Photodiagnosis and Photodynamic Therapy (2015) xxx, xxx—xxx

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Photodynamic therapy as salvage therapy for patients with nasopharyngeal carcinoma experiencing local failures following definitive radiotherapy S.D. Stoker a,1, S.R. Indrasari b,1, C. Herdini b, B. Hariwiyanto b, B. Karakullukcu a, W. Dhamiyati c, K. Widayati d, A.C. Romdhoni e, R. Fles a, S.M. Haryana f, M.A.M. Wildeman a,g, I.B. Tan MD, PhD a,b,h,∗ a

Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands b Department of Otorhinolaryngology, Dr. Sardjito General Hospital/Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia c Department of Radiotherapy, Faculty of Medicine/Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia d Department of Internal Medicine, Faculty of Medicine/Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia e Department of Otorhinolaryngology-Head & Neck Surgery, Faculty of Medicine, Airlangga University, Surabaya, Indonesia f Department of Bio-Molecular, Faculty of Medicine/Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia g Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, The Netherlands h Department of Maxillofacial Surgery, Academic Medical Centre, Amsterdam, The Netherlands

KEYWORDS Nasopharyngeal carcinoma; Recurrent disease; Residual disease; Local failures; Photodynamic therapy

Summary Background: Treating local failures of nasopharyngeal carcinoma (NPC) is a challenge. This study evaluates photodynamic therapy (PDT) in the treatment of residual and recurrent NPC. Method: In this phase II study, patients with local recurrent or residual NPC after curative intent (chemo-) radiation could be included. Exclusion criterion was a tumour depth more than 10 mm. Foscan® 0.15 mg/kg was administered intravenously. After 96 h, the illumination was performed under local anaesthesia with a nasopharyngeal light applicator. Tumour response was measured 10 weeks after illumination by endoscopy, biopsy and CT-scan. Kaplan—Meier method was used for survival analysis.



Corresponding author at: Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Tel.: +31 20 512 2550; fax: +31 20 512 2554. E-mail address: [email protected] (I.B. Tan). 1 Both these authors contributed equally to this article. http://dx.doi.org/10.1016/j.pdpdt.2015.04.005 1572-1000/© 2015 Published by Elsevier B.V.

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S.D. Stoker et al. Results: Twenty-one patients were included. Fourteen patients were treated for residual disease (67%), and two for recurrent (10%). For five patients this distinction could not be made, due to uncertainty about complete response after initial treatment. The median follow-up time was 32 months. Twenty patients (95%) had a complete response 10 weeks post-treatment. Two patients had recurrent local disease at 5 and 7 months post-PDT. They received another course of PDT, one with success. The 2-year local control rate was 75%, progression free survival was 49% and overall survival was 65%. Nine patients (43%) had no evidence of disease and were in a good clinical condition (ECOG Performance Scale 0) at the end of the study period. No serious adverse events were observed. Conclusion: This study showed that PDT is effective in treating local failures of NPC with a depth of less than 10 mm. The treatment was easy to perform under local anaesthesia. Especially in regions were other modalities like radiation and surgery are limited PDT can be a good alternative treatment. © 2015 Published by Elsevier B.V.

