Advanced-stage and metastatic non-small cell lung cancer are associated with a grave prognosis, with a median survival of less than one year. Patients with advanced-stage lung cancer are often debilitated and have significant morbidity and decreased quality of life (9)
. Palliative care, therefore, plays a prominent role in the care and management of these patients. The utility of palliative care in improving the quality of life for patients with advanced non-small cell lung cancer is now widely recognized. Several studies have reported an association between depressed mood and/or poor quality of life and shorter survival among patients with metastatic non-small cell lung cancer (11)
For patients with locally advanced or metastatic non-small cell lung cancer, PDT has been most commonly utilized to palliate symptoms. Endobronchial PDT can decrease airway obstruction and allow for improved respiratory function and quality of life (14)
. PDT can also be used to palliative patients with uncontrollable life-threatening hemoptysis. In this manner, PDT can cause thrombosis and control small vessel bleeding from a variety of locations and etiologies (15)
. One of the earlier reports on PDT for palliation for lung cancer describes its utilization to treat 15 consecutive patients with advanced squamous bronchogenic carcinomas in London, in which all tumors responded and symptomatic relief was achieved (16)
. PDT was also used to successfully palliate symptoms among seven patients with thoracic metastases and three primary lung cancers at the National Cancer Institute (17)
It should be noted, however, that early studies reporting on PDT to treat advanced lung cancer found this modality to be less successful in controlling disease than when used for other primary cancer sites. Of the variety of tumors treated with PDT in Beijing from 1982-1985, the complete response rate for lung cancer lesions (n=54) was significantly lower than the remaining 486 lesions (17% vs.
45%). The overall response rate for patients with lung cancer, however, was 89% (18)
. Investigators from the University of California, Irvine Medical Center similarly found five lung cancer patients to be less likely to achieve complete responses when compared to 72 patients with head and neck and breast malignancies treated with PDT between 1981-1983 (19)
Additionally, among the 26 patients with inoperable non-small cell lung cancer treated with PDT at the Netherlands Cancer Institute, 10 of 11 patients with stage I disease achieved a complete response. However, among the 15 patients with stage III disease, all of whom had previously received external beam radiation therapy, brachytherapy, or Nd:YAG laser therapy, 11 patients had a partial response and four had tumor progression and died of pulmonary hemorrhages within six months of receiving PDT (20)
. PDT was also administered at the National Cancer Center Hospital in Japan to 28 patients with early lung cancer and 38 patients with advanced lung cancer having 69 unresectable malignant lesions of the trachea and bronchus. Patients were not suitable for radical treatment with chemotherapy or radiation therapy. Most patients achieve a complete response (13%), partial response (64%), or tumor regression (19%), whereas disease progression was only seen in 4% (21)
Despite these difficulties, several studies have demonstrated the ability of PDT to successfully palliate patients with symptomatic locally-advanced non-small cell lung cancer. Among 10 patients with surgically unresectable advanced endobronchial obstructing non-small cell lung cancer treated with PDT by Northwestern University Medical School investigators from 1985-1989, PDT reduced pulmonary obstruction from 86% +/-2% to 57% +/-3%, and all patients had a decrease in symptoms (22)
. A study in the United Kingdom prospectively evaluated PDT as palliation for 100 patients with stage IIIa-IV advanced inoperable bronchogenic carcinoma with endobronchial luminal obstruction, of which 90% had non-small cell lung cancer and 82% had previously received chemotherapy or radiation therapy. The mean endoluminal obstruction fell from 85.8% to 17.5% following PDT, with similar improvements in mean forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). The cohort achieved a 9-month mean survival and had a 19% 2-year overall survival (23)
. Russian investigators also demonstrated that PDT reduced bronchial obstruction among patients with stage IIIb-IV disease in 75% of cases (9/12) and achieved a 100% complete response rate for early-stage cancers (8/8), although two patients developed recurrent disease within 3 months of PDT (24)
When University of California, Irvine investigators reviewed their first 10 patients with stage III-IV obstructive inoperable non-small cell lung cancer with hemoptysis, dyspnea, and airway obstruction treated with PDT, they found all 10 patients had a response to therapy and reduction in airway obstruction, and seven patients had resolution of acute hemoptysis (25)
