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980
An Early Phase II Study of Intratumoral P-32 Chromic
Phosphate Injection Therapy for Patients with
Refractory Solid Tumors and Solitary Metastases
Nosrat Firusian, M.D.1
Wolfram Dempke, M.D.1,2
1
Department of Medical Oncology and Haematology, Elisabeth Hospital, Recklinghausen, Germany.
2
Martin-Luther-University Halle-Wittenberg, Medical School, Department of Internal Medicine IV,
Halle, Germany.
BACKGROUND. In this early Phase II study, the authors investigated the efficacy of
intratumoral injection of P-32 chromic phosphate in 17 patients with refractory
solid tumors or solitary metastases in terms of response rates and overall survival.
METHODS. Seventeen patients (median age, 60 years) with either cytostatic drugresistant tumors or tumors known to be primarily chemotherapy-resistant were
entered into the study. After sonographic determination of the tumor volume, P-32
chromic phosphate (74 –555 MBq) was injected into the central part of the tumor
under sonographic guidance. Follow-up investigations included serial scintigraphy, sonographic examinations, and hematologic studies.
RESULTS. Injection of P-32 chromic phosphate into refractory tumors resulted in
remarkable regression. The median survival of all patients was 13 months (range,
8 –25 months). The response rate was 71% (12 patients). A complete remission was
seen in 7 patients (41%), and the rate of partial remissions was 29% (5 patients).
However, 5 patients (30%) did not respond to the treatment. In one patient
thrombocytopenia was observed, but no other side effects were apparent. Important pathologic and anatomic changes within the tumor tissue were demonstrated
in solitary liver metastases of gastrointestinal malignancies excised in second-look
operations. In all cases examined, formation of a cyst within the area of central
activity, surrounded by a centrifugal necrotic ring and a marginal fibrotic structure,
was found.
CONCLUSIONS. Lack of persistent systemic or local side effects, as well as noteworthy efficacy, are properties of this optimal regional treatment modality with P-32
chromic phosphate. This modality deserves consideration for further clinical trials.
Cancer 1999;85:980 –7. © 1999 American Cancer Society.
KEYWORDS: refractory solid cancers, intratumoral injection, P-32 chromic phosphate, response rates, side effects.
D
Address for reprints: Wolfram C. M. Dempke, M.D.,
Martin-Luther-University Halle-Wittenberg Medical
School, Dept. of Internal Medicine IV, Ernst-GrubeStr., 40 06120 Halle/Saale, Germany.
Received April 27, 1998; revision received August
19, 1998; accepted August 19, 1998.
© 1999 American Cancer Society
espite new developments in clinical oncology by the establishment of new potent cytostatic drugs, antiemetics, and hematopoietic growth factors, there are still significant problems in treating
the majority of solid tumors. In particular, patients with gastrointestinal and bronchogenic carcinomas need alternative treatment modalities; among conventional methods of therapy, however, radioisotope potentials are not fully eluciated so far.
Nuclear medicine is an integral part of the Department of Hematology and Oncology at our hospital. Because of this, we have already
presented our newly established P-32 chromic phosphate therapy for
patients with refractory thoracic wall recurrence associated with
breast carcinoma.1–3 Colloidal radiopharmaceutics are most important compounds for the therapy of solid tumors; they are useful not
P-32 Therapy of Refractory Solid Tumors/Firusian and Dempke
TABLE 1
Properties of Some Radiocolloids
981
PATIENTS AND METHODS
Colloid
t 1/2
(days)
Energy
(MeV)
Range
(mm)
Particle size
(nm)
P-32 chromic phosphate
Au-198 colloid
Y-90 silicate
14.3
2.7
2.7
1.71
0.96
2.28
8.0
3.8
11.0
600–1300
20–70
100
only for the palliation of malignant effusions but are
relevant even in the treatment of solid tumors and
bulky solitary metastases. Among several colloidal radiopharmaceutics, P-32 chromic phosphate has enormous importance due to adequate physical properties
(Table 1).
