Photodynamic Therapy Treatment of Early Oral and Laryngeal Cancers†
This invited paper is part of the Symposium-in-Print: Photodynamic Therapy.
Abstract
Photodynamic therapy (PDT) is a nonsurgical, minimally invasive treatment that uses a light source to activate light-sensitive drugs or photosensitizers in the treatment of cancer and other diseases. PDT has been successfully employed to treat early carcinomas of the oral cavity and larynx preserving normal tissue and vital functions of speech and swallowing. Two hundred seventy-six patients with early carcinomas of the oral cavity and larynx were treated from 1990 to 2006. Cure rates with a single treatment for early laryngeal and oral cancers were 91% and 94%, respectively. PDT is an effective primary and alternative treatment modality for early oral cavity and laryngeal cancers.
Introduction
Photodynamic therapy (PDT) is an FDA-approved minimally invasive medical treatment modality that utilizes light in the presence of oxygen to activate photosensitizing agents that are relatively selectively concentrated in abnormal or neoplastic cells resulting in cell death. Currently, PDT has been approved for clinical treatment in the United States, European Union, Canada, Russia and Japan. In the United States, US FDA approval has been given for the use of PDT in the treatment of Barrett’s esophagus, obstructing esophageal carcinoma and early and obstructing tracheobronchial carcinoma using the photosensitizer Photofrin; actinic keratosis using the photosensitizer Levulan (aminolevulinic acid); and macular degeneration using the photosensitizer BPD. In the EU, the above noted indications have been approved in addition to the treatment of early head and neck cancers and palliative treatment of head and neck cancer using the photosensitizer Foscan; and treatment of basal and squamous cell skin cancers using the photosensitizer Metvix.
The method of PDT involves the use of a photosensitizing agent that is relatively selectively concentrated in abnormal or neoplastic cells. Depending on the type of photosensitizer, it may be injected intravenously, ingested orally or applied topically. After application of the photosensitizer, the photosensitizer is relatively selectively retained by tumor cells so that after several hours to days, determined by the kinetics of the compound’s distribution, there is more sensitizer in the neoplastic tissue than in the normal tissue. The photosensitizer is then activated with a specific wavelength of light matching the absorption characteristics that are unique to that specific photosensitizer, usually using a laser. This results in tumor necrosis via several mechanisms including oxygen radical production as well as vascular shutdown to the tumor (1). Because there is less sensitizer in the adjacent normal tissue, only the neoplastic tissue necroses and the normal tissue are preserved. The advantage of PDT over the other conventional modalities of surgery, radiation and chemotherapy is that it is a minimally invasive treatment technique that lacks systemic toxicity yet results in selective tumor destruction with normal tissue preservation. This advantage is of particular importance for cancers of the oral cavity and larynx, where excessive tissue loss results in significant functional debilities that affect speech, swallowing and voice. In addition, as this is an entirely different process, the use of chemotherapy, ionizing radiation or surgery does not preclude the use of PDT. Also, unlike ionizing radiation, repeated applications of the photosensitizer and activating light treatments can be performed indefinitely.
Data are available for over 1500 patients treated with PDT using Photofrin, hematoporphyrin derivative (HPD), amino-levulinic acid (ALA) or Foscan for the treatment of head and neck cancers. These patients include a mixture of presentations including primary, recurrent and metastatic lesions. The predominant histology is squamous cell carcinoma, but other histologies treated include mucosal melanoma, Kaposi’s sarcoma, adenocarcinoma, metastatic breast carcinoma and adenoid cystic carcinoma. Fortunately in the last 2 years, the first multi-institutional Phase II–III clinical trials evaluating Foscan PDT treatment of head and neck cancers have been completed. These trials have demonstrated the efficacy of this minimally invasive therapy in the treatment of early orophayngeal primary and recurrent cancers as well as the palliative treatment of refractory head and neck cancers using Foscan PDT. The following is a retrospective review of the author’s 276 patients treated with Photofrin-based PDT for early head and neck cancers between 1990 and 2006.