Introduction The management of nasopharyngeal carcinoma leads nowadays to a relatively good 5-years overall survival of approximately 70—80%. Nevertheless, local failure occurs in approximately 5—30% of the patients [1—4]. This is probably an underestimation, since these statistics are derived from centres of excellence. A study in Indonesia, where NPC has an incidence of at least 6.2:100,000 (14,000 cases a year), revealed that only 29% of the patients treated with curative intent got a complete response directly after treatment. Local persistent disease was seen in 31% of the patients who were evaluable for therapy assessment [5]. The treatment of local failures is challenging. Surgeons working in clinics specialized in NPC, recommend surgery (open and/or endoscopic) [6—8]. However, extensive experience is required to get access to the nasopharyngeal space and to achieve free tumour margins, which is prerequisite for successful surgery. Radiotherapy options are also limited, due to the dose-related toxicity. Sometimes brachytherapy or stereotactic radiotherapy is given. For selective cases good tumour response rates are achieved with surgery or re-irradiation (or a combination), although the side effects can be of significant proportion. Besides, many hospitals in Indonesia lack the required surgical equipment and have only limited radiation capacity. In Indonesia, it is not exceptional to wait for more than 6 months for radiation [9,10]. Therefore, readily available, easy to perform, and preferably inexpensive alternative modalities are needed. Photodynamic therapy (PDT) is a treatment based on the activation of an intravenously administered photosensitizer by a light source [11,12]. During light exposure, reactive oxygen species are generated which will harm and destroy the tumour cells. This treatment procedure is easy to learn and can be performed in the outpatient clinic. For the treatment of recurrent or residual NPC, the only requirements are a photosensitizer, a laser, a nasopharyngeal light-applicator and a lux-metre [13]. PDT can be performed under local anaesthesia. A number of studies showed good clinical response with acceptable side effects when treating head

and neck carcinomas, including nasopharyngeal carcinomas [14—19]. However PDT has not yet been integrated to routine treatment regimes. This phase II study focused on the clinical effect of PDT for recurrent and persistent NPC. For uniformly distribution of the light to the nasopharyngeal space the Amsterdam—Rotterdam (AMRO) light applicator was used [13]. A previous study with PDT for NPC with Temoporfin Foscan® showed that the optimal dose was 0.15 mg/kg, a drug-light interval of 96 h, and a light dose of 20 J/cm2 [20]. This regimen was used in the current study. Clinical response, local control, progression free survival and overall survival were the primary endpoints.

Method This phase II study was conducted between 2009 and 2014 at Dr. Sardjito Hospital/Gadjah Mada University, and Dr. Sutomo Hospital/Airlangga University, tertiary referral hospitals in respectively Yogyakarta and Surabaya, Indonesia. The study was approved by the ethic committee in both institutions. Informed consent was obtained from all patients.

Patients Patients were eligible for inclusion if they had a local failure of NPC after in onset curative intent radiotherapy with or without chemotherapy. Local failure had to be confirmed by biopsy (WHO 1, 2 or 3). All patients underwent computerized tomography (CT) of the head and neck area, ultra sound of the abdomen, X-ray of the thorax and a bone survey to assess the extent of the disease. In case of neck lymph node metastases patients could undergo a neck dissection before or after the PDT treatment. Exclusion criteria were: (1) a tumour depth of more than 10 mm (surface illumination with temoporfin has an effective penetration of 10 mm), (2) the nasopharyngeal area was not accessible for surface illumination by using the nasopharyngeal applicator, (3) distant metastasis and/or (4) a Karnofsky performance status less than 70%.

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3 channels, 20 J/cm diffuser length was delivered at a fluence rate of 100 mW/cm. The light source was a 652 nm diode laser (Biolitec, Bonn, Germany). The same procedure was repeated for the second treatment channel. After the treatment the applicator was removed. The procedure is described more in detail in previous publications of our group [13,20].

Clinical outcome Tumour response was assessed 8—12 weeks post-treatment by endoscopy, biopsy and CT imaging. Gold standard for a complete response was a negative histological result of the biopsy taken from the location of the treated recurrent/residual lesion. In the first 2 years, patients visited the outpatient clinic every 3 months, and thereafter every half-year. During these visits physical examination, including endoscopy was performed. In case of any suspicion for recurrent disease, imaging and/or a biopsy was performed. Patients were followed until dead or till July 2014, when the study period ended.

Statistical analysis

Fig. 1 (A) Nasopharynx applicator and (B) schematic view of positioning and illumination. (1) Cylindrical diffuser in shielding tube. (2) Target area. (3) Soft palate is shielded. This figure has been used previously by our group (13, 14, 20).

