Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

Photodiagnosis and Photodynamic Therapy (2012) 9, 16—31

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/pdpdt

REVIEW

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer Laurie Guyon MD a,b, Manuel Ascencio MD PhD a,b, Pierre Collinet MD PhD a,b, Serge Mordon PhD b,∗ a

Department of Gynaecology and Obstetrics, Lille University Hospital, Lille, France INSERM, U703, Univ Lille Nord de France, Lille University Hospital, 152 rue du Dr. Yersin, 59120 Loos, Lille, France Available online 1 October 2011

b

KEYWORDS Ovarian cancer; 5-Aminolevulinic acid (ALA); Fluorescence detection; Second look; Laparoscopy; Photodynamic therapy

Summary Ovarian cancer is among the deadliest in women. Current treatment strategies fail to cure many patients owing to the difficulties of eradicating peritoneal implants frequently associated with this pathology. Photodynamic therapy represents a promising treatment as it offers many advantages over alternative strategies: diagnostic properties, specific targeting of abnormal cells, possibility to be combined with other therapies. © 2011 Elsevier B.V. All rights reserved.

Contents Introduction............................................................................................................... Current management strategies of ovarian cancer .................................................................... Principles of photodiagnosis and photodynamic therapy .............................................................. Methods ................................................................................................................... Results and discussion ..................................................................................................... Photodynamic diagnosis .............................................................................................. Results of pre-clinical studies .................................................................................. Clinical data ................................................................................................... Minimally invasive approach ................................................................................... Photodynamic therapy................................................................................................ Selectivity of PDT for ovarian tumour and adverse effect ...................................................... Specific aspects of intraperitoneal PDT ........................................................................ Assessment of the results of PDT .....................................................................................

∗

Corresponding author. Tel.: +33 320 446 708; fax: +33 320 446 708. E-mail address: [email protected] (S. Mordon).

1572-1000/$ — see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2011.08.003

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Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer Association with other treatments...................................................................................... Chemotherapy ................................................................................................. PDT and immunotherapy....................................................................................... PDT and antiangiogenic drugs .................................................................................. Sonodynamic therapy (SDT) .................................................................................... Conclusion ................................................................................................................ Acknowledgement......................................................................................................... References ................................................................................................................

Introduction Current management strategies of ovarian cancer Ovarian cancer is the 5th most frequent cancer and the 6th cause of death from cancer among women [1]. Initially confined to the ovary, the tumour cells gradually break through the ovarian capsule and spread beyond the pelvis to the peritoneal cavity by direct extension or transportation by the peritoneal fluid, following the paracolic gutter, liver capsule and diaphragm. This accounts for the distribution of the lesions in the most advanced cases: peritoneal epithelium, liver capsule, diaphragmatic surfaces, omentum and bowel. Exhaustive detection of intraperitoneal lesions is crucial to appropriately stage ovarian cancer and decide on the appropriate treatment course. When bulky enough, intraperitoneal nodules may be diagnosed with MRI or TDM. However, the sensitivity of CT scans is low, as is that of PET-CTs (that cannot diagnose peritoneal nodules smaller than 7 mm [2]). As far as CA 125 is concerned, the sensitivity is only 53% for a threshold of 16 IU and the dosage has no localizing value [3]. Laparoscopy must be performed to confirm the diagnosis, assess the extent of the disease and perform biopsies. However, microscopic lesions cannot be seen and are consequently ignored. Furthermore, reactional inflammatory lesions can sometimes be confused with authentic cancerous ones. Current standards of treatment include cytoreductive surgery and platinum-based chemotherapy. But despite treatment, the prognosis is poor with an overall 5-year survival rate of 46% [4]. Around 60% of epithelial ovarian cancers are diagnosed at an advanced stage [4,5]. Less than 1/3 of the women diagnosed with a stage III or IV disease survive 5 years compared with 73—93% for stage II or I diseases respectively [4]. The prognosis is also markedly linked to the size of the post-operative residual disease [6—8]. The capacity of surgery to eradicate all intraperitoneal tumour implants is decisive. Meeting this objective is not easy because of the difficulty and the risk of complications of aggressive debulking strategies that may also require bowel or diaphragmatic resections [9—11]. Besides, conventional surgery discards microscopic lesions that may have an impact on the patients’ survival. Diagnosis and treatment of peritoneal carcinomatosis is key to successfully managing ovarian cancer. Photodynamic therapy (PDT) represents a promising treatment offering many advantages over alternative

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strategies: diagnostic properties, specific targeting of abnormal cells, possibility to be combined with other therapies.

