Brachytherapy
Volume 10, Issue 1 , Pages 44-50, January 2011

Cross-linked hyaluronan gel improves the quality of life of prostate cancer patients undergoing radiotherapy

Cancer Center of Irvine, Irvine, CA

Received 29 September 2009; received in revised form 6 November 2009; accepted 31 December 2009. published online 01 July 2010.

Article Outline

Abstract 

Purpose

To test the hypothesis that cross-linked hyaluronan gel (Hylaform) does not affect the quality of life (QOL) of prostate cancer patients undergoing radiotherapy.

Methods and Materials

Thirty-five patients with early stage prostate cancer underwent high-dose-rate brachytherapy to 2200cGy and intensity modulated radiation therapy to 5040cGy on a prospective study. Thirty patients received a single transperineal injection of 9-mL Hylaform between the prostate and rectum under transrectal ultrasound guidance immediately before the start of radiotherapy. Hylaform increased the separation between the prostate and rectum by 6–19mm (median, 13mm) at the start of radiotherapy. Five patients did not receive Hylaform and served as controls. We assessed gastrointestinal-related QOL using Expanded Prostate Cancer Index Composite Bowel Bother scores immediately before the start of and during the last week of radiotherapy.

Results

At the beginning of intensity modulated radiation therapy, daily mean rectal doses were 74±8cGy (mean±standard deviation) and 105±25cGy (mean±standard deviation) with vs. without Hylaform, respectively (p=0.01). Expanded Prostate Cancer Index Composite Bowel Bother scores decreased by 0±3 (mean±standard deviation) and 11±14 (mean±standard deviation) in patients who did and did not receive Hylaform, respectively (p=0.03).

Conclusions

Hylaform increased the separation between the prostate and rectum and decreased the mean rectal dose, thereby improving the gastrointestinal-related acute QOL of prostate cancer patients undergoing radiotherapy. Patients will be followed up long term to determine if the improvement in acute QOL also translates into an improvement in late QOL.

Keywords: Hylaform, Radiotherapy, Quality of life

 

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Introduction 

Prostate cancer is the most common cancer in men, accounting for 25% of all the cancers in the United States (1). One in six American men will be diagnosed with prostate cancer during their lifetime (2).

Randomized trials have shown that escalation of radiotherapy doses improves biochemical disease-free survival in prostate cancer patients [3], [4], [5], [6]. Dose escalation may also improve distant metastasis-free survival [7], [8], [9], [10].

Rectal injury is the dose-limiting toxicity of radiotherapy for prostate cancer [3], [4], [9]. Dose escalation using conventional radiotherapy techniques results in high morbidity when rectal doses exceed 7500cGy [5], [11], [12]. Three-dimensional conformal radiotherapy reduces the risk of toxicity, although an 11% incidence of Grade 2 and 3 late gastrointestinal (GI) toxicity remains [3], [5]. Intensity modulated radiation therapy (IMRT) reduces the risk of Grade 2 and 3 late rectal bleeding to 2% [4], [6], [13].

With high-dose-rate (HDR) brachytherapy, intrafraction prostate motion does not have to be accounted for as it does with IMRT [9], [10] because the radioactive source moves with the prostate. As a result, by using HDR brachytherapy, one can safely escalate radiation doses [7], [8], [11], [12], [14].

Cross-linked hyaluronan, that is, hyaluronic acid, is a sugar that occurs naturally in the skin, cartilage, joints, and eyes. Cross-linked hyaluronan gel (Hylaform) acts as a tissue filler (15).

One group in Spain previously studied the ability of cross-linked hyaluronan gel to reduce mean rectal doses and rectal toxicity in prostate cancer patients undergoing brachytherapy±IMRT by increasing the separation between the prostate and rectum [16], [17]. We conducted the first study of Hylaform in American men with prostate cancer (18) based on the Spanish group's encouraging results. We needed to obtain an investigational device exemption from the United States Food and Drug Administration to conduct the prospective study. The Western Institutional Review Board also granted approval for the single-institution, open-label, Phase I study. In accordance with the Food and Drug Amendments Act (Title VIII. Sec. 801), we registered the trial online with ClinicalTrials.gov. All of the patients provided informed consent for treatment with HDR brachytherapy and IMRT±Hylaform.