Treatment All patients were treated with Foscan® 0.15 mg/kg of body weight, administered by slow intravenous injection into a proximal deep vein. Then patients remained in a lightrestricted room for 24 h and made a gradual return to light exposure with an increase of 100 lux per day. After a period of two to three weeks patients could return into daylight exposure. Guidelines for light exposure and a lux-metre were given to the patients. To ensure homogeneous light administration to the nasopharyngeal area, the Amsterdam—Rotterdam light applicator was used (Fig. 1). This applicator has two treatment channels (one channel per nostril), which can accommodate a linear light diffuser each. After decongestion (R/xylometazoline hydrochloride 1%) and topical anaesthesia, the applicator was introduced into the nasopharyngeal space transorally over two guiding tubes (four French). By using a small silicone flange, the applicator remains fixed in a stable position. A linear light diffuser of 5 cm length was introduced into one of the treatment

Kaplan—Meier analysis was used for survival analysis. Local control (LC) was calculated from the day of illumination till the day of recurrent local disease or local progression. Patients without local disease were censored at the last moment of contact or at the date they died. In case a patient was treated twice with PDT it was analyzed as two separate treatments. Progression free survival (PFS) was calculated from the day of illumination till the day of local progression, relapse in the neck or at distant site, or death. In case a patient was treated twice with PDT it was analyzed as two separate treatments. Patients with a second primary were excluded from PFS analysis. Overall survival (OS) was calculated from the day of illumination till the date of death from any cause. In case patients were treated twice with PDT, the date of the first illumination was used for OS analysis.

Adverse events On every visit patients were asked for side effects. Structural evaluation was performed by forms on pain, burning wounds and skin hyperpigmentation. These symptoms where scored on a scale from 0 to 10; 0 represented no pain/burns/pigmentation and 10 represented the worst possible pain/burns/pigmentation.

Results Between June 2009 and March 2013, 21 patients were included in the study. Details of the patients concerning their age, sex, initial disease stage and treatment before PDT are shown in Table 1. Fourteen patients were treated for persistent disease (local failure within 6 months) after in onset curative (chemo-) radiation, and two patients for recurrent disease. For five patients it was not possible to PDPDT 644 1—7

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S.D. Stoker et al. Table 1

Patient characteristics and summary of the therapy outcome.

Patient

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13.1 13.2 14 15 16 17 18 19.1 19.2 20 21

Age

Primary disease Primary treatment

Type of failure

TA

Local

Regional

Recurrent Persistent Persistent Persistent Persistent Persistent Persistent Persistent Persistent Recurrent Unknown Persistent Unknown Post-PDT Persistent Persistent Persistent Persistent Persistent Unknown Post-PDT Unknown Unknown

CR CR CR CR CR CR CR CR CR CR PD CR CR PD CR CR CR CR CR CR CR CR CR

40

29 6

48 48 42 36 28 52 47 77 18 51 22 61 42

T3N1 T1N1 T3N0 T1N1 T4N0 T1N2 T1N2 T1N0 T2N1 T2N1

CRT RT CRT CRT CRT CRT CRT CRT CRT CRT

T1N3a T1N1

CRT CRT

m m f f f f

31 54 43 41 58 49

T1N1 T3N2 T3N3a T1N2 T4N2 T4N0

CRT CRT CRT CRT CRT CRT

64 37

Progression (months)

Initial stage m f m f m m m m f f f m m

m m

Post-PDT

T4N3a T4N0

CRT CRT

Distant

4 7 41 9

4 6 7 4

4

19

19

19

4

LFU (months)

Status

48 21 47 23 60 7 48 14 46 16 19 27

Alive Death Alive, NED Death Alive, NED Death Death Death Alive, NED Alive, NED Death Alive

27a 32 31 30 29 5

Death Alive, NED Death Alive, NED Alive, NED Death

25a 13 14

Alive, NED Death, 2ndP Alive, NED

5

TA, therapy assessment; CR, complete response; PD, persistent disease; LFU, time to last follow up; NED, no evidence of disease; 2ndP, second primary. a Measured from date of first PDT treatment.

categorize them in recurrent or persistent disease, since therapy response assessment after the primary treatment was not performed/retrievable. These local failures were confirmed between 8 and 20 months after the primary treatment. Except for one, all patients had rT1N0. Patient number 17 had rT1N1 disease on CT imaging, however the N stage was not confirmed by fine needle aspiration cytology. This patient was planned for a neck dissection after PDT. The lump in the neck had disappeared after PDT. Therefore no neck dissection was performed.