Principles of photodiagnosis and photodynamic therapy Fluorescence imaging has become an important diagnostic tool able to detect cancer at an early stage of development and to guide biopsying of representative samples. Photodiagnosis is based on the principle that abnormal tissues absorb light and fluoresce differently from normal tissues at specific wavelengths of light. Autofluorescence takes advantage of this principle. Fluorescence and thus definition can be enhanced by the use of exogenous markers (i.e. photosensitizing drugs). PDT uses the property demonstrated by photosensitizers to create cytotoxicity when exposed to light of an appropriate wavelength. When stimulated, the photosensitizer is activated from a ground (singlet state) to an excited state (triplet state). By returning to its ground state, it releases energy which is transferred to oxygen to generate reactive oxygen species such as singlet oxygen (type II reaction) and free radicals (type I reaction). These reactive oxygen species mediate cell toxicity. The activated photosensitizer can also directly interact with cellular substrates such as cell, lysosomial or mitochondrial membranes to cause damage and hence cellular death. During the PDT process, tumour cell death is induced either directly or indirectly by vascular damage, source of thrombosis and ischemia within the tumour [12,13] and/or by the mediation of an antitumour immune response [14]. Protoporphyrin IX (PPIX) is a hydrophilic molecule produced by cells during the heme cycle and has spontaneous photosensitizing properties. Synthetic photosensitizers were developed to allow high concentration inside cells. Some are photoreactive compounds: hematoporphyrin derivative (HPD) or porfimer sodium (Photofrin® ) for the oldest and the most widely used. Others are pro-drugs converted inside the tissue into a photoreactive compound (aminolevulinic acid and its derivatives); these induce PPIX build-up by overrunning the heme cycle enzymes. Photosensitizers preferentially localize tumours. Second and third generation photosensitizers were designed to improve tumour uptake, specificity of action and reduce general phototoxicity. Each photosensitizer can be activated by specific wavelengths. PPIX has 5 peaks of absorption. When exposed to blue light, it has the ability to become fluorescent.

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L. Guyon et al.

These properties allow for diagnosis and treatment of neoplastic lesions, in a specific way and without development of any resistance. The aim of this article is to review the current level of knowledge about photodynamic therapy and diagnosis applied to ovarian cancer and to highlight future possible developments.

Methods Pubmed and Embase databases were reviewed for works dealing with photodynamic therapy or diagnosis for ovarian cancer or intraperitoneal carcinomatosis. The search was restricted to articles in English or French. Clinical works on photodynamic diagnosis or therapy for ovarian cancer, as well as in vivo or in vitro preclinical works using human or animal ovarian cancer cell lines were selected and analysed. Case reports were excluded, but no other selection criteria were applied. A complementary bibliography was performed when general information was considered useful to the reader. All articles dealt with ovarian cancer, unless otherwise specified.

Results and discussion Photodynamic diagnosis Photodiagnosis uses the characteristic of PPIX to become fluorescent when excited with blue light. Prodrugs converted into PPIX are consequently employed to enhance diagnosis. The ease of identification of the tumour implants can assist the surgeon with his diagnosis and lead to a more accurate staging (Figs. 1 and 2). Though photodiagnosis and photodynamic therapy have thus far been studied separately, photodiagnosis could easily be integrated into the therapeutic strategy. The first step of the procedure would be a blue light laparoscopy a few hours after administration of the photosensitizer, allowing for visual confirmation of the diagnosis, sampling of lesions for pathologic analysis and staging of the disease. The second phase would consist of the treatment itself, using a light wavelength appropriate for the activation of the photosensitizer, while its concentration is at its highest. Last, during or right after treatment, another photodiagnosis step would allow to verify treatment efficacy. Results of pre-clinical studies Several pre-clinical studies have been carried out that assess the possibility of photodiagnosis in ovarian cancer. Almost all of them report the use of second generation photosensitizers: aminolevulinic acid (ALA) and hexylester aminolevulinic acid (HAL). Table 1 sums up the pre-clinical data published to date [15—25]. These studies showed that the fluorescent signal induced is specific to neoplastic lesions. Indeed, tumour-to-normal epithelium fluorescence ratio is around 1.6—4 and fluorescence microscopy confirms that PPIX remains confined to the cancerous epithelium [15,20,21], in keeping with results obtained on colon carcinoma cell-lines [23].

Figures 1 and 2 White light and blue light laparoscopy 4 hours after injection of hexaminolevulinate in the Fischer 344 rat ovarian peritoneal carcinomatosis model.

These studies also proved that photodiagnosis does better than conventional white light laparoscopy. It allows for the diagnosis of between 1.3 and 2 times as many lesions as conventional laparoscopy [16,17,19,20], probably because it enables the diagnosis of smaller lesions (approximately 30% smaller) [15]. Several factors can affect photodetection by altering the enhancement of contrast between normal peritoneum and lesions. Route of administration of the photosensitizer. Menon et al. [26,27] showed that peritoneal nodules of 1—5 mm incorporated porfimer sodium administered intravenously and that the photosensitizer uptake was independent on the oxygenation status of the lesions. This questions the theory that small nodules lack a functional vasculature and the suggestion that intravenous or oral routes should be avoided. But though photodiagnosis is possible after administration of photosensitizers by oral, intravenous (IV) or intraperitoneal (IP) route, the latter gives the best results in terms of number of lesions and ease of detection. For colon carcinoma cells [24], IP administration leads to more visible lesions and fewer false negatives. The improvement of

Preclinical studies on photodiagnosis of peritoneal carcinomatosis (of ovarian carcinoma/of colon carcinoma).