The purpose of this study was to test the hypothesis that Hylaform does not affect the GI-related acute quality of life (QOL) of early stage prostate cancer patients undergoing HDR brachytherapy and IMRT.

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Methods and materials 

Bostwick Laboratories (Tempe, AZ) reviewed prostate biopsies. Patient characteristics are presented in Table 1.

Table 1. Patient characteristics
Patient characteristicHylaform (n=30)No Hylaform (n=5)
Age, y, median (range)70 (52–83)70 (59–78)
Followup, mo, median (range)5 (2–12)11 (2–11)
Clinical T stage
T1a0% (0)0% (0)
T1b0% (0)0% (0)
T1c52% (16)40% (2)
T2a17% (5)60% (3)
T2b7% (2)0% (0)
T2c17% (5)0% (0)
T3a7% (2)0% (0)

Gleason score
2–633% (10)60% (3)
747% (14)40% (2)
8–1020% (6)0% (0)

Prostate-specific antigen (ng/mL)
<1080% (24)80% (4)
10–2013% (4)0% (0)
>207% (2)20% (1)

Androgen deprivation therapy
Yes30% (9)20% (1)
No70% (21)80% (4)
Pelvic lymph node irradiation37% (11)20% (1)

Between June 2008 and June 2009, we treated 35 early stage prostate cancer patients at the Cancer Center of Irvine with HDR brachytherapy and IMRT on a clinical trial. All of the patients provided informed consent for treatment. In patients with benign prostatic hypertrophy who underwent HDR brachytherapy and IMRT, we administered neoadjuvant androgen deprivation therapy for 3–12 months to decrease the size of the prostate to <50cc [19], [20].

Fiducial gold seed placement in the prostate 

Using transrectal ultrasound (TRUS) guidance, five fiducial gold seeds were inserted into the patient's prostate gland under anesthesia before the delivery of radiotherapy (21). Fiducial markers were placed at the following sites: (1) base, (2) posterior mid gland, (3) right mid gland, (4) left mid gland, and (5) apex. The gold seeds made it possible to determine the location of the prostate using electronic portal imaging immediately before each IMRT treatment (22). We adjusted the patient's IMRT setup each day based on the location of the prostate.

Hylaform 

Genzyme Corporation (Cambridge, MA) has several types of cross-linked hyaluronan gels, including the one used in this study: Hylaform (23). Hylaform is a safe, strong hydrogel manufactured from rooster combs (24). Rooster combs consist predominantly of hyaluronic acid. The combs were processed to remove as much unrelated material as possible, leaving only hyaluronic acid.

Hylaform is swelled to equilibrium with physiologic saline in order for it to act as a tissue filler. The body absorbs irradiated Hylaform over approximately 4–8 months.

Injection of Hylaform 

Once we had inserted treatment needles into the prostate under anesthesia as described in the first paragraph of “HDR brachytherapy and IMRT” below, we removed the TRUS probe from the stand and held it by hand. Using TRUS guidance, we advanced a 17-G needle transperineally into anterior perirectal fat. We first placed the needle tip at the apex of the prostate. Care was taken not to perforate the posterior prostatic capsule or the anterior rectal wall. It is easier to inject the gel when a small, for example, 3-mL syringe, is used. Consequently, we attached a 3-mL syringe containing Hylaform to the needle. After aspirating to assure that the tip of the needle was not in a blood vessel, we injected 3mL of Hylaform into the anterior perirectal fat extending from the level of the apex of the prostate superiorly along the posterior border of the midline of the lower half of the prostate. We used axial TRUS images to guide placement of the gel. We then attached a second 3-mL syringe containing Hylaform to the needle. After aspirating to assure that the tip of the needle was not in a blood vessel, we injected 3mL of gel into the anterior perirectal fat extending superiorly along the posterior border of the midline of the upper half of the prostate. Next, we attached a third 3-mL syringe containing Hylaform to the needle. After aspirating to assure that the tip of the needle was not in a blood vessel, we injected 3mL of gel into the anterior perirectal fat extending superiorly from the base of the prostate along the seminal vesicles. We created an additional 6–19mm (median, 13mm) anteroposterior (AP) separation between the prostate and the rectum immediately before the start of radiotherapy using 9mL of Hylaform (Fig. 1).

