- Email: [email protected]
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GYNECOLOGY
A randomized study of hexaminolevulinate photodynamic therapy in patients with cervical intraepithelial neoplasia 1/2 Peter Hillemanns, MD; Francisco Garcia, MD, MPH; Karl Ulrich Petry, MD; Vladimı´r Dvorak, MD; Oliver Sadovsky, MD; Ole-Erik Iversen, MD; Mark H. Einstein, MD, MS OBJECTIVE: The objective of the study was to investigate the efficacy
and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN) 1/2, to define the appropriate population and endpoints for a phase 3 program. STUDY DESIGN: This was a double-blind, randomized, placebocontrolled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months. RESULTS: There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A
clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P < .001) was observed at 3 months in women with CIN2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local selflimiting adverse reactions including discharge, discomfort, and spotting were reported. CONCLUSION: HAL PDT is a novel therapy that shows promise in the
treatment of CIN2 including clearance of oncogenic HPV, but not of CIN1. The positive risk/benefit balance makes HAL PDT a tissuepreserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned. Key words: cervical intraepithelial neoplasia, hexaminolevulinate, human papillomavirus, photodynamic therapy
Cite this article as: Hillemanns P, Garcia F, Petry KU, et al. A randomized study of hexaminolevulinate photodynamic therapy in patients with cervical intraepithelial neoplasia 1/2. Am J Obstet Gynecol 2014;212:x.ex-x.ex.
C
ervical cancer is the third most common cancer in women worldwide and is caused by persistent infection with oncogenic human papillomavirus (HPV). HPV is the most prevalent sexually transmitted infection,
with a peak prevalence of 25-35% of young women in their early twenties, but with a high spontaneous regression rate of 90% in 2 years.1 However, persistent oncogenic HPV infections may lead to development of precancerous lesions
with increasing risk of progression to invasive cancer. Subjects with precancerous lesions are routinely treated with surgical intervention such as loop electrosurgical excision procedure (LEEP) or cone
From the Department of Obstetrics and Gynecology, Hannover Medical School, Hannover (Dr Hillemanns), and Clinic for Gynecology, Obstetrics, and Gynecological Oncology, Clinic of the City of Wolfsburg, Wolfsburg (Dr Petry), Germany; Center of Excellence in Women’s Health, University of Arizona, Tucson, AZ (Dr Garcia); Center of Outpatient Gynecology Clinic and Primary Care, Brno, Czech Republic (Dr Dvorak); private practice, Bratislava, Slovak Republic (Dr Sadovsky); Institute of Clinical Medicine, University of Bergen and Women’s Clinic, Haukeland University Hospital, Bergen, Norway (Dr Iversen); and Department of Obstetrics and Gynecology and Women’s Health, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY (Dr Einstein). Received June 9, 2014; revised Sept. 9, 2014; accepted Oct. 29, 2014. The study was funded by Photocure ASA, Oslo, Norway. P.H. received honoraria and research support from Photocure. O.-E.I. received lecture fee. M.H.E. received travel expenses and grant funding for research-related costs of this clinical trial. The remaining authors report no conflict of interest. Presented at EUROGIN 2013, European Research Organization on Genital Infection and Neoplasia, Florence, Italy, Nov. 3-6, 2013, and at the 44th annual meeting on Women’s Cancer, Society of Gynecologic Oncology, Los Angeles, CA, March 9-12, 2013. Corresponding author: Peter Hillemanns, MD, PhD. [email protected] 0002-9378/$36.00 ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1107
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biopsy. Surgery may, however, be associated with an increased risk of subsequent late abortion, preterm delivery, and other perinatal complications.2-5 Because of these adverse consequences, recent US management guidelines recommend initial conservative management in young women with cervical intraepithelial neoplasia (CIN) 2/3 to reduce the risks of perinatal side effects.6 For decades, extirpative procedures have been the mainstay of treatment due to the lack of other therapeutic modalities for CIN. The need for an effective nonsurgical therapy was highlighted in the recommendations of the American Association for Cancer Research Task Force on the treatment and prevention of intraepithelial neoplasia,7 underlining the urgent need for new modalities with an adequate safety profile. Therapeutic vaccines have shown promise, but have not demonstrated definitive clinical efficacy and appropriate immunological responses for cervical neoplasia.8 Topical hexaminolevulinate (HAL) (Photocure ASA, Hoffsveien 4, NO0275, Oslo, Norway) photodynamic therapy (PDT) has the potential to address the medical need for a tissuepreserving treatment of persistent HPV infections and CIN, treating the entire portio of the cervix and maintaining cervical competence. PDT involves the accumulation of a photoactive compound in target cells, which are then illuminated to generate highly reactive oxygen species that destroy tumor cells by inducing apoptosis and necrosis.9-11 HAL is administered as an ointment via an intravaginal photoactivation device, which is programmed to deliver 100 J/cm2 of red light with a lightemitting diode at a wavelength of 629 nm. The device is removed by the patient once treatment has been completed. The technology has also been shown to stimulate the systemic immune system by enhancing the immune recognition of antigens.12,13 HAL PDT previously showed a favorable safety profile and promising efficacy in subjects with CIN 1-3.14 The more recent easyto-use outpatient PDT procedure was tested in a small pilot study that showed high patient and gynecologist acceptance
ajog.org and efficacy in subjects with low-grade cervical lesions.15 The objective of this phase 2b study was to further investigate the safety and efficacy of HAL PDT in subjects with CIN 1 and CIN 2 and to define the optimal HAL dose and patient population for further clinical development.
