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Photodynamic Therapy Center [B. W. H., T. M. B., L. A. V., D. A. B., M. T. C.], Department of Dermatology [N. P. F., D. B., T. A. S., J. D. Z., A. S. D., A. R. O.] and Biomathematics/Biostatistics Resource [W. R. G.], Roswell Park Cancer Institute, Buffalo, New York 14263
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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The occurrence of oxygen depletion in clinical Photofrin-PDT has been
unknown. Because of the complexity of clinical trials, there is little
information whether effective treatment conditions also are optimal.
Using empirically derived parameters of 1 mg/kg Photofrin with 150
mW/cm2 irradiance and a light dose 
215
J/cm2, we have found PDT highly effective for human BCCs,
with a >90 % durable complete response rate. We report highly
significant and opposing changes in tumor oxygenation levels during
treatment of nBCCs with Photofrin-PDT, using both "standard" and
reduced light fluence rates. The data suggest that the efficiency of
clinical PDT might be improved by reduced fluence rates.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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(abc), where a, b, and c are the radii
of length, width, and height of the lesion. For PDT treatment, patients
received 1 mg/kg Photofrin, followed by illumination with 630 nm light
after an interval of 48–72 h. The total treatment fluence was 215
J/cm2. The study was approved by the Institutional Review
Board, and all patients signed informed consent.
Measurement of Tumor pO2.
Intratumor pO2 was measured in resting, awake patients
using a polarographic device (Eppendorf pO2 Histograph;
Eppendorf Scientific, Inc., Madison, WI; Refs. 8, 9
).
Before and between measurements, the instrument was calibrated in 0.9%
sterile saline bubbled alternately with air and nitrogen to set 100 and
0% pO2 currents. Ambient air pressure and tumor
temperature (measured using an Omega HYP-0 30 gauge, 1/2-inch
needle thermocouple) were recorded and used to postcalibrate the data.
Before measurement commenced, each lesion was cleansed with betadine
and anesthetized with 2% lidocaine without vasoconstricting agent. The
300-µm-diameter polarographic needle probe was aligned at the tumor
surface, and the probe was advanced one step to ensure the tip was
within the tumor, and automatic probe advancement was begun after the
pO2 values had stabilized. Probe advancement was set to a
0.7-mm forward step and a 0.3-mm retraction step for each reading.
Probe track lengths and number of tracks measured were determined
according to tumor dimensions. Tracking through the tumor was parallel
to the skin surface at a depth of 1–3 mm, and care was taken to
choose comparable track positions (depth and tumor periphery
versus center) for control and experimental measurements, as
well as to keep tracks physically well separated from each other. One
to three tracks per tumor were measured for each experimental condition
(see below), with a maximum of six tracks per tumor. Averages of
28 ± 3 (SE) and 38 ± 5 measured values
per lesion were accumulated for pre-PDT and during-PDT conditions,
respectively. Tumor temperature was recorded by inserting the
thermocouple into each track immediately after oxygen measurements.
During the entire procedure, the patient’s arterial oxyhemoglobin
saturation was monitored by a pulse oximeter (median for all patients,
97.0%; range, 94.0%–98.0%).
The effects of PDT on tumor oxygenation were evaluated at two fluence rates. Considering the known large variability of oxygen levels among different tumors (10) , the experiments were designed so that each tumor provided its own control.
For the 150 mW/cm2 fluence rate group, baseline pO2 values of the lesion under study were measured immediately before light treatment, and the lesion was illuminated at 150 mW/cm2. In 8 carcinomas, pO2 was again measured during light exposure at selected time points between 0.5 and 10 min (4.5–90 J/cm2) without interruption of laser light; care was taken to record the illumination time elapsed (i.e., fluence delivered) during these measurements. In five lesions, pO2 was measured near completion of treatment, between 15 and 20 min (135–180 J/cm2) of light exposure. After completion of measurements, the remainder of the total 215 J/cm2 treatment fluence was delivered at 150 mW/cm2 without interruption, according to current standard practice for patient benefit.