Reference

Drug

Scheme of administration

Light/drug interval

Number of lesions detected: BL/WL

Size of lesions detected

Tumour/normal tissue fluorescence ratio

False negative

[15]

ALA

IV 100 mg/kg

3h

?

Mean 3.83

0

[16]

ALA

IP II 100 mg/kg

3h

?

?

[17]

ALA

IP 2 mL of 8 mM solution IP 2 mL of 4 mM solution 8 mM solution 12 mM solution IV 100 mg/kg

2h

5/3 (anterior peritoneal wall only) 1.6

0.3—2.5; mean 1 mm Vs 0.5—2.9; mean 1.5 mm for WL 0.5—2 mm

?

?

2h 2h 2h

2.6 1.8 2.7

3h

?

Between 2.7 and 10 2.7 10 Between 2.7 and 10 Grade 2 fluorescence

HAL

IP 100 mg/kg 50 mg/kg 25 mg/kg

1.5; 3 and 6 h 3h 3h

IP 100 mg/kg IP 100 mg/kg

[21]

Autofluo-rescence ALA HAL ALA HAL HAL

[22]

Liposomal BPD-MA

NA 2h 2h 2h 2h 4h 4h 4h 4h 75 min (prior microendoscopy)

HAL

[18]

[19]

[20]

ALA

IP 100 mg/kg IP 100 mg/kg IP 100 mg/kg IV 100 mg/kg Oral 100 mg/kg 200 mg/kg IP 1 mg/kg

<0.5 mm <0.5 mm

17.9/28.7 32/20.7 42.9/33.6 29.3/24.7 31/24.9 ?

?

?

Tens of microns

? ?

Grade 2 fluorescence Grade 2 Grade 1 Vs grade 0 for normal tissues (subjective evaluation) 1.01 1.17 1.22 1.45 1.55 2.69 1.34 1.13 1.35 Between 2 and 3

?

?

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

Table 1

? ?

14%

19

20

Table 1 (Continued) Reference

Drug

Scheme of administration

Light/drug interval

Number of lesions detected: BL/WL

Size of lesions detected

Tumour/normal tissue fluorescence ratio

False negative

[23]

ALA comparison 1.5/3%

IP 5 mL à 1.5 ou 3%

30 min 1h 2h 4h 8h

15/0 19/7 27/23 35/17 10/3

1—20 mm

3.82 at 8 h to 6.27 at 1 h

2—14.6%, up to 1 h after injection; 0%, from 2 h after injection whatever the concentration

[24]

ALA

[25] (same population as ref 144)

ALA

IP 440—550 mg/kg IV 100 m/kg IP 3%

4h 4h 4h

172/142 124/116 172/142

1—10 mm

Vs 2.91 at 8 h to 6.01 at 30 min ?

?

?

?

0

BL: blue light exploration; WL: white light exploration; ALA: aminolevulinic acid; IV: intravenous administration; II IP: intraperitoneal administration; HAL: hexylester aminolevulinic acid; NA: not applicable.

L. Guyon et al.

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer contrast probably accounts for the good detection results. In a study evaluating different routes of administration in a rodent model of ovarian cancer [21], mean tumour-tonormal tissue ratio of fluorescence calculated with a specific software was 2.69 after IP administration, 1.34 after IV administration and up to 1.35 (depending on the dose administered) by oral route. However, these differences may only become evident for the human eye when the fluorescence is markedly modified and another study, in which the fluorescence was subjectively analyzed, did not find any difference between IP and IV administrations [18]. Time between drug exposure and treatment. Fluorescence contrast is better 3—4 h post IP administration of HAL [18]. These results are consistent with those obtained on carcinomatosis of a colonic origin [23], where evaluation 4 h post ALA IP administration gives the best contrast between normal and abnormal epithelium. Around 23—35% of additional lesions are detected and no false negatives are reported compared to shorter application times. Drug concentration. A concentration of 8 mM of HAL administrated by the IP route offers better contrast between cancerous and normal tissue than 4 or 12 mM [17], and 1.5% ALA solution than 3% [23]. However, this does not always reflect on the number of lesions detected. 1.5% ALA allows for the diagnosis of slightly more lesions than 3% ALA, but 8 mM HAL surprisingly seems to lead to fewer lesions detected than 4 mM. Clinical data The ability to accurately differentiate between inflammatory and cancerous lesions and to apply the technique with the same efficacy after adjuvant therapies remains to be assessed. A clinical study was conducted in 30 patients during a follow-up laparoscopy [28]. Patients had previously undergone surgery and/or chemotherapy for ovarian cancer. ALA was injected intraperitoneally 5 h before laparoscopy. Sensitivity was 92% and specificity 95%. The presence of endometriosis explained the false positive cases, but no reason was given for the false negative. Maybe prior treatments precluded an optimal absorption of the photosensitizer by the tumour implants. This question warrants further investigation. Minimally invasive approach Other authors developed a minimally invasive approach that could prove particularly useful for an earlier diagnosis of recurrence than conventional non invasive techniques. Zhong et al. [22] designed a fluorescence micro-endoscope with a miniature flexible probe that allows for the diagnosis of micrometastasis with a diameter in the order of tens of microns. Sensitivity was similar to that of the laparoscopic approach (86%) but specificity was only 53%, maybe due to the photosensitizer used (liposomal BPD-MA).