M ATERIALS
AND
M ETHODS
The clinical trial was conducted according to European Medicines Agency and Food and Drug Administration guidelines, and in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. The study is registered in the Clinicaltrials. gov (National Institutes of Health) database (NCT01256424). Ethical approval was obtained from all clinical sites and all subjects provided written informed consent before inclusion. This was a phase 2b, prospective, randomized, double-blind, placebocontrolled, multicenter study conducted at 23 centers in the United States, Germany, Czech Republic, Slovak Republic, and Norway. A total of 262 adult women (age 18 years) with satisfactory colposcopy examination including visibility of the entire transformation zone with the entire lesion margin, averagesized uterine cervix (approximately 27-mm diameter), and colposcopically identified CIN 1 or CIN 2 based on local pathology read of biopsy were included. Main patient exclusion criteria were inadequate colposcopy, lesion(s) extending to the vaginal vault, suspicion of endocervical disease on colposcopy, previous treatment of CIN or invasive disease, significant vaginal infection or bleeding, porphyria, known drug sensitivity, pregnancy, or breast-feeding. The expected proportions of patients with complete or partial response were set to 20% for placebo and 50% for HAL PDT. A 2-sided significance level of 5% and statistical power of 80% were used to calculate the sample sizes. Eligible subjects were randomized equally to 4 arms: HAL 5%, 1%, 0.2%; and placebo ointments. Randomization was stratified by site in a block size of 4. Drug and illumination were
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administered by the intravaginal device (Figure 1). The gynecologist spread the ointment evenly in the device cavity before positioning it on the cervix, thereafter the patient was free to return to normal daily activities. The device supported targeted delivery of HAL ointment to the portio for 5 hours, enabling selective enrichment of photoactive porphyrins in the diseased area in subjects who received active drug, followed by automatic photoactivation (illumination) for another 4.6 hours. The device was designed and programmed to deliver red light (629 nm) with a total dose of 100 J/cm2 exclusively to the portio of the ectocervix in the active treatment groups, with no light in the placebo ointment group. The primary study endpoint was patient response at 3 months with assessment of histology and cytology regression and clearance of oncogenic HPV. Subjects with abnormal histology or cytology at 3 months received a second treatment followed by a new biopsy 3 months after retreatment. Secondary endpoints were patient response (cytology and oncogenic HPV) 6 months after treatment and safety assessments. Subjects with disease progression or a need for immediate treatment were offered standard-of-care treatment at the discretion of the investigator. Colposcopic-directed biopsies were FIGURE 1
Cevira device for drug and light delivery
Drug and illumination were administered by Cevira intravaginal device (Photocure ASA, Oslo, Norway) that remains in place for around 5 hours, before removal by patient. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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ajog.org obtained from all suspicious areas at baseline and 3-month follow-up. In normal-appearing epithelium at colposcopy follow-up, biopsies were obtained from the most severe baseline lesion areas. For efficacy analyses all baseline and follow-up biopsies were reviewed by a central expert gynecology pathologist (DCL Laboratories, Urbana, IL) blinded to other study data. Oncogenic HPV DNA was performed using an in-house polymerase chain reaction method, genotyping high-risk HPV DNA 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 (NorChip, Klokkarstua, Norway). Only the oncogenic HPV genotypes present at baseline were evaluated for clearance. Subjects with baseline CIN 1 were a priori determined to have a clinical response at 3 months’ follow-up if: (i) histology and cytology were both normal; or (ii) histology and/or cytology showed low grade (CIN 1/atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions) and the baseline HPV infection was cleared. At 6 and 9 months, subjects with baseline CIN 1 had a clinical response if: (i) cytology was negative; or (ii) cytology was atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions and baseline HPV infection was
cleared. Subjects with baseline CIN 2 were regarded as having response at 3 months’ follow-up if histology and cytology were normal or low grade. At 6 and 9 months, subjects with CIN 2 at baseline were responders if cytology was normal or low grade. According to clinical guidelines, patients underwent LEEP or colposcopy follow-up including cytology and HPV testing when indicated. Safety was evaluated by recording adverse events, vital signs, blood biochemistry, and concomitant medication use. Statistical analyses were performed on the total CIN 1/2 population and on the CIN 1 and CIN 2 subsets. Each of the active treatment groups were compared with the placebo group. Summary statistics and data analysis were performed using software (SAS; SAS Institute Inc, Cary, NC). The efficacy endpoint analyses were based on the Fisher exact test. Safety data were summarized by treatment group. In patients who were withdrawn during follow-up, data from the previous follow-up were used for efficacy assessment (last observation carried forward).
R ESULTS All randomized patients who received at least 1 treatment were included in the safety evaluations. A total of 262 patients
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were enrolled and treated. The median age was 27 years (range, 18e60), and 258 subjects (98%) were Caucasian, the remaining subjects were sub-Sahara African. Mean body mass index was 23.2 (range, 16e54). Age, race, and body mass index characteristics were similar across the treatment groups. After central pathology review of screening biopsies, 118 subjects were classified as having CIN 1 and 89 subjects with CIN 2 (Table 1). The remaining subjects were normal or reclassified as having CIN 3, and were not included in the efficacy analyses. Oncogenic HPV infections were observed in 49% of subjects with CIN 1 and 83% of subjects with CIN 2. The majority of patients (88%) completed the study. Of 31 patients who discontinued, 13 withdrew consent, 8 were lost to follow-up, and 10 were withdrawn: 3 by the gynecologist, 1 patient due to noncompliance, and 6 due to other causes (eg pregnancy and progression to CIN 3). The number of withdrawals was similar across treatment groups. In all, 136 patients (52%) received a retreatment, due to initial noncomplete response. A lower number of retreatments in the low-dose and placebo groups were due to patient withdrawal in these groups.
TABLE 1
Baseline human papillomavirus status of cervical intraepithelial neoplasia 1/2 patients Variable, n (%)
HAL 5% (n [ 65)
HAL 1% (n [ 67)
HAL 0.2% (n [ 62)
Placebo (n [ 68)
Totala (n [ 262)
CIN 1
34 (52)
27 (40)
26 (43)
31 (46)
118 (45)
19 (56)
12 (44)
12 (46)
15 (48)
58 (49)
7 (37)
3 (25)
4 (33)
3 (20)
17 (29)
15 (44)
15 (57)
14 (54)
16 (52)
60 (51)
19 (29)
30 (45)
19 (31)
21 (31)
89 (34)
13 (68)
26 (87)
17 (89)
18 (86)
74 (83)
6 (46)
15 (58)
7 (41)
6 (33)
33 (46)
Oncogenic HPV DNA-
6 (32)
4 (13)
2 (11)
3 921)
15 (20)
Normal, CIN 3, or missing
12 (18)
10 (15)
17 (2)
16 (24)
55 (21)
Oncogenic HPV DNAþ HPV 16/18 b Oncogenic HPV DNACIN 2 Oncogenic HPV DNAþ HPV 16/18
b
CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate; HPV, human papillomavirus. a
Of 262 patients included, based on local pathology, 207 subjects were verified as having CIN 1 or CIN 2 based on central read and included in main statistical analysis. 55 of 262 subjects were diagnosed with CIN 3, normal, or missing histology after central read; b Percentage of high-risk HPV 16/18 that is oncogenic DNA positive.
Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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Efficacy There were 262 patients in the intentionto-treat set, which was used for all statistical analyses. In the CIN 1 and combined CIN 1/2 populations there were no statistically significant differences in the number of responders in the HAL dose groups compared to placebo at any time point. In subjects with CIN 2, HAL 5% showed a significantly higher response of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P ¼ .009), with a clear dose response (Figure 2 and Table 2). Of the 18 responders in the HAL 5% group, 4 had normal histology and cytology. In the placebo group, no patients had normal histology and cytology at 3 months after last treatment. Six months after last treatment a sustained response of 95% (18/19 patients) was observed in the HAL 5% group, still significantly higher compared to the placebo effect of 62% (13/21 patients) (P ¼ .021) (Figure 2). HAL 1% and HAL 0.2% were not significantly different from placebo at any time points.
ajog.org Retreatment of 2 subjects in the HAL 5% group with remaining high-grade disease (CIN 2þ) after first treatment demonstrated histological regression and HPV 16/18 clearance in both patients. Retreatment of 5 subjects with remaining low-grade disease (histology or cytology) demonstrated lesion clearance in 1 patient. The proportion of CIN 2 subjects with oncogenic HPV clearance 3 months after last treatment was 62% (8/13 subjects) in the HAL 5% group and 28% (5/18 subjects) in the placebo group (P ¼ .079). At 6 months after last treatment, this increased to 77% (10/13 patients) in the HAL 5% group and 39% (7/18 patients) in the placebo group (P ¼ .067) (Figure 3). Among subjects with CIN 2, the clearance of high-risk oncogenic HPV 16/18 in the HAL 5% group demonstrated a sustainable 83% response (5/6 patients) at both 3 and 6 months after last treatment compared to 0% (0/6 patients) and 33% (2/6 patients), respectively, after 3 and 6 months in the placebo group (Figure 4).
FIGURE 2
Patient response, CIN 2
As HPV clearance is an important goal of effective treatment, a post hoc analysis was conducted in subjects with CIN 2 at 6 months’ follow-up after last treatment defining complete response as absence of CIN 2þ and HPV. Using 3-month histology results at 6 months together with 6-month HPV results, there was again a clear dose-related response of 84% (16/19 patients) in the HAL 5% group, 48% (14/29 patients) in the HAL 1% group, 42% (8/19 patients) in the HAL 0.2% group, and 38% (8/21 patients) in the placebo group.
Safety A total of 261 adverse events were reported by 125 patients. Mainly local and self-limiting adverse reactions were reported, with vaginal discharge, local discomfort, and spotting being the most common. A higher proportion of subjects in the HAL 5% group reported adverse reactions (54%) compared with the other groups (31-34%) (Table 3). One patient who received HAL 0.2% terminated treatment 40 minutes early due to urinary retention believed to be related to the PDT treatment. The patient was under treatment for urinary frequency and the adverse reaction resolved immediately after device removal. Three subjects reported serious adverse events, none of which were considered related to study treatment and all of the subjects recovered and completed the study. Five women became pregnant within 3 months of last PDT. All women delivered healthy fullterm infants.
C OMMENT
In subjects with CIN 2, HAL 5% showed significantly higher response compared to placebo group (P ¼ .009), with clear dose response. Six months after last treatment, sustained response was observed in HAL 5% group, still significantly higher compared to placebo group. CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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The aim of this phase 2b study was to investigate the efficacy and safety of topical HAL PDT in subjects with CIN 1 and CIN 2 to determine the optimal dose, patient population, and endpoints for further clinical development. In the CIN 2 population, HAL PDT demonstrated a dose-response efficacy with HAL 5% being significantly better (95%, 18/19) than placebo (57%, 12/21, P ¼ .009) 3 months after last treatment. The significant effect was sustained at 6 months, which is thought to be a more appropriate endpoint to allow for HPV
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TABLE 2
Patient response CIN 2 Variable
HAL 5%
HAL 1%
HAL 0.2%
Placebo
Patients with CIN 2, n
19
29
19
21
3 mo after last treatment Responders, n (%) P value
18 (95)
20 (69)
12 (63)
.009
.551
.755
18 (95)
23 (79)
15 (79)
.021
.213
.311
12 (57)
6 mo after last treatment Responders, n (%) P value
13 (62)
CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
clearance and normalization of the epithelium. Clearance of persistent oncogenic HPV infections is important as the virus is the driving force behind the development of CIN. HAL 5% showed an initial oncogenic HPV clearance of 62% at 3 months, increasing to 77% (10/13) clearance at 6 months, compared to 28% (5/18) and 39% (7/18) in the placebo group. This included an 83% (5/6)
clearance of high-risk oncogenic HPV 16/18 at both 3 and 6 months vs 0% and 33% (2/6) in the placebo arm 6 months after treatment. Although the groups included a limited number of subjects, the high clearance of high-risk oncogenic HPV 16/18 is encouraging and supports the potential usefulness of HAL PDT in subjects with persistent oncogenic HPV 16/18 infections and CIN. Our data suggest that retreatment may
FIGURE 3
Oncogenic HPV clearance, in patients with CIN 2
Proportion of CIN 2 subjects with oncogenic HPV clearance 3 and 6 months after last treatment was higher in hexaminolevulinate (HAL) 5% group than placebo group (3 months P ¼ .079; 6 months P ¼ .067). CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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also be useful in subjects with persistent oncogenic HPV infections. The antiviral mechanism of PDT is not fully understood, but includes stimulation of the host immune system through maturation of local immune cells facilitating increased uptake of HPV antigens.16 Complete oncogenic HPV clearance is an essential goal of an effective treatment. Therefore a post hoc analysis was carried out in subjects with CIN 2 defining complete response as absence of CIN 2þ and oncogenic HPV. Cytology was omitted as it was nonspecific and insensitive as a response parameter in this study (data not shown) for detecting high-grade disease, in addition to histology and oncogenic HPV. Using absence of CIN 2þ and oncogenic HPV as the response definition, the data again revealed a doserelated response in the CIN 2 population with a high patient complete response of 84% (16/19) in the HAL 5% group compared to a placebo response of 38% (8/21) in line with the literature.17 The improved efficacy vs placebo again supported the beneficial effect of HAL 5% PDT in subjects with high-grade disease (CIN 2). The HAL PDT response in the CIN 1 and overall CIN 1/2 population was not significantly different to placebo, due to a high rate of spontaneous regression in the CIN 1 population. This was probably caused by the inclusion of oncogenic HPV-negative patients as well as a higher number of subjects with high-risk oncogenic HPV 16/18 in the HAL 5% compared to the placebo group. The safety profile of HAL PDT was favorable with mainly local, self-limiting side effects that resolved within a few days of treatment. There were no signs of systemic effects. The device was easily applied by the gynecologist and removed by the subjects. This was the first large phase 2 study using HAL PDT with this novel outpatient-applied device and drug combination. Previous studies with HAL PDT using topical drug application of various drug formulations followed by laser photoactivation14,18,19 showed similar patient responses, but the procedure was inconvenient to the patient
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FIGURE 4
High-risk oncogenic HPV 16/18 clearance, in patients with CIN 2
