Clinical and technical characteristics of intraoperative radiotherapy. Analysis of the ISIORT-Europe database.

BACKGROUND: A joint analysis of clinical data from centres within the European section of the International Society of Intraoperative Radiation Therapy (ISIORT-Europe) was undertaken in order to define the range of intraoperative radiotherapy (IORT) techniques and indications encompassed by its member institutions. MATERIALS AND METHODS: In 2007, the ISIORT-Europe centres were invited to record demographic, clinical and technical data relating to their IORT procedures in a joint online database. Retrospective data entry was possible. RESULTS: The survey encompassed 21 centres and data from 3754 IORT procedures performed between 1992 and 2011. The average annual number of patients treated per institution was 42, with three centres treating more than 100 patients per year. The most frequent tumour was breast cancer with 2395 cases (63.8 %), followed by rectal cancer (598 cases, 15.9 %), sarcoma (221 cases, 5.9 %), prostate cancer (108 cases, 2.9 %) and pancreatic cancer (80 cases, 2.1 %). Clinical details and IORT technical data from these five tumour types are reported. CONCLUSION: This is the first report on a large cohort of patients treated with IORT in Europe. It gives a picture of patient selection methods and treatment modalities, with emphasis on the main tumour types that are typically treated by this technique and may benefit from it.

Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study.

BACKGROUND: Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). We evaluated the efficacy of induction docetaxel (Taxotere), cisplatin, and 5-fluorouracil (TPF) before CT/RT versus CT/RT alone. PATIENTS AND METHODS: Patients with stage III-IVM0 SCCHN, Eastern Cooperative Oncology Group performance status of zero to one, were randomly assigned to receive CT/RT alone (arm A: two cycles of cisplatin 20 mg/m(2), days1-4, plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, during weeks 1 and 6 of radiotherapy) or three cycles of TPF (arm B: docetaxel 75 mg/m(2) and cisplatin 80 mg/m(2), day 1, and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT. The primary end point was the rate of radiologic complete response (CR) at 6-8 weeks after the end of CT/RT. RESULTS: A total of 101 patients were randomly allocated to the study (51 arm A; 50 arm B). CR rates were 21.2% (arm A) versus 50% (arm B). Median progression-free survival and overall survival were, respectively, 19.7 and 33.3 months (arm A) and 30.4 and 39.6 months (arm B). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms. CONCLUSION: Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility.

Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo.

BACKGROUND: The standard treatment for advanced (stage III and IV) head and neck squamous cell carcinoma (i.e., surgery with postoperative radiotherapy in operable patients and radiotherapy alone in inoperable patients) has had poor results. A series of randomized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival. PURPOSE: This trial was designed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease. METHODS: Patients had previously untreated, advanced nonmetastatic (stages III and IV) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and paranasal sinuses. The study design was a randomized, multi-institutional, phase III trial. Eligible patients (n = 237) were randomly assigned to receive either initial chemotherapy (cisplatin and infusional fluorouracil) followed by loco-regional treatment (group A, n = 118) or loco-regional treatment alone (group B, n = 119). For operable patients (group A, n = 34; group B, n = 32), loco-regional treatment included resection followed by adjuvant radiotherapy. For inoperable patients, radical irradiation was performed with a planned dose of 65-70 Gy to involved areas. A dose of 45-50 Gy was also planned to the uninvolved neck or postoperatively. The statistical (log-rank) test was performed no earlier than 2 years after the randomization of the last patient. RESULTS: Seventy-one patients (60%) in group A and 67 patients (56%) in group B were considered free of disease after they completed the treatment sequence. The analysis of time to distant metastases showed an advantage for group A patients. (Respective 2- and 3-year values for inoperable patients were 15% and 24% for group A versus 36% and 42% for group B, P = .04; only one operable group A patient had distant metastases after 49 months versus 26% [2 years] and 31% [3 years] for operable group B patients, P = .01.) For inoperable patients, the combined treatment was significantly associated with an increase in complete remission rate (group A, 44%) as compared with radiotherapy alone (group B, 30%) (P = .037). Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival (49% and 34% for group A versus 28% and 26% for group B; P = .06) and of overall survival (30% and 24% for group A versus 19% and 10% for group B; P = .04). CONCLUSIONS: When all 237 randomly assigned patients were analyzed, there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival, although the development of distant metastases was reduced. For operable patients, the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases. For inoperable patients, neoadjuvant chemotherapy improved local control, decreased the incidence of distant metastases, and improved the complete remission rate and overall survival. IMPLICATIONS: Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required.