Materials and Methods
The author’s clinical experience with PDT for the treatment of the head and neck spans 16 years. Two hundred seventy-six patients with focal Cis, T1, T2 and superficial T3 carcinomas of the oral cavity and larynx with N0 necks were treated with PDT from February 1990 to November 2006. All patients were treated according to specific protocols in accordance with FDA and local IRB approvals. Pretreatment evaluation included a history and physical examination, endoscopic examination with tumor mapping and biopsy, routine laboratory evaluation and photographic documentation. All treatments were performed using the photosensitizer Photofrin (Axcan Pharma, Montreal, Canada) as an off label use indication. The male-to-female ratio was 201:75, with an age range of 24–90 years.
Photofrin was injected intravenously at a dose of 2.0 mg kg−1 over a 5 min period as an outpatient procedure. Forty-eight hours after the injection, the patients underwent treatment with light from an Nd:Yag pumped-dye laser (Laserscope) at 630 nm wavelength. Light was delivered to the tissue bed with a 400 μm fused silica optical fiber (Laserguide, Inc., Buelton, CA). A microlens treatment was used for all tumors with a depth of less than 3 mm. These light treatments were performed at 50–75 J cm−2 and 150 mW cm−2 in the oral cavity, and 80 J cm−2 and 150 mW cm−2 in the larynx. For nonlaryngeal tumors greater than 3 mm in depth on clinical examination or T2 laryngeal tumors, cylindrical diffusers 0.5–2.5 cm in length were placed in the tumor bed using an 18 gauge catheter under local or general anesthesia. These light treatments were performed at 100 J cm−1 fiber length and 400 mW cm−1 fiber length. All treatments were performed on an outpatient basis under local or general anesthesia.
On completion of treatment, each patient received Decadron 10 mg intravenously for one dose to reduce tissue edema and was discharged on oral pain medications. All patients were instructed to avoid daylight for 30 days. Tumor response was evaluated at 1 week, 1 month and then monthly thereafter for 1 year and every 3 months thereafter. Multiple biopsy specimens of the treated area were obtained for most patients 1 month after treatment to evaluate a complete histopathologic response.
Results
One hundred fifteen patients with recurrent or primary carcinoma-in-situ (CIS), T1N0 and T2N0 laryngeal tumors were treated with PDT for cure. Three patients had recurrent CIS, 96 patients had T1N0 carcinomas of the true vocal cord of which 25 were radiation failures, and 16 patients had T2N0 carcinomas of the true vocal cord of which eight were radiation failures. All patients underwent a single microlens light treatment and most T2 tumors also underwent cylindrical diffuser implants into the paraglottic space. All treatments were performed under general anesthesia with standard laryngoscopy and all patients were discharged home on the same day of PDT treatment. All patients obtained a complete histopathologic response after a single light treatment. With follow-up for 201 months (mean 91 months) there were 10 recurrences for a 5 year cure rate of 91%. Importantly all the recurrences were salvaged by using either PDT, surgery or radiation for a total 5 year cure rate of 100%. In the entire treatment group there were no episodes of airway compromise and the degree of postoperative pain was minimal and easily controlled with oral analgesics. After treatment all patients developed an immediate breathy voice that persisted for 2–3 weeks. At 4–6 weeks after treatment, the quality of voice was universally much improved over the pretreatment state. In addition, videostroboscopy 6 weeks post-PDT treatment performed on 10 patients demonstrated a normal vocal cord mucosal fluid wave on the treated vocal cord.
One hundred thirteen patients with recurrent or primary CIS and T1N0 squamous cell carcinomas of the oral cavity were treated. Two patients had recurrent CIS and 111 patients had T1N0 lesions. All patients were treated with a microlens and if the tumors clinically were invasive greater than 3 mm, they were also treated with cylindrical diffuser implantation to distribute the light deeper into the tissues. The diffusers were spaced 1 cm apart from one another. All patients obtained a complete pathologic and clinical response after a single PDT treatment. With follow-up for 202 months (mean 90 months), there were six local recurrences within 8 months of PDT treatment. These were all salvaged with either repeat PDT treatment or surgical resection. Two patients with T1 tongue tumors developed regional lymph nodes within 3 months of PDT treatment and went on to conventional neck dissection and have remained free of disease for at least 5 years. Five year cure rate for these patients therefore remains at 100%. Unfortunately, there was one peri-PDT treatment death unrelated to PDT because of a drug overdose.