Among subjects with CIN 2, clearance of high-risk oncogenic HPV 16/18 in HAL 5% group demonstrated sustainable 83% response at 3 and 6 months after last treatment compared to 0% and 33% after 3 and 6 months in placebo group. CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate; HPV, human papillomavirus. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
and the gynecologist as it needed to be performed in hospital. The new HAL treatment offers a quick and easy, singleuse procedure with no patient down time. HAL PDT selectively targets the CIN lesions, clears the oncogenic HPV infections, and leaves a competent uterine cervix.18,20 HAL PDT is unlikely to interfere with follow-up colposcopies and avoids the risk of preterm birth in later pregnancies
that is associated with surgical procedures as it selectively targets epithelial disease.21,22 In many countries (eg, Germany), conization is often performed under general anesthesia, and hospitalization and disability are main cost drivers.19 Pregnancyerelated morbidity associated with surgical procedures is substantial, and the average incremental cost per preterm birth (all causes) in the United States was
TABLE 3
Summary of adverse reactions, all patients HAL 5% (n [ 65)
HAL 1% (n [ 67)
HAL 0.2% (n [ 62)
Placebo (n [ 68)
Adverse reactiona
35 (54)
21 (31)
21 (34)
22 (32)
Discharge
21 (32)
12 (18)
9 (15)
8 (12)
24 (37)
12 (18)
9 (15)
10 (15)
5 (8)
8 (12)
5 (8)
4 (6)
Variable, n (%) Patients with at least 1
Local discomfort
b
Hemorrhage (spotting) HAL, hexaminolevulinate. a
Adverse event reported as possibly related or related to treatment; b Includes pelvic pain, vulvovaginal discomfort, vulvovaginal burning sensation, vulvovaginal pain, genital discomfort, abdominal pain, upper abdominal pain, procedural pain, and postprocedural discomfort.
Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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estimated to be $51,600.23 This indicates the high potential savings with reduction of the number of surgical interventions in patients with cervical high-grade disease through the use of tissue-preserving modalities. For this study we chose not to include patients with CIN 3 since this grade of CIN is regarded as being precancerous, and is more likely to harbor invasive lesions. Therefore, excisional procedures will be preferred over new methods that have not been tested in this patient population. Some European countries recommend follow-up in CIN 2 patients for up to 12 months instead of immediate LEEP leaving open the possibility for HAL PDT. Even the 2012 American Society for Colposcopy and Cervical Pathology (ASCCP) updated consensus guidelines advocate that young women with a histologic diagnosis of CIN 2/3 should either be treated or observed up to months providing colposcopy is adequate.6 This recommendation that corresponds with patient preference will encourage further research to find effective nonsurgical and tissuepreserving treatment methods for women with CIN 2 and CIN 3. For women with high-grade neoplasia (CIN 2) of childbearing potential who wish to preserve cervical competence, HAL PDT might one day be proven to be a good alternative to invasive procedures. The promising effects on oncogenic HPV infections and in particular in high-risk oncogenic HPV 16/18 that carry a high risk of CIN 2þ24 suggested that HAL PDTmight be a good alternative to watchful waiting as the safety profile of HAL in this study was favorable. Current limitations to the uptake of HAL PDT are the requirement for adequate colposcopy, as the device does not support treatment of endocervical disease; the need to define durability of response; and the need to assess tolerability in large-scale use. In this study, HAL 5% demonstrated a robust effect in subjects with CIN 2 or high-grade squamous intraepithelial lesion (CIN 2) that supports clinical confirmation in phase 3. HAL PDT will be investigated further in other
Gynecology
ajog.org populations of women with persistent oncogenic HPV and low-grade disease.
Conclusion HAL 5% demonstrated a significant response compared to placebo in subjects with CIN 2, including a clear dose-response efficacy. Despite a lack of efficacy in the CIN 1 population, HAL 5% shows promise in the treatment of women with clinically relevant CIN and persistent oncogenic HPV infections. ACKNOWLEDGMENTS The authors acknowledge Ms Jude Douglass of Healthcom Partners Ltd, Oxford, United Kingdom, for editorial assistance and manuscript preparation (funding from Photocure ASA); and Dr Philipp Soergel for general advice and support.
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5. Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284. 6. Massad LS, Einstein MH, Huh WK, et al. 2012 Updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol 2013;121:829-46. 7. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002;8:314-46. 8. Kawana K, Katsuyuki A, Kojima S, Kozuma S, Fujii T. Therapeutic human papillomavirus vaccines: a novel approach. Open Virol J 2012;5(Suppl):S264-9. 9. Francois A, Salvadori A, Bressenot A, Bezdetnaya L, Guillemin F, D’Hallewin MA. How to avoid local side effects of bladder photodynamic therapy: impact of the fluence rate. J Urol 2013;190:731-6. 10. Luksiene Z, Eggen I, Moan J, Nesland JM, Peng Q. Evaluation of protoporphyrin IX production, phototoxicity and cell death pathway induced by hexylester of 5-aminolevulinic acid in Reh and HPB-ALL cells. Cancer Lett 2001;169:33-9. 11. Furre IE, Shahzidi S, Luksiene Z, et al. Targeting PBR by hexaminolevulinate-mediated photodynamic therapy induces apoptosis through translocation of apoptosis-inducing factor in human leukemia cells. Cancer Res 2005;65:11051-60. 12. Kabingu E, Oseroff AR, Wilding GE, Gollnick SO. Enhanced systemic immune reactivity to a basal cell carcinoma associated antigen following photodynamic therapy. Clin Cancer Res 2009;15:4460-6. 13. Gollnick SO, Brackett CM. Enhancement of anti-tumor immunity by photodynamic therapy. Immunol Res 2010;46:216-26. 14. Soergel P, Dahl GF, Onsrud M, Hillemanns P. Photodynamic therapy of cervical intraepithelial neoplasia 1-3 and human papilloma virus (HMV) infection with methylaminolevulinate and hexaminolevulinateea double-blind, dose-finding study. Lasers Surg Med 2012;44:468-74. 15. Einstein M, Sordal T, Lunde T. Safety of hexaminolevulinate photodynamic therapyea non-extirpative treatment for cervical neoplasia
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(CIN). Paper presented at: American Society for Colposcopy and Cervical Pathology (ASCCP): 2012; San Francisco, CA. 16. Etminan N, Peters C, Bünemann E, et al. Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro. Br J Cancer 2011;105: 961-9. 17. Östör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993;12:186-92. 18. Soergel P, Wang X, Stepp H, Hertel H, Hillemanns P. Photodynamic therapy of cervical intraepithelial neoplasia with hexaminolevulinate. Lasers Surg Med 2008;40:611-5. 19. Soergel P, Dannecker C, Petry KU, Collinet P, Runnebaum I, Hillemanns P. Hexaminolevulinate photodynamic therapy in patients with CIN1. Paper presented at: 27th International Papillomavirus Conference; Sept. 17-22, 2011; Berlin, Germany. 20. Soergel P, Loehr-Schulz R, Hillemanns M, Landwehr S, Makowski L, Hillemanns P. Effects of photodynamic therapy using topical applied hexylaminolevulinate and methylaminolevulinate upon the integrity of cervical epithelium. Lasers Surg Med 2010;42: 624-30. 21. Hillemanns P, Wang X, Hertel H, et al. Pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate in patients with cervical intraepithelial neoplasia. Am J Obstet Gynecol 2008;198:300. e1-7. 22. Andrejevic-Blant S, Major A, Lüdicke F, et al. Time-dependent hexaminolevulinateinduced protoporphyrin IX distribution after topical application in patients with cervical intraepithelial neoplasia: a fluorescence microscopy study. Lasers Surg Med 2004;35: 276-83. 23. Behrman RE, Butler AS; Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm birth: causes, consequences and prevention. Washington, DC: National Academies Press; 2007. 24. Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst 2010;102: 1478-88.
