Photoradiation Therapy in Advanced Carcinoma of the Trachea and Bronchus

Photoradiation Therapy in Advanced Carcinoma of the Trachea and Bronchus* Ronald G. Vincent, M.D., F.C.C.P.;t Thomas]. Dougherty, Ph.D.;f, Uma Rao, M.D.;§ Donn G. Boyle;ll and William R. Potter, M.AII

Photoradiation therapy is a new technique being investigated for the treatment of solid malignant tumors. In this study, 17 patients with advanced, recurrent, biopsy-proven malignant lesions of the trachea or main-stem bronchus were treated by photoradiation therapy. Patients received hematoporphyrin derivative intravenously three days prior to light therapy. 'Ihe light was delivered from a &beroptic &ber attached to the output beam of a dye laser (633 ±3om~ 'Ihe &ber was passed through the large channel of a

bronchoscope (Olympus BF 2T~ 0£ the 17 patients, two had no measurable response to the photoradiation therapy, six had partial necrosis of the tumor, seven patients had a greater than 50 percent reduction in the intraluminal volume of tumor, and two were lost to follow-up. Survival ranged from 5 to 210 days (median survival, 40 days~ Complications of the treatment were signiflcant in this group o£ advanced-stage patients and included excessive secretions, fever, pneumonia, and abseess formation.

photoradiation therapy is a new technique being investigated fur treatment of a variety of solid malignant tumors. 1-3 It is based upon the tumorlocalizing ability and efficient photodynamic action of hematoporphyrin derivative resulting in a relatively specific photosensitization of malignant tissue upon exposure to activating visible light in the red region of the spectrum ....a It is fOrtuitous that the properties of tumor localization, photodynamic action, and absorption in the red combine in this single material. Absorption in the red (near 630 nm) is an important property, since wavelengths in the red portion of the visible spectrum are attenuated least in tissue, dropping to approximately 1 percent in a distance of5 to 10 mm in a variety of tissues. w The cytotoxic agent appears to be singlet oxygen fOrmed by energy transfer from the porphyrin to endogenous oxygen. 11 Oxidation and cross-linking of membrane components, fOllowed by cell lysis, are the likely modes of cell death.n. 12 A further property of hematoporphyrin derivative, useful in tumor localization, is its red fluorescence, allowing fur its easy identification in situ. This property, known fur many years, is currently being used fur localization of radiologically occult lung tumors in high-risk patients. Hl3 This report presents the results of photoradiation therapy in patients with a carcinoma of the trachea and

bronchus. The majority of these patients were in a very advanced stage of disease, with obstructions and considerable extrabronchial tumor. Most had respiratory distress upon minimal exertion.

*From the Departments of Thoracic Surgery and Radiation Medicine, Roswelf Park Memorial Institute, New York State Department of Health, BuftBlo. tDirector, Ellis Fischel State Cancer Center, Columbia, Mo. tHead, Division of Radiation Biology, Department of Radiation. §Cancer Research Clinician II, Department of Pathology. !!Cancer Research Scientist, Division of Radiation Biology, Department of Radiation Medicine. Manuscript received March 19; revision ~MX:epted July 21.

Beprint requem: Dr. Vincent, EUU Fllchel Stau Cancer Cenur, ll5 8wjneu Loop 70W, Columbia, Miuoun 65201

MATERIALS AND METHODS

Hematoporphyrin derivative (Photofrin) (5.0 mg/ml in sterile saline solution) was obtained (Oncology Research and Development,

Cheektowaga, NY).

Ught Sourcu A dye laser system was used which produced up to 4.0 W of power at 633 ± 3 nm. An 18-W argon laser (Spectra Physics modell71) was

used to pump the dye laser (Spectra Physics model 375) using rhodamine B dye. The output beam from the dye laser was coupled

into a single 400-"" quartz fiberoptic with modified ends to produce peripheral illumination (Oncology Research and Development). Coupling efficiencies of nearly 80 percent could be achieved over any desirable length of fiber up to 40 feet.