Forty-eight patients with superficial T2N0 and T3N0 squamous cell carcinomas of the oral cavity were treated. All of these patients had extensive areas of tumor involvement up to 7 cm in size. The maximal depth of the tumor, however, was clinically less than 1 cm. These patients were treated with a microlens and for those areas where there was clinical invasion greater than 3 mm, cylindrical diffusers of 0.5–1.0 cm were employed to distribute the 630 nm light deeper into the tissues. All patients obtained a complete clinical and pathologic response after a single PDT treatment. With follow-up for 128 months (mean 56 months), there were five recurrences, most of them at the edge of the PDT treatment field. These were all salvaged with either repeat PDT treatment or surgical resection. No patients developed regional lymph node involvement. Three year cure rate for these patients is 100%. Importantly, the post-PDT healing of these patients demonstrated normal mobile oral mucosa without scar formation and preservation of the patency of the submandibular and parotid salivary ducts. Histologic evaluation of the post-PDT healing process demonstrated preservation of the cellular collagen matrix with repopulation of the normal mucosal cells into the preserved collagen matrix resulting in normal mucosa and submucosa.
In the entire series of 276 patients only two patients sustained a significant sun-induced photosensitivity reaction with significant facial edema. This resolved with oral steroids in 5 days without sloughing of skin. In all patients the treated area demonstrated maximal necrosis by 7 days after light treatment, and there was complete healing by 4 weeks after treatment. The degree of treatment-related pain was quite variable with some patients having mild pain and others, usually those with extensive oral tumors, having severe pain. In all cases however, the pain was adequately controlled with oral analgesics. The pain was uniformly resolved within 2–3 weeks of treatment.
Discussion
Although this author has presented the results of Photofrin-based PDT for the treatment of head and neck cancers, it is important to recognize that other photosensitizers have been used and continue to be investigated for the treatment of head and neck cancers with very similar results.
Early stage head and neck cancer: Photofrin-HPD-based PDT
Patients with early stage cancers or early recurrences in the oral cavity and larynx (Cis, Tl, T2) tend to have an excellent response to PDT. Of 518 patients treated with Cis, T1 or T2 cancers of the oral cavity, larynx, pharynx and nasopharynx, 462 (89.1%) obtained a complete clinical response after one PDT treatment (Table 1). Laryngeal cancers, comprising 171 patients in this group, obtained a durable complete response rate of 89% with up to a 16 year follow-up.
| Study | Patients | Lesion and site | Drug, dose (mg kg−1) | Response, n | ||
|---|---|---|---|---|---|---|
| Complete | Partial | None | ||||
| Keller et al. (2) | 3 | T1 and T2, oral cavity | Photofrin, 1.5-2 | 3 | 0 | 0 |
| Feyh et al. (3,4) | 15 | T1 and T2, oral cavity | Photosan III | 13 | 2 | 0 |
| 12 | T1 and T2, larynx | Photosan III | 11 | 1 | 0 | |
| Wenig et al. (5) | 26 | T1 recurrent, various sites | Photofrin, 2 | 20 | 6 | 0 |
| Grossweiner et al. (6) | 9 | Early oral cavity and pharynx | Photofrin, 2 | 8 | 1 | 0 |
| Freche and DeCorbiere (7) | 32 | T1, larynx | HPD, 3 | 25 | 7 | 0 |
| Photofrin, 2 | ||||||
| Schweitzer (8,9) | 10 | T1, oral cavity | Photofrin, 2 | 8 | 2 | 0 |
| 10 | T1, larynx | 8 | 2 | 0 | ||
| Gluckman (10) | 13 | T1, oral cavity | Photofrin, 2 | 11 | 2 | 0 |
| 2 | T1, larynx | 2 | 0 | 2 | ||
| 8 | Cis, condemned mucosa | 7 | 1 | 0 | ||
| Grant et al. (11) | 12 | T1, oral cavity | Photofrin, 2 | 11 | 1 | 0 |
| Biel (12–15) | 115 | T1 and T2 larynx | Photofrin, 2 | 105 | 10 | 0 |
| 113 | T1 and T2 oral cavity | 107 | 6 | 0 | ||
| 48 | T2, T3 superficial | 43 | 5 | 0 | ||
| Zhao et al. (16) | 50 | Lip cancer | HPD, 3 | 50 | 0 | 0 |
| Kulapaditharom and Boonkitticharoen (18,19) | 41 | Oral and nasopharynx | Photofrin, 2 | 30 | 11 | 0 |
Keller et al. reported on three patients with T1 and T2 oral carcinomas treated with HPD, all of whom obtained a complete response without recurrence (2).