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GYNECOLOGY
A randomized study of hexaminolevulinate photodynamic therapy in patients with cervical intraepithelial neoplasia 1/2 Peter Hillemanns, MD; Francisco Garcia, MD, MPH; Karl Ulrich Petry, MD; Vladimı´r Dvorak, MD; Oliver Sadovsky, MD; Ole-Erik Iversen, MD; Mark H. Einstein, MD, MS OBJECTIVE: The objective of the study was to investigate the efficacy
and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN) 1/2, to define the appropriate population and endpoints for a phase 3 program. STUDY DESIGN: This was a double-blind, randomized, placebocontrolled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months. RESULTS: There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A
clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P < .001) was observed at 3 months in women with CIN2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local selflimiting adverse reactions including discharge, discomfort, and spotting were reported. CONCLUSION: HAL PDT is a novel therapy that shows promise in the
treatment of CIN2 including clearance of oncogenic HPV, but not of CIN1. The positive risk/benefit balance makes HAL PDT a tissuepreserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned. Key words: cervical intraepithelial neoplasia, hexaminolevulinate, human papillomavirus, photodynamic therapy
Cite this article as: Hillemanns P, Garcia F, Petry KU, et al. A randomized study of hexaminolevulinate photodynamic therapy in patients with cervical intraepithelial neoplasia 1/2. Am J Obstet Gynecol 2014;212:x.ex-x.ex.
C
ervical cancer is the third most common cancer in women worldwide and is caused by persistent infection with oncogenic human papillomavirus (HPV). HPV is the most prevalent sexually transmitted infection,
with a peak prevalence of 25-35% of young women in their early twenties, but with a high spontaneous regression rate of 90% in 2 years.1 However, persistent oncogenic HPV infections may lead to development of precancerous lesions
with increasing risk of progression to invasive cancer. Subjects with precancerous lesions are routinely treated with surgical intervention such as loop electrosurgical excision procedure (LEEP) or cone
From the Department of Obstetrics and Gynecology, Hannover Medical School, Hannover (Dr Hillemanns), and Clinic for Gynecology, Obstetrics, and Gynecological Oncology, Clinic of the City of Wolfsburg, Wolfsburg (Dr Petry), Germany; Center of Excellence in Women’s Health, University of Arizona, Tucson, AZ (Dr Garcia); Center of Outpatient Gynecology Clinic and Primary Care, Brno, Czech Republic (Dr Dvorak); private practice, Bratislava, Slovak Republic (Dr Sadovsky); Institute of Clinical Medicine, University of Bergen and Women’s Clinic, Haukeland University Hospital, Bergen, Norway (Dr Iversen); and Department of Obstetrics and Gynecology and Women’s Health, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY (Dr Einstein). Received June 9, 2014; revised Sept. 9, 2014; accepted Oct. 29, 2014. The study was funded by Photocure ASA, Oslo, Norway. P.H. received honoraria and research support from Photocure. O.-E.I. received lecture fee. M.H.E. received travel expenses and grant funding for research-related costs of this clinical trial. The remaining authors report no conflict of interest. Presented at EUROGIN 2013, European Research Organization on Genital Infection and Neoplasia, Florence, Italy, Nov. 3-6, 2013, and at the 44th annual meeting on Women’s Cancer, Society of Gynecologic Oncology, Los Angeles, CA, March 9-12, 2013. Corresponding author: Peter Hillemanns, MD, PhD. [email protected] 0002-9378/$36.00 ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1107
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biopsy. Surgery may, however, be associated with an increased risk of subsequent late abortion, preterm delivery, and other perinatal complications.2-5 Because of these adverse consequences, recent US management guidelines recommend initial conservative management in young women with cervical intraepithelial neoplasia (CIN) 2/3 to reduce the risks of perinatal side effects.6 For decades, extirpative procedures have been the mainstay of treatment due to the lack of other therapeutic modalities for CIN. The need for an effective nonsurgical therapy was highlighted in the recommendations of the American Association for Cancer Research Task Force on the treatment and prevention of intraepithelial neoplasia,7 underlining the urgent need for new modalities with an adequate safety profile. Therapeutic vaccines have shown promise, but have not demonstrated definitive clinical efficacy and appropriate immunological responses for cervical neoplasia.8 Topical hexaminolevulinate (HAL) (Photocure ASA, Hoffsveien 4, NO0275, Oslo, Norway) photodynamic therapy (PDT) has the potential to address the medical need for a tissuepreserving treatment of persistent HPV infections and CIN, treating the entire portio of the cervix and maintaining cervical competence. PDT involves the accumulation of a photoactive compound in target cells, which are then illuminated to generate highly reactive oxygen species that destroy tumor cells by inducing apoptosis and necrosis.9-11 HAL is administered as an ointment via an intravaginal photoactivation device, which is programmed to deliver 100 J/cm2 of red light with a lightemitting diode at a wavelength of 629 nm. The device is removed by the patient once treatment has been completed. The technology has also been shown to stimulate the systemic immune system by enhancing the immune recognition of antigens.12,13 HAL PDT previously showed a favorable safety profile and promising efficacy in subjects with CIN 1-3.14 The more recent easyto-use outpatient PDT procedure was tested in a small pilot study that showed high patient and gynecologist acceptance
ajog.org and efficacy in subjects with low-grade cervical lesions.15 The objective of this phase 2b study was to further investigate the safety and efficacy of HAL PDT in subjects with CIN 1 and CIN 2 and to define the optimal HAL dose and patient population for further clinical development.