Selection of lbtientl Seventeen patients with biopsy-prown malignant lesions of the trachea or main-stem bronchus were treated by photoradiation therapy (Fig 1). All patients had been treated previously with standard therapy, and the disease was regarded to be life-threatening due to progressive occlusion of a major airway. Eleven patients had squamous cell carcinoma, five had adenocarcinoma, and one had large cell carcinoma.

Procedure Patients received hematoporphyrin derivative (2.5 to 3.0 mg/kg of body weight) intravenously three days prior to light therapy. They were cautioned repeatedly to avoid bright light indoors and outdoors, particularly sunlight, for 30 days. Patients who disregarded this advice frequently experienced mild to severe sunburn of

exposed parts. The endotracheal and endobronchial lesion was viewed through a bronchoscope (2'1'8 Olympus). The quartz fiber was passed through the large channel of the fiberscope and positioned to achieve maximum exposure of the tumor by light delivered from the laser through the fiber. In order to achieve best exposure of the anatomic profile of the tumor, special fibers were used with diffusing tips CHEST I 85 I 1 I JANUARY, 11184

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FIGURE 1. Anatomic location and relative size of 17 endotracheal and endobronchial lesions treated by photoradiation therapy. To allow lOr comparison, numbers used to identify patients are same in Figure 1 and 'Illble 1. designed to illuminate in a cylindrical field lOr up to 4 em in length. These same fibers were also used lOr direct implantation into the obstructing tumors. Generally, treatment was given lOr an interval of 10 to 30 minutes every other day lOr three treatments. Depending on tone reactions and response, the treatments were repeated at threeweek to six-week intervals. The estimated amount of light delivered to the tumor per treatment ranged from 200 to 300 joules/sq em lOr small lesions (100 mW/sq em) to3,000 joules lOr large or obstructing tumors. ln the latter case the diffuser portion of the fiber was inserted into the obstructing tumor, and 1.50 to 400 m Wof power was applied lOr each 1-cm length of fiber (up to 4 em).

treatment for &om 1 to 84 months prior to photoradiation therapy (mean, 33.5 months). Standard therapy usually included surgical resection of the primary lesion, followed by radiation therapy, immunotherapy, or chemotherapy of the residual disease. Four patients were female, and 13 were male, with a mean age of 57 years. Survival ranged &om 5 to 210 days after treatment, with a mean survival of 40 days.

fu:SUU'S

Four patients had no measurable response to the photoradiation. Six patients had necrosis of the tumor surface, and seven patients had a greater than 50 percent estimated reduction in the volume of intraluminal tumor, with partial opening of the airway. After treatment, two patients had no residual tumor that could be biopsied within the lumen of the airway.

Data relating to treatment and response are summarized in 'Dlble 1. In five patients the obstructing lesion was located in the trachea between the larynx and carina. In five patients the lesion was in the carina, usually involving trachea and bronchus bilaterally. Seven lesions were primarily of a single bronchus, extending to the level of the carina (Fig 1). All lesions but three were extensions of primary lung cancer (one a metastasis &om colon cancer, one an extension of nasopharyngeal cancer, and one a primary adenocystic carcinoma of the trachea). All had been under standard 30

Response

Complications

All but three patients had significant complications following photoradiation, necessitating the placing of eight patients in the intensive care unit, usually with a

Table !-Summary rf CG~~a Case•

Histology

Survival, days

Light Dose Ratet

Total Delivemi. Light Doset

Acute Complications§

Adenocarcinoma

5

300 mW/sq em (s) ·

600 joules (s)

2

Squamous

6

100 mW/sq em (s x 3)

360 joules (s x 3)

3

Squamous

8

400 mW/cm (i

3)

1,440 joules (i)

Respiratory distress; pneumonia

4

Squamous

33

1; 75 mW/sq em (s)