Clinical outcome The median follow up time was 32 months. All patients were evaluable for therapy outcome assessment 8—12 weeks after PDT. Except for one, all post-treatment biopsies were negative for NPC. One patient (number 11) had a positive biopsy and showed local progression towards the sphenoid sinus on CT imaging. This tumour was not suitable for re-treatment with PDT. She passed away 19 months after the illumination. Patient number 13 had a local relapse 7 months after PDT. He received another course of PDT without success. He had local persistent disease and a relapse in the neck, and died 27 months after the first PDT treatment. Patient number 19 had a local relapse 5 months post-PDT. This patient received another treatment with PDT, and was disease free at the moment of last evaluation.

Survival analysis The 2-year LC rate was 75% (Fig. 2A). Five patients (24%) had local relapse post-PDT. Two of them were treated again with PDT; one had a complete response and is still alive without disease. The 2-year PFS was 49% (median 19 months) (Fig. 2B). Regional relapse was seen in six patients, and five patients developed distant metastasis. Patient number 20 had a 2nd primary in the tonsil (nasopharyngeal biopsy showed non-differentiated carcinoma, and the tonsil biopsy was a well-differentiated squamous cell carcinoma), and also developed distant metastasis. Since the histological type of the distant metastasis was uncertain, this patient was excluded for PFS analysis. In none of the patients surgery or re-irradiation was performed. Patient 7, 12, 15 and 20 received palliative chemotherapy. Reasons for not giving additional treatment to the other patients were; poor condition, death soon after assessment of recurrent disease, and refusal of palliative treatment (some preferred traditional treatment). The 2-year OS was 65% (median 31 months) (Fig. 2C). Nine (43%) patients were alive without any evidence of disease at the end of the study period. Two patients (10%) were alive with disease. Ten patients died in the study period. The actual cause of death was difficult to retrieve, because most patients died at home without

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Fig. 2 Survival plots. (A) Local control (event: local progression). (B) Progression free survival (event: loco-regional progression, distant metastasis or death). (C) Overall survival (event: death).

medical surveillance. All deceased patients had recurrent disease. By hetero anamneses there was no other cause than the cancer for their death identifiable. Therefore it is assumable that (except for patient 20), all deceased patients died because of NPC. Patient number 20 had a 2nd primary tumour in the tonsil.

Adverse events No serious adverse events were observed. None of the patients suffered from burn wounds or skin hyperpigmentation. In the first month, the mean pain level was 3.4 (median 3, range 1—8), in the second month the mean was 2.5 (median 2, range 1—5), and in the third month 2.1 (0—7) (Fig. 3). In the third month three patients had a pain score above 3; all had tumour relapse and died 5, 7 and 14 months after the PDT treatment.