  • View full-size image.
  • Fig. 1 

    (a) Sagittal T2-weighted pelvic MRI scans before injection of cross-linked hyaluronan gel (Hylaform), (b) after injection of Hylaform and at the start of radiotherapy, and (c) at the end of radiotherapy. Hylaform between the prostate and rectum appears hyperintense (white). The 10-mm anteroposterior dimension of Hylaform (b) at the start of radiotherapy decreased to 5mm (c) at the end of radiotherapy because of absorption by the body.

HDR brachytherapy and IMRT planning and treatment 

We obtained a treatment planning pelvic computed tomography (CT) scan before and after the injection of Hylaform. Next, we constructed a dose–volume histogram for each CT scan, contouring the rectum as a solid organ from the ischial tuberosities to the rectosigmoid junction. We then calculated mean rectal doses for the IMRT portion of the treatment with vs. without Hylaform. We did not calculate the mean rectal doses for the brachytherapy portion of the treatment without Hylaform because we preplan brachytherapy with ultrasound.

In preparation for HDR brachytherapy treatment needle insertion, we placed each patient in the dorsal lithotomy position under spinal or general anesthesia and prepared and draped him. We then inserted a #16 Foley catheter into the bladder and inflated its balloon with 5cc of contrast material. Next, we inserted a 6.5-MHz endorectal ultrasound probe into the rectum. We placed a Tayman-Tokita template against the perineum to guide brachytherapy treatment needle placement. We then inserted 16- to 18-HDR treatment needles into the prostate transperineally under TRUS guidance.

We delivered 550cGy fractions bid separated by 6h on the days of the first and second prostate implants. The two implants were performed 1 week apart, resulting in a total HDR brachytherapy dose of 2200cGy in four fractions over 8 days. The prostate gland constituted the clinical target volume (CTV) for the brachytherapy. We planned cases using a CT scan of the prostate implant (25) and the SIMUPLAN treatment planning system (Advanced Brachytherapy Solutions, Madrid, Spain). The brachytherapy dose was prescribed to the 100% isodose line that encompassed the planning target volume (PTV). The PTV included a 5-mm margin anterior and lateral to and a 2-mm margin posterior to the CTV. The dose to the CTV was ≥110% of the nominal prescription dose. The maximum urethral dose was 120% of the prescribed dose, and the maximum rectal dose was 80% of the prescribed dose.

IMRT began 1–4 days after the completion of HDR brachytherapy. We used the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) for IMRT.

If the risk of pelvic lymph node involvement was ≤15% according to the formula % lymph node risk=(2/3×prostate-specific antigen)+([Gleason score−6]×10) (26), then the CTV for IMRT was the prostate gland and inferomedial 10mm of the seminal vesicles. The CTV was treated to 5040cGy using daily 180-cGy fractions. The PTV included 10-mm right and left, 7-mm anterior and superior, and 5-mm inferior and posterior margins on the CTV. At least 98% of the PTV received 100% of the prescribed dose.

If the risk of pelvic lymph node involvement was >15%, then the initial CTV for the IMRT also included pelvic lymph nodes as defined by Hsu et al. (27). The superior border of the CTV was at the aortic bifurcation (which was typically near the bottom of the L5 vertebra), and the inferior border was at the top of the inguinal nodes. The PTV margin on the pelvic lymph nodes was 5mm. We delivered 4500cGy to the prostate, seminal vesicles, and pelvic nodes using daily 180-cGy fractions. We then administered three daily 180-cGy fractions to the final CTV consisting only of the prostate and inferomedial 10mm of the seminal vesicles.

Magnetic resonance imaging 

Hylaform is clearly visible on T2-weighted magnetic resonance imaging (MRI) scans without contrast and ultrasound images but not on CT scans. We obtained the first pelvic MRI scan before Hylaform injection (time point 1). We then obtained a second pelvic MRI scan 2 days after the injection of Hylaform (time point 2). Next, we obtained a third pelvic MRI scan at the end of radiotherapy (time point 3), which was 7 weeks after the injection of Hylaform. The maximum AP dimension of Hylaform was measured on MRI scans.