1; 90 joules (s)

Pneumonia; atelectasis

2; 1,800 joules/em (i) 3; 1,200 joules/em (i) 4; 120 joules (s) 120 joules (s x 2)

X

Respiratory failure Mild toxicity with fever

5

Squamous

19

2; 400 mW/cm (i) 3; 300 mW/em (i) 4; 100 mW/sq em (s) 100 mW/sq em (s x 2)

6

Squamous

120

100-200 mW/sq em (s)

1,400 joules.(s

7

Squamous

60

200 mW/sq em (s x 3)

360 joules (s)

8

Adenocarcinoma

35

300 mW/cm (i)

1,500 joules (i)

9

Squamous

120

150 joules (s)

10

Squamous

90

11

Squamous

21

1; 100 mW/sq em (s} 2; 40 mW/sq em (s} 1; 200 mW/sq em (s) 2; 300 mW/cm (i) 3; 300 mW/cm (i) 4; 200 mW/sq em (s) 150 mW/sq em (s)

1; 240 joules (s) 2; 1,500 joules/em (i) 3; 1,500 joules/em (i) 4; 1,200 joules/em (i) 200 joules (s)

12

Adenocarcinoma

400 mW/cm (i)

2, 700 joules/em (i)

13

Squamous

210

150 mW/sq em (s} (2)

270 joules (s}

14

Adenocarcinoma

174

15

Adenocarcinoma

42

1; 200 mW/sq em (s) 2; 200 mW/sq em (s) 3; 200 mW/cm (i) 4; 150 mW/cm (i) 5; 200 mW/em (i) 1; 200 mW/sq em (s) 2; 250 mW/em (i)

1; 240 joules (s} 2; 240 joules (s) 3; 240 joules (s) 4; 180 joules/em (i) 5; 240 joules/em (i) 1; 240 joules (s x 3) 2; 400 joules/em (i x 2)

16

Squamous

110 mW/sq em (s)

390 joules (s)

17

Adenocarcinoma

1; 300 mW/sq em (s} 2; 300 mW/em (I)

1; 360 joules (s) 2; 840 joules/em (i}

4

7

Alive after resection

X

2)

Pneumonia; respiratory failure; abscess hemorrhage Secretions; fever

Respiratory failure; pneumonia Respiratory distress, controlled None Secretions; casts; pneumonia; toxic Respiratory insufficiency; pneumonia Bilateral pneumonia. toxic Toxic; pulmonary congestion Candidiasis

Pneumonia

Ueacheal obstruction by casts Minimal

Thmor Responsell 10 percent tumor necrosis 30 percent reduction of tumor (visual) at3mo 80 percent tumor response within trachea (autopsy) 30 percent tumor necrosis

Thmor absent within trachea (autoPsy)

60 percent reduction of intraluminal tumor (visual) 20 percent tumor necrosis (visual) No rollow-up; died at 3 mo No rollow-up; died at4 mo No response at 1 mo 15-mm depth of necrosis (autopsy) 10-mm depth of tumor necrosis (autopsy) 100 percent at 3 mo (visual) 100 percent (3 mo); died at 4 mo; brain metastases Some tumor necrosis up to 3-cm depth (autopsy) Necrosis to 1 em

No response

*To allow lOr comparison, numbers used to identify patients are same in 'IIIble 1 and Figure 1. tLight dose rate Is estimated power density during either surface (s) treatment (in mW/s(t em) or during interstitial (I) treatment (in mW/em). *Delivered dose is total dose delivered to surface (s} (in joules) or Interstitially (i) (in joules/em); It is estimate of total amount of)ight delivered to whole area. §Acute complications are those arising within one week or less of treatment. I!Thmor response in some cases was estimated bronchoscopically (visual) and in some cases was determined at autopsy. CHEST I 85 I 1 I JANUARY, 1984

