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. 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