. At the University of Alabama Hospital, 133 symptomatic patients were treated with PDT for endobronchial lung lesions of varying histologies, the majority of which were non-small cell lung cancer (n=89). PDT allowed for significant improvements in dyspnea in 74% of patients as assessed by the Modified Medical Research Council Dyspnea Scale (26)
PDT may also improve the efficacy of surgery or allow for surgical resection among patients with locally-advanced non-small cell lung cancer. Based on the 191 patients treated by Russian investigators with endotracheobronchial surgeries, including 153 patients with advanced non-small cell lung cancer causing respiratory obstruction, the addition of PDT to surgery may improve patient outcomes when compared with surgery alone (27)
. PDT has also been successfully employed as a means to reduce the extent of resection by allowing patients with non-small cell lung cancer who were initially planned to undergo pneumonectomy the ability to undergo lobectomy (28)
, or to convert originally inoperable patients to surgical candidates (29)
. Of the 26 patients with various stages of non-small cell lung cancer that received preoperative PDT at Tokyo Medical University Hospital to reduce the extent of resection or convert inoperable disease to operable status, surgical goals were achieved in 85% of patients treated. Four of five originally inoperable patients were converted to resectable and 18 of 21 patients who were originally candidates only for pneumonectomy were able to undergo lobectomy (29)
As PDT is based upon a photochemical reaction that is limited by the availability of molecular oxygen in the target tissue, 30 patients in Austria with inoperable non-small cell bronchogenic carcinoma and endobronchial stenosis were enrolled in a prospective pilot study from 1997-1999 assessing the combination of PDT with hyperbaric oxygen. Following PDT, without any therapy-related complications, patients reported significant improvements in dyspnea, hemoptysis, and poststenotic pneumonia (all P<0.05), and they had reductions in tumor stenosis (P<0.05) and improvements in performance status (P<0.05) (30)
As with malignant pleural mesothelioma, PDT may be utilized as part of multi-modality management for patients with non-small cell lung cancer with pleural spread. A phase II trial enrolling 22 patients with pleural spread and clinical T4 non-small cell lung cancer was conducted at the University of Pennsylvania. Patients underwent surgery with complete (n=17) or partial tumor debulking (n=3), followed by hemithoracic pleural PDT (n=20) or PDT alone (n=2). The rate of 6-month local control for the cohort was 73.3% and the median overall survival was 21.7 months, compared with 6-9 months for similar patients based on historical controls (31)
Summary: Patients with advanced-stage and metastatic non-small cell lung cancer have a grave prognosis and often require palliative interventions for symptomatic management. Although these patients are less likely to achieve a complete response to therapy than those with early-stage bronchogenic carcinomas, tumor response rates to PDT for patients with advanced bronchogenic carcinomas are still high and PDT is effective in palliating this patient population. PDT can reduce endobronchial luminal obstruction and tumor stenosis, allowing for improvements in patient dyspnea and pulmonary function. PDT can also resolve acute hemoptysis and poststenotic pneumonia and improve patient performance status. Furthermore, when used in the neoadjuvant setting, PDT can increase operability or reduce the extent of operation required. With limited available data, PDT also appears to be an effective component of multi-modality therapy for patients with locally advanced disease and may prolong survival for patients with non-small cell lung cancer with pleural spread when included as a component of multi-modality therapy.
PDT vs. Nd:YAG Laser Therapy for Advanced-stage Non-small Cell Lung Cancer
Patients with non-small cell lung cancer with symptomatic central airway obstruction often require palliative intervention, particularly for life-threatening obstruction or bleeding. Endobronchial treatment is typically associated with a rapid relief of symptoms and limited side effects. Central airway obstruction may be endoluminal, extraluminal, or infiltrating, and treatment should be tailored to the type of obstruction identified. Endoluminal obstruction is amenable to treatment with external beam radiation therapy, PDT, laser therapy, or brachytherapy (32)
. Treatment recommendations for extraluminal obstructions and detailed discussions of radiation therapy and laser therapy are beyond the scope of this review.