31

need for endotracheal intubation to a point beyond the obstructing 'lesion (where possible). Fifty percent of the patients had symptoms of fever, acute pneumonia, excessive bronchial secretions, and mucosal sloughing. Without mechanical removal the sloughing of necrotic tissue lasted for several weeks. In two patients the secretions hardened into bronchial casts, necessitating mechanical removal. In one instance the cast could not be removed and resulted in asphyxiation. One patient developed an abscess within the tumor, resulting in a significant hemorrhage. Two patients developed severe endotracheal candidiasis. Postmortem Data

Eight patients came to autopsy, and all had significant evidence of severe acute pneumonia with pulmonary edema. Candida was cultured in two patients. Four patients demonstrated extensive tumor necrosis to 1 em, three of which had no tumor in the field of treatment. Two patients had abscess fOrmation, one of which had bled extensively. Serial pathologic sections 1 were made of the treated areas of the bronchus and trachea. in 14 patients, there was necrosis of the intraluminal tumor for a depth of 4 to 15 mm. Unaffecteq viable tumor was evident at tissue depths beyond 20 mm from the site of treatment (Fig 2). '

DISCUSSION

Photoradiation therapy fur treatment of malignant tumors of the bronchus and trachea is at an early stage of development. The ability of this technique to cause necrosis of tumors up to 1 em is evident not only from

FIGURE 2. Histologic section of tracheal wall six days after treatment with photoradiation. Effects on tissue in each zone are as fullows: zone 1, from 0 to 2 mm from point of laser therapy (note sloughing of necrotic tumor with tracheal mucosal regeneration); zone 2, from 2 to 7 mm from point of laser therapy (tissue shows extensive tumor necrosis with fibrosis and degenerating vacuolated cells); zone 3, from 7 to 12 mm from point of laser therapy (histologically, there is mixture ofviable and degenerating malignant cells); and zone 4, from 12 to 20 mm from point oflaser therapy (tissues show little or no effect of treatment and viable tumor is evident).

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this work, but also from that of Hayata et al, 14 Kato et al, 15 Balchum and Doiron, 16 and Cortese and Kinsey; 17 however, it is evident that the selection of patients is crucial to providing benefit to those undergoing photoradiation therapy. The very high rate of complications in the patients in this series is attributed to the location of obstructing or near-obstructing lesions in the main airways and the inability of these advancedstage patients to clear the heavy secretions induced by the treatment. Hayata et al14 recommend that these secretions be removed mechanically within one or two days of treatment, whether or not symptoms occur. Also, Balchum and Doiron 16 ro'Qtinely do a clean-up bronchoscopic procedure two or three days after photoradiation therapy fur the same reason. Balchum and Doiron have recently reported excellent results with photoradiation fur the treatment of obstructing tumors. It is instructive to compare our results to those of Balchum and Doiron. 16 Several differences are apparent. One is the selection of patients. In all of the cases in the recent series of Balchum and Doiron, 16 the patients were in stable condition prior to photoradiation therapy, meaning they had no active respiratory distress upon mild exertion. Also, Balchum and Doiron18 routinely did a clean-up bronchoscopic procedure two to three days after treatment to remove secretions and dead debris. While, in general, the light doses and frequency of treatment used in our series were much greater than in the study ofBalchum and Doiron, 16 who used a single treatment with 100 to 200 joules/sq em, this of itself does not seem to be the major reason fur the high rate of complications in our series. As presently used, there was little effect of photoradiation beyond a tissue depth of2 em; however, a purified version of hematoporphyrin derivative, (Photofrin II) is now available, which has been shown to have a more selective biologic effect in :animal systems and is currently being evaluated in clinical · trials. 18 Our recommendation is that photoradiation therapy be used primarily in earlier stages of disease, when complete control may be possible, eg, carcinoma in situ, as recommended by Cortese and Kinsey, 17 or if palliation is the intent, that the approach of Balchum and Doiron 18 be used, particularly in regard to the selection of patients. We believe it is very important that the patients to be treated should have sufficient pulmonary function to be able to cough up secretions and debris on their own, even if mechanical removal of secretions and debris is carried out subsequent to photoradiation therapy. Furthermore, Balchum and Doiron18 have indicated that their recent excellent results are primarily because of selecting patients who demonstrate little or no respiratory difficulty upon