For the 30 mW/cm2 fluence rate group, baseline pO2 was measured as above; the lesion was illuminated with light at a fluence rate of 30 mW/cm2, and pO2 was again measured as above during light exposure at selected time points between 3.0 and 10 min (5.4–18 J/cm2) as above. After completion of measurements, the remainder of the treatment dose was delivered at 150 mW/cm2 for patient benefit.
Quantitation of Photofrin in Tumor Tissue.
Because of the destructive nature of biopsies, quantitation of
photosensitizer in the lesions designated for pO2
measurements was not possible. However, to get a sense of the
photosensitizer levels to be expected in BCCs explored in this study,
tissue samples from biopsies of lesions other than those designated for
pO2 studies and from surgically removed tumor tissue were
examined for Photofrin content. Freshly obtained tissue was dissolved
in Solvable, followed by porphyrin-specific fluorescence detection as
described earlier (11)
.
Computer Simulation of Oxygen Distribution during PDT.
Computer software (PDT MODeM), developed by Henning et al.
(12)
and based on previous mathematical modeling by Foster
et al. (3)
, was used to simulate the effects of
150 mW/cm2 fluence rate light on oxygen distribution in
lesions with high or low porphyrin content. The model assumes a
capillary-to-capillary spacing of 300 µm. Porphyrin-specific input
parameters have been described before (6)
.
Statistical Considerations.
To determine significant differences between median pO2
values, as well as the proportions of values 
2.5 mm Hg, before and
during PDT, the pooled raw pO2 values from all lesions for
each fluence rate were analyzed by the Mann-Whitney test. The Wilcoxon
signed rank test was used to examine for each lesion the statistical
significance of differences in median pO2 before and during
PDT and proportion of values 2.5 mm Hg. The Student’s t
test was used for comparison of all other measurements.
P < 0.05 was considered to be significant.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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200
J/cm2 fluence in >1500 superficial and nodular BCCs, with
an initial complete response rate >90%, determined at 6 months after
treatment; the response was quite durable past 5 years
(13)
.5
Thus, we did not expect the above treatment conditions to cause
substantial depletion in oxygen during the course of treatment.
150 mW/cm2 Fluence Rate PDT Can Deplete Tumor Oxygen.
Intratumor pO2 was assessed before and during treatment in
the first eight nBCC lesions accrued that met the criteria for
pO2 measurements. Baseline, pre-PDT values for
pO2 are shown together with tumor temperature for each
lesion in Fig. 1A
and summarized in Table 1
. Median pO2 levels ranged from 2–50 mmHg. There was a
linear increase in tumor temperature with pO2 up to
34°C and 20 mm Hg; above 20 mm Hg, the temperature was relatively
constant. Because tumor temperatures depend on vascular perfusion, the
relationship is not unexpected. Initial tumor temperatures appeared to
depend, at least in part, on ambient room temperatures, which varied by
about 2°C. Lesion temperatures during PDT were dominated by heating
attributable to laser irradiation (see below).
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and plotted
for each lesion as a function of tumor temperature in Fig. 1B
. When measured during lesion illumination between 0.5 and
10 min (4.5–90 J/cm2) light, six of the eight carcinomas
had a decrease in median pO2, with five lesions 10 mm Hg.
BCC #5 had a drop of 36 mm Hg. Despite pO2 increases in
two lesions, overall there was a significant decrease from baseline in
the median of pO2 values (from 25.4 to 9.2 mm Hg). Even
more significant was the increase in values 2.5 mm Hg, which
indicates severe hypoxia. The median frequency at which these low
values were encountered increased almost 5-fold from 6.7% before PDT
to 35.1% during PDT. In murine tumor models, marked shifts toward
tumor hypoxia during PDT treatment have been demonstrated at high
fluence rates, but these have been associated with treatment failures
(5)
. Clinical follow up 
6 months is available for six of
the lesions (nos. 1, 2, 3, 4, 5, and 7), and all have had complete
clinical responses.