Nd: YAG laser therapy has historically been the most widely utilized modality to achieve tumor ablation within the tracheobronchial tree. As PDT may offer a safer and easier to perform alternative treatment (34)
, thermal ablation has been compared to PDT in an attempt to identify the optimal treatment modality for patients with obstructing bronchogenic carcinomas. One of the earliest reports comparing PDT with Nd:YAG laser therapy for palliation of patients with symptomatic non-small cell lung cancer was a retrospective study performed by Bulgarian investigators. They reported that a complete response was achieved in 58% of the 12 patients with central bronchial carcinoma patients treated with PDT, compared with 42% of 12 similar patients treated with Nd:YAG laser therapy (35)
Of the 258 advanced lung carcinoma lesions causing endobronchial stenosis or obstruction treated with PDT (n=81) or Nd:YAG laser treatment (n=177) at Tokyo Medical University in the 1980's and 1990's, the overall treatment effectiveness was 75% with PDT and 81% with Nd:YAG laser. Nd:YAG laser was somewhat more effective for tumors in the trachea or main bronchi (93% vs.
73%) but not for tumors in lobar or segmental bronchi (73% vs.
76%). PDT, however, had an improved safety profile. No major complications occurred in patients receiving PDT, whereas Nd:YAG resulted in massive bleeding in 6%, perforations in 3%, and a procedural mortality rate of 1.7% (36)
. In contrast, University of Louisville School of Medicine investigators retrospectively compared treatment side effect profiles for 102 patients with bronchial obstruction treated from 1988-1999 with PDT (n=19) or Nd:YAG laser therapy (n=83) and found no differences in morbidity or mortality rates between the groups (34)
In a retrospective review of 75 patients with obstructing primary lung cancer with airway obstruction or hemoptysis who were not surgical candidates treated from 1994-2002 at Allegheny General Hospital, no differences in patient or tumor characteristics were found between patients treating with varying therapeutic modalities or combinations of modalities that included Nd:YAG laser therapy, PDT, stenting, and endoluminal brachytherapy. The type of modality used in patients receiving a single type of intervention had no impact on survival. When compared with patients treated with a single type of intervention, patients receiving multiple treatment modalities had similar 1-year (50% vs.
51%) but significantly improved 3-year (22% vs.
2%, P=0.04) cumulative survival rates without increased complication rates (37)
Spanish investigators performed a prospective randomized controlled trial comparing PDT (n=14) to Nd-YAG laser therapy (n=17) in 31 patients with partial or complete tracheobronchial obstruction due to inoperable non-small cell lung cancer. Although patients in both groups experienced symptomatic relief after treatment (P=0.003), patients receiving PDT experienced a significantly longer time until treatment failure (P=0.03) and longer median survival (P=0.007) (38)
A recent systematic review was conducted to evaluate the clinical effectiveness and safety of PDT in the treatment of a variety of cancers and precancerous conditions. Among the 88 trials reported in 141 publications that were analyzed, only seven trials of 329 patients investigated PDT for lung cancer. Only five of these trials were published, and no trials were more recent than 2002. Despite this, the authors concluded that two trials suggested that PDT plus radiation therapy may be more effective than radiation therapy alone in the palliative treatment of non-small cell lung cancer. However, the authors concluded that three trials do not answer if PDT is superior, equivalent, or inferior to Nd:YAG (39)
Summary: With limited comparative data available, PDT and Nd:YAG laser therapy appear to be equally effective in relieving intraluminal obstruction by tumor and palliating patient symptoms. Although Nd:YAG therapy does not result in subsequent photosensitivity, PDT is perhaps easier to perform, does not require general anesthesia, and may have a somewhat better safety profile. PDT may allow for a longer time to treatment failure. The use of each modality should be tailed to the clinical situation and may be dependent on practitioner preference and experience. The combined use of these modalities or the use of each modality in conjunction with another local therapy, such as external beam radiation therapy or endobronchial brachytherapy, may allow for improved local control or a longer duration of symptomatic control at the expense of increased treatment toxicity.