Quality of life 

We prospectively assessed QOL by using Expanded Prostate Cancer Index Composite (EPIC) self-assessment questionnaires that were completed by patients before and during the last week of radiotherapy (28). The EPIC questionnaire consists of 50 questions divided into four domains (Urinary, Bowel, Sexual, and Hormonal). Within the Bowel Domain, a subset of Bowel Function questions target symptom severity, and Bowel Bother (BB) questions assess GI-related QOL. The questionnaire is scored on a scale of 0–100 where higher Expanded Prostate Cancer Index Composite Bowel Bother (EPIC-BB) scores correlate with higher QOL. We provided the EPIC questionnaire to 5 consecutive prostate cancer patients who underwent HDR brachytherapy and IMRT immediately before the start of the Phase I study and to the subsequent 30 patients who consented to receive Hylaform, HDR brachytherapy, and IMRT. Because the study was approved by the Western Institutional Review Board in 3 weeks, we did not have more patients as controls.

Statistics 

We used a two-tailed Mann–Whitney U test (29) to assess whether the two independent samples of observations came from the same distribution. We used a two-tailed Fisher exact test (29) to analyze contingency tables where sample sizes were small.

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Results 

Median followup was 5 months (range, 2–12 months). There was no significant difference in the proportions of patients who received pelvic lymph node irradiation with vs. without Hylaform (p=0.64, Table 1).

The AP dimensions of Hylaform at the start and end of the radiotherapy were 13±3mm (mean±standard deviation) and 10±4mm (mean±standard deviation), respectively.

At the start of IMRT, daily mean rectal doses were 74±8cGy (mean±standard deviation) and 105±25cGy with vs. without Hylaform, respectively (p=0.01). EPIC-BB scores decreased by 0±3 (mean±standard deviation) and 11±14 (mean±standard deviation) in patients who did and did not receive Hylaform, respectively (p=0.03).

There were no complications attributable to injection of Hylaform into anterior perirectal fat.

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Discussion 

The main weaknesses of our Phase I clinical trial are a small sample size for the control arm, the inability to calculate mean rectal doses for the brachytherapy portion of the treatment, and short followup. In contrast, the main strengths are the prospective nature of the study and collection of patient-reported QOL data. Another strength of our study is that, unlike Prada et al. (16), we injected Hylaform before the start of HDR brachytherapy and IMRT to improve GI-related QOL as much as possible.

Treatment design was challenging because there is no consensus on how best to deliver HDR brachytherapy in combination with IMRT. When HDR brachytherapy is combined with IMRT, most groups deliver brachytherapy to the prostate gland to a total dose of 1200–2100cGy in two to three fractions using a single implant [8], [11], [30], [31], [32], [33]. In contrast, Prada et al. (34) deliver 2300Gy in two fractions using two implants that are separated by 2 weeks. For the external beam portion of the treatment, groups typically administer 4600cGy in 23 fractions [12], [32], [34] or 5040cGy in 28 fractions [8], [31], [33] to the prostate and seminal vesicles±pelvic nodes. In the present study, we delivered a cumulative HDR brachytherapy dose of 2200cGy in four fractions via two implants followed by external beam radiotherapy to 5040cGy. The biologically effective dose with this approach is similar to the one used by Prada et al. (34).

In a prior report (18), we observed that Hylaform reduces the severity of acute diarrhea caused by radiotherapy. We also calculated rectal wall volumes that would have received 6000cGy (V60) and 7000cGy (V70) relative to the total rectal wall volume based on the premise that patients would be treated with IMRT alone [35], [36]. These dosimetric measures are known as the rectal wall relative V60 and V70, respectively. Rectal wall relative V60 and V70 correlate with the patient's risk of developing chronic Grade ≥2 rectal toxicity [35], [36]. Hylaform decreased rectal wall relative V60 and V70, suggesting that the gel may decrease the patient's risk of developing late rectal toxicity.