Photodynamic therapy In the event of a positive photodiagnosis, photodynamic therapy can treat the lesions during the same intervention. PDT for the treatment of ovarian carcinoma restricted to the peritoneum (and of an intraperitoneal neoplasm)

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was first described in a mouse model in 1985 and results appeared to offer the possibility of a cure in these animals [29]. 15 years later, the first clinical trial studying PDT in peritoneal carcinomatosis of ovarian or digestive origin was carried out in which the best results were obtained for ovarian cancers. Phase 1 demonstrated the feasibility of the technique in a clinical setting and reported acceptable tolerance of Photofrin-mediated PDT, though the procedure proved to be time-consuming with an average length of 4 h [30]. Phase 2 was conducted in 100 patients and showed interesting results with a reduction of the number of lesions but without leading to the control of carcinomatosis. 6 months after debulking surgery followed by PDT, only 9.1% of ovarian cancers had demonstrated a complete response [31]. All patients finally experienced a loco-regional recurrence, which may be correlated to an incomplete treatment [32]. However, pre-clinical studies are encouraging, showing a significant necrosis of ovarian peritoneal implants, reduced tumour weight and prolonged survival (Table 2 [22,33—41]).

Selectivity of PDT for ovarian tumour and adverse effect PDT specifically targets ovarian cancer cells. Ascencio et al. showed the selective necrosis of neoplastic epithelium induced by PDT with HAL and either red or green light: PDT performed on healthy rats did not induce any necrosis [42]. The degree of selectivity might be dependent on the photosensitizer, the wavelength, the fluence and the fluence rate used as observed in the studies dealing with skin treatments and fibrosarcomas [43,44]. Major et al. reported partial intestinal wall destruction due to PDT with ALA and violet light. This observation was dependent on the fluence and no histological changes appeared below 0.8 J/cm2 . However, no bowel perforations were observed, irrespective of the fluence used [36]. Intraperitoneal PDT with red light and hematoporphyrin monomethyl ether (HMME) as the sensitizer did not induce any intraperitoneal phototoxicity, including bowel toxicity even though debulking surgery was associated with the procedure [35]. On the other hand, the authors who used porfimer sodium (Photofrin® ) activated by red light reported bowel perforations, in rats [45] as well as in humans [46]. In the clinical study, 3 small bowel perforations were reported for 54 treatments. 630 nm laser light had been used to treat the whole peritoneal cavity that had been previously filed with an intralipid solution. Following these observations and based on the conclusions of animal experiments that proved that green light induced less phototoxicity than red light [47], green light was subsequently used to treat the bowel and the mesentery. This resulted in an elimination of perforation for the next 46 patients [31]. Along with bowel, liver, fat and muscle necrosis [36,44,46] observed with porfimer sodium or mesotetrahydroxy phenylchlorin (mTHPC, Foscan® ) and red light, toxicity mostly consisted of inflammation, edema and congestion of the peritoneal cavity [33,47] (manifesting as a capillary leak syndrome that required massive fluid resuscitation in humans [31,48]), and hematological, liver and kidney function changes (low hemoglobin level, elevation

22

Table 2

Inraperitoneal PDT for peritoneal metastasis of ovarian cancer in the animal.