In an earlier study, kinetic investigations of several
colloidal radiopharmaceutics were performed in patients with thoracic wall recurrence associated with
breast carcinoma to address the behavior of these
pharmaceutics in terms of retention and diffusibility
through the involved and infiltrated areas.2 Administration of P-32 chromic phosphate showed virtually no
diffusion from infiltrated areas to noninfiltrated regions. Total activity 1–24 hours after application revealed no significant decrease. Determination of biologic half-life by quantitative and scintigraphic
investigation of bremsstrahlung indicated a remarkable correlation between physical half-life and conditions of infiltration therapy.2 Using a murine tumor
model, McCready et al. also provided evidence that
intratumoral injection of P-32 showed virtually no diffusion through the tumors tested, suggesting that P-32
chromic phosphate is the most suitable radionuclide
for this purpose.4
Infiltration therapy administered to 20 patients
with refractory thoracic wall recurrence of breast carcinoma (185 MBq, 5 mCi/100 cm2) resulted in complete remission in 33%, partial remission in 53%, and
stabilization within 6 months in 70% of patients
treated, with an overall response rate of 86%. No remarkable systemic side effects were observed, and the
unique episode of development of a circumscript necrosis was caused by unavoidable inhomogenous accumulation of activity.2
This observation drew our attention to the fact
that it might be possible, by focal injection of P-32
chromic phosphate under ultrasound guidance into
the central part of bulky tumors, to induce a desirable necrosis in the center, followed by cyst formation. Under these circumstances, irradiation perpetuation would be the logical consequence of such a
model.
P-32 colloid as a chromic suspension was supplied by
Mallinckrodt Nuclear (St. Louis, MO). Ninety percent
of these particles were in the range of 0.6 to 2 mm.
Between March 1993 and April 1994, 17 patients
were entered into our Phase II study of P-32 chromic
phosphate injection therapy. Informed consent was
obtained from all patients. Patients with secondary
resistant tumors following standard chemotherapy
treatment and patients with bulky tumors known to be
primarily chemotherapy-resistant were eligible for this
study. A total of 10 patients (59%) previously had
multimodal treatment, whereas 7 patients (41%) had
widespread bulky tumors regarded as drug-resistant.
In all cases histologic investigations were performed.
The median age of the group was 60 years (range,
44 – 86 years). Of the patients treated, 3 had hepatoma;
5 had solitary hepatic metastases related to gastrointestinal and breast carcinoma; 1 had pancreatic carcinoma; 5 had bulky lymph node metastases related to
head and neck cancer, breast carcinoma, and others; 2
hadprimary and secondary pulmonary malignancies;
and 1 had thyroid carcinoma.
After determination of tumor volume by sonography and computed tomography, P-32 chromic
phosphate was injected into the central part of the
tumor under sonographic guidance and local anesthesia with different volumes depending on tissue
pressure and tumor volume (betwen 5 and 15 mL).
Tumor volume (V) was calculated according to the
formula V 5 1/2 ab2 (a,b: diameters). The following
doses were injected: up to 20 mL in volume: 2 mCi 5
74 MBq; 20 – 40mL: 4 mCi 5 148 MBq; 50 –100 mL: 6
mCi 5 222 MBq; 100 –200 mL: 10 mCi 5 370 MBq;
200 –300 mL: 15 mCi 5 555 MBq. In cases with
tumor volumes of more than 100 mL or 200 mL, the
total activity was administered in 2–3 sessions with
time intervals of 6 weeks in between, respectively.
The total injected doses, which depended on tumor
size, were in a range of 74 –555 MBq (for tumor
volumes 10 –300 mL). No patient received external
beam radiotherapy to the lesion subsequently injected. In addition, no systemic chemotherapy was
concurrently performed.
