled randomized clinical trial with magnesium oxide to reduce intrafraction prostate motion for prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 2012;83:653-660. 13. Chan P, Dinniwell R, Haider MA, et al. Inter- and intrafractional tumor and organ movement in patients with cervical cancer undergoing radiotherapy: A cinematic-MRI point-of-interest study. Int J Radiat Oncol Biol Phys 2008;70:1507-1515. 14. Smitsmans MH, Pos FJ, de Bois J, et al. The influence of a dietary protocol on cone beam CT-guided radiotherapy for prostate cancer patients. Int J Radiat Oncol Biol Phys 2008;71:1279-1286. 15. Fuji H, Murayama S, Niwakawa M, et al. Changes in rectal volume and prostate localization due to placement of a rectum-emptying tube. Jpn J Radiol 2009;27:205-212. 16. Ogino I, Uemura H, Inoue T, et al. Reduction of prostate motion by removal of gas in rectum during radiotherapy. Int J Radiat Oncol Biol Phys 2008;72:456-466. 17. Hasler WL. Approach to the patient with gas and bloating. In: Yamada T, Alpers DH, editors. Principles of Clinical Gastroenterology. Chichester, UK and Hoboken, NJ: Wiley-Blackwell; 2008. p. 255-270. 18. Ringel-Kulka T, Palsson OS, Maier D, et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: A double-blind study. J Clin Gastroenterol 2011;45:518-525. 19. Del Piano M, Carmagnola S, Anderloni A, et al. The use of probiotics in healthy volunteers with evacuation disorders and hard stools: A double-blind, randomized, placebo-controlled study. J Clin Gastroenterol 2010;44(suppl 1):S30-S34. 20. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005;17:687-696.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Probiotics for Rectal Volume Variation During Radiation Therapy for Prostate Cancer Yongkan Ki, MD,* Wontaek Kim, MD,* Jiho Nam, MD,* Donghyun Kim, MD,* Juhye Lee, MD,* Dahl Park, PhD,* Hosang Jeon, PhD,* Honggu Ha, MD,y Taenam Kim, MD,y and Dongwon Kim, MD* Departments of *Radiation Oncology and yUrology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea Received Apr 29, 2013, and in revised form Jul 2, 2013. Accepted for publication Jul 30, 2013.
Summary The aim of this study was to evaluate the effect of the probiotic Lactobacillus acidophilus on the percentage volume change of the rectum (PVCR) during radiation therapy for prostate cancer. A significantly lower rectal volume variance was observed in the probiotics group. Therefore, L acidophilus was useful in reducing the PVCR during radiation therapy for prostate cancer.
Purpose: To investigate the effect of the probiotic Lactobacillus acidophilus on the percentage volume change of the rectum (PVCR), a crucial factor of prostate movement. Methods and Materials: Prostate cancer patients managed with tomotherapy as a radical treatment were enrolled in the study to take a probiotic capsule containing 1.0 108 colony-forming units of L acidophilus or a placebo capsule twice daily. Radiation therapy was performed at a dose of 78 Gy in 39 fractions. The PVCR, defined as the difference in rectal volume between the planning computed tomographic (CT) and daily megavoltage CT images, was analyzed. Results: Forty patients were randomized into 2 groups. The L acidophilus group showed significantly lower median rectal volume and median PVCR values than the placebo group. L acidophilus showed a significant reduction effect on the PVCR (P<.001). However, the radiation therapy fraction number did not significantly influence the PVCR. Conclusions: L acidophilus was useful in reducing the PVCR, which is the most important determining factor of prostate position, during radiation therapy for prostate cancer. Ó 2013 Elsevier Inc.
Introduction Highly conformal irradiation techniques such as intensity modulated radiation therapy and image guided radiation therapy (IGRT) may allow a smaller margin and a higher dose in radiation therapy for prostate cancer. These precise technologies can improve cure rate and decrease toxicity. However, inter- and intrafraction organ motion emerge as important issues. The position error or Reprint requests to: Wontaek Kim, MD, Department of Radiation Oncology, School of Medicine, Pusan National University, 1-10 Ami-dong,
Int J Radiation Oncol Biol Phys, Vol. 87, No. 4, pp. 646e650, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.07.038
movement of an internal organ can be corrected using an IGRT system such as megavoltage computed tomography (MVCT) or cone-beam computed tomography. However, they are limited with regard to adjusting for a change in volume or the shape of internal organs. The prostate is known to move in response to bladder or rectal filling, leg rotation, and respiration (1-3). It is generally accepted that rectal volume is among the most significant factors influencing the location of the prostate (4, 5). Rectal volume is Seo-gu, Busan, Republic of Korea. Tel: (þ82) 51-2407383; E-mail: rokwt@ hanmail.net Conflict of interest: none.