Discussion and conclusion Residual local disease of NPC after curative intent radiotherapy is a major problem in this academic hospital in Yogyakarta. Worldwide, local recurrence is more frequently seen than local residual disease. Therefore, little is known about the best treatment for this type of failure. This study included 14 (67%) patients with residual disease. Probably more patients had persistent disease, because five patients did not have post-treatment imaging, which made the distinction between residual disease and recurrent disease impossible. This study showed that PDT was an effective treatment for local failures of NPC with a tumour depth of less than 10 mm. The 2-year OS was 65% and the LC rate was 75%. Pain was the most common complication. No treatment related deaths or other serious adverse events where seen. Also during the intervention no complications were encountered and all patients were treated under local anaesthesia. A few others have studied the role of PDT for local failures in the nasopharynx. They included both recurrent and persistent disease. Kulapaditharom et al. [16] treated six patients with rT1-2 disease; all of them had a complete response and a mean disease free survival of 26 months [16]. Lofgren et al. [18] treated five patients with a tumour depth 50% [21]. In summary, PDT has shown to be effective for limited local failures with a 2-year local disease free survival of over 50%. Conventional treatments for small local failures of NPC are surgery and re-irradiation. Studies using surgery for local failures did not report separate results for recurrent or residual disease. Hao et al. showed that surgery for T1 lesions gave a 5-year local control rate of 58% and an OS of 65% [7]. Wei et al. [6] performed the maxillary swing procedure with curative intent on 246 patients. Radical margins were achieved in 78% and the 5-year disease free survival was 56%. Vlantis et al. [22] retrospectively reviewed open surgery of 80 patients. The majority (95%) had rT1-2 stage. In 69% pathological clean margins were achieved. In case of positive margins, patients were treated with brachytherapy. The 5-year overall survival was 43—59%. Chen et al. [8] treated 37 patients with endoscopic surgery; radical margins were achieved in 97%. During follow up, no recurrences were seen for the rT1. When taken these results together, the 5-year disease free survival after surgery for small local failures is approximately >55%. Radiation as salvage treatment for local failures is disputable since a full dose (60—70 Gy) was unsuccessful in the primary treatment, suggesting that the residual tumour cells are insensitive for radiation. Besides, the cumulative dose toxicity makes side effects the limiting factor, i.e. brain necrosis, cranial nerve palsy and endocrine dysfunction [23]. Brachytherapy is the most used modality for small local failures. Cheah et al. [23] retrospectively reviewed the outcome of 33 patients treated with brachytherapy. The 5-year local disease free interval was 45% and overall survival was 28%. Major complications were seen in 35% of the patients. Recently, Ren et al. [24] published very promising results of 3D-image-guided high-dose-rate intra cavitary brachytherapy in 32 patients. They had a 100% complete response rate for the small local failures and a 5-year overall survival of 97%. Xerostomia and mucositis were frequently seen, but limited to grades 1—2. There were no neurological complications. Direct comparison between the studies with PDT, reirradiation and surgery is difficult due to different patient

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Fig. 3 Pain score. Pain was scored on a scale between 0 and 10; 0 being no pain, and 10 being the worst posible pain. In the third month three patients had a pain score above 3; all had tumour relapse and died 5, 7 and 14 months after the PDT treatment.

populations, the indistinctness about residual and recurrent disease and the use of different study outcome parameters. Nevertheless, it seems that PDT is not underachieving in clinical efficacy. In Indonesia, the availability of radiation units is a serious problem. On Java, one radiation unit is available per 10,000,000 people [9]. In our study population, the waiting time for radiotherapy was 4 months. Nowadays, due to a change in the insurance system, which makes health care available for all inhabitants of Indonesia, the waiting time exceeds 1 year. This makes re-irradiation for local failures difficult. Surgery of the nasopharynx needs extensive experience and sophisticated tools, which are both limited in Yogyakarta. PDT is readily available, and the procedure is easy to learn. It can be performed in the outpatient clinic, under local anaesthesia. Besides pain, which was controlled by medication, no significant morbidity or mortality was encountered in the study. This makes PDT a very good option, or even the only option when treating NPC failures in Yogyakarta. A limitation of our study was that some patients might have had distant metastasis at inclusion. A PET-scan is not available in this hospital. For evaluation of dissemination an X-ray of the thorax and bones and an ultrasound of the abdomen were performed. The sensitivity of these diagnostics for pulmonary and bone metastases is low. Three patients had distant metastasis within 7 months after the PDT treatment. It is likely that these lesions were already present before PDT treatment and these patients have worsened the overall survival. These patients might have been excluded when other imaging diagnostics would have been available, which could have improved the disease free and overall survival of our study population. This study shows that PDT is comparable to surgery and re-irradiation. The advantage of PDT above surgery and re-irradiation is that it is simple and short procedure