M ATERIALS
AND
M ETHODS
The clinical trial was conducted according to European Medicines Agency and Food and Drug Administration guidelines, and in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. The study is registered in the Clinicaltrials. gov (National Institutes of Health) database (NCT01256424). Ethical approval was obtained from all clinical sites and all subjects provided written informed consent before inclusion. This was a phase 2b, prospective, randomized, double-blind, placebocontrolled, multicenter study conducted at 23 centers in the United States, Germany, Czech Republic, Slovak Republic, and Norway. A total of 262 adult women (age 18 years) with satisfactory colposcopy examination including visibility of the entire transformation zone with the entire lesion margin, averagesized uterine cervix (approximately 27-mm diameter), and colposcopically identified CIN 1 or CIN 2 based on local pathology read of biopsy were included. Main patient exclusion criteria were inadequate colposcopy, lesion(s) extending to the vaginal vault, suspicion of endocervical disease on colposcopy, previous treatment of CIN or invasive disease, significant vaginal infection or bleeding, porphyria, known drug sensitivity, pregnancy, or breast-feeding. The expected proportions of patients with complete or partial response were set to 20% for placebo and 50% for HAL PDT. A 2-sided significance level of 5% and statistical power of 80% were used to calculate the sample sizes. Eligible subjects were randomized equally to 4 arms: HAL 5%, 1%, 0.2%; and placebo ointments. Randomization was stratified by site in a block size of 4. Drug and illumination were
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administered by the intravaginal device (Figure 1). The gynecologist spread the ointment evenly in the device cavity before positioning it on the cervix, thereafter the patient was free to return to normal daily activities. The device supported targeted delivery of HAL ointment to the portio for 5 hours, enabling selective enrichment of photoactive porphyrins in the diseased area in subjects who received active drug, followed by automatic photoactivation (illumination) for another 4.6 hours. The device was designed and programmed to deliver red light (629 nm) with a total dose of 100 J/cm2 exclusively to the portio of the ectocervix in the active treatment groups, with no light in the placebo ointment group. The primary study endpoint was patient response at 3 months with assessment of histology and cytology regression and clearance of oncogenic HPV. Subjects with abnormal histology or cytology at 3 months received a second treatment followed by a new biopsy 3 months after retreatment. Secondary endpoints were patient response (cytology and oncogenic HPV) 6 months after treatment and safety assessments. Subjects with disease progression or a need for immediate treatment were offered standard-of-care treatment at the discretion of the investigator. Colposcopic-directed biopsies were FIGURE 1
Cevira device for drug and light delivery
Drug and illumination were administered by Cevira intravaginal device (Photocure ASA, Oslo, Norway) that remains in place for around 5 hours, before removal by patient. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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ajog.org obtained from all suspicious areas at baseline and 3-month follow-up. In normal-appearing epithelium at colposcopy follow-up, biopsies were obtained from the most severe baseline lesion areas. For efficacy analyses all baseline and follow-up biopsies were reviewed by a central expert gynecology pathologist (DCL Laboratories, Urbana, IL) blinded to other study data. Oncogenic HPV DNA was performed using an in-house polymerase chain reaction method, genotyping high-risk HPV DNA 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 (NorChip, Klokkarstua, Norway). Only the oncogenic HPV genotypes present at baseline were evaluated for clearance. Subjects with baseline CIN 1 were a priori determined to have a clinical response at 3 months’ follow-up if: (i) histology and cytology were both normal; or (ii) histology and/or cytology showed low grade (CIN 1/atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions) and the baseline HPV infection was cleared. At 6 and 9 months, subjects with baseline CIN 1 had a clinical response if: (i) cytology was negative; or (ii) cytology was atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions and baseline HPV infection was
cleared. Subjects with baseline CIN 2 were regarded as having response at 3 months’ follow-up if histology and cytology were normal or low grade. At 6 and 9 months, subjects with CIN 2 at baseline were responders if cytology was normal or low grade. According to clinical guidelines, patients underwent LEEP or colposcopy follow-up including cytology and HPV testing when indicated. Safety was evaluated by recording adverse events, vital signs, blood biochemistry, and concomitant medication use. Statistical analyses were performed on the total CIN 1/2 population and on the CIN 1 and CIN 2 subsets. Each of the active treatment groups were compared with the placebo group. Summary statistics and data analysis were performed using software (SAS; SAS Institute Inc, Cary, NC). The efficacy endpoint analyses were based on the Fisher exact test. Safety data were summarized by treatment group. In patients who were withdrawn during follow-up, data from the previous follow-up were used for efficacy assessment (last observation carried forward).
R ESULTS All randomized patients who received at least 1 treatment were included in the safety evaluations. A total of 262 patients
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were enrolled and treated. The median age was 27 years (range, 18e60), and 258 subjects (98%) were Caucasian, the remaining subjects were sub-Sahara African. Mean body mass index was 23.2 (range, 16e54). Age, race, and body mass index characteristics were similar across the treatment groups. After central pathology review of screening biopsies, 118 subjects were classified as having CIN 1 and 89 subjects with CIN 2 (Table 1). The remaining subjects were normal or reclassified as having CIN 3, and were not included in the efficacy analyses. Oncogenic HPV infections were observed in 49% of subjects with CIN 1 and 83% of subjects with CIN 2. The majority of patients (88%) completed the study. Of 31 patients who discontinued, 13 withdrew consent, 8 were lost to follow-up, and 10 were withdrawn: 3 by the gynecologist, 1 patient due to noncompliance, and 6 due to other causes (eg pregnancy and progression to CIN 3). The number of withdrawals was similar across treatment groups. In all, 136 patients (52%) received a retreatment, due to initial noncomplete response. A lower number of retreatments in the low-dose and placebo groups were due to patient withdrawal in these groups.