Feyh et al. treated 27 patients with Cis-T2 carcinomas of the oral cavity and larynx. Of 15 patients with oral cancers 13 obtained a complete response. One patient with recurrent disease occurred submucosally in the tongue. Of 12 patients with laryngeal cancers, 11 obtained a complete response (91%) (3,4).
Wenig et al. reported on 26 patients treated with early recurrent squamous cell carcinomas. Light delivery was at 75–125 J cm−2. A complete response was achieved in 20 of 26 (77%) patients treated with 6–51 months’ follow-up (5). Grossweiner et al. treated nine patients with early recurrent carcinomas of the oral cavity with light administration 24 h after intravenous Photofrin injection. Eight of nine (88%) patients had a complete response after one PDT treatment (6).
Freche and DeCorbiere treated 32 patients with T1 carcinomas of the true vocal cords treated with HPD or Photofrin. A complete response was achieved in 25 of 32 patients (78%), with 12–48 months’ follow-up. (7). Schweitzer reported on 20 patients with Tis-T2 carcinomas, 10 of the oral cavity and 10 of the larynx, treated with Photofrin and 50–150 J cm−2 laser light. Eight of ten (80%) patients with oral carcinoma and eight of ten (80%) patients with laryngeal carcinoma obtained a complete response (8,9).
Gluckman reported on 23 patients with early head and neck carcinomas (Cis, T1, T2) treated with Photofrin. Twenty of twenty-three (87%) patients obtained a complete response with an 8–53 month follow-up. Carcinomas of the oral cavity were particularly sensitive to PDT treatment (10).
Grant et al. reported on 12 patients with T1 carcinoma (field cancerization) of the oral cavity treated with Photofrin at 2 mg kg−1 and light administered 48 h after injection at 50–100 J cm−2 at 150mW cm−2. Ninety-two percent (11/12) obtained a complete response with up to 19 months’ follow-up (11).
Biel treated 276 patients with early head and neck squamous cell carcinomas. Of these, 115 were early laryngeal tumors (Tis, T1 and T2), 33 of which were radiation failures, treated with Photofrin 2 mg kg−1 using a microlens fiber at 80 J cm−2, 48 h after Photofrin injection. All but 10 patients (91%) obtained a durable complete response after a single PDT treatment (100% salvage) with follow-up for 201 months (mean 91 months) (12–15). In addition, 113 patients with early carcinomas (Tis, T1 and T2) of the oral cavity, nasal cavity and nasopharynx and 48 patients with superficial T2-T3 carcinomas of the oral cavity were treated. All obtained a complete response after a single PDT treatment. With follow-up of 6–202 months (mean 90 months), 106 of 113 (93.8%) patients with Tis-T2 carcinomas remained free of disease after a single PDT treatment (100% salvage) and 43 of 48 patients (89.5%) with superficial T2-T3 oral carcinomas remained free of disease after a single PDT treatment (100% salvage) with 6–28 months of follow-up. Two of these patients, however, recurred at the margins of the PDT treatment but were treated with limited laser resections of the recurrence and remain free of disease. Only one patient developed regional metastases 2 months post-PDT (12–15).
Zhao et al. treated 50 patients with lip cancer using HPD with a 100% cure rate (50/50) (16). In addition, they treated 31 patients with combined cobalt radiation therapy and HPD-PDT for various head and neck cancers. They demonstrated a 100% response rate and suggested that HPD-PDT may enhance the effects of radiotherapy when carried out 48 h after intravenous HPD injection (17).
Kulapaditharom and Boonkitticharoen treated 41 patients with precancerous and T1-T2 nasopharyngeal and oral carcinomas. They achieved a 91.67% complete response rate for T1 primary and recurrent tumors with a recurrence rate of 27.27% (mean follow-up 28.3 months). All T1 and T2 nasopharyngeal tumors responded completely (18,19).