mild exertion (walking). Other more successful methods using the YAG and the carbon dioxide lasers for opening tumor obstructions of major airways have been reported by Dumon, 19 McElvein, 10 McDougall and Cortese, 11 and Dumon et al. 111 Each of these laser systems has great and exciting potential in dealing with the obstructive airway lesion, but each system has its limitations, many of which are amenable to solution through untried investigation. REFERENCES 1 Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle DG, Mittelman A. Photoradiation therapy tOr the treatment of malignant tumors. Canqer Res 1978; 38:2628-85 2 Dougherty TJ, Lawrence G, Kaufman JE, Boyle DG, Weishaupt KR, Goldfarb A. Photoradiation in the treatment of recurrent breast carcinoma. J Natl Cancer Inst 1979; 62:231-37 3 Proceedings of the UICC workshop on hematoporphyrin derivative tOr detection and treatment of malignant tumors. Buffalo: Roswell Park Memorial Institute, October, 1979 4 Lipson RL, Baldes EJ, Olsen AM. The use of derivative of hematoporphyrin in tumor detection. J Natl Cancer Inst 196l;

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murine tumor. Cancer Res 1976; 36:2326-29 10 Svaasand LO, Doiron DR, Dougherty TJ. Temperature rise during photoradiation therapy of malignant tumors. Med Phys 1983;.10:10-7 11 Dubbelman TMAR, DeGoeij AFOM, van Steveninck J. Protoporphyrin-sensitized photodynamic modification of proteins in isolated human red blood cell membranes. Photochem Photobiol 1978; 28:197-204 12 Kessel D: Effects of photo-activated porphyrins in cell surface properties. Biochem Soc 'Uans 1977; 5:139-40 13 Profio AE, Doiron DR, King EG. Laser fluorescence bronchoscope fur localization of occult lung tumors. Med Phys 1979; 6:523-35 14 ~ayata Y, Kato H, Konaka C, Ono J, Thkizawa N. Hematoporphyrin derivative and laser photoradiation in the treatment oflung cancer. Chest 1982; 81:269-77 15 Kato H, Konaka C, Ono J, et al. Effectiveness of Hpd and radiation therapy in lung cancer. In: Kessel D, Dougherty TJ, eds. Porphyrin photosensitization. New York: Plenum Press, 1983:23-40 . 16 Balchum OJ, Doiron DR. Photoradiation therapy of obstructing endobronchial lung cancer employing the photodynamic action of hematoporphyrin derivative. In: The Clayton Foundation syn}posium on porphyrin localization and treatment of tumors. Santa Barbara, CalifOrnia: Clayton Foundation, April24-28, 1983 17 CorteseDA, KinseyJH. Endoscopicmanagementoflungcancer with hematoporphyrin derivative phototherapy. Mayo Clinic Proc 1982; 57:543-47 18 Dougherty TJ. Photoradiation therapy (PKI') of malignant tumors. CRC Crit Rev Oncol Hematol 1983 19 Dumon JF. YAG laser photoirradiation of tracheobronchial lesions. WAB Newsletter 1980; 3 20 McElvein RB. Laser endoscopy. Ann Thorac Surg 1981; 32:463-67 21 McDougall JC, Cortese DA. Neodymium-YAG laser therapy of malignant airway obstruction. Mayo Clin Proc 1983; 58:35-9 22 Dumon JF, Reboud E, Garbe L, Aucomte F, Merle B. '&eatment of tracheobronchial lesions by laser photoresection. Chest 1982; 81:278-83

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