Two mechanisms could be invoked as the cause for the observed changes:
photochemical consumption of oxygen and changes in vascular supply. In
rodent models, photochemical oxygen depletion as well as vessel
constriction can occur very rapidly during PDT, whereas other vascular
effects, such as thrombosis and vessel collapse, can affect blood flow
in a delayed manner (1
, 14) . To examine the time kinetics
of tumor oxygenation changes in the BCCs, the data were separated into
measurements taken between 0.5 and 2 min of light (4.5–18
J/cm2; lesions 1, 3, and 4), and between 2.5 and 10 min of
light (18–90 J/cm2; lesions 2, 5, 6, 7, and 8). The latter
group included two lesions (nos. 5 and 6) measured at 10 min (90
J/cm2), or 42% of the total light dose. Both groups showed
similar changes from their preillumination values. In the 0.5–2-min
group, median pO2 dropped from 29.2 to 3.9 mm Hg, and the
percentage of values 2.5 mm Hg increased from 14.3 to 45.3%. In the
2.5–10-min group, median pO2 changed from 22.2 to 9.5 mm
Hg, and the percentage of values 2.5 mm Hg increased from 3.4 to
28.9%. The difference between pO2 data from the two groups
is not significant, although after longer illuminations, the intratumor
temperatures were higher (Fig. 1B)
. For the two groups,
median temperature increased from a baseline of 33.6°C (range,
32.0–34.2) to 34.6°C (range, 33.0–35.3), and from 34.6°C (range,
30.9–35.4) to 37.1°C (range, 36.8–38.3, P < 0.0001), respectively.
This analysis shows that oxygen depletion during PDT light exposure can be rapid and can persist through at least the initial 40% of the treatment. The data are consistent with a photochemical depletion process but do not exclude consequences of possible vascular constriction.
Although the combined data from all lesions measured during 150
mW/cm2 illumination with 90
J/cm2 light fluence indicate significant overall decreases
in ground-state oxygen, the degree of depletion varied between
carcinomas. An increase in median pO2 was found in two of
the eight lesions (Fig. 1B)
. Photochemical oxygen depletion
will depend on photosensitizer tissue content. Although we can measure
in situ fluorescence from the Photofrin, we lack a proven
noninvasive method to quantitate photosensitizer concentration.
Therefore, to obtain an estimate of Photofrin tissue levels, we
determined average porphyrin content in biopsies from seven BCCs not
used for pO2 measurement from three of the study patients.
These samples showed a 5-fold range of porphyrin levels (median, 0.53
µg/g; range, 0.29–1.59 µg/g). In mice, using typical treatment
conditions of 5 mg/kg Photofrin, porphyrin levels were 11 µg/g
(6)
.
The lower levels of photosensitizer in human BCCs and the successful
clinical outcomes raise the question as to whether photochemical oxygen
depletion could be expected to occur. To answer this question, we
calculated tissue oxygen levels as described by Foster et
al. (3)
using the PDT MODeM program (12)
to simulate oxygen depletion for tissue Photofrin concentrations in the
upper and lower range of the above-measured values. As seen in Fig. 2
, this simulation predicts that oxygen will be depleted to severely
hypoxic values (2.5 mm Hg) within the distance of 150 µm from the
capillary by exposure to light at 150 mW/cm2, if the lesion
contained porphyrin concentrations above the median value of 0.5
µg/g. Porphyrin concentrations below the median value
(e.g., 0.2 µg/g) will cause moderate to minimal oxygen
depletion. Although these calculations do not take into consideration
effects such as photobleaching of the sensitizer and changes in blood
supply, they nevertheless strongly suggest that the failure of some
lesions to be oxygen depleted by high fluence rate was caused by their
low photosensitizer content.
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In addition to the above lesions, the oxygenation changes in five nBCCs
were examined at 15–20 min (135–180 J/cm2) of
illumination, a point where 60% of the treatment light dose had
been delivered. Of these lesions, the median pO2 value
remained unchanged in one and increased in the remaining four. Overall,
the pooled data reveal an increase in median pO2 from 15.6
to 28.3 mm Hg. The proportion of values 2.5 mm Hg decreased from a
baseline of 12.7 to 0.7%. Median tumor temperatures rose by 5.4°C
(range, 3.1–7.9°C). The lack of oxygen depletion in these two
lesions could be attributable to low porphyrin levels, as was suggested
for lesions 7 and 8 in Fig. 1B
. More likely, it was
attributable to gradual photobleaching of the porphyrin during
illumination. We found that Photofrin fluorescence measured at the
tumor surface disappeared by the end of the irradiation, consistent
with photobleaching (data not shown). Photosensitizer photobleaching
was demonstrated by Georgakoudi et al. (15)
in
a spheroid model that showed a progressive decrease in photochemical
oxygen consumption with sustained illumination that was consistent with
theoretical calculations of sensitizer photobleaching. Our own studies
in a rodent tumor model also support such a mechanism (6)
.