Follow-up investigation by serial scintigraphy of
bremsstrahlung, sonographic examination, and hematologic investigation began immediately after treatment and lasted up to 3–25 months. For patients with
remarkable tumor remission, histologic examination
of biopsy specimen or surgically removed metastatic
material was performed. Four patients with solitary
hepatic metastases underwent surgery 12 months after radionuclide treatment. Macroscopic and histo-
982
CANCER February 15, 1999 / Volume 85 / Number 4
TABLE 2
Characteristics of Patients Treated with Intratumoral P-32 Injections
Case
no.
Age (yrs),
gender
Localization of tumor or metastasis
resp.
Volume of tumor
(mL)
1
44, M
50
2
86, F
3
75, F
Lymph node and metastasis right
angle of the mandible
Right lobe of thyroid with regional
lymph node metastasis
Solitary metastasis of the right lobe
of the liver
4
64, F
5
60, F
6
30
12
65, M
Right supraclavicular lymph node
metastasis
Right supraclavicular lymph node
metastasis
Extensive Pancoast’s left upper lobe
11
50
7
70, F
Extensive metastasis left upper lobe
30
8
72, M
240
9
72, M
10
59, M
Extensive metastatic focus of left
lobe of the liver
Extensive focus of the thoracic wall
(left parasternal)
Metastasis of the right hepatic lobe
11
60, M
12
10
12
21
45
Tumor
response
Histology
Previous treatment
Squamous cell carcinoma
of the pharynx
Clear cell carcinoma of
the thyroid
Adenocarcinoma of the
breast
Palliative operation for the purpose of
histologic confirmation
No previous treatment, histologic
confirmation only
Mastectomy, radiotherapy,
chemotherapy, hormonal
treatment
Mastectomy, cytostatic treatment,
radiotherapy, hormonal treatment
Mastectomy, chemotherapy,
radiotherapy, hormonal treatment
No previous treatment, histologic
confirmation only
Right hemicolectomy, chemotherapy
PD
Gastrectomy, cytostatic treatment
CR
Gastrectomy, chemotherapy, partial
resection of liver (left lobe)
Hemicolectomy with extirpation of
liver metastases, chemotherapy
Protectomy, partial resection of liver,
cytostatic treatment
Total colectomy because of familial
polyposis of colon, hepatic
metastasis
Esophagectomy, chemotherapy
PR
Adenocarcinoma of the
breast
Adenocarcinoma of the
breast
Squamous cell carcinoma
of the lung
Adenocarcinoma of the
cecum
Adenocarcinoma of the
stomach
Adenocarcinoma of the
stomach
Adenocarcinoma of the
colon
Adenocarcinoma of the
rectum
Adenocarcinoma of the
colon
30, F
Metastatic focus of right hepatic
lobe
Metastasis of the right hepatic lobe
28
13
52, F
Extensive left pulmonary metastasis
60
14
58, F
290
15
65, M
210
Hepatocellular carcinoma
16
75, M
12
Hepatocellular carcinoma
17
59, F
Large solitary tumor of right lobe of
the liver
Extensive solitary focus of the right
hepatic lobe
Circumscribed tumorous formation
of the ventral area of the right
hepatic lobe
Extensive tumor of the pancreatic
region
Squamous cell carcinoma
of the esophagus
Hepatocellular carcinoma
40
Adenocarcinoma
Regional intraarterial cytostatic
treatment
No previous treatment, histologic
confirmation only
No previous treatment only, histologic
confirmation
No previous treatment, histologic
confirmation only
CR
CR
CR
PR
CR
PD
CR
PR
PR
PD
PD
CR
PR
PD
CR: complete remission; PR: partial remission; PD: progression of disease.
logic investigations in these cases were documented.
Measurements of tumor size served as confirmation
for assignment of clinical response.
In all patients treated, blood samples were analyzed for P-32 contamination immediately after drug
injection and then twice weekly using a Beckmann
liquid scintillation counter (Beckmann, Munich, Germany).