Pre-operative chemoradiotherapy in non-small cell lung cancer stage III patients. Feasibility, toxicity and long-term results of a phase II study.

The aim of this study was to evaluate the feasibility, the response rate and the effect on survival of full dose polychemotherapy delivered concurrently with bifractionated radiotherapy at a radical dose, in a subset of patients with marginally resectable or unresectable stage IIIA-B non-small cell lung cancer (NSCLC). Treatment consisted of two courses of cisplatin 100 mg/m2 for 1 day plus etoposide 120 mg/m2 for 3 days delivered from day 1 to day 22, plus radiotherapy delivered in two cycles of 2560 cGy each from day 3 to day 12 and from day 24 to 33 (total dose 5120 cGy in 31 days). The daily dose was 320 cGy in two equal fractions. After surgery, three additional courses of cisplatin plus etoposide were planned. From February 1988 to June 1991, 39 patients with stage III NSCLC (19 were judged as having marginally resectable, 20 as having unresectable disease) were entered into the study. Out of 39 patients (22 squamous cell carcinoma, 17 adeno/large cell carcinoma), 24 had stage IIIa (62%) and 15 stage IIIb (38%). Median PS was 80 (70-90). A total of 78 (74 evaluable) concurrent cycles of pre-operative chemoradiotherapy were delivered. The prominent side-effect was leucopenia: leucopenia > or = grade 3 at nadir occurred in 20 cycles (27%), thrombocytopenia > or = grade 3 at nadir in seven cycles (9%), 19 patients (54%) had a treatment delay of 1 week between the two cycles. Other important toxicities were sepsis in 5 patients (13%), oesophagitis > grade 2 in 9 patients (23%) and pneumonitis in 5 patients (13%). The response rate was 67% (6 CR (complete response), 16%; 19 PR (partial response), 51%). A resection was subsequently performed in 20 (51%) patients: 14 out of 19 marginally resectable (74%) and 6 out 20 initially unresectable (30%) patients. One other patient had an exploratory thoracotomy. Surgical specimens were tumour-free in 3 patients (14%); in 8 patients (38%) only microscopic tumour was found, and in 10 (48%) macroscopic residual tumour was found. Out of 23 patients attaining a CR, 5 relapsed locally and 11 only distantly. At present, with a follow-up ranging from 64 to 90 months, 34 patients have died, 1 is alive with recurrent disease and 4 (17%) are alive without evidence of disease. Median survival was 16 months, with 18% 3-year survivors and 13% 5-year survivors. Resected patients had a median survival of 21 months, versus 10 months for unresected patients (P = 0.01). No significant difference was evident between stage IIIa and stage IIIb patients.

Evidence for a major role of plasma lipoproteins as hematoporphyrin carriers in vivo.

Hematoporphyrin (5 mg/ml), administered intravenously to tumor-bearing patients, becomes associated with different serum proteins, including lipoproteins (mainly HDL), globulin and albumin. No residual porphyrin is bound to the two latter classes of proteins after 48 h, whereas the complexation with the lipoproteins appears to be particularly stable probably owing to the hydrophobic nature of hematoporphyrin. The late persistence of hematoporphyrin in serum is due to the binding to the VLDL fraction with special regard to its cholesterol moiety. The importance of hematoporphyrin transport by lipoproteins for the photodynamic therapy of tumors is briefly discussed.

Quality of life after radiotherapy for early-stage testicular seminoma.

BACKGROUND AND PURPOSE: Standard therapy in early-stage testicular seminoma (TS) includes inguinal orchiectomy followed by irradiation (XRT) of the pelvic and para-aortic nodes. Since this treatment is highly effective in controlling the disease and leads to many long survivors, the quality of life (QL) may be impaired by treatment-induced side-effects. The aim of this study was to provide a QL evaluation of patients treated with XRT after orchiectomy for TS. MATERIALS AND METHODS: We used a validated self-completed questionnaire based on a series of 44 items covering all QL fields. The items were grouped into six subscales with standardized scores. The questionnaire was mailed to a consecutive series of 143 patients treated between 1961 and 1995 for TS with no evidence of disease after primary treatment. RESULTS: Ninety-eight questionnaires (68.5%) were returned and are assessable. The median age of the patients was 48 years (range, 26-85 years) at the time of completing the questionnaire, with a median follow-up after completion of treatment of 123 months (range, 15-432 months). The physical and autonomy subscale standardized scores were > or =1 in 83 and 95% of the cases, respectively. Psychological problems were reported by a small percentage of patients, ranging from 13, who reported a depressive condition, to 16%, who declared feeling tense. Of the patients, 86 and 89% have regularly met relatives and friends. The urinary score was above the central point in 99% of the patients. Only 6% of the patients perceived their body image as worsened by treatment. The patients who were more informed about the disease and therapy had a better physical and psychological adjustment. CONCLUSIONS: The QL in our patients resulted as satisfactory, with a maintained body image and few side-effects. The information given to the patients about their disease and its treatment influenced the post-treatment QL adjustment.