Finally, the data indicate that at least in these lesions, no vascular
occlusion had occurred by the time 80% of the total treatment dose had
been delivered.
30 mW/cm2 Fluence Rate PDT Preserves or Increases Tumor
Oxygenation.
Both theoretical modeling (3)
and preclinical studies have
shown (6)
that lowering the light fluence rate will reduce
the rate of 1O2 generation and therefore
3O2 consumption. Calculation of pO2
levels (Fig. 2)
to be expected under illumination at a fluence rate of
30 mW/cm2 and tumor porphyrin concentrations within the
range determined in this patient population revealed that moderate
oxygen depletion might occur at the highest measured porphyrin levels
(1.5 µg/g). We therefore assessed pO2 changes in the next
group of nine BCC lesions before and during illumination at a fluence
rate of 30 mW/cm2 (Table 1
; Fig. 1C
). These
lesions included the largest lesion evaluated (lesion 2), but the
differences in overall lesion thickness or volume from the high fluence
rate group were not statistically significant. Median baseline
pO2 values were slightly lower than in the high fluence
rate group, but this difference was also not significant.
Upon illumination at 30 mW/cm2 and measured at time points
between 3 and 10 min of light (5.4–19 J/cm2), the fraction
of values 2.5 mm Hg remained essentially unchanged. However, in six
of the nine lesions, increases in median pO2 were observed
(median pre-PDT, 12.8 mm Hg; during PDT, 35.0 mm Hg), in contrast to
the decrease in median pO2 in the higher fluence rate
group. The median change in pO2 in these lesions was an
increase of 11.7 mm Hg, with a maximum increase of 45 mm Hg.
Although there were small decreases in pO2 in lesions 7, 8,
and 9 (Fig. 1C)
, the overall increase among the nine lesions
was highly significant when the data from all lesions were pooled
(Table 1)
. These data are consistent with preclinical observations that
lowering treatment fluence rate maintains or improves tumor oxygenation
during PDT (3
, 6)
.
To determine the role of the light dose delivered at the two fluence
rates, we can compare tumor oxygenation after comparable fluences of
5–18 J/cm2 [0.5–2 min at 150 mW/cm2 (3
lesions); 3–10 min at 30 mW/cm2 (9 lesions)]. Median
pO2 values decreased from 29.2 to 3.9 mm Hg, and the
percentage of values 2.5 mm Hg increased from 14.3 to 45.3% in the
higher fluence rate group, whereas in the lower fluence rate group,
median pO2 values increased and the percentage of values
2.5 mm Hg remained unchanged (see above). It is clear from this
comparison that tumor oxygenation changes are dependent on fluence rate
rather than fluence.
Table 2
, which contains the data from 13 BCCs in two patients evaluated at both
fluence rates, shows that the pattern of fluence rate-dependent changes
in tumor oxygenation holds despite large intra- and interpatient
variations. In both patients, the pooled lesion median pO2
value decreased under illumination at 150 mW/cm2, although
oxygen in one lesion in patient A (lesion 7, Fig. 1B
)
increased. Oxygenation increased in five and declined slightly in two
BCCs exposed to 30 mW/cm2 light in both patients.