TABLE 1
Baseline human papillomavirus status of cervical intraepithelial neoplasia 1/2 patients Variable, n (%)
HAL 5% (n [ 65)
HAL 1% (n [ 67)
HAL 0.2% (n [ 62)
Placebo (n [ 68)
Totala (n [ 262)
CIN 1
34 (52)
27 (40)
26 (43)
31 (46)
118 (45)
19 (56)
12 (44)
12 (46)
15 (48)
58 (49)
7 (37)
3 (25)
4 (33)
3 (20)
17 (29)
15 (44)
15 (57)
14 (54)
16 (52)
60 (51)
19 (29)
30 (45)
19 (31)
21 (31)
89 (34)
13 (68)
26 (87)
17 (89)
18 (86)
74 (83)
6 (46)
15 (58)
7 (41)
6 (33)
33 (46)
Oncogenic HPV DNA-
6 (32)
4 (13)
2 (11)
3 921)
15 (20)
Normal, CIN 3, or missing
12 (18)
10 (15)
17 (2)
16 (24)
55 (21)
Oncogenic HPV DNAþ HPV 16/18 b Oncogenic HPV DNACIN 2 Oncogenic HPV DNAþ HPV 16/18
b
CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate; HPV, human papillomavirus. a
Of 262 patients included, based on local pathology, 207 subjects were verified as having CIN 1 or CIN 2 based on central read and included in main statistical analysis. 55 of 262 subjects were diagnosed with CIN 3, normal, or missing histology after central read; b Percentage of high-risk HPV 16/18 that is oncogenic DNA positive.
Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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Efficacy There were 262 patients in the intentionto-treat set, which was used for all statistical analyses. In the CIN 1 and combined CIN 1/2 populations there were no statistically significant differences in the number of responders in the HAL dose groups compared to placebo at any time point. In subjects with CIN 2, HAL 5% showed a significantly higher response of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P ¼ .009), with a clear dose response (Figure 2 and Table 2). Of the 18 responders in the HAL 5% group, 4 had normal histology and cytology. In the placebo group, no patients had normal histology and cytology at 3 months after last treatment. Six months after last treatment a sustained response of 95% (18/19 patients) was observed in the HAL 5% group, still significantly higher compared to the placebo effect of 62% (13/21 patients) (P ¼ .021) (Figure 2). HAL 1% and HAL 0.2% were not significantly different from placebo at any time points.
ajog.org Retreatment of 2 subjects in the HAL 5% group with remaining high-grade disease (CIN 2þ) after first treatment demonstrated histological regression and HPV 16/18 clearance in both patients. Retreatment of 5 subjects with remaining low-grade disease (histology or cytology) demonstrated lesion clearance in 1 patient. The proportion of CIN 2 subjects with oncogenic HPV clearance 3 months after last treatment was 62% (8/13 subjects) in the HAL 5% group and 28% (5/18 subjects) in the placebo group (P ¼ .079). At 6 months after last treatment, this increased to 77% (10/13 patients) in the HAL 5% group and 39% (7/18 patients) in the placebo group (P ¼ .067) (Figure 3). Among subjects with CIN 2, the clearance of high-risk oncogenic HPV 16/18 in the HAL 5% group demonstrated a sustainable 83% response (5/6 patients) at both 3 and 6 months after last treatment compared to 0% (0/6 patients) and 33% (2/6 patients), respectively, after 3 and 6 months in the placebo group (Figure 4).
FIGURE 2
Patient response, CIN 2
As HPV clearance is an important goal of effective treatment, a post hoc analysis was conducted in subjects with CIN 2 at 6 months’ follow-up after last treatment defining complete response as absence of CIN 2þ and HPV. Using 3-month histology results at 6 months together with 6-month HPV results, there was again a clear dose-related response of 84% (16/19 patients) in the HAL 5% group, 48% (14/29 patients) in the HAL 1% group, 42% (8/19 patients) in the HAL 0.2% group, and 38% (8/21 patients) in the placebo group.
Safety A total of 261 adverse events were reported by 125 patients. Mainly local and self-limiting adverse reactions were reported, with vaginal discharge, local discomfort, and spotting being the most common. A higher proportion of subjects in the HAL 5% group reported adverse reactions (54%) compared with the other groups (31-34%) (Table 3). One patient who received HAL 0.2% terminated treatment 40 minutes early due to urinary retention believed to be related to the PDT treatment. The patient was under treatment for urinary frequency and the adverse reaction resolved immediately after device removal. Three subjects reported serious adverse events, none of which were considered related to study treatment and all of the subjects recovered and completed the study. Five women became pregnant within 3 months of last PDT. All women delivered healthy fullterm infants.
