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Eur J Cardiothorac Surg 2001;19:549-554
© 2001 Elsevier Science NL
a Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University Medical School, Auenbruggerplatz 29A-8036 Graz, Austria
b Department of Radiotherapy, University Medical School, Graz, Austria
Received 21 November 2000; received in revised form 13 February 2001; accepted 20 February 2001.
Corresponding author. Tel.: +43-3163853302; fax: +43-3163854679
e-mail: florian.tomaselli{at}kfunigraz.ac.at
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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Key Words: Photodynamic therapy • Hyperbaric oxygenation • Malignant bronchial stenosis
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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The aim of any palliation protocol in advanced malignant bronchogenic stenosis is a rapid reopening of the bronchial lumen thereby enhancing the quality of life and preventing tumor associated complications such as asphyxia, poststenotic pneumonia and arrosional bleeding.
Photodynamic tumor therapy (PDT) is based on the illumination of malignant tissue after selective accumulation of photosensitizers in tumor cells. Photosensitizing agents can absorb photons of appropriate wavelength and become excited to a triplet species. The photon is transferred to ground-state triplet oxygen producing the excited singlet oxygen (type II photo-oxygenation reaction). In the other type of photo-oxidative process (type I) the excited sensitizer itself initiates a free radical reaction. Both types of reaction are associated with PDT. Potentially, they cause an acute necrosis of tumor in the illuminated tumor region [3].
In vitro experiments, however, have shown that oxygen is a key component in PDT. There is decreased cell sensitivity to PDT in the presence of low oxygen. Furthermore, animal tumor models have demonstrated a decreased effect to PDT under hypoxemic conditions [4,5].
The rationale of this clinical trial was to prove the technical feasibility and to study the acute effect of PDT under hyperbaric oxygenation (HBO) regarding relief of poststenotic symptoms in case of 40 malignant bronchogenic stenosis.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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2.1. PDT under hyperbaric oxygenation
Forty-eight hours after intravenous administration of 2 mg/kg bw of a hematoporphyrin derivative (Photosan-3, Seehof Laboratory, Wesselburenkoog, Germany) bronchoscopically guided PDT/HBO was performed under general anesthesia and routine cardiorespiratory monitoring [6].
Through the endotracheal tube the fibrescope was introduced and the laser application system, using a balloon-catheter (PhotoDynamicTherapy®, Vienna, Austria) was inserted through the biopsy channel close to the surface of the histologically proven tumor. In case of tumor stenosis preventing passage by the endoscope, interstitial therapy was done guiding the fiber endoscopically.
The patient was transferred into the multiplace hyperbaric chamber and hyperbaric oxygenation (100% oxygen, 2 ATA pressure) (Fig. 1) was initiated under continuing cardiorespiratory monitoring and recording of the transcutaneous pO2-levels as an indirect indicator of the oxygen load. After a steady state of transcutaneous pO2 had been reached, PDT was started. Transcutaneous steady-state oxygen pressure levels (tcpO2) of 500–750 mmHg under 2 ATA HBO versus tcpO2-levels of 60–75 mmHg under normobaric conditions were found [7].
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Following PDT, debulking of post-therapeutic tumor necroses was done endoscopically after 3 and 7 days, respectively, removing necrotic tumor fragments by forceps or by mere suction.
2.2. Follow-up
Follow-up investigations were scheduled at 1 and 4 weeks after combined PDT/HBO. The acute effects on tumor stenosis were assessed by bronchoscopy, chest roentgenograms, spirometry, and subjective relief of dyspnea and hemoptysis, as well as by evaluation of the Karnofsky performance status.
The acute effect (Figs. 2 and 3) on tumor stenosis was determined by comparing the pre- and posttherapeutic increase of luminal diameter measured at the point of maximum constriction. All luminal diameters were confirmed by easy passage of graduated bronchoscopes of known diameter (3.2, 5, 6, 7 mm) and/or easy passage of balloon catheters of known diameter (8–12 mm). The minimum lumen of the treated bronchial region was recorded at each endoscopy.
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2.3. Statistical analysis
For statistical comparison of numeric parameters, the Wilcoxon test for paired observations was used. All data are presented as mean values±SEM. P<0.05 was considered as the level of significance.
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3. Results (Table 2) |
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TopAbstract1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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In 7 out of 15 patients initially admitted due to inflammatory infiltration the clinical and radiological signs of poststenotic pneumonia improved 1 week after PDT/HBO. After 4 weeks 11 out of 15 patients improved. The initial symptom of hemoptysis in 12 patients subsided in 10/12 cases at 1 and 4-week follow up.
At the time of admission the Karnofsky performance status showed a mean of 70; range: 50–80. One and 4 weeks after PDT/HBO a significant improvement (P<0.05) with a mean of 80 and 85, respectively, could be achieved.
One week after PDT/HBO there was a significant overall decrease of tumor stenosis from a mean of 3.4 to 7.0 mm (range: 0–6 mm and 4–11 mm, respectively; P<0.05). Four weeks after PDT/HBO the mean decrease of tumor stenosis was mean: 8 mm; range: 5–13 mm. After 4 weeks, the overall percentage of free lumen was 84% of normal.
3.1. Survival
Six patients are still alive with a median survival of 11.6 months (range: 1–32 months). Three of the patients who survived had brachyradiotherapy, in two of them radiation was completed with external beam irradiation. The patient had three cycles of chemotherapy.
34 patients died from their disease. Thirty-two due to distant metastasis and two due to severe intrabronchial hemorrhage, 2 and 13 months after PDT/HBO, respectively. The median survival of those patients who died was 10.7 months; range: 2–27 months.
