The Development of a [At]-Astatinated Endoradiotherapeutic Drug: Part IV—Late Radiation Effects

Purpose: 6-[²¹¹At]-astato-MNDP is a high-LET endoradiotherapeutic drug that selectively targets to an oncogenically associated alkaline phosphatase isoenzyme expressed by certain tumors. A detailed histopathological study of the late tissue effects of its endogenous α-particle emissions has been carried out in a murine tumor model.Materials and Methods: Thyroid-blocked male C57Bl/10 mice bearing a s.c. transplanted rectal adenocarcinoma were treated with a single i.p. injection of 10–750 kBq 6-[²¹¹At]-astato-MNDP. Cured mice (131) were studied. Detailed autopsies and histological examinations were performed on all mice. The study was concluded after 756 days.Results: Lymphoma, plasmacytoma, and intercurrent infections secondary to chronic pulmonary fibrosis were the most commonly found late manifestations of α-radiation exposure. Low grade B-cell non-Hodgkin’s lymphoma occurred in 19 (24.7%) of 77 mice, 13–17 months after receiving 3.5–185 kBq 6-[²¹¹At]-astato-MNDP. The incidence of lymphoma alone and its latency was similar to that of the control population (23.3%). Treatment doses exceeding 200 kBq 6-[²¹¹At]-astato-MNDP, were associated with the development of soft tissue plasmacytoma in 7 (13%) of 54 mice, after 17–22 months. Generalized debilitation and nonspecific infections supervening pulmonary fibrosis significantly contributed to the late morbidity and mortality observed in mice treated with 300–750 kBq 6-[²¹¹At]-astato-MNDP. Dosimetry has afforded LD_50/360 and LD_50/420 estimates of 12–14 and 10–12 Cobalt–Gray equivalent (CGyE), respectively, for chronic lung damage. There was no histological evidence of chronic radiation damage to other critical healthy tissues. Normal thyroid morphology was preserved.Conclusions: Dose activities of 6-[²¹¹At]-astato-MNDP exceeding 300 kBq, were associated an increased risk of tumor induction and development of varying degrees of chronic pulmonary fibrosis implicated in the onset of terminal intercurrent infections. Within the therapeutic dose range 55–300 kBq 6-[²¹¹At]-astato-MNDP, mortality associated with the incidence of significant late radiation damage in critical normal tissues and latent carcinogenesis was less than 15%. Data from this murine model suggest that clinically relevant activities of 6-[²¹¹At]-astato-MNDP may be given without unacceptable toxicity.     

The effect of chemotherapy on the supragingival plaque of pediatric cancer patients

The anaerobic cultivable flora of the dental plaque was investigated in 16 cancer children at days 0, 7, 14 and 21 of a first cure of chemotherapy. Results were compared with those obtained in 16 healthy children. Diseased children showed more quantitative variations of the flora than the controls, especially during the first week of chemotherapy. Whatever the day of sampling, the flora of the diseased children was significantly less complex than that of the controls. Viridans streptococci, Capnocytophaga, and to a lesser extent staphylococci, appeared to be the most strongly affected in diseased children. This could be explained by different mechanisms: uncontrolled recolonization of the dental plaque, selection of multidrug-resistant strains or nosocomial acquisition. These results indicate that variations in quantity, complexity and quality of the oral flora occur during chemotherapy, leading to a major imbalance of the ecosystem.     

Concurrent Cisplatin, Prolonged Oral Etoposide, and Vincristine plus Chest and Brain Irradiation for Limited Small Cell Lung Cancer: A Phase II Study of the Southwest Oncology Group (SWOG-9229)

Purpose: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting.

Methods and Materials: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m² i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m² (days 1–14, 29–42, and 57–70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m² i.v., doxorubicin 50 mg/m² i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy.

Results: Among 56 eligible patients, 93% had SWOG performance status 0–1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimun follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3).