Volume 87 Number 4 2013 affected primarily by the amount of rectal gas, which makes estimation or control of rectal volume difficult (6, 7). Minimizing rectal gas is important to reduce the prostate movement in radiation therapy for prostate cancer. Many institutes ask patients with prostate cancer to evacuate their rectums to decrease rectal volume. However, if the patients have an excessive production of bowel gas, the gas can accumulate in the rectum even after emptying. Furthermore, patients with chronic constipation or evacuation disorder have difficulty emptying their rectums. Therefore, inhibiting intestinal gas formation and relieving an evacuation disorder are no less important than emptying the rectum. Intestinal microflora imbalance may induce the production of excessive gas and exacerbate bloating or distension (8). Probiotics are defined as live microorganisms such as Lactobacillus acidophilus that exert specific favorable effects on the host (9). They have been reported to modify gut microbial balance and thereby reduce gas accumulation within the bowel (10). In this study, we aimed to develop a method to reduce rectal gas formation using probiotics. In addition, we evaluated the effect of L acidophilus to stabilize rectal volume during radiation therapy for prostate cancer.
Methods and Materials Patients In the present study, prostate cancer patients managed with tomotherapy as a radical treatment between May 2011 and September 2012 were enrolled. The exclusion criteria were as follows: pelvic lymph node or distant metastasis on computed tomography (CT) scan, magnetic resonance imaging, or bone scan; another primary tumor; inflammatory bowel disease; history of abdominal surgery; and taking antibiotics or laxatives for other diseases. Informed consent was obtained from all the patients. The trial protocol was approved by the institutional review board of our hospital.
Probiotics The patients were randomly assigned to the L acidophilus and placebo groups on the basis of a computer-generated random allocation sequence by simple randomization. The L acidophilus group was prescribed a probiotic capsule (300 mg, 2 times a day) that contained 1.0 108 colony-forming units of L acidophilus. Meanwhile, the placebo group was prescribed a placebo capsule (300 mg, twice daily). All patients were instructed to start taking the capsules from the day of simulation, 5 to 7 days before a first radiation therapy session, and to keep taking them continuously until the last session. No prohibitions were imposed with regard to the intake of fermented foods or drinks except for probiotic drugs.
Radiation therapy Radiation therapy was performed using the TomoTherapy Hi-Art Treatment System (TomoTherapy Inc, Madison, WI) at a dose of up to 78 Gy at 2 Gy per fraction. The prescribed dose was 54 Gy in 27 fractions for the prostate and the entire or proximal seminal vesicles and then a 24-Gy boost in 12 fractions for the prostate and proximal seminal vesicles. The patients were treated in the supine
Probiotics for rectal volume variation
647
position on a whole-body vacuum cushion. All the patients were ordered to empty their rectum and bladder and to drink 500 mL of water to fill their bladders 1 hour before the planning CT scan and each radiation therapy session. An enema was used routinely to empty the rectum properly regardless of the group assignment only before the planning CT scan. MVCT images were obtained without daily enema before every treatment session to identify the patient alignment and position of the prostate and seminal vesicles. If dilated with feces or gas, the rectum was then emptied using enema and rescanned. In this case, the first MVCT image before enema in each treatment session was used in this study.
Rectal volume measurement The particular part of the rectum that lies between the upper (proximal) and lower (distal) margins of the femoral heads was delineated on planning CT and MVCT images by 2 blinded observers independently using Pinnacle (Philips Radiation Oncology System, Milpitas, CA), and the larger of the 2 volumes was selected. The reason for the selection of this particular level of the rectum was because rectal gas usually accumulates and has the greatest influence on prostate dislocation in that level. Furthermore, that level was delineated more accurately, even on the MVCT images because it was distinct from the levator ani muscle. An analysis was performed for the percentage volume change of the rectum (PVCR), which was defined as the difference between the rectal volume of the planning CT images (VP) and that of the daily MVCT images (VMV). The PVCR was calculated using the equation (VMV VP)/Vp 100. The effect of L acidophilus on prostate movement was not evaluated because the objective movement was difficult to measure without fiducial markers, and the prostate position could be corrected by the MVCT images.