Reference

Animal model and type of lesion treated

Drug

Light/drug interval

Scheme of treatment

Results

Toxicity

[33]

Nude mice Whole peritoneal cavity

Liposomal BPD-MA IP 0.25 mg/kg

90 min

690 nm, 5 J per quadrant, treatment every 72 h until 3 treatments completed Or at 7 days intervals until animal death 690 nm, fluence rate of 150 mW/cm2 , 6.25 J/cm per quadrant +Intralipid 0.1%

Mean weight of residual tumour: 0.034 g vs 0.379 g for control group

Diffuse inflammation and edema most notably in the bowel and peritoneum; severity depending on sensitizer dose and fluence

[22]

[34]

[35]

Control group = untreated mice Nude mice Whole peritoneal cavity

90 min

Liposomal BPD IP 0.25 mg/kg

90 min

HMME IP 10 mg/kg

3h

690 nm, fluence rate of 150 mW/cm2 , total dose of 20 J/cm2 +Intralipid 0.1%

620 nm, power 160 mW, fluence of 50 J/cm2 +Refracting prism to cover the whole cavity height

Median survival: 36 days vs 28 for control Median survival: 45 days vs 15 and 19 days for control group

L. Guyon et al.

Control group = untreated mice Nude mice Whole peritoneal cavity (comparison with PDT + anti-EGFR) Control group = untreated mice Fischer 344 rats Whole peritoneal cavity Control group = cytoreductive surgery alone or cytoreductive surgery and laser illumination

Liposomal BPD-MA IP 0.25 mg/kg

Median survival: 57 days vs 47 for control group Percentage of tumour re-growth on day 4, assessed by the evolution of fluorescence: −30 to −58% vs +17 to +59% Mean tumour burden treated/control: 38.2%

Reference

Animal model and type of lesion treated

Drug

Light/drug interval

Scheme of treatment

[36]

Fischer 344 rats Intestinal spot (2 cm2 )

ALA IP 50,100,200 mg/kg

3h

407 nm, fluence rate of 100 mW/cm2 , fluence of 0.8; 1.6 or 3.2 J/cm2 +Intralipid 0.02% Or fluence of 1.6 J/cm2 , 300 mW, 5 min for 5 abdominal regions (total 280 cm2 ) +Intralipid 0.02%

Fischer 344 rats Whole peritoneal cavity

[37]

Nude mice Peritoneal spot

Mce6 IV 1.25; 2.5; 5; 10 mg/kg Or IP 2.5 mg/kg

2h

Comparison with the association PDT-adriamycin conjugate

Conjugated Mce6 IV 1.5; 2.9; 8.7 equivalent mg/kg

18 h

650 nm, fluence rate of 244 mW/cm2 , fluence of 220 J/cm2

Results

Toxicity

Destruction of smooth muscle layers of the intestine

Significant tumour ablation (80%) if dose > 2.5 mg/kg IV Not effective at 1.25 mg/kg

Not effective at equivalent dose 1.5 mg/kg Significant tumour growth reduction from equivalent dose 2.9 mg/kg

50% lethal toxicity: extensive rhabdomyolysis of the abdominal wall and diaphragm, partial destruction of bowel wall Morality rate of 83% if dose > 2.5 mg/kg IV; vs no death if dose < 2.5 mg/kg; vs 17% if dose = 2.5 mg/kg; vs 100% if IP No death at equivalent 8.7 mg/kg

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

Table 2 (Continued)

23

24

Table 2 (Continued) Reference

Animal model and type of lesion treated

Drug

Light/drug interval

Scheme of treatment

Results

[38]

Fischer 344 rat Peritoneal spot (1 cm2 )

HAL IP 100 mg/kg

4h

532 nm, fluence of 30 J/cm2 +Fractionated illumination for 25 min (120 s illumination periods followed by 60 s dark periods) Or fluence of 45 J/cm2 +Continuous illumination Or fluence of 30 J/cm2 +Continuous illumination Wavelength not specified Twice a week for three weeks

Mean depth of necrosis: 213 ␮m NV II: 3.2

[39]

Nude mice 3 mm subcutaneously induced tumour

Methyl-ALA IP 250 mg/kg

3h

Hemoporfin IP 10 mg/kg

1h

Control group = untreated mice [40]

Nude mice 0.5 cm3 subcutaneously induced tumour

Mean depth of necrosis: 154 ␮m NV: 2.2 Mean depth of necrosis: 171 ␮m NV: 2.55 Mean necrotic area of 27.1% of serosal tumour area, vs 23.2% for control group Difference non significant for other tumour types Ratio tumour before/after treatment on day 4: 0.49 vs 1.75—2.29 for control groups

L. Guyon et al.

620 nm, fluence rate of 100 mW/cm2 , fluence of 120 J/cm2

Toxicity

Reference

Animal model and type of lesion treated

Drug

Light/drug interval

Scheme of treatment

Results

Toxicity

[41]

Fischer 344 rats 2.5 cm intramusculary induced tumour Control group = untreated rats

PEG-m-THPC IV 0.3; 3.9 or 30 mg/kg

8 days

Interstitial PDT 652 nm, 100, 300, 500, 700 or 900 J/cm

Light and photosensitizer dose threshold for a significant necrosis: no effect at 0.3 mg/kg whatever the light dose; Significant necrosis at 3 mg/kg, between 300 and 500 J/cm; Significant necrosis at 30 mg/kg, between 100 and 300 J/cm

Edema and necrosis of some normal pelvic organs for a photosensitizer dose of 30 mg/kg associated with a light dose from 700 J/cm

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

Table 2 (Continued)

IP: intraperitoneal; ALA: aminolevulinic acid; IV: intravenous; HAL: hexylester aminolevulinic acid; II NV: necrosis value, scoring system evaluating the thickness of necrosis in relation to the total thickness of the lesion; results between 0 and 4.