Conclusion: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

The Final Report of the Expert Panel for the Radiation Oncology Bone Metastasis Work Group of the American College of Radiology

Background: In the United States, at least half of the patients who are irradiated are done so with palliative intent. The most common presentation is the patient with bone metastasis. However, because current scientific outcome and technology techniques are insufficient for the creation of guidelines, the American College of Radiology created a work group of experts to formulate appropriateness criteria for the irradiation of bone metastasis.

Method: A MEDLINE search to help review the community practices was initiated. Twenty-five clinical vignettes were reviewed by a panel of experts. Recommendations for each vignette were prioritized and selected based on choices proposed by panel members.

Result: Doses in the range of 20 Gy in 5 fractions, 30 Gy in 10 fractions, or 35 Gy in 14 fractions are acceptable in most circumstances. Daily doses > 4.0 Gy were not commonly suggested.

Circumstances: To determine optimal dose fractionation schemes, more emphasis needs to be put on the life expectancy of the patients. Rapid schedules are acceptable in patients with short life expectancy (i.e., <3 months), but this hypothesis needs to be tested. Further research to better define the clinical indications of hemibody irradiation and strontium-89 is recommended.     

Management of chemotherapy-related anaemia with low-dose recombinant human erythropoietin in patients with small cell lung cancer

We examined the efficacy of low-dose erythropoietin in the management of chemotherapy-related anaemia in patients with small cell lung cancer (SCLC). We gave recombinant human erythropoietin A (rHuEPO) to 63 SCLC patients, 30 with limited disease (LD) and 33 with extensive disease (ED) who underwent chemotherapy with carboplatin, etoposide and ifosfamide and had previously received blood transfusions for chemotherapy-related anaemia. rHuEPO was given at a dose of 2000 IU subcutaneously three times per week for 2 weeks after every chemotherapy cycle, starting 48 h after the end of chemotherapy. Before the use of rHuEPO, all patients in both groups had to be transfused after a mean of 5.5 CT cycles. In 64 CT cycles following administration of rHuEPO, only 5/30 LD patients (17%) had to be transfused in six cycles (9%). In 88 cycles following the use of rHuEPO, 7/33 ED patients (21%) had to be transfused in 11 cycles (12.5%). Haemoglobin values in patients with ED (but not those with LD) were significantly improved after rHuEPO administration on both day 14 and day 28 after chemotherapy. No adverse effects were recorded. rHuEPO considerably decreased the degree of anaemia and the need for blood transfusion at doses markedly lower (25–30 IU/kg body weight) than those reported in the literature so far (150 IU/kg body weight), without toxicity.     

前列腺~(125)Ⅰ射粒子植入结合去势治疗C期前列腺癌(附10例报告)

 目的　探讨前列腺12 5I放射粒子植入内放疗在前列腺癌治疗中的意义。方法　依据治疗计划 ,在直肠B超引导下 ,经会阴穿刺植入前列腺12 5I放射粒子对 10例C期前列腺癌行三维适形内放疗并结合手术去势治疗。结果　全组手术顺利 ,平均植入12 5I放射粒子 5 8粒 ,平均手术时间 80分钟 ,术后平均住院时间 5 .9天 ,随访 9例术后 3个月结果 :前列腺体积及PSA均有不同程度降低 ,前列腺平均体积由35 .2cm3 降至 2 4 .7cm3 ,平均PSA由 19.8ng/ml降至0 .74ng/ml,随访 6例术后 6个月结果 :5例PSA进一步降低 ,平均 0 .11ng/ml,1例升高 ,由 0 .5 1ng/ml升高至 1.6 5ng/ml,无一例出现严重的并发症。结论　采用永久性放射粒子植入前列腺三维适形内放疗是一种有效、微创的治疗前列腺癌的方法。     

Breast cancer in patients treated for hodgkin’s disease: clinical and pathological analysis of 76 cases in 63 patients