Statistical analysis The rectal volume on planning CT and MVCT and PVCR were compared between the 2 groups with Mann-Whitney U test. The t test for independent samples and c2 test were used to compare the other variables of the groups. The change of PVCR according to fraction number was analyzed by repeated-measures analysis of variance. A statistical analysis was performed using SPSS, version 19.0 (IBM, Somers, NY).
Results Forty-two patients were initially included in this study. However, 1 patient in each group discontinued their regular intake of the capsules and skipped taking the capsules for >2 days for nonmedical reasons. All the remaining 40 patients completed the radiation therapy without suspension of the treatment. The patients were randomized into the L acidophilus and placebo groups, with 20 patients in each group. The characteristics of the patients are summarized in Table 1. The median treatment period was 54 days (range, 53-61 days). Ultimately, 1600 images, including 40 planning CT images and 1560 MVCT images, were obtained from the 40 patients and analyzed. The overall median rectal volumes on the planning CT and MVCT images were 25.0 cm3 (17.5-38.0 cm3) and 28.1 cm3 (15.4-101.1 cm3), respectively. On the MVCT images, the L acidophilus group showed a median rectal volume of 27.9 cm3 (15.6-78.6 cm3), indicating
International Journal of Radiation Oncology Biology Physics
Ki et al.
Table 1
100
Patients’ characteristics Placebo group
Age Median Range Tumor stage T1-2 T3 Gleason score 4-6 7 8-10 Pretreatment PSA (ng/mL) Mean Range Androgen deprivation
Lactobacillus acidophilus group
P value .612
69 58-79
70 54-80
7 13
9 11
3 5 12
5 5 10
.456
.711
95% CI Rectal volume change (%)
648
50
0
-50
22.4 5.8-52.0 12
.507
a significantly smaller rectal volume than the 28.5 cm3 (15.4101.1 cm3) of the placebo group (PZ.018). Table 2 and Figure 1 present a significant difference in median PVCR between the L acidophilus (8.0%) and placebo groups (18.5%). Each patient showed varied PVCR distributions (Fig. 2). However, most of the patients in the L acidophilus group were localized in a lower distribution than that of the placebo group. The mean PVCR of each group according to the radiation therapy fraction is shown in Figure 3, which indicates that the L acidophilus group had a significantly smaller PVCR than that of the placebo group. In addition, we evaluated the frequency of emptying the rectum with enema and repeating MVCT because of rectal dilatation. The average numbers of rescanning during the 39 fractions were 2.1 times in L acidophilus group and 2.8 times in placebo group (PZ.054). The change in PVCR according to fraction number demonstrated no significant variation (PZ.202).
Table 2 Comparison of the rectal volume and percentage volume change of the rectum between the groups Lactobacillus acidophilus group
Lactobacillus acidophilus
Fig. 1. Comparison of the percentage volume change of the rectum between groups. CI Z confidence interval.
Abbreviation: PSA Z prostate-specific antigen.
Placebo group
Placebo
Groups
.414 21.8 2.3-65.1 14
p<.001
P value
Rectal volume on .478 planning CT scan (cm3) Median value 24.6 25.9 Range 17.5-35.8 18.4-38.0 Rectal volume on .018 MVCT (cm3) Median value 28.5 27.9 Range 15.4-101.1 15.6-78.6 PVCR (%) <.001 Median value 18.5 8.0 Range 29.2 to 264.5 33.9 to 147.5 Abbreviations: CT Z computed tomography; MVCT Z megavoltage computed tomography; PVCR Z percentage volume change of the rectum.
Only 1 patient (5%) in the L acidophilus group complained of mild bloating 3 weeks after taking the L Acidophilus-containing probiotic capsule; however, the symptom was relieved within several days without discontinuing the medication during radiation therapy. No other L acidophilus-related adverse effect was encountered.