25

26 of liver enzymes and kidney function impairment), hypocalcemia and hypomagnesemia [31,47]. As could be expected, grade 1 or 2 phototoxicity was observed in 20% of the patients treated with porfimer sodium. As discussed previously, PDT works through a direct and indirect cell destruction (vascular destruction). One of the first manifestations of vascular alterations is vascular permeability, which can account for the congestive manifestations encountered after treatment. Then, occlusion of the vessels appears and can induce damage to normal intraperitoneal structures. A short time interval between administration of the photosensitizer and PDT leads to preferential localization of the drug in the vessels and mostly induces tumour necrosis by destroying microvessels (antivascular PDT) [49—51]. Some photosensitizers such as porfimer sodium also have a preferential vascular location independent of the timing of administration and generate more endothelial cell death [52]. This can lead to a loss of specificity of action. Further, the level of porfimer sodium in ovarian cancer lesions is close to or lower than in many tissues (3.72 ng/mg of tissue compared to 2.99 for the small intestine, 3.95 for the appendix or 21.5 for the spleen for instance) which contributes to the narrow therapeutic window of the molecule [53]. Both mechanisms may explain the differences in the occurrence of adverse events like bowel necrosis and perforation between different photosensitizers.

Specific aspects of intraperitoneal PDT The photosensitizer. Porfimer sodium and mTHPC for intraperitoneal PDT appear to induce more complications than other photosensitizers [36,45,47]. Second generation photosensitizers can increase the uptake by cancerous lesions, hence improving the selectivity of action of PDT. For instance, ALA is responsible for less endothelial cell death than porfimer sodium [52]. Preclinical studies also showed that HAL had an even better tumour penetration and led to more porphyrin formation than ALA [1]. Compared to ALA, it consequently leads to improved contrast between normal and cancerous epithelium [20]. With photoimmunotherapy, antibodies are used to target the sensitizer to tumour cells and further enhance tumour cytotoxicity. Several monoclonal antibodies have been developed that target ovarian cancer cells antigens: OC 125 for CA 125, OV TL3 for OA 3, 139 H2 for episialin. They all improve tumour uptake and tumour-to-normal tissue fluorescence ratios [54,55], but they also sometimes target normal cells. OC 125 is the most studied. The corresponding antigen is expressed in 80% of non mucinous ovarian cancers. Tissue concentration of the photosensitizer targeted with OC 125 is twice that of the free photosensitizer with a tumour to intestine ratio of 3.5 at 24 h. Post PDT, cell viability is reduced and life of the animal prolonged [56—58]. Molpus et al. [59] also reported improved tumour response and survival when using cationic OC 125 to target the photosensitizer. With regards to toxicity, after drug dose adjustment, no digestive, renal nor splenic toxicities were observed [57,59]. Another way to improve specific drug delivery and reduce toxicity is the development of conjugates. They are the

L. Guyon et al. result of the combination of an anticancer drug and a carrier, which aims to limit the distribution to normal tissues. In a study carried out combining chemotherapy and Mce6 conjugate, the conjugates allowed to reduce toxicity of the treatment: a sevenfold increase of the safety margin of PDT was observed with no specific adriamycin-related toxicity [37]. The illumination procedure. The different options available to improve PDT outcome (like fractionation of light administration, use of adjuvant drugs aiming to alter the metabolism of PPIX like iron chelator) will not be discussed. As the schemes of illumination are not specific to peritoneal carcinomatosis, except for the sensitivity of the bowel to laser light. Two points must be emphasized. First, green light is better tolerated [47] than red light and improves treatment outcomes (necrosis value of 3.22/4 vs 2.67/4 [42]). But the trade off is that it excludes thick lesions as the depth of penetration is smaller −5 mm smaller for the liver for instance[60,61] and cytoreductive surgery thus remains an important part of the therapy. Second, antivascular PDT schemes may not be desirable as they are responsible for more systemic side effects, even when used as a local treatment [50]. The illumination device. With its recesses and irregularities, the peritoneal cavity presents a challenge as yet unsolved by the current design of light delivery systems. The use of flat optical fibres, refracting prisms and inflatable balloons or rectangular blocks (Table 2) has been reported, yet the perfect answer remains to be designed. Lipid emulsions are widely used to fill the peritoneal cavity during treatment [22,33,34,36,45]. Working as a diffusing medium, it is meant to enhance light distribution. Despite these strategies, the parieto-colic gutters, diaphragmatic surfaces and posterior face of intraabdominal organs remain difficult to reach.

