Contraindications

\1.\ Porphyria or porphyrins allergy

\2.\ Main vessel in ltration (high risk of bleeding)

\3.\ Tracheoesophageal or bronchopleural stula \4.\ In situ carcinoma with lymph node

involvement

\5.\ Extrinsic compression or submucosal in ltration

\6.\ Severe airway obstruction (more than 50%), compromise of the main carina or patients with pneumonectomy, acute airway obstruction. PDT causes infammatory reactions, and airway edema worsening the airway obstruction that can go from partial to complete, risking respiratory failure and death, so a fast-acting treatment, such as laser therapy, should be employed instead.

\7.\ Leukocyte count less than 2000/mm3, thrombocyte count less than 100,000/mm3, or prothrombin time upper than 1.5 normal limit.

Applications ofPDT

Rationale for Use in Early-Stage Lung Cancer

The average survival of patients with lung cancer is about 13% [64]. One third of these tumors are non-small cell carcinomas. At the moment of diagnosis, approximately one third of patients are stage I or II. Surgery is the standard treatment for patients in stage I, II, or IIIA. Survival for stage I patients has been established from 55 to 75%. For the subgroup of patients with T1N0 disease, survival at 5 years is around 60–82% [65, 66].

In one series, recurrences were about 27%, 60% of them during the rst 2 years after resection. Recurrence in the same lung or in the stump area was more common in squamous cell carcinoma. The incidence of a second primary was 34% and was constituted by synchronous (12%) and metachronous (88%) tumors. Therefore, despite surgery, patients with early stage lung cancer have a high rate of tumor recurrence and a high probability of developing a second tumor [67].

Radiation therapy is the standard second-line treatment for patients who are inoperable, with a range of complete response from 50 to 70% and a median survival of 22–48 months for stage I disease [68]. The 5-year survival for patients with T1 tumors who are treated with external radiation varies from 10 to 40% [69]. The best results observed in surgical patients may be due to the fact that patients are less compromised and the extent of the condition is more carefully staged. Patients who are inoperable due to a poor pulmonary reserve will suffer further deterioration after radiation, due to secondary radiation pneumonitis and/or brosis. Patients who received surgery or maximum radiation doses cannot be retreated in most cases, which is a great disadvantage in a disease with a high recurrence rate.

Therefore, there is a need for therapeutic modalities that can be applied at multiple occasions, if necessary, and do not exclude the use of other methods in case of need. So far, treatment modalities that produce local damage to the tumor include brachytherapy, cryotherapy, electrocoagulation, laser, and photodynamic therapy. They all, however, are limited to centrally located tumors within the endoscopic view and have a penetration power of millime-

ters. While most of these treatments cause nonspeci c tumor damage, PDT causes selective death of cancer cells with subsequent necrosis of the tumor, without injury of the adjacent healthy tissue.

The curative effect of PDT in early stage and super cial tumors has been studied extensively and has been documented in several studies in phase II and III. Since 1980, more than 800 patients have been treated. Success rate oscillates from 80 to 100% in short-term follow-up and between 50 and 60% in longterm follow-up. The main and infuencing factors for survival are tumor size and penetration in depth. It also depends on the ability to visualize the full extent of the tumor during bronchoscopy, and its complete irradiation with laser light. Evaluating the location and tumor size is therefore very important. The use of bronchoscopy and high-­resolution computed tomography may improve staging and response assessment. Ultrasound has also been used to estimate the depth of the tumor in patients with roentgenographically occult cancer and determine the presence of nodal compromise.

One of the reasons for long-term photodynamic therapy failure is the high incidence of a second primary tumor. Therefore, patients must be followed with regular bronchoscopies, to control local recurrence and to exclude the presence of metachronous lesions, which can be treated with PDT if present.

Complete and prolonged remissions that have been published are promising, but they do not reach the success of surgery (more than 80%). However, it is essential to consider that the term “early cancer” is generic and includes different histological types, with different biological properties and prognosis.