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irradiated at 30
mW/cm2 were characterized by very low baseline
pO2 values. Low baseline lesion temperatures in these
cutaneous tumors were likely attributable to low ambient room
temperature during that treatment session. All light exposures
increased the tumor temperature as measured immediately after
pO2 measurement (Table 1)
. Both fluence rate groups showed
a highly significant median lesion temperature increase of 2°C,
although the temperature in the two lesions with highest initial values
(nos. 5 and 6, Fig. 1C
) in the low fluence rate group
declined slightly upon illumination. During treatment, the lesion
temperature will be affected by both light energy deposited in the skin
and by the blood flow, and our current data cannot distinguish these
contributions. As evident from Fig. 1A
, perfusion alone can
account for tumor temperatures up to 34–35°C. In summary, we have found that a clinically successful PDT treatment protocol using 150 mW/cm2 irradiation with 1 mg/kg Photofrin can substantially deplete intratumor oxygenation in the majority of nodular BCCs. The oxygen depletion can extend at least through the first 40% of illumination, although it appears to have resolved after delivery of 80% of the light dose. Oxygen depletion and loss of efficacy might be expected to be even more significant at the 2 mg/kg Photofrin dose used in noncutaneous carcinomas (1) . A lower fluence rate of 30 mW/cm2 can minimize or abrogate oxygen depletion. Lesions sampled for Photofrin content showed a 5-fold variation in photosensitizer levels, and a wide range of oxygen depletions also was found. Thus, it is likely that the differences in oxygenation were attributable, at least in part, to biological variances in photosensitizer content, as well as to differences in vascularity.
There are several possibilities as to why Photofrin-PDT at 150 mW/cm2 is clinically successful, despite the apparent oxygen depletion. Oxygen-independent, type I processes might play a role in human phototoxicity, although this has not been observed in preclinical models (16) . BCCs are relatively indolent tumors that might respond to PDT-induced inflammation or disturbance of tissue stroma [e.g., in the 29% placebo response in studies of intralesional interferon therapy (17) ]. PDT also can affect host immune responses (1 , 18 , 19) , which might contribute to tumor responses. Endothelial cells in the carcinoma and surrounding stroma will have the highest oxygen levels, and delayed vascular damage and collapse might lead to eventual tumor control. More importantly, it is likely that Photofrin photobleaching during illumination eventually lowers the sensitizer level to the point where oxygen consumption is reduced, an assumption supported by the relatively high oxygen levels in the tumors examined toward the end of treatment. The current treatment light dose of 215 J/cm2 may be sufficient to overcome poor efficiency in such a way. The low clinical porphyrin levels compared with those found in mice (6) would enhance the effect of photobleaching, contributing both to efficacy and also to selectivity (20) .
Clinical therapies generally seek to minimize treatment times. Although low fluence rates preserve oxygenation, they also prolong illumination (5) . However, if PDT efficiency is enhanced, the light dose and treatment time could be reduced. Our results indicate that a large portion of the treatment at 150 mW/cm2 must be highly inefficient and suggest that efficiency might be increased at a lower fluence rate. Photochemical oxygen consumption is proportional to the product of photosensitizer absorption coefficient, photosensitizer concentration, and light fluence rate. Photofrin has a relatively low absorption coefficient. Thus, oxygen depletion and therapeutic inefficiency may be even more of an issue for new sensitizers that have much higher absorbances, as well as for topical aminolevulinic acid, which produces high levels of endogenous porphyrin. This study was not designed to evaluate the therapeutic effectiveness of low fluence rate treatment. Additional clinical protocols are being designed to optimize fluence rate and fluence. However, the large interlesion variations in photosensitizer content and baseline oxygenation make it unlikely that one optimal fluence rate can be identified and emphasize the need for noninvasive in situ dosimetry.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH Grants CA42278 and CA55791 and
Roswell Park Cancer Center Support Grant P30 CA16056. 
2 To whom requests for reprints should be
addressed, at Photodynamic Therapy Center, Roswell Park Cancer
Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716)
845-4429; Fax: (716) 845-8920.
3 Present address: Department of Radiation
Oncology, School of Medicine, University of Pennsylvania, Philadelphia,
PA 19104.
4 The abbreviations used are: PDT, photodynamic
therapy; BCC, basal cell carcinoma; nBCC, nodular basal cell carcinoma;
PDT MODeM, PDT molecular oxygen-depletion model.
5 A. R. Oseroff, manuscript in
preparation.
Received 11/15/99. Accepted 12/10/99.
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, 0.2
µg/g; 
, 0.5 µg/g; •, 1.5 µg/g. 30 mW/cm2: 
,
0.2 µg/g; 
, 1.5 µg/g.