Hyperfractionated radiation in combination with local hyperthermia in the treatment of advanced squamous cell carcinoma of the head and neck: a phase I-II study.

Twenty-seven patients with cervical metastases from squamous cell head and neck tumours were treated with hyperfractionated XRT (total dose 69.60-76.80 Gy, 1.2 Gy b.i.d. five times a week) combined with a total of two to six sessions of superficial external HT. Acute local toxicity was mild; as major acute side effects, only one ulceration was recorded. No severe late side effects were observed. Late toxicity was similar to that observed in our previous studies with the combination of heat and radiation. Nodal complete response was observed in 77% of patients, partial response was observed in 15% of patients and no change was observed in 8% of patients. Five-year actuarial nodal control was 64.5 +/- 19% and 5-year actuarial survival was 24 +/- 10%. The treatment of nodal metastases from head and neck tumours with the combination of HT and hyperfractionated XRT is feasible with an acceptable acute and late toxicity profile.

Carcinoma of the superior pulmonary sulcus. Results of irradiation and radical resection.

Fifty-six patients with superior sulcus syndrome were evaluated at the First Surgical Department of the University of Padua between 1981 and 1990. Forty-two patients with the characteristic of Pancoast's tumor received preoperative irradiation and then en bloc resection of the tumor, chest wall, and adjacent structures. Seven lobectomies and 35 segmentectomies or wedge resections were performed. There was one early postoperative death. Median survival was 14 months, and actuarial survival was 25% at 5 years. Patients with pain relief had better 5-year survival (36.4%) than patients without pain relief (9%). We have no patients with vertebral invasion who survived more than 1 year. Of the five patients with subclavian artery invasion, only one survived more than 1 year. Of five patients with N2 disease, only one survived more than 1 year. Our results suggest that pain relief after irradiation is a good prognostic factor, whereas N2 involvement and vertebral body and great vessel invasion are ominous factors. Another ominous prognostic factor is the Claude Bernard-Horner syndrome even if it is not a contraindication to resection.

p21 expression in colorectal carcinomas: a study on 103 cases with analysis of p53 gene mutation/expression and clinic-pathological correlations.

The WAF1/CIP1 gene product, p21, an inhibitor of cyclin-dependent kinases, is a critical downstream effector in the p53 pathway. The expression of p21 in human neoplasms is heterogeneous, and may be related to p53 functional status. We evaluated p21 immunoreactivity in 103 colorectal carcinomas (CC) in relation to the p53 gene and protein alterations and clinico-pathologic parameters. High p21 expression (more than 10% reactive cells) was seen in 39% of cases. p21 staining was heterogeneous and often detected in clusters of tumour cells; in some tumours p21 staining was more pronounced in superficial areas. No relation was seen between p21 immunoreactivity and site of the tumours (right vs left), TNM stage and grade. p21 expression was related to p53 status as evaluated with IHC or with SSCP analyses, low p21 expression usually being associated with p53 protein overexpression (P=0.048) and p53 gene alteration (P=0.005). The strongest associations were seen when the combined p53/p21 immunophenotype was compared with p53 gene alterations (P=0.0002). These data support the hypothesis that p21 expression in CC is mainly related to p53 functional status, suggesting that p21 expression could be an interesting adjunct in the evaluation of the functional status of the p53 pathway in CC.

Primary non-Hodgkin's lymphoma of the female genital tract.