3.2. Complications
No major complications related to either to photosensitization, to PDT or to HBO were observed during or after the intervention. Side-effects included mild skin photosensensitivity in two patients who had neglected the instructions to avoid sunlight after PDT and use a sun-blocker for at least 12 weeks. A single episode of fever up to 39°C in the afternoon after the PDT-procedure (n=14) and mild chest pain corresponding to the treated area for 1 or 2 days (n=19). None of these effects required specific treatment.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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PDT has become a widely accepted method in the palliation of malignant bronchogenic stenosis and is currently performed dependent on its availability [9–13].
PDT can be included into any local or systemic treatment protocol along with other modalities like Nd-Yag laser desobliteration, brachytherapy, external beam radiation, chemotherapy and stenting. The guiding principles are that PDT is more selective than other methods of treatment and that it can, in theory, be applied repetitively without a limitation of the cumulative dosage. However, PDT cannot be expected to eliminate bulky tumor outside the lumen or in lymph nodes i.e. beyond the reach of the laser beam.
PDT involves the interaction of photosensitizers, light and oxygen. Sensitizers, originally in a low energy state, are excited to a maximum by absorption of monochromatic light of appropriate wave length and energy. In this energetic state, they react directly through a free radical mechanism, or indirectly via molecular oxygen which undergoes a spin-state transition to reactive singlet oxygen. Both pathways yield potentially cytotoxic compounds, although the singlet oxygen process is thought to be predominant in PDT [14] and oxygen has been shown to be fuelling the hematoporphyrin-derivative based photodynamic action in vitro [15].
Considering the interactions of photosensitizers, light and oxygen, with singlet oxygen as the final common mediator of photodynamic cytotoxicity, an enhanced tumoricidal effect may be achieved by increasing the amount of oxygen available for the photochemical reaction. This concept is of crucial importance, as PDT by itself induces reduced blood flow and causes a shutdown of tumor vessels resulting in hypoxia with decreased oxygen tension [16].
The use of HBO in this particular field of cancer treatment could be the key to obtain high levels of molecular oxygen in tumor tissue in order to increase cytotoxicity. According to the experimental studies by Dong [4], use of HBO in PDT accelerates the photodynamic reaction processes by raising the transmission efficiency of light energy, increasing the quantum amount of oxygen and extending its radius of effective distance. In an experimental animal model, Jirsa [5] studied the influence of HBO and PDT in tumor-bearing nude mice. They concluded that combining HBO and PDT improves the efficiency of PDT by increasing the depth of tumor cell damage, and/or by reducing the doses of sensitizers.
Under HBO oxygen physically dissolves in all fluid components of the body, resulting in the fact, that oxygenation is no longer dependent on the presence of red blood cells. Lambertson et al. [17] determined that the arteriovenous oxygen difference rises to 350 mmHg when 100% oxygen is respirated at 3 ATA in a typical tissue. Even if the blood flow to the tissues is reduced by a half, the corresponding values of capillary pO2 will be 288 mmHg and 50 mmHg.
In spite of vasoconstriction and a bradycardia-induced reduction of the stroke volume which have been known as physiological side-effects of HBO, oxygenation is pushed to high levels of up to 1000–2000 paO2 at 2 or 3 atmospheres, respectively. In this context, HBO-induced vasoconstriction may be viewed as a regulatory mechanism to protect the healthy organs from exposure to excessive pO2. A very important phenomenon in this concept is that the vasoconstrictor response does not take place in hypoxic tissues [18, 19]. Transcutaneous paO2 in our patients was lower than to be expected but it is a well known fact, that the oxygen pressure recorded at the transcutaneous electrode tends to be lower than the true arterial pO2 due to the oxygen consumption of the skin itself [7].
Side-effects of HBO may affect the central nervous system and the lung but they are easily reversible and are very rarely seen at pressures below 2 ATA and exposure times less than 90 min and we did not see any of them in our patients.
From the technical point of view, combined PDT and HBO did not include any problems provided the laser light generator was positioned outside the hyperbaric chamber with only the fiber being led into the hyperbaric atmosphere.
The aim of the study was, to assess the acute tumoricidal effects of PDT under HBO. As there were no preexisting guidelines concerning both the required laser energy, and the photosensitizer dose or the intensity of HBO, we decided for a moderate therapeutic pressure of 2 ATA at ‘conventional’ sensitizer and light doses. The fact, that we observed local tumor necrosis at the very end of the PDT/HBO session illustrates the high potential of the treatment. Frank necroses developed in each case and could be easily removed during control bronchoscopies. The reopening of the airway was quickly effectuated. In this study, a statistically significant PDT-induced reduction of tumor stenosis and enhancement of performance status, followed by an increased quality of life could be observed. Airway stenosis itself was no reason for hospitalization in the later course of the patients.
Theoretically, the effect of PDT could cause severe pulmonary hemorrhage due to rapid tumor destruction. There was, however, a long interval (7 weeks and 13 months) between PDT in the two patients in whom fatal bleeding occurred. Moreover, additional endoluminal treatment (in both cases endoluminal brachytherapy using a total treatment dose of 15 Gy/Ir 192) could have contributed to tissue damage.
Dougherty et al. [20] reported skin photosensitivity in 25–35% of the patients treated with PDT. HBO does not seem to increase the rate of photosensitivity, with only 2 out of 40 patients experiencing mild skin photosensitivity after neglecting the instructions to avoid sunlight.
Although the study only includes a small number of patients not allowing definite conclusions, it indicates that PDT under HBO represents a new, safe and technically feasible approach in the treatment of advanced malignant bronchogenic stenosis.
It enables efficient and rapid reduction of the endoluminal tumor load and helps conditioning the patient for further treatment procedures.
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results (Table 2)4. DiscussionReferences |
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