Assessment of the results of PDT Photobleaching is the fading of the fluorescence of cancerous lesions. It can be spontaneous if enough time is left for photosensitizer to be eliminated from the body or induced by treatment (Figs. 3 and 4). This aspect of the question was less studied though photobleaching represents one of the main advantages of phototherapy over alternative strategies. It can be used to assess the results of PDT and to adapt treatment in real time. Photobleaching highlights the extent of necrosis of the peritoneal lesions (Fig. 5) and the same relationship as in dermatologic and gastrointestinal PDT is observed [62—64]: the mean ratio of fluorescence intensity immediately after/before intraperitoneal PDT is 0.29 for the complete responders and 0.81 for the non-responders [65]. Zhong et al. [22] re-injected mice with benzoporphyrin derivative monoacid (BPD-MA) 4 days post PDT and explored the peritoneal cavity with a micro-endoscope. They found that the downwards shift of fluorescence intensity corresponded to tumour destruction and that the evolution of fluorescence intensity was linked with tumour growth. Calculated differences in fluorescence intensities are significant, but subjective evaluation is less precise as what

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

27

evaluation may well be required for an accurate assessment. So far, this has been a two step procedure —recording of the fluorescent lesions then post-procedure calculation of the fluorescence ratio — especially when bearing in mind that access to intra-abdominal lesions during laparoscopy is limited. Real-time photobleaching evaluation devices need to be developed, in the way they were for dermatologic PDT [64,66].

Association with other treatments Except in the case of recurrent microscopic lesions, surgery will always be necessary in order to reduce the tumour burden to a size compatible with PDT action and to excise associated lymph nodes. Homogeneous light delivery to all intra-abdominal areas is difficult because of the irregularities of intraperitoneal organs. Associated therapies could have a complementary action when PDT cannot reach the lesions. PDT can also help improve the results of other treatments.

Figures 3 and 4 Blue light laparoscopy before and after PDT in the Fischer rat ovarian peritoneal carcinomatosis model.

can be inferred from the studies evaluating photodiagnosis (cf supra). Further studies are needed to assess the possibilities of evaluation with photobleaching, but computer-assisted

Figure 5 Variation of the normalized fluorescence intensity (ratio of the fluorescence intensity before and after illumination, expressed as a percentage) according to the necrosis value (reflecting the extent of tumour necrosis from 0 -no necrosisup to 4 -full necrosis). Photobleaching is predictive of PDT response.

Chemotherapy In order to be efficacious, IV chemotherapy needs a functional tumour vasculature. Peritoneal nodules as small as 1 mm show a vasculature [26] that is likely to be absent from smaller lesions. Peritoneal micrometastasis of ovarian cancer consists of small colonies of cells probably mainly sustained by diffusion from the peritoneal fluid. It is thus difficult for chemotherapy drugs to reach cytotoxic concentration and to eradicate micrometastasis. Furthermore, resistance to chemotherapy agents develops quickly. The association with PDT is thus particularly interesting. Several in vitro studies have been conducted, showing a synergy in associating of PDT with chemotherapy [37,55,67,68]. Rizvi et al. [67] studied the association of carboplatin with BPD PDT on a 3D ovarian cancer model. They showed that micro-nodules treated with chemotherapy alone contained a core of viable cells that indicates either resistance or impermeability to the drug, whereas PDT creates an overlapping pattern of destruction inside the nodules. Combination of treatments produced a synergistic reduction of the residual tumour volume and of the viability of the cells, but only when PDT was administered before carboplatin. This last observation can be explained by the fact that the disruption of the micronodules architecture enhances the uptake of chemotherapy drugs, as the surface of contact is wider. It can also be explained by the vascular permeability induced by PDT that enhances drug delivery inside the tumour [69]. Duska et al. [68] evaluated photoimmunotherapy associated with cisplatin chemotherapy on ovarian cancer cell cultures. Cisplatin and PDT had a synergistic cytotoxic action over cisplatin alone, but this effect was only reported on chemoresistant cells. The association of PDT-chemotherapy may only be beneficial to the sub-group of patients presenting with a chemotherapy resistant cancer.