RESULTS
Patient Characteristics and Toxicity
Characteristics of patients are listed in Table 2, taking into account localization and histology of the
tumor as well as previous treatment. Number of
fractions and injected activity depending on tumor
volume are listed in Table 3. Among 17 cases, only in
1 (Case 14) was thrombocytopenia found (Grade 4,
according to World Health Organization classification) 10 days after the last P-32 application (a total
of 3 were given); the thrombocytopenia demanded
supportive treatment for a short time. In 2 other
cases with superficial lymph node metastases, transient erythema followed by a moderate burning sensation occurred without late effects (Cases 1 and 2).
No other side effects or toxicities were observed. In
addition, no alteration of the hepatic function was
observed when the radiocolloids were injected into
liver metastases.
P-32 Therapy of Refractory Solid Tumors/Firusian and Dempke
TABLE 3
Applied P-32 Activity and Number of Fractions for Each Patient
Treated
Patient no.
Activity of P-32 (MBq)
No. of fractions
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
185
148
74
74
74
185
148
555
74
148
185
148
222
555
555
74
148
1
2
1
1
1
1
1
3
1
3
3
2
1
3
3
2
2
983
and vital cells. This significant structure of solitary
metastases after application of P-32 chromic phosphate is demonstrated in Figure 2. Histologic examination revealed a marginal zone with only about 30%
morphologically vital tumor cells (data not shown).
Comparable with this finding, 2 cases with pulmonary tumors within 2– 4 weeks showed development of a central cyst surrounded by fibrosis and
marginal rest tumor. This was followed by shrinking of
the whole tumor mass within 4 –5 weeks (Fig. 3).
Survival Rates
A significant tumor regression was found in 12 patients (70% overall response rate). In 7 patients (41%)
a complete remission was achieved, whereas a partial
remission was seen in 5 patients (30%). Five patients
(30%), however, did not respond to this treatment
schedule. The median survival of all patients was 13
months (range, 8 –25 months).
DISCUSSION
Kinetic Investigations
Kinetic investigations by determination of biologic
half-life (t1/2) in all cases except one with a third
application revealed duration similar to that of the
physical t1/2 of P-32. Additional scintigraphy of the
region of interest showed objective confirmation of
persistent activity in accordance with the above-mentioned biologic t1/2 (a typical kinetic is shown in Fig.
1). In all blood samples tested, only traces of P-32
activity were found (,0.3 nCi/mL), indicating that no
significant capillary leakage or tissue diffusion had
occurred.
Sonographic, Radiologic, and Pathologic Findings
Remarkable tumor regression approximately 4 weeks
after P-32 chromic phosphate application was demonstrated. Development of a solitary central cystic
formation with liquid content appeared in tumors
with volumes above 50 mL (Cases 6, 7, 10 –12). In cases
with hepatic tumors, this finding remained during 12
months without any change in size. After a remarkably
stable phase of disease without any evidence for further metastatic dissemination, 4 patients with solitary
hepatic metastases underwent surgery (Cases 8, 10 –
12). In all cases, total excision was achieved, and macroscopic selection of the region of interest in 3 cases
(10 –12) revealed a solitary cyst with liquid content in
the central part followed by a middle layer of necrosis
measuring 6 – 8 mm. This layer in the marginal part
was surrounded by a thin fibrotic structure. Tissue
that was borderline to normal hepatic tissue showed a
mixed structure consisting of disseminated necrosis
Assuming that it might be possible to induce remarkable tumor regression by induction of a central necrosis by intratumoral injection of P-32 chromic phosphate, the Phase II study described herein was
performed. The rationale for this study was the possible induction of a central necrosis (cyst) with extremely high b-irradiation doses of about 50,000 cGy
within a spheric area followed by centrifugal irradiation. This concept was realized by achieving a characteristic morphology demonstrated by pathologic examination of excised, treated metastases of the liver
associated with gastrointestinal tumors and comparable radiologic changes in patients with primary and
secondary pulmonary tumors.
