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Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Renal Cell Carcinoma With Bone Metastases: RADICAL (Alliance A031801).

PURPOSE: Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS: This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS: The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% (P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION: Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Humans

Radium-induced malignant tumors of the mastoid and paranasal sinuses.

In the records of 5,058 persons with therapeutic or occupational exposure to radium, 21 patients with carcinoma of the mastoid and 11 with malignant tumors of the paranasal sinuses were identified. Tumor induction times were 21-50 years for mastoid tumors (median, 33) and 19-52 years for paranasal sinus tumors (median, 34). Dosimetric data are given for the patients whose body burdens of radium have been measured. We found a high proportion of mucoepidermoid carcinoma, comprising 38% of the mastoid and 36% of the paranasal sinus tumors. Three patients had antecedent bone sarcoma at 20, 11, and 5 years, respectively, and a bone sarcoma was discovered at autopsy in a fourth patient. Radiographic changes in the mastoid and paranasal sinuses were similar to those seen in nonradium malignant tumors. More than 800 known persons exposed to radium before 1930 and another group of unknown size who received radium water or injections of radium from physicians are still alive and at risk of developing malignant tumors of the mastoid and paranasal sinuses.

Adenocarcinoma

Controlled trial of repeated halothane anaesthetics in patients with carcinoma of the uterine cervix treated with radium.

39 patients with carcinoma of the uterine cervix who were treated with radium and required repeated general anaesthetics were randomised to halothane and control groups. Their serum-alanine-aminotransferase (S.G.P.T.) levels were measured before each general anaesthetic, and those patients whose S.G.P.T. levels rose above 100 I.U. per litre were freed from the restriction determined by the initial allocation and treated as indicated clinically. None of the 21 patients in the control group had S.G.P.T. levels rising above 100 I.U. per litre. 4 out of 18 patients in the halothane group developed S.G.P.T. levels above 100 i.u. per litre before their third radium treatment. None of these had any symptoms or alteration in other liver-function tests, but liver biopsies in 2 of these patients showed changes characteristic of Hepatitis. Arbitrary selection of 18 out of the 39 patients would only give rise to the degree of abnormality observed in the halothane-treated group with a probability of about 0-02. In the patients studied who required repeated general anaesthetics at short time intervals, the monitoring of S.G.P.T. levels before each operation was useful screen for liver damage and may have reduced postoperative hepatic necrosis by preventing further anaesthetics with halothane when the liver was already damaged.

Adult

[Bowen carcinoma following many years' use of a "radium cushion" (author's transl)].

A case is reported of a 73-year old female patient in whom precancerous symptoms appeared in the mid-abdominal area of application which for a long time were mistaken for chronic eczema, until after 7 years the development of a skin carcinoma was clinically and histologically confirmed. The case provides a reason to draw attention to the "Radium Cushion" and to restate publicly that they should be delivered to the health authorities. Suspected cases must be thoroughly investigated medically.

Aged

Cytochemical studies of respiratory enzymes in carcinoma of the cervix uteri after irradiation by radium and cobalt 60.

Enzymological studies of succinic dehydrogenase and cytochrome oxidase were made on human squamous cell carcinoma of the cervix uteri before, during and after radiation therapy by radium and 60CO. The enzymatic activities of the two enzymes were higher in cells of stage III than in the corresponding cells of stage II. In addition, after treatment, no enzymatic activity could be detected. These changes may be explained on the basis of mitochondrial damage as a result of radiation effect.

Biopsy

[Functional results obtained by radium contact irradiation of the glottic carcinoma].

45 patients having been treated with radium contact irradiation on account of a glottic carcinoma were continually checked up with a view to ascertaining the functional results obtained. By means of indirect and direct laryngoscopy as well as by stroboscopy vocal organ and vocal quality were tested for a period of few days up to 3 years 6 months. The findings were systematically compiled in a schedule, analized and discussed.

Adult

[Radium treatment of primary vaginal carcinoma (author's transl)].

Between 1951 and 1970, 263 cases with primary carcinoma of the vagina were observed at the Irradiation-Department of the Ist University Clinic of Obstetrics and Gynecology in Vienna. As method of choice the individual, fractioned and protracted Radium-Röntgen-Telekoalt-therapy is recommended. Of the 263 primary vaginal carcinomas 112 (42,5%) were cured. During the time mentioned in this report, we did not have any primary mortality; 24 women, however, could only be subjected to a palliative therapy, 20 patients died from an intercurrent disease and 20 women succumbed to a second carcinoma. Conclusively, the authors present a survey about the results in vaginal carcinoma.