Discussion The results of this trial show the significant benefit of L acidophilus for reducing the change in rectal volume. Although individual differences in effect were observed, L acidophilus generally reduced the production of rectal gas and stabilized the rectal volume. Rectal volume is an important determining factor of the position of the prostate and seminal vesicles during radiation therapy for prostate cancer (7). In particular, excessive rectal gas is the main factor related to variation in rectal volume and prostate displacement and can be a major obstacle in IGRT for prostate cancer because of its unpredictability (11). Although many institutes request that patients empty their rectum before each treatment fraction to reduce rectal volume, a consistent rectal evacuation is difficult to achieve. Recently, cone-beam CT or MVCT have been widely used in IGRT to overcome certain variations in target position. However, an immoderate target displacement may be uncorrectable by couch movement or rotation in most cases. Some efforts to reduce rectal gas production and manage the prostate position are laxatives, diet protocol, and direct removal of gas by finger or tube. Laxatives have been used to reduce interfractional or intrafractional setup errors due to rectal gas (12-14). Increased bowel movements from laxative use make it difficult for the colon to absorb water, causing loose stool or diarrhea, which in turn facilitates easy rectal evacuation. However, active fecal movement may cause rectal distension during irradiation and influence intrafractional prostate movement (12). Long-term use of laxatives is also associated with adverse gastrointestinal effects such as severe diarrhea, which is also a common toxicity in pelvic irradiation. The effects of a dietary protocol to decrease rectal gas formation were reported. The protocol included increasing physical activity, drinking enough water, taking magnesium oxide
Volume 87 Number 4 2013
Probiotics for rectal volume variation
649
95% CI Rectal volume change (%)
200
150
100
50
0
Pl a Pl ce a b Pl ce o 1 a b Pl ce o 2 a b Pl ce o 3 a b Pl ce o 4 a b Pl ce o 5 a b Pl ce o 6 a b P ce o 7 Pl lac bo ac eb 8 Pl e o a b 9 Pl ce o 1 a b 0 Pl ce o 1 a b 1 Pl ce o 1 a b 2 Pl ce o 1 a b 3 Pl ce o 1 a b 4 Pl ce o 1 a b 5 Pl ce o 1 a b 6 Pl ce o 1 a b 7 Pl ce o 1 ac bo 8 eb 1 o 9 LB 20 LBA 1 LBA 2 LBA 3 LBA 4 LBA 5 LBA 6 LBA 7 L A8 LBBA 9 LBA 1 0 LBA 1 1 LBA 1 2 LBA 1 3 LBA 1 4 LBA 1 5 LBA 1 6 LBA 1 7 LBA 1 8 LBA 1 A 9 20
-50
Patients
Fig. 2. Percentage volume change of the rectum in each patient. CI Z confidence interval; LBA Z Lactobacillus acidophilus.
daily, and avoiding certain foods (14). The authors who introduced the dietary protocol revealed that the incidence of feces and gas in the rectum were significantly decreased by using this protocol; however, the effects of the diet control alone on rectal gas accumulation were overlapped by the effects of the laxatives, which might have also caused the severe diarrhea (data not shown). Among previously reported methods, rectal emptying by mechanical rectal gas removal using a tube or index finger may be the most effective technique (15, 16). The mean difference in rectal volume decreased significantly from 24.9 to 7.8 cm3 using the rectal emptying tube (15). Nonetheless, routine daily tube insertion into the rectum before treatment is uncomfortable for patients and requires caution not to irritate the irradiated rectal mucosa. Increased intestinal gas production and bloating are consequences of lactase deficiency, functional bowel disorders, small intestinal bacterial overgrowth, and other factors (17). Probiotics are considered safe microbial supplements, and are also contained in fermented foods such as yogurt, fermented milk, and juice. Probiotics were reported to prevent radiation-induced enteritis and diarrhea in abdominal or pelvic irradiation. The patients taking probiotics (1.4%) had a significantly lower incidence of grade 3 or 4 diarrhea than the placebo group (54.4%) (9). Continuous intake
of probiotics may restore bowel microflora and reinforce the intestinal barrier capacity. Probiotics eventually stabilize normal bowel microflora and decrease excessive gas production and bloating (18). The intake of an appropriate amount of probiotics was demonstrated to be effective in relieving flatulence and hard stool in patients with evacuation disorder (19). Probiotics were also reported to reduce bloating and stool-related symptoms of irritable bowel syndrome (20). We presumed that L acidophilus could replace the excessive gas-forming bacteria and stabilize the bowel flora and consequently reduce bowel gas production, relieve constipation, and help empty the rectum. We assessed the effectiveness of L acidophilus for suppressing rectal gas accumulation. Our findings indicate that probiotics were useful in reducing the median PVCR from 18.5% to 8.0%, although it had only a marginally significant effect on the frequency of the need for enema and rescan. However, some patients in the L acidophilus group also showed unexpected excessive rectal extension. The specific characteristics of these patients need to be elucidated. Furthermore, the PVCR did not show a significant variation according to fraction number. Radiation therapy seemed to have little influence on the gas formation and rectal volume. The application of probiotics during radiation therapy had benefits such as the reduction of the radiation
95% CI Rectal volume change (%)
100 80 60 40 20 0 -20
0
5
10
15
20
25
30
35
40
Fraction number
Fig. 3. Mean percentage volume change of the rectum according to fraction number. CI Z confidence interval.