Dosimetric investigations after focal injections of
P-32 chromic phosphate have not yet been carried out
thoroughly. The MIRD (Medical Internal Radiation
Dose Committee)7 scheme is the accepted method for
calculating tumor radiation dose from internally administered radiopharmaceuticals. This method of calculating the tumor radiation doses assumes two
sources of radiation: first, the source of radiation that
is within the tumor target, and second, radiation from
the surrounding normal tissue. The main error in this
dosimetric calculation is that it assumes a uniform
distribution of the radiopharmaceuticals within the
tumor, which is often erroneous, given by the heterogeneity of many tumors and the variability of the
blood supply.
In our opinion, characteristic tissue structures under P-32 chromic phosphate therapy and application
modalities appeared to be most important for dose
calculations. Development of a central cyst following
984
CANCER February 15, 1999 / Volume 85 / Number 4
FIGURE 1. Determination of biologic half-life revealed a similar duration as the physical half-life of P-32 (14.3 days).
FIGURE 2.
Liver metastasis after a
P-32 injection followed by total excision
(Case 10) is shown. A solitary cyst with
liquid content in the central part is followed by a layer of necrosis and is then
surrounded by a thin fibrotic ring.
central point irradiation (probably more than 50,000
cGy) must be assumed as a late effect of initial necrosis. In the cyst stage, which transpires after 2–3 weeks,
there are two possibilities of further irradiation: 1) by
precipitation of b-particles on the cyst wall, and 2) by
homogenous distribution of radiation within the liquid compartment of the cyst (Fig. 4).
In this context, some clinical trials using P-32
chromic phosphate as a treatment strategy for cystic
craniopharyngeoma are of interest. The use of intracystic radiocolloid therapy of craniopharyngeoma was
first described by Leksel and Liden in 1953.5 Shortly
thereafter, Wycis et al.6 injected 1.1 mCi (40 MBq) of
P-32 colloid into a cyst of 11 mL volume. They estimated an absorbed dose between 17,200 and 53,000
cGy to the cyst wall, depending on dosimetric assumptions. After injection, the cyst was reduced in size, and
6 months later all symptoms disappeared. The activity
P-32 Therapy of Refractory Solid Tumors/Firusian and Dempke
985
FIGURE 3. Chest computed tomography scans of two patients with pulmonary tumors before and after intratumoral P-32 injection are shown (left
panel: Case 6; right panel: Case 13).
Note the central cyst after therapy.
of P-32 colloid injected to deliver 10,000 – 40,000 cGy
has usually been determined from b-dose calculations
derived by Loevinger,7 who assumes a uniform distribution within a spherical cyst throughout the decay of
P-32. The Loevinger formula can be simplified as injected activty (A) 5 27.47V 3 f-1 with V 5 cyst volume
in mL, and f 5 volume depended dosimetric factor.
The usually accepted source geometry for intracavitary radiocolloids assumes that the colloid “plates out”
on the cavity surface to become a plane surface. With
intratumoral application, we must assume the development of a centrifugally fast-growing cyst without
anatomic wall and with high content of activity (74 –
185 MBq). The greatest dimension of the central cyst
was 2–3.5 cm. Assuming both possibilities of activty
distribution, Table 4 demonstrated absorbed doses
from spherical sources of P-32 activity.
Considering the P-32 colloid activities in our
study, we suggest for the marginal zone of the secondarily developed cyst a dose of 40,000 – 60,000 cGy. For
the central part of the tumor, however, which is the
location of initial injection, a significantly higher dose
of about 100,000 cGy was calculated.6
Using our newly developed intratumoral injection
technique of P-32 chromic phosphate, we have provided the first evidence that high response rates could
be achieved in pretreated chemotherapy-resistant patients without any significant side effects. In addition,
five patients without cytostatic pretreatment were also
entered into the study. Among them, in 3 cases a
tumor regression was found after P-32 injection. Be-
cause these cancers are generally known to be primarily chemotherapy-resistant, the reported overall response rate of 71% should not be hampered.