Carcinoma “in situ” is an indication of PDTrst-line treatment. Microinvasive carcinoma, however, is an optional indication to be only used in high risk or inoperable patients. Invasive carcinoma is an indication only in a highly selected group of inoperable patients. Severe dysplasia is not a formal indication of this treatment so far.

PDT Results in Early-Stage Lung

Cancer

The most useful application of PDT is the management of early-stage lung cancer (ESLC) for a curative intent minimizing the loss of lung tissue. Conventional treatment for patients with ESLC is surgery, and regardless of lesion size, approximately 70% of them require lobectomy. The remaining 30% will require bi-lobectomy or pneumonectomy [70]. Furthermore, a majority of these patients with lung cancer had a diminished pulmonary function. In addition, the cumulative risk of a second primary cancer in patients with non-small cell lung cancer ranges from 20 to 30% within 6–8 years after initial treatment. Patients successfully treated for small cell lung cancer develop a second primary cancer at an average rate of approximately 6% per year, which increases from 2 to more than 10% per patient per year 10 years after the initial treatment [71, 72].

In Japan, Hayata and colleagues have studied extensively PDT in ESLC, showing that approximately 90% of super cial tumors less than 1 cm of diameter can be completely eradicated with PDT. Patients with nodular tumors less than 0.5 cm diameter showed the same results [73].

Of 81 patients who had complete response to treatment, only 2 died of primary disease during the follow-up period. Fifteen patients were alive and free from disease at 5 years, and three showed similar results at 10 years of follow-up. Complete response (CR) rate was 71%.

PDT is not useful if there is nodal involvement, so that it is very important to verify absence of nodular compromise before starting treatment. Endobronchial ultrasound has been presented as a useful and complementary method to determine the depth of invasion of small tumors and to detect nodular invasion.

Cortese and colleagues reported a group of 21 patients with ESLC treated with PDT Fifty-two percent of them had a CR over 1 year. A total of nine patients, who were followed for an average of 68 months, were able to avoid surgery. Ten patients treated with PDT required a second time

surgery, and in 30% of them, N1 nodal staging was found. It is dif cult to know if nodal involvement in that series was due to a surgery delay while they were treated with PDT, or it was present before treatment. In any case, it shows the need to aggressively search for nodal involvement before PDT indication.

Authors concluded that 43% of patients (range 22–66.6%) who are candidates for treatment with PDT could be treated without surgery [74].

Therefore, PDT offers a better quality of life particularly in patients with multiple tumors or elderly ones [75].

Table 14.4 modi ed by Sutedja et al. summarizes the results of early lung cancer treated by PDT with curative intent [71].

Regarding tumor extension, several studies demonstrated that tumor length on the bronchial surface is strongly related to outcome. Kato and colleagues reported complete remission (CR) in 84.8% of patients using Photofrin® for central early-stage lung cancer. Outcome varied according to size of the treated lesions. Four groups were de ned as follows: <0.5; 0.5–0.9; 1.0–2.0; and >2.0 cm. The CR rates of the rst two groups were 94.6% and 93.5%, respectively, while 80 and 44.1% were reported for lesions from 1.0 to 2.0 cm, and for lesions >2.0 cm, respectively [72].

Usuda et al. reported results of 91 consecutive central early-stage lung cancer (CELC) lesions treated with NPe6 at Tokyo Medical University between June 2004 and December 2008. CR was obtained in 93.4% of patients. Of the 91 lesions examined in this study, 70 had a diameter of ≤1.0 cm and the rest of the 21 cancer lesions were>1.0 cm in size. The CR rate of CELC ≤1.0 cm in diameter was 94% and for those >1.0 cm in diameter 90.4%, respectively [81].

Those studies suggest that central early-stage lung cancer lesions less than 1 cm in diameter showed a favorable cure rate using PDT.

Regarding treatment of patients with roentgenographically occult carcinoma, surgical resection is the historical indication, but it has signi cant morbidity. PDT is a minimally invasive option associated with less side effects and morbidity than surgery. Most often, those patients with roentgenographically occult carcinoma present a centrally located early-stage squamous cell carcinoma. Endo et al. [82] treated 48 patients with a follow-up of 12 years. They were all surgical candidates presenting with occult bronchogenic squamous cell tumors of less than 10 mm in length. Ninety-four percent of them have a complete response with a survival rate of 81% at 5 years and 71% at 10 years.