In this report and the two reports by Prada et al. [16], [17], there were no complications attributable to a single injection of Hylaform into anterior perirectal fat. The most potentially serious adverse event because of injection of Hylaform is infection (37). We administered prophylactic antibiotics (cefazolin and gentamicin), decreasing the risk of infection to less than 5%. Because Hylaform is gradually absorbed by the body over a period of months, the risk of an infection developing more than 1 year after injection is minimal (38). If an infection had developed, it would have been treated with antibiotics or, in the case of an abscess, excision (39). There was a less than 5% risk of an allergic reaction because patients who were allergic to avian products were excluded from the study [40], [41]. Tenderness and pain at the injection site were also possible (42). In addition, bleeding, bruising, redness, discoloration, or formation of a granuloma or keloid at the injection site were possible [42], [43], [44]. Lastly, embolization of Hylaform through the blood was a potential although unlikely complication (45).

Ben-Yosef et al. (46) in Israel used an animal model to study an implantable, biodegradable balloon made of polylactic acid and caprolactone copolymers that is 10–20mm in the AP dimension and 35mm in the lateral dimension when fully inflated. The balloon requires a 2- to 3-mm dilator and a sheath over it for insertion. The Israeli group plans clinical testing in prostate cancer patients undergoing radiotherapy. Although advantages of their approach are that the tissue spacer has a 35mm lateral dimension and maintains its AP and lateral dimensions throughout the course of radiotherapy, the balloon requires a large dilator and sheath for insertion and remains for approximately 8 months after the completion of the radiotherapy during which time the balloon causes a foreign body reaction. Balloon placement theoretically places patients at risk for rectal ulceration or fistula formation. In addition, a minor surgical procedure is required for removal of the balloon. The lack of a billing code in the United States for balloon placement and removal has tempered the enthusiasm of American companies to develop a similar balloon. In contrast to balloon placement and removal, a single injection of Hylaform is simple and safe. For example, hyaluronic acid is injected using a needle that has an outer diameter of only 1.5mm. Because hyaluronic acid is a naturally occurring polysaccharide, there is no foreign body reaction (47). The main weakness of this approach is that, on average, a 9-mL injection of Hylaform created only a 13mm separation between the prostate and rectum at the start of radiotherapy that decreased to 10mm by the end of radiotherapy.

Other groups have previously attempted to improve the QOL of prostate cancer patients undergoing radiotherapy by taking a different approach. Amifostine, for example, is a radioprotector that improves acute and late QOL in prostate cancer patients undergoing radiotherapy (48). Intravenous delivery of amifostine is not well tolerated because of hypotension, nausea, and a rash (49). Subcutaneous administration is tolerated better; however, it still produces nausea and a rash [50], [51]. Although intrarectal administration typically does not cause any systemic or local side effects (51), amifostine still needs to be delivered on a daily basis before each radiotherapy treatment, which some patients may find unacceptable.

The EPIC score was developed at the University of Michigan as an expansion of the University of California at Los Angeles Prostate Cancer Index and was validated as an instrument for the assessment of QOL in men with prostate cancer (52). EPIC questionnaires have been used in several radiotherapy studies to assess GI-related QOL [28], [48], [53], [54]. On the basis of EPIC scores, a single injection of Hylaform before the start of treatment improved the GI-related acute QOL of prostate cancer patients undergoing radiotherapy.

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Conclusions 

Our results suggest that a single injection of 9mL of Hylaform into the anterior perirectal fat increases the separation between the prostate and rectum (Fig. 1) and decreases the mean rectal dose, thereby improving the GI-related acute QOL of prostate cancer patients. Mean rectal dose is a strong predictor of GI-related acute toxicity (55). We previously reported that Hylaform decreases the GI-related acute toxicity of radiotherapy (18). Patients who experience GI-related acute toxicity are more likely to experience late toxicity [36], [56]. Patients will be followedup long term to determine if the improvement in GI-related acute QOL and toxicity with Hylaform also translates into an improvement in late QOL and toxicity.

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 Reprint requests to: Diane Oshiro, Cancer Center of Irvine, 16100 Sand Canyon Avenue, Suite 130, Irvine, CA 92618. Tel.: +1-949-417-1100; fax: +1-949-417-1165. E-mail: doshiro@ccoi.org.

 Conflicts of interest notification: The Cancer Center of Irvine received a $55,000 research grant from Genzyme Corporation to study Hylaform as a tissue spacer in patients undergoing radiotherapy for localized prostate cancer.

PII: S1538-4721(10)00235-7

doi:10.1016/j.brachy.2009.12.005

Brachytherapy
Volume 10, Issue 1 , Pages 44-50, January 2011

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