650
Ki et al.
toxicities and interfractional setup error. We used L acidophilus alone for bowel gas reduction because it is one of the most commonly prescribed probiotic species for bloating. The L acidophilus capsule (containing 1.0 108 colony-forming units of the microorganism) was prescribed 2 times a day because an excessive dose of L acidophilus may cause occasional flatulence. Further evaluation of various probiotics to determine the ideal combination and proper dose is needed.
References 1. Ten Haken RK, Forman JD, Heimburger DK, et al. Treatment planning issues related to prostate movement in response to differential filling of the rectum and bladder. Int J Radiat Oncol Biol Phys 1991; 20:1317-1324. 2. Malone S, Crook JM, Kendal WS, et al. Respiratory-induced prostate motion: Quantification and characterization. Int J Radiat Oncol Biol Phys 2000;48:105-109. 3. van Herk M, Bruce A, Kroes AP, et al. Quantification of organ motion during conformal radiotherapy of the prostate by three dimensional image registration. Int J Radiat Oncol Biol Phys 1995;33:1311-1320. 4. Antolak JA, Rosen II, Childress CH, et al. Prostate target volume variations during a course of radiotherapy. Int J Radiat Oncol Biol Phys 1998;42:661-672. 5. Kupelian PA, Langen KM, Zeidan OA, et al. Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2006;66:876-882. 6. Ogino I, Kaneko T, Suzuki R, et al. Rectal content and intrafractional prostate gland motion assessed by magnetic resonance imaging. J Radiat Res 2011;52:199-207. 7. Frank SJ, Dong L, Kudchadker RJ, et al. Quantification of prostate and seminal vesicle interfraction variation during IMRT. Int J Radiat Oncol Biol Phys 2008;71:813-820. 8. Schmulson M, Chang L. Review article: The treatment of functional abdominal bloating and distension. Aliment Pharmacol Ther 2011;33: 1071-1086. 9. Delia P, Sansotta G, Donato V, et al. Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 2007;13:912-915.
International Journal of Radiation Oncology Biology Physics 10. Gill HS, Guarner F. Probiotics and human health: A clinical perspective. Postgrad Med J 2004;80:516-526. 11. Stasi M, Munoz F, Fiorino C, et al. Emptying the rectum before treatment delivery limits the variations of rectal dose-volume parameters during 3DCRT of prostate cancer. Radiother Oncol 2006;80:363370. 12. Lips IM, van Gils CH, Kotte AN, et al. A double-blind placebocontrolled randomized clinical trial with magnesium oxide to reduce intrafraction prostate motion for prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 2012;83:653-660. 13. Chan P, Dinniwell R, Haider MA, et al. Inter- and intrafractional tumor and organ movement in patients with cervical cancer undergoing radiotherapy: A cinematic-MRI point-of-interest study. Int J Radiat Oncol Biol Phys 2008;70:1507-1515. 14. Smitsmans MH, Pos FJ, de Bois J, et al. The influence of a dietary protocol on cone beam CT-guided radiotherapy for prostate cancer patients. Int J Radiat Oncol Biol Phys 2008;71:1279-1286. 15. Fuji H, Murayama S, Niwakawa M, et al. Changes in rectal volume and prostate localization due to placement of a rectum-emptying tube. Jpn J Radiol 2009;27:205-212. 16. Ogino I, Uemura H, Inoue T, et al. Reduction of prostate motion by removal of gas in rectum during radiotherapy. Int J Radiat Oncol Biol Phys 2008;72:456-466. 17. Hasler WL. Approach to the patient with gas and bloating. In: Yamada T, Alpers DH, editors. Principles of Clinical Gastroenterology. Chichester, UK and Hoboken, NJ: Wiley-Blackwell; 2008. p. 255-270. 18. Ringel-Kulka T, Palsson OS, Maier D, et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: A double-blind study. J Clin Gastroenterol 2011;45:518-525. 19. Del Piano M, Carmagnola S, Anderloni A, et al. The use of probiotics in healthy volunteers with evacuation disorders and hard stools: A double-blind, randomized, placebo-controlled study. J Clin Gastroenterol 2010;44(suppl 1):S30-S34. 20. Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005;17:687-696.