Fujimura and colleagues consider PDT as arst-line treatment modality for patients with roentgenographically occult carcinoma of the lung, bronchoscopically visible and less than 1 cm in length, without extra cartilaginous invasion or lymphatic node involvement [83].

Finally, in treating patients, careful monitoring is necessary. Recurrences following PDT can be treated with surgery or radiation therapy.

About synchronous bronchogenic tumors, they present mainly in a central location and they are more often squamous cell tumors [84].

In these cases, PDT should be considered for those patients who are medically or surgically inoperable. Also, it proved bene ts in properly selected patients who can be surgical candidates with a tumor less than 1 cm in diameter. Sokolov and colleagues reported 104 patients with synchronous lung primary tumors treated with PDT that had a signi cant correlation between tumor size and regression. A complete regression was observed in tumors less than 1 cm in diameter [85].

Application of PDT in Advanced

Lung Cancer

Rationale

A review of lung cancer death showed that 57% of patients with nonsurgical disease die of local complications such as asphyxia, hemoptysis, pneumonia, and empyema [86–88].

Other studies show that 36% die from the same causes, whether or not they had surgery. Similar causes of death were found in 58% of patients with surgery versus 83% without surgery [89]. Considering that at most, 20–30% of patients with bronchogenic carcinoma are surgical candidates at the time of diagnosis, it can be assumed that the majority of inoperable patients will require palliative treatment at some point during the course of their disease.

However, the use of PDT as palliation in inoperable obstructive cancer patients should be evaluated in the context of what can be obtained with conventional treatment. By applying Nd-YAG laser, coagulation and vaporization of the tumor tissue is achieved. Laser therapy is usually performed under general anesthesia and is highly effective for debulking airways, especially in centrally located tumors. Massive hemorrhage, respiratory failure, or cardiac arrests are possible severe complications of laser photoresection, but their incidence is quite low (1.5%). Patients can also experience a minor complication in the order of 0.5% of cases.

PDT has proven to be an effective palliative treatment. The rst treatment with PDT was performed in the 1980s, and since then the number of patients who have bene ted from it is increasing day by day. The best results are obtained when the tumor is in early stage (carcinoma “in situ”) as shown by several publications and discussed previously [90–94]. When results are depicted according to the stage, tumors in stage I responded with complete response in 80% of cases. Patients who presented in stages II, III, and IV did not obtain complete response except in one patient in 24 cases. Some studies have reported a longer duration response and lower risk of local recurrence when PDT is applied.

Photosensitivity is still a problem. However, it is expected that the second generation of photosensitizers will decrease it signi cantly. The photosensitizing agent used in most clinical trials is Photofrin®, which produces photosensitivity for approximately 6 weeks since the skin, liver, kidneys, and spleen retain the photosensitizer longer than the rest of the organs. As a consequence, skin protection is essential, and patients must avoid sunlight for a period of 4–6 weeks; otherwise severe retinal and skin damage can occur [95, 96]. No bene t was found in sunscreen creams for the skin, so its use is not recommended.

PDT vs. Nd-YAG Laser Therapy

for Advanced-Stage Non-small Cell Lung Cancer

PDT as a palliation method was compared to Nd-YAG laser, which has been used for palliation since 1970s. Photoresection using Nd-YAG laser is considered, by many experts, as the “gold standard” for central airway partial or complete tumor obstruction which is due to nonsurgical malignant primary or metastatic disease. There are enough publications supporting this statement [97, 98].

However, PDT is a useful palliative method with some advantages over laser therapy, particularly in peripheral tumor localization. In fact, PDT produces more complete tumor destruction, and a better survival rate has been objecti ed as shown in many studies comparing laser versus photodynamic therapy.