Early stage head and neck cancer: Foscan (mTHPC)-mediated PDT
Second-generation photosensitizers have the potential to improve the effectiveness of PDT by providing for greater tumor selectivity and deeper light penetration into tissue with the use of longer wavelengths of activating light. In addition, side effects such as the length of skin photosensitivity are reduced.
Foscan (mTHPC, Biolitec, Germany) is a potent second-generation photosensitizer that is activated at 652 nm light. To date, this is the only photosensitizer that has been evaluated in multi-institutional trials for the treatment of head and neck cancers. The use of Foscan-mediated PDT by single investigators demonstrated the efficacy of this treatment for early oral and pharyngeal cancers (Table 2). Dilkes reported on 19 patients with T1 and T2 lesions of the oral cavity and pharynx using Foscan and 20 J cm−2 laser light. Some patients received multiple PDT treatments. Of the 19 patients treated, 90% obtained a documented complete response and 10 of 19 patients remained free of disease with follow-up of 6–100 months (20–22). Savary et al. treated four patients with Cis and T1 lesions of the oral cavity with a complete response (23). Fan et al. treated 19 patients with Cis-T4 carcinomas of the oral cavity. A single treatment with Foscan PDT was able to eradicate Cis-T2 lesions (24). Kubler et al. treated 25 patients with Tis-T2 lip cancers and reported a 96% cure rate at 3 months with two recurrences, one at 4 months and one at 18 months post-PDT (25). Dilkes et al. treated five patients with T1-2 laryngeal tumors with Foscan PDT. Only one of the five patients had no recurrence of disease (22).
| Study | Patients | Lesion and site | Drug | Response, n | ||
|---|---|---|---|---|---|---|
| Complete | Partial | None | ||||
| Grant et al. (29) | 4 | Oral cavity | ALA | 3 | 1 | 0 |
| Fan et al. (30) | 18 | Dysplasia and oral cavity | ALA | 14 | 4 | 0 |
| Sieron et al. (31) | 5 | Larynx and hypopharynx | ALA | 0 | 5 | 0 |
| Kubler et al. (32) | 12 | Oral leukoplakia | ALA | 5 | 4 | 3 |
| Dilkes et al. (22) | 19 | T1, T2, oral cavity and pharynx | Foscan | 10 | 9 | 0 |
| Savary et al. (23) | 4 | Tis, T1 and oral cavity | Foscan | 4 | 0 | 0 |
| Fan et al. (24) | 6 | Tis, T1, T2 and oral cavity | Foscan | 6 | 0 | 0 |
| Kubler et al. (25) | 25 | Tis-T2 lip cancer | Foscan | 22 | 3 | 0 |
| Hopper et al. (26) | 114 | Tis-T2, oral cavity | Foscan | 97 | 17 | 0 |
| Cooper et al. (27) | 25 | T1, T2, oral cavity and pharynx | Foscan | 25 | 4 | 0 |
Two large multi-institutional Phase II trials have recently been completed evaluating the efficacy of Foscan PDT in the treatment of primary oropharyngeal cancers and recurrent and second primary oral carcinomas. The trial evaluating Foscan PDT for the treatment of primary oropharyngeal cancers involved 114 patients with Cis-T2 oropharyngeal cancers. These patients received Foscan 0.15 mg kg−1 intravenously and underwent light activation at 652 nm light at 20 J cm−2 at 100mW cm−2. Up to three light treatments were allowed under the protocol. A complete response rate of 85% (97/114) was achieved at completion of therapy. With 2 year follow-up there was a 77% complete response rate at 2 years with disease-free survival of 89% and 75% at 1 and 2 years after PDT treatment, respectively. This trial demonstrated complete durable response rates that are equivalent to those obtained with conventional therapies (26,27). The second trial evaluated Foscan PDT in 96 patients with recurrent or second primary carcinomas in the oral cavity. These patients demonstrated a 50% histologically confirmed complete response rate with a 79% survival rate at 1 year (28). Further follow-up is ongoing. Adverse events in these two trials consisted of pain at the treatment site, easily treated with oral analgesics and narcotics, and residual skin photosensitivity which lasted up to 2 weeks post-Foscan injection. Both of these events were expected and manageable. These two clinical trials, the first multi-institutional PDT trials to be performed in the treatment of head and neck cancers, demonstrated that Foscan PDT results in cure rates that are equivalent to conventional therapy with less treatment-associated morbidity, especially systemic toxicities (26–28).