PDT in Combination with Radiation Therapy, Chemotherapy for Advanced-stage Non-small Cell Lung Cancer
External beam radiation therapy and endobronchial brachytherapy are two of the most established and effective palliative treatment modalities for patients with central obstruction from non-small cell lung cancer. The role of brachytherapy in this setting may optimally be reserved for patients who have failed a prior course of external beam radiation therapy (33)
. The addition of external beam radiation therapy to endobronchial brachytherapy can, in rare cases, can be associated with potentially fatal massive hemoptysis, formation of tracheoesophageal fistulas, radiation-induced bronchitis, bronchial stenosis, and bronchospasms (40)
. The administration of PDT following external beam radiation therapy may have a more favorable toxicity profile than the administration of endobronchial brachytherapy and may be a viable treatment option as part of multi-modality therapy for patients with symptomatic obstructive non-small cell lung cancer.
Although very limited in patient numbers (n=11), Vancouver investigators completed a randomized trial to determine if PDT improves outcomes when combined with external beam radiation therapy to 30 Gy in 10 fractions over two weeks for patients with inoperable bronchogenic non-small cell carcinoma obstructing a central airway. All patients achieved symptomatic improvement and objective evidence of tumor regression at four weeks following therapy. However, at longer follow-up, based on post-treatment spirometry, ventilation-perfusion lung scans, CT scans, bronchoscopies, and quality of life scores, the addition of PDT prior to radiation therapy provided significantly improved and more durable local control (41)
Additionally, 41 patients with locally advanced non-small cell lung cancer, including 78% with stage III disease, received induction PDT and chemotherapy and/or radiation therapy at Ohio State University Medical Center. PDT-based induction allowed 57% of patients initially deemed unresectable to undergo definitive surgical resection and 27% initially deemed in need of pneumonectomy to undergo lobectomy, pathological downstaging in 64%, and a pathologic complete response in 18% undergoing surgery. Overall, 46% of patients were alive at 3 years following therapy, and the mean survival was greatest in patients undergoing lobectomy (35.9 months) and shortest in those unable to undergo surgery after multi-modality therapy (14.7 months) (42)
Prospective studies have also suggesting a possible synergistic effect when combining PDT and ionizing radiation, particularly brachytherapy. Among 32 patients with bulky endobronchial non-small cell bronchogenic carcinoma (range 10-60 mm along the bronchus) treated at Beth Israel Deaconess Medical Center with PDT followed six weeks later with brachytherapy (Iridium-192, 4 Gy weekly for five weeks), patients achieved 81% local control, 94% distant metastasis-free survival, and 100% overall survival at a mean follow-up of 24 months. There were no severe complications, including hemoptysis, fistula formation, post-obstructive pneumonia, or obstructive bronchial scarring requiring intervention (43)
. Brody School of Medicine at East Carolina University investigators also safely combined PDT with high-dose-rate brachytherapy for patients with symptomatic obstruction from endobronchial non-small cell lung cancer (44)
. However, patients with upper aerodigestive tract carcinomas who previously received treatment with both external beam radiation therapy and intraluminal brachytherapy may be at higher risk for complications when subsequently treated with PDT (45)
PDT may be most effective when delivered as part of multi-modality therapy. The combination of PDT with external beam radiation therapy or endobronchial brachytherapy may have a more favorable safety profile than the combination of external beam radiation therapy with endobronchial brachytherapy. The addition of PDT to external beam radiation therapy or endobronchial brachytherapy may significantly improve symptomatic relief and lengthen the duration of local control among patients with symptomatic obstructing non-small cell lung cancer. Although the optimal sequence for combined therapy is undetermined, local control may be best when high-dose-rate brachytherapy is administered prior to PDT and when PDT is delivered prior to external beam radiation therapy. Tumor control may be optimized when PDT and radiation therapy are delivered within one month of brachytherapy therapy (44)
. PDT may also be administered as induction therapy before chemotherapy and can increase tumor resectability and decrease the extent of surgery required when delivered as part of multi-modality therapy.