C OMMENT
In subjects with CIN 2, HAL 5% showed significantly higher response compared to placebo group (P ¼ .009), with clear dose response. Six months after last treatment, sustained response was observed in HAL 5% group, still significantly higher compared to placebo group. CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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The aim of this phase 2b study was to investigate the efficacy and safety of topical HAL PDT in subjects with CIN 1 and CIN 2 to determine the optimal dose, patient population, and endpoints for further clinical development. In the CIN 2 population, HAL PDT demonstrated a dose-response efficacy with HAL 5% being significantly better (95%, 18/19) than placebo (57%, 12/21, P ¼ .009) 3 months after last treatment. The significant effect was sustained at 6 months, which is thought to be a more appropriate endpoint to allow for HPV
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TABLE 2
Patient response CIN 2 Variable
HAL 5%
HAL 1%
HAL 0.2%
Placebo
Patients with CIN 2, n
19
29
19
21
3 mo after last treatment Responders, n (%) P value
18 (95)
20 (69)
12 (63)
.009
.551
.755
18 (95)
23 (79)
15 (79)
.021
.213
.311
12 (57)
6 mo after last treatment Responders, n (%) P value
13 (62)
CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
clearance and normalization of the epithelium. Clearance of persistent oncogenic HPV infections is important as the virus is the driving force behind the development of CIN. HAL 5% showed an initial oncogenic HPV clearance of 62% at 3 months, increasing to 77% (10/13) clearance at 6 months, compared to 28% (5/18) and 39% (7/18) in the placebo group. This included an 83% (5/6)
clearance of high-risk oncogenic HPV 16/18 at both 3 and 6 months vs 0% and 33% (2/6) in the placebo arm 6 months after treatment. Although the groups included a limited number of subjects, the high clearance of high-risk oncogenic HPV 16/18 is encouraging and supports the potential usefulness of HAL PDT in subjects with persistent oncogenic HPV 16/18 infections and CIN. Our data suggest that retreatment may
FIGURE 3
Oncogenic HPV clearance, in patients with CIN 2
Proportion of CIN 2 subjects with oncogenic HPV clearance 3 and 6 months after last treatment was higher in hexaminolevulinate (HAL) 5% group than placebo group (3 months P ¼ .079; 6 months P ¼ .067). CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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also be useful in subjects with persistent oncogenic HPV infections. The antiviral mechanism of PDT is not fully understood, but includes stimulation of the host immune system through maturation of local immune cells facilitating increased uptake of HPV antigens.16 Complete oncogenic HPV clearance is an essential goal of an effective treatment. Therefore a post hoc analysis was carried out in subjects with CIN 2 defining complete response as absence of CIN 2þ and oncogenic HPV. Cytology was omitted as it was nonspecific and insensitive as a response parameter in this study (data not shown) for detecting high-grade disease, in addition to histology and oncogenic HPV. Using absence of CIN 2þ and oncogenic HPV as the response definition, the data again revealed a doserelated response in the CIN 2 population with a high patient complete response of 84% (16/19) in the HAL 5% group compared to a placebo response of 38% (8/21) in line with the literature.17 The improved efficacy vs placebo again supported the beneficial effect of HAL 5% PDT in subjects with high-grade disease (CIN 2). The HAL PDT response in the CIN 1 and overall CIN 1/2 population was not significantly different to placebo, due to a high rate of spontaneous regression in the CIN 1 population. This was probably caused by the inclusion of oncogenic HPV-negative patients as well as a higher number of subjects with high-risk oncogenic HPV 16/18 in the HAL 5% compared to the placebo group. The safety profile of HAL PDT was favorable with mainly local, self-limiting side effects that resolved within a few days of treatment. There were no signs of systemic effects. The device was easily applied by the gynecologist and removed by the subjects. This was the first large phase 2 study using HAL PDT with this novel outpatient-applied device and drug combination. Previous studies with HAL PDT using topical drug application of various drug formulations followed by laser photoactivation14,18,19 showed similar patient responses, but the procedure was inconvenient to the patient
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FIGURE 4
High-risk oncogenic HPV 16/18 clearance, in patients with CIN 2
Among subjects with CIN 2, clearance of high-risk oncogenic HPV 16/18 in HAL 5% group demonstrated sustainable 83% response at 3 and 6 months after last treatment compared to 0% and 33% after 3 and 6 months in placebo group. CIN, cervical intraepithelial neoplasia; HAL, hexaminolevulinate; HPV, human papillomavirus. Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
and the gynecologist as it needed to be performed in hospital. The new HAL treatment offers a quick and easy, singleuse procedure with no patient down time. HAL PDT selectively targets the CIN lesions, clears the oncogenic HPV infections, and leaves a competent uterine cervix.18,20 HAL PDT is unlikely to interfere with follow-up colposcopies and avoids the risk of preterm birth in later pregnancies
that is associated with surgical procedures as it selectively targets epithelial disease.21,22 In many countries (eg, Germany), conization is often performed under general anesthesia, and hospitalization and disability are main cost drivers.19 Pregnancyerelated morbidity associated with surgical procedures is substantial, and the average incremental cost per preterm birth (all causes) in the United States was
TABLE 3
Summary of adverse reactions, all patients HAL 5% (n [ 65)
HAL 1% (n [ 67)
HAL 0.2% (n [ 62)
Placebo (n [ 68)
Adverse reactiona
35 (54)
21 (31)
21 (34)
22 (32)
Discharge
21 (32)
12 (18)
9 (15)
8 (12)
24 (37)
12 (18)
9 (15)
10 (15)
5 (8)
8 (12)
5 (8)
4 (6)
Variable, n (%) Patients with at least 1
Local discomfort
b
Hemorrhage (spotting) HAL, hexaminolevulinate. a
Adverse event reported as possibly related or related to treatment; b Includes pelvic pain, vulvovaginal discomfort, vulvovaginal burning sensation, vulvovaginal pain, genital discomfort, abdominal pain, upper abdominal pain, procedural pain, and postprocedural discomfort.
Hillemanns. Hexaminolevulinate PDT in CIN 1 or 2. Am J Obstet Gynecol 2014.
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estimated to be $51,600.23 This indicates the high potential savings with reduction of the number of surgical interventions in patients with cervical high-grade disease through the use of tissue-preserving modalities. For this study we chose not to include patients with CIN 3 since this grade of CIN is regarded as being precancerous, and is more likely to harbor invasive lesions. Therefore, excisional procedures will be preferred over new methods that have not been tested in this patient population. Some European countries recommend follow-up in CIN 2 patients for up to 12 months instead of immediate LEEP leaving open the possibility for HAL PDT. Even the 2012 American Society for Colposcopy and Cervical Pathology (ASCCP) updated consensus guidelines advocate that young women with a histologic diagnosis of CIN 2/3 should either be treated or observed up to months providing colposcopy is adequate.6 This recommendation that corresponds with patient preference will encourage further research to find effective nonsurgical and tissuepreserving treatment methods for women with CIN 2 and CIN 3. For women with high-grade neoplasia (CIN 2) of childbearing potential who wish to preserve cervical competence, HAL PDT might one day be proven to be a good alternative to invasive procedures. The promising effects on oncogenic HPV infections and in particular in high-risk oncogenic HPV 16/18 that carry a high risk of CIN 2þ24 suggested that HAL PDTmight be a good alternative to watchful waiting as the safety profile of HAL in this study was favorable. Current limitations to the uptake of HAL PDT are the requirement for adequate colposcopy, as the device does not support treatment of endocervical disease; the need to define durability of response; and the need to assess tolerability in large-scale use. In this study, HAL 5% demonstrated a robust effect in subjects with CIN 2 or high-grade squamous intraepithelial lesion (CIN 2) that supports clinical confirmation in phase 3. HAL PDT will be investigated further in other
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ajog.org populations of women with persistent oncogenic HPV and low-grade disease.
Conclusion HAL 5% demonstrated a significant response compared to placebo in subjects with CIN 2, including a clear dose-response efficacy. Despite a lack of efficacy in the CIN 1 population, HAL 5% shows promise in the treatment of women with clinically relevant CIN and persistent oncogenic HPV infections. ACKNOWLEDGMENTS The authors acknowledge Ms Jude Douglass of Healthcom Partners Ltd, Oxford, United Kingdom, for editorial assistance and manuscript preparation (funding from Photocure ASA); and Dr Philipp Soergel for general advice and support.
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