Cobalt Radioisotopes

Clinical use of high dose methotrexate within the Queensland Radium Institute.

The Royal Brisbane Hospitals Group is the second largest user of methotrexate in Australia. The Queensland Radium Institute and the Royal Children's Hospital are both members of the Royal Brisbane Hospitals Group and they are responsible for high dose methotrexate treatment of adults and children within the Group. Children requiring such treatment are seen by staff from both centres. Therefore, the report which follows describes the usage in both adults and children.

Australia

Squamous cell carcinoma of the oral tongue and floor of mouth. Evaluation of interstitial radium therapy.

From January, 1965, to December, 1972, 46 patients with squamous cell carcinoma of the floor of the mouth and 102 patients with squamous cell carcinoma of the oral tongue were treated at M.D. Anderson Hospital and Tumor Institute by interstitial irradiation alone or in combination with external irradiation. Through the years the combination of radiation therapy modalities has been adjusted in an attempt to improve local control, keeping complications to a minimum. In this paper we analyze local control, causes of failure and complications as related to the primary size (T stage) and radiation therapy techniques employed.

Carcinoma, Squamous Cell

Carcinoma of the vagina.

Twenty-two patients with Stage I through IV primary vaginal squamous cell carcinomas treated for cure with radiation therapy are reviewed, with particular emphasis on the relationship of dose to complications and local control. All but 2 patients received 4000 to 6000 rad whole pelvis irradiation plus at least one radium application. Local control was 91%, with an absolute 2-year disease-free survival of 82%. The degree of anaplasia was found to influence prognosis, with all local and distant failures resulting from high-grade lesions. The complication rate was modest, with no fistulae or serious bowel complications. An analysis of total dose (external plus radium) with respect to local failure and complications showed that no major complications occurred at a combined dose below 9000 rad. An analysis of the individual contributions of external irradiation and radium implants showed that all but one very minor complication occurred at a radium dose of 4000 rad or higher. From these data, overall treatment planning and total dose recommendations are made.

Carcinoma, Squamous Cell

Uterine cervical cancer: treatment with megavoltage radiation results and afterloading intracavitary techniques.

Results were evaluated for 651 consecutive patients with invasive cancer of the intact uterine cervix. From 1963 through 1967 319 patients were treated primarily with the older Los Angeles County Hospital system of orthovoltage radiation and intracavitary radium therapy. Thereafter, 1968--1974, 332 patients were treated primarily with a newer modified M. D. Anderson Tumor Institute system of megavoltage radiation and afterloading intracavitary radium therapy. Age distribution and histology were similar for both groups, but clinical stage was slightly more advanced for patients treated earlier. Crude and net 5 year survival rates were 36% and 49% for the early group and 54% and 67% for the later group. Net 5 year survival rates for the earlier group by stage were: stage I, 74%; II, 62%; III, 23%; and IV, 6%. Survival rates for the later group were: I, 81%; II 76%; III, 50%; and IV, 15%. We believe this improvement can be attributed to more effective intracavitary radium therapy for handling local cancer and to delivery of cancericidal doses of radiation to regional nodes with the megavoltage radiation apparatus, as well as to the greater cooperative efforts put forth in the management of County Hospital patients.

Adenocarcinoma

Radiation treatment of primary carcinoma of the female urethra.

Because of the rarity of the primary carcinoma of the female urethra, there has been limited experience of individual institutions in management of this disease. Treatment by radiation alone required radium implant skill in early cases and individualized consideration for integrating external and internal irradiation in more advanced cases. From 1961 to 1975 a total of 16 women with histologically verified primary urethral carcinoma were given radiation treatment at the University of Maryland Hospital. Six of 16 patients were primarily treated for palliation only and 10 were receiving curative radiation treatment. The results show an excellent local control in anterior urethral disease (3/3), entire urethral disease (2/3) and urethral disease with involvement of vulva and/or vagina (3/3). Bladder neck, parametrial, inguinal lymph node, or paraortic involvement represents a poor prognosis and failure is close to 100%. Eight of 10 patients who were treated with aggressive radium alone or combination of external irradiation and interstitial therapy show complete control of disease (80%). Total dosage between 5500 to 6500 rad appears to be adequate to control the disease. Palliative treatment by irradiation alone can only offer a short term symptom-free result, and should be considered as an occasional alternative modality of choice.

Adenocarcinoma