Early stage head and neck cancer: ALA-mediated PDT
Grant et al. treated four patients with oral carcinoma following the oral administration of ALA (29). 630 nm light of 50–100 J cm−2 was delivered 6 h after oral ingestion of ALA. All patients sustained tumor necrosis but normal surrounding tissue also necrosed, indicating no tumor selectivity. Fan et al. treated 18 patients with dysplasia and malignant lesions of the oral cavity with ALA. Only two of six patients with carcinomas obtained a complete response (30). Sieron et al. treated five patients with larynx and hypopharynx carcinomas using ALA-PDT. All five patients only achieved a partial response (31). Transient liver function abnormalities occurred in all patients. Because of the limited depth of accumulation of ALA and the limited penetration of 635 nm light, tumors of greater than 2 mm depth are not consistently cured (29–31).
Kubler et al. treated 12 patients with oral leukoplakia with 20% ALA cream and 630 nm light. Five patients demonstrated a complete response, four patients a partial response and three patients no response. One patient with a partial response was retreated resulting in a complete response (32).
The present studies indicate the effectiveness of PDT in the treatment of specific anatomic areas in the head and neck. In particular, Cis and T1 carcinomas of the larynx appear to be particularly effectively treated with PDT. A literature review of control rates of various treatments for Cis of the vocal cord revealed the following: Laser excision (104 patients) 20% initial failure rate requiring further therapy, 1% larynx lost; Vocal cord stripping (235 patients) 34% failure rate, 12% larynx lost; Radiotherapy (481 patients) 16% failure rate, 7% larynx lost (33). The literature demonstrated that surgical techniques to treat Cis are best limited to those patients where the Cis does not involve the anterior commissure or the bilateral vocal cords. The present clinical series demonstrates the efficacy of Photofrin-mediated PDT as a curative treatment for Cis, T1 (85–92%) and T2 (72%) squamous cell carcinomas of the larynx. PDT for laryngeal carcinomas results in no glottic scarring as compared to conventional laser or surgical excision or vocal cord stripping. For recurrent carcinomas of the larynx that have failed conventional radiation therapy, PDT allows excellent voice preservation and may eliminate the need for partial or total laryngectomy. Also, PDT can be repeated without additional functional laryngeal compromise that can occur from repeated conventional laser surgery or cordectomy. Importantly, PDT treatment of primary T1 and T2 laryngeal carcinomas reserves radiation therapy for treatment of recurrences or of second head and neck primaries that may occur in these high-risk patients.
The side effects of PDT treatment of laryngeal carcinomas are quite minimal as compared to conventional radiotherapy or surgery. PDT treatment is performed as a single outpatient procedure as compared to 6–7 weeks of radiotherapy or the hospitalization associated with a partial or total laryngectomy. The photosensitivity of Photofrin is a temporary inconvenience not associated with systemic toxicity and is minimized by patient education and temporary changes in daily outdoor activities. The photosensitivity does however last for approximately 4 weeks.
Photodynamic therapy for treatment of T1 and T2 laryngeal carcinomas in the present series has cure rates that are comparable to, if not better than, that of conventional therapies with less morbidity of treatment. PDT should be considered as a reasonable option for the treatment of primary and recurrent Cis, T1 and T2 squamous cell carcinomas of the larynx.
Photodynamic therapy is also effective in the treatment of Cis and T1 primary and recurrent carcinomas of the oral cavity including the palate, floor of the mouth, nasopharynx and posterior pharyngeal walls. These results have been demonstrated in the multi-institutional Phase II Foscan PDT clinical trials and in single investigator Photofrin trials in which cure rates were comparable to those of conventional therapy with less morbidity.
Conclusion
Photodynamic therapy is an excellent modality for the treatment of primary and recurrent early and superficial carcinomas of the oral cavity and larynx. In order to assess further the effectiveness of this treatment on various areas within the head and neck, further standardized controlled studies are necessary. In addition, the development of new, more tumor-specific photosensitizing agents and light delivery systems will improve the effectiveness of this therapy. The present studies indicate that PDT is an effective primary or alternative treatment modality for carcinomas in the oral cavity and larynx.