In a 1998 prospective randomized study comparing PDT versus Nd-YAG laser in partial obstruction of lung cancer, data of 16 centers in Europe and 20 in the USA and Canada were compared. In the European study, only 40% of patients had prior treatment, while in the American group, all patients had some type of treatment. Results showed that tumor response was similar for the 2 therapies in the rst week, but within a month, 61% and 42% of patients treated with PDT in Europe and the USA/Canada, respectively, had a response, while patients treated with NdYAG, 36% and 19%, respectively, were responding in the 2 work groups

(Europe and USA/Canada). Twelve percent and 6% of patients treated with PDT versus 3% and 5% of patients treated with Nd-YAG experienced complete response, with biopsy proven in Europe and the USA/Canada, respectively. The improvement in dyspnea and cough was higher in patients treated with PDT in Europe and was similar in both treatments in the USA/Canada group. The study conclusion was that PDT is superior to the Nd-YAG laser to improve dyspnea, cough, and hemoptysis. The incidence of adverse events was similar in both groups, and 20% of patients treated with PDT showed photosensitivity reactions. Those events were due to failure to comply with the precautions suggested [99].

Our group participated in that study, and the above results were con rmed in a most recent publication (Table 14.5). We found patients had variable degrees of central airway obstruction due to inoperable non-small cell lung cancer and were prospectively randomized to PDT or Nd-YAG laser. Fourteen of these patients received Photofrin® therapy, 17 conventional laser therapy with Nd:YAG laser. The success of recanalization was veri ed by control bronchoscopy 1 week and

Table 14.5  PDT versus Nd-Yag laser in advanced NSCLC

Tumor response at 1 week and 1 month. Treatment response was similar in both groups. At 1-week follow-up examination, response rate was 43% in the PDT group versus 53% in the NdYAG laser resection group; the corresponding gures at 1 month were 38.5% versus 23.5% [100], Diaz-Jimenez et al. Eur Respir J 1999; 14 :800-5 a No tumor on bronchoscopy and biopsy

b No tumor on bronchoscopy, evidence of malignancy in biopsy samples

c Unable to undergo bronchoscopy or loss of follow-up. PDT photodynamic therapy, Nd-YAG Neodymium Yttrium Aluminium Garnet

4 weeks after treatment. After 1 week, success rates were 43% in the PDT group and 53% in the Nd:YAG laser group. However, the endoscopic control after 1 month showed that in the PDT group, 38.5% of the open bronchi were still patent, while in the Nd:YAG group the rst positive result was reduced from 53% to 23.5%. Survival time was also signi cantly longer in the PDT arm. Palliation of symptoms as for Karnofsky index was similar in both groups. PDT group had a higher incidence of adverse effects, and these were more severe than in the group treated with Nd-YAG laser. Photosensitivity was the most important one [100].

In a series of 258 patients with symptomatic advanced lung cancer 81 patients with PDT and 177 with Nd-Yag laser were treated at Tokyo Medical College. The overall treatment effectiveness was 75% with PDT and 81% with Laser. Nd:YAG laser was more effective for tumors in the trachea or main bronchi (93% vs. 73%); however, PDT was a little bit better for tumors in lobar or segmental bronchi (73% vs. 76%) [52].

Another study from 1997 shows a 14-year prospective experience in 175 patients treated with PDT for squamous cell tumor, endobronchial adenocarcinoma, and tracheal adenocarcinoma [54]. It included patients that had failed or refused conventional treatment or were ineligible for it. Results showed that survival was affected mainly by the stage of cancer, are presented in Table 14.6 (modi ed from McCaughan and Williams) [54]. Analysis of the period of time after treatment until re-obstruction in patients treated by Nd-YAG laser or PDT showed that immediate results were better in patients treated by Nd-YAG laser bronchoscopy. Airway re-­ obstruction was faster in patients treated by Nd-YAG laser than PDT (2 weeks with Nd-YAG vs. 4 weeks with PDT).

A randomized study conducted in the USA, which compared the ef cacy and safety of PDT versus Nd-YAG laser, showed that both treatments are equally effective in relieving tumor endobronchial obstruction. The time to treatment failure was slightly longer in the group treated with PDT, and the risk of local recurrence after PDT was lower than after Nd-YAG laser treat-