with limited side effects. Moreover, since there is no dose cumulative effect, the treatment can be repeated in case of an incomplete response or progression. Especially in regions were other modalities are limited or suboptimal PDT can serve as a good salvage treatment. Interesting ideas for a future study in Indonesia (or other low income countries with poor primary treatment outcome results) could be to use PDT as adjuvant treatment for patients with an expected poor outcome, like an extended overall treatment time or for those with a very long diagnose-to-treatment interval. Also interesting is the use of PDT for more advanced lesions of NPC. PDT showed clinical benefit in a certain number of patients with recurrent advanced local NPC [6,19,25]. The exact mechanism of these outstanding responses remains uncertain, since full illumination of the tumour surface and depth penetration was not possible. It suggests that an immunological response might have controlled tumour progression. Future study can also focus on the role of PDT in combination with immunotherapy for NPC.

Acknowledgement This project was supported by Biolitec Pharma Ltd., Dublin, Ireland.

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7 [14] Wildeman MA, Nyst HJ, Karakullukcu B, Tan BI. Photodynamic therapy in the therapy for recurrent/persistent nasopharyngeal cancer. Head Neck Oncol 2009;1:40. [15] Kulapaditharom B, Boonkitticharoen V. Photodynamic therapy in management of head and neck cancers and precancerous lesions. J Med Assoc Thai 2000;83(3):249—58. [16] Kulapaditharom B, Boonkitticharoen V. Photodynamic therapy for residual or recurrent cancer of the nasopharynx. J Med Assoc Thai 1999;82(11):1111—7. [17] Tong MC, van Hasselt CA, Woo JK. Preliminary results of photodynamic therapy for recurrent nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol 1996;253(3):189—92. [18] Lofgren LA, Hallgren S, Nilsson E, Westerborn A, Nilsson C, Reizenstein J. Photodynamic therapy for recurrent nasopharyngeal cancer. Arch Otolaryngol Head Neck Surg 1995;121(9):997—1002. [19] Abbas S, Jerjes W, Upile T, Vaz F, Hopper C. The palliative role of PDT in recurrent advanced nasopharyngeal carcinoma: case series. Photodiagnosis Photodyn Ther 2012;9(2):142—7. [20] Nyst HJ, Wildeman MA, Indrasari SR, Karakullukcu B, van Veen RL, Adham M, et al. Temoporfin mediated photodynamic therapy in patients with local persistent and recurrent nasopharyngeal carcinoma after curative radiotherapy: a feasibility study. Photodiagnosis Photodyn Ther 2012;9(3):274—81. [21] Succo G, Rosso S, Fadda GL, Fantini M, Crosetti E. Salvage photodynamic therapy for recurrent nasopharyngeal carcinoma. Photodiagnosis Photodyn Ther 2014;11(2):63—70. [22] Vlantis AC, Yu BK, Kam MK, Hung T, Lo PS, King AD, et al. Nasopharyngectomy: does the approach to the nasopharynx influence survival? Otolaryngol Head Neck Surg 2008;139(1):40—6. [23] Cheah SK, Lau FN, Yusof MM, Phua VC. Treatment outcome with brachytherapy for recurrent nasopharyngeal carcinoma. Asian Pac J Cancer Prev 2014;14(11):6513—8. [24] Ren YF, Cao XP, Xu J, Ye WJ, Gao YH, Teh BS, et al. 3Dimage-guided high-dose-rate intracavitary brachytherapy for salvage treatment of locally persistent nasopharyngeal carcinoma. Radiat Oncol 2013;8:165. [25] Indrasari SR, Timmermans AJ, Wildeman MA, Karakullukcu MB, Herdini C, Hariwiyanto B, et al. Remarkable response to photodynamic therapy in residual T4N0M0 nasopharyngeal carcinoma: a case report. Photodiagnosis Photodyn Ther 2012;9(4):319—20.

PDPDT 644 1—7

Photodynamic therapy as salvage therapy for patients with nasopharyngeal carcinoma experiencing local failures following definitive radiotherapy.

Treating local failures of nasopharyngeal carcinoma (NPC) is a challenge. This study evaluates photodynamic therapy (PDT) in the treatment of residual...
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