In a retrospective multicentric analysis, 63 women treated between 1941 to 1988 for Hodgkin’s disease (HD) subsequently developed 76 breast cancers (BC). The median age at diagnosis of HD was 26 years (range 7–67), and 22 women (35%) were 20 years old or less. Exclusive radiotherapy (RT) was used in 36 women (57%) and combined modalities with chemotherapy (CT) in 25 (39%). Breast cancer occurred after a median interval of 16 years (range 2–40) and the median age at diagnosis of the first BC was 42 years (range 25–73). TNM classification (UICC, 1978) showed 10 T0 (non-palpable lesions) (13%), 20 T1 (26%), 22 T2 (29%), 8 T3 (11%), 7 T4 (9%) and 9 Tx (12%), giving altogether a total of 76 tumours, including, respectively, 5 and 8 bilateral synchronous and metachronous lesions. Among the 68 tumours initially discovered, 53 ductal infiltrating, one lobular infiltrating and two medullary carcinomas were found. Moreover, two fibrosarcomas and 10 ductal carcinoma in situ (DCIS) were also found. Among 50 axillary dissections for invasive carcinomas, histological involvement was found in 31 cases (62%). 45 tumours were treated by mastectomy, without (n = 35) or with (n = 10) RT. 27 tumours had lumpectomy, without (n = 7) or with RT (n = 20). 2 others received RT only, and one only CT. 7 patients (11%) developed isolated local recurrence. 20 patients (32%) developed metastases and all died; 38 are in complete remission, whereas 5 died of intercurrent disease. The 5-year disease-specific survival rate by the Kaplan–Meier method was 61%. The 5-year disease-specific survival rate for pN0, pN1–3 and pN ≥ 3 groups were 91%, 66% and 0%, respectively (P < 0.0001) and 100%, 88%, 64% and 23% for the T0, T1, T2 and T3T4 groups, respectively. These secondary BCs seem to be of two types: a large number of aggressive tumours with a very unfavourable prognosis (especially in the case of pN > 3 and/or T3T4); and many tumours with a ‘slow development’ such as DCIS and microinvasive lesions, especially in patients treated exclusively by RT. Moreover, a very unusual rate of bilateral tumours (21%) was observed. These secondary BC could be ‘in field’, in ‘border of field’ or ‘out of field’. However, a complete analysis of doses delivered by supradiaphragmatic irradiation was often very difficult, due to large variations in several parameters. We conclude that young women and girls treated for HD should be carefully monitored by clinical examination, mammography and ultrasonography.     

‘Dosimetric breast size’: A new and useful parameter for the prediction of local recurrence after breast conservative treatment

To evaluate the risk of local recurrence following breast-concerving therapy for breast cancer, we measured the distance between each entry point of the irradiation on the surface of the breast in line with the axis of the external and internal tangential fields (dosimetric breast size). 652 breast cancer patients were retrospectively analysed, with a median age of 51 years and a median follow-up of 99 months (range 84–192). There were 50 local recurrences, 44 isolated and 6 associated with nodal recurrence or metastases. The global rates of local recurrence at 5 and 10 years were 5.3% and 9%, respectively (Kaplan–Meier analysis). Following a Cox’s multivariate analysis, the only significant and independent parameters related to local recurrence were quality of excision, age at diagnosis and dosimetric breast size. For a small dosimetric breast size (≤ 10 cm), the rate of local recurrence was 14.1 compared with 11.8 for medium dosimetric breast size (> 10 cm–≤ 12 cm) and 5.2 for large dosimetric breast size (> 12 cm). If the analysis was restricted to only those with complete excision, then the relative risk for a patient with a small dosimetric breast size was three times that for a large breast size.     

High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study

This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m²/day from day 1 to day 5 for the 6 first patients and 350 mg/m²/day from day 1 to day 5 for the other patients), etoposide (350 mg/m²/day from day 1 to day 5) and cyclophosphamide (1.6 g/m²/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.