28 Peterson et al. [37] studied the efficacy and safety of the association of IV adriamycin and PDT with intravenous or intraperitoneal mesochlorin e6 monoethylenediamine (Mce6) photosensitizer conjugates in a rodent model. With an adapted dose of photosensitizer conjugate, tumour volume reduction was significantly increased compared to adriamycin conjugate or photosensitizer conjugate alone. It was even able to induce complete tumour destruction. PDT and immunotherapy Immunotherapy targeting factors implied in cell proliferation: The development of ovarian carcinomas is linked to the EGF-TGF␣ signal pathway. EGFR promotes cell proliferation by inducing progression from G1 to S phase. It is overexpressed in 35—70% of ovarian primary carcinomas. Overexpression of EGF, EGF-R, TGF␣ and c-erb is associated with a more aggressive phenotype and a poorer prognosis [70]. Del Carmen et al. [34] studied in vivo the association of PDT with C225 (cetuximab, Erbitux® ), a chimeric monoclonal antibody blocking the epidermal growth factor receptor (EGFR). PDT was delivered after sensitization by BPD and C225 was administered 24 h after PDT and at 3, 6 and 8 days post. C225 produced a treated to untreated mice tumour burden ratio of 66% and PDT alone of 38%. The combination of both treatments produced a synergistic response with a treated to untreated mice tumour burden ratio of 9.8%. It also had a synergistic effect on survival compared to both treatments. However, the authors observed more adhesions in the mice which treatment included C225 than in those treated with PDT only. Adhesions were localized along the anterior abdominal wall, among the loops of the bowel and in the pelvis, with the potential to become a source of abdominal complications and make subsequent intrabdominal explorations more difficult. Anti-cancer vaccines: Many approaches have been developed to induce active or passive anti-cancer immune response against ovarian cancer [71], but their combination with PDT has not been studied. PDT and antiangiogenic drugs This association was mostly studied in age-related macular degeneration because of its possibility to further reduce abnormal vascularization. Several studies showed that PDT induces the production of vascular endothelial growth factor (VEGF) in vitro and in vivo, in normal tissues as well as in tumours [72—75]. PDT induces microvascular damage which fosters tumour hypoxia and thus enhances the production of different molecules, including VEGF. VEGF levels increase in solid tumour under hypoxia in order to maintain neovascularization. The increase in VEGF is mediated by IL-2 which, with VEGF, could represent a target for antiangiogenic approaches. The association of PDT with antiangiogenic factors significantly improved the cure rate of mammary carcinoma bearing mice [72]. One study was carried out for peritoneal carcinomatosis (on a sarcoma cell line). A combination of PDT and bevacizumab (Avastin® ), a monoclonal antibody targeting VEGF and inhibiting its fixation to its receptor, was used. The drug is already approved for the treatment of

L. Guyon et al. breast, lung, colon and kidney cancers and is currently being investigated in many other malignancies including ovarian cancer. Administered prior to PDT, it induced a mean necrosis percentage of 89% compared to 69% for PDT and 41% for Avastin® alone [76]. Digestive complications may become a concern with this treatment in the context of PDT. Clinical studies reported between 0 and 11% of bowel perforations after treatment of recurrent ovarian cancer with bevacizumab [77,78]. Sonodynamic therapy (SDT) The mechanism of sonodynamic action has been suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen [79]. Due to the good tissue penetration of ultrasound waves, SDT may represent a non invasive way to overcome the difficulties for the light delivery systems to reach all the lesions within the peritoneal cavity. Many compounds, including anticancer drugs and photosensitizers also have sonosensitizing properties [80]. Cavitation, produced by ultrasound waves, directly induces cell membrane damages through the production of free radicals and mechanical effects due to shear stress [80]. Sonosensitizers may enhance the chemical action of ultrasounds and ultrasounds may conversely enhance delivery of sonosensitizers to the cell by permeabilizing the cell membrane. On the other hand, SDT also increases the depth of action of PDT by a ratio of 2—3 times [80]. The mechanisms of action are highly dependent on the sonosensitizer, the ultrasound exposure parameters and the characteristics of the biological tissue. Kenyon et al. [81] reported the results of PDT associated with SDT using Sonnelux® as the photo-sonosensitizer. Patients first received PDT with red light and then ultrasounds at the known tumour sites. Among 115 cases reported, 6 had ovarian cancer. All but one presented with recurrent cancer. She had a stage 1C disease but refused all conventional therapies and was reported as tumour free after PDT-SDT. However, the lack of systematically collected data limits the conclusions we can draw from these observations. The sequence of treatment can also be: SDT, then PDT. This seems to lead to a synergistic effect compared to PDT followed by SDT. PDT makes complete the cell destruction initiated with the ultrasound waves, as those cells have only undergone sublethal damage [82].

Conclusion Photodiagnosis and photodynamic therapy have the potential to significantly improve the management of ovarian cancers. However, a number of issues must first be resolved. The scheme of treatment and the way the peritoneal cavity is illuminated must be improved and the place of photodynamic therapy within the current strategy or in association with other therapies remains to be determined. Conversely, photodiagnosis is beginning to be better understood, but must still be thoroughly evaluated. Finally, the design of easy-to-use photobleaching evaluation devices would be particularly useful to improve the management with PDT.

Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer

Acknowledgement The authors wish to thank Pascal Servell for his careful review of the English language of this manuscript.

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