So far, only a few institutions worldwide have
dealt with unsealed source radioisotope treatments.
Order et al.8 recently presented results of P-32 chromic phosphate infusion therapy for patients with unresectable pancreatic carcinoma; however, these authors did not mention survival times and morphologic
changes. A comparison of our technique with other
published intratumoral treatment strategies is given in
Table 5.
In the early 1970s, it was discovered that cis-diamminedichloroplatinum(II) (CDDP) could potentiate
the effects of ionizing radiation.19 Since that time,
many studies have suggested that combination exposure of tumor cells to CDDP and X-irradiation may
lead to an overadditive toxic effect.20 –22 Only recently
have studies provided the first evidence that CDDP
can inhibit DNA damage repair after ionizing radiation. The maximum combined treatment effect was
usually seen when the drug was given concurrently
with radiation.21 Based on these experimental findings, we have now started to inject P-32 chromic phosphate immediately followed by intratumoral injection
of 10 –20 mg CDDP (depending on tumor volume).
Preliminary results after combined treatment of a few
patients indicate that this schedule is more effective
than injection of P-32 chromic phosphate alone, and
adverse side effects did not increase. Similar results
have been achieved using the topoisomerase I inhib-
986
CANCER February 15, 1999 / Volume 85 / Number 4
FIGURE 4. A proposed model for cyst development after intratumoral P-32 injection is shown.
There are two possibilities for further irradiation:
either by precipitation of b-particles on the cyst wall
(III a,b) or by homogenous distribution of irradiation
within the liquid compartment of the cyst (IV a,b).
TABLE 4
Absorbed Doses from Spheric Sources of P-32 in Water for Complete Decay (Initial Concentration, 1 mCi/mL)6,7
Absorbed dose (cm from surface)
Volume (mL)
Greatest dimension
(cm)
0 Gy
0.1 Gy
0.3 Gy
0.5 Gy
1
5
10
20
50
100
1000
0.62
1.06
1.33
1.68
2.29
2.88
6.20
3100
3300
3400
3400
3500
3500
3600
880
1000
1000
1100
1100
1120
1200
69
83
88
93
97
100
110
1.3
1.6
1.7
1.9
2.0
2.1
2.3
itor topotecan (2– 4 mg, depending on tumor volume).
This drug is currently under clinical investigation in
combined modality tretment approaches because it is
the most potent radiosensitizer clinically available.22
However, preliminary data indicate a limited efficacy
of topotecan; severe episodes of thrombocytopenia
occurred.
Considering the results for patients with refractory cancers presented here, the encouraging effects of
P-32 chromic phosphate injection may draw clinical
P-32 Therapy of Refractory Solid Tumors/Firusian and Dempke
TABLE 5
Overview of Intratumoral Treatment Techniques for Cancer Patients
Tumor
Malignant
melanoma
Breast
carcinoma
Colorectal
carcinoma
Several tumors
Liver
Head and neck
Liver
Prostate
Agent
Response
rate
Toxicity
Study
IFN-a
47%
Fever, pain, nausea
Rosso11
IFN-a
91%
Fever, pain, nausea
Habif12
INF-b
TNF-a
TNF-a
IL-2
Ethanol
125
I
78%
13%
53%
5%
71%
60%
Fever, pain, nausea
Fever, pain, nausea
Fever, pain, nausea
Fever, pain, nausea
Thrombosis, pain
Necrosis,
perforation
Wildfang13
Watanabe14
Ijzermans15
Vlock16
Livraghi et al.17
Peschel et al.18
8.
9.
10.
11.
12.
13.
14.
INF: interferon; TNF: tumor necrosis factor; IL: interleukin.
15.
attention to its significant therapeutic potential. Because the majority of solid tumors in adults belong to
the resistant group, it is of major importance to integrate new innovative methods in treatment strategies.
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