Genital tract lymphoma is a rare disease; information on diagnosis, treatment and outcome are limited. We report on eight patients affected by non-Hodgkin's lymphoma of the genital tract, five from the cervix, two from the vagina and one from the vulva collected between 1987 and 1998. Age at presentation ranged from 36 to 82 (median 67) years. The commonest initial symptom was vaginal bleeding, post coital in 1 patient. Three patients complained of vescical symptoms. Ann Arbor classification was stage IAE for 6 patients. Histology, according to the IWF, was either intermediate grade (4 patients), or high grade (3 patients), not evaluable in one case. Seven patients were treated with chemotherapy (anthracycline based in four) followed by pelvic radiotherapy in five; one patient received irradiation alone. Five patients are currently alive and free of disease with follow-up ranging from 8 to 126 months. Based on our experience in this series, we support a management scheme of combination chemotherapy and radiotherapy for patients with non-Hodgkin's lymphoma of the genital tract.

Quadruple cancer in a single patient: a report of four cases.

Multiple primary neoplasia was once considered a rare curiosity but is now a well recognized phenomenon. Only a few papers have been published in the English literature with regard to occurrence of four or more primary malignancies in a single patient. We report four cases of quadruple cancer; a review of the literature about this topic is discussed.

Distribution of endogenous and injected porphyrins at the subcellular level in rat hepatocytes and in ascites hepatoma.

Different doses (0.5-20 mg/kg) of hematoporphyrin (HP) have been injected intraperitoneally into normal rats and rats affected by Yoshida ascites hepatoma. About 80% of HP reaching the liver was recovered in the extracellular compartment after liver perfusion, the ratio of extra- to intracellular HP being essentially independent of the administered dose. Similar data were obtained at different times after injection of 20 mg/kg HP. Intracellular HP largely accumulates in the mitochondria and in the membrane components of the nuclear fraction of isolated hepatocytes. Kinetic studies suggest that the cell receptors of highest affinity for HP are present in the external membrane. The latter result obtains for ascites hepatoma cells in an even more evident way, although the latter cells exhibit secondary HP binding sites probably constituted by cytoplasmatic proteins. Moreover, the clearance of intracellular HP from malignant cells occurs at a remarkably lower rate as compared with HP clearance from liver cells.

A pilot study of concomitant radiation and chemotherapy in patients with locally advanced head and neck cancer.

Cisplatin and 5-fluorouracil act as radiosensitizers and are active cytotoxic drugs in head and neck cancer. Therefore, from May 1987 to June 1990, we gave a continuous course of radiotherapy (70 Gy/35 fractions/7 weeks) combined with the simultaneous administration, once a week, of cisplatin (40 mg/m2, i.v. bolus) and 5-fluorouracil (400 mg/m2, i.v. bolus) to 21 patients with locally advanced or recurrent tumors of the head and neck. The complete and partial response rates were 65% and 15%, respectively. With a median follow-up of 17 months (range: 4-42) and with 19/21 patients having stages III and IV tumors, 12 patients are NED (no evidence of disease), 8 died with tumor, and 1 died of bronchopneumonia during the treatment. The main toxicity was mucositis and the median length of therapy was higher than with irradiation alone. This regimen appears very encouraging and could be an improvement over radiation alone for patients with locally advanced head and neck cancer.

Ultrarapid high-dose course of prophylactic cranial irradiation in small-cell lung cancer: evaluation of late neurologic morbidity in 16 long-term survivors.

Despite the reduction in the incidence of brain metastases following prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC), the use of this modality is still controversial due to the lack of improvement in survival and the appearance of neurotoxicity in long-term survivors. Moreover, the optimum dose, fraction size, and timing are not known. From 1980 to 1988, 70 patients with limited stage SCLC underwent PCI after or during multimodality treatment of their primary tumor. Most of these patients (75.7%) received an unconventional ultrarapid high-dose course of 17 Gy in two fractions over 3 days. Long-term (range 60-138 months) survivors (n = 16) were invited to have a complete neurological evaluation including computed cranial tomography (CCT), 99mTc-HMPAO single photon emission computerized tomography (SPECT) scan, electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychometry. Delayed neurologic complications or psychometric impairment was observed in 46% of patients. One or more abnormalities were detected by CCT in all patients, and the presence of neurologic complications seemed to correlate with periventricular and subcortical white matter changes. A strong correlation was found between CCT and SPECT periventricular white matter changes. Although the incidence of late neurologic toxicity following this rapid course of irradiation was high, clinical findings were less severe than expected, and all the patients were capable of self-care.

Oesophageal cancer treated by photodynamic therapy alone or followed by radiation therapy.

Photodynamic therapy (PDT) with porphyrins and red light is receiving increasing attention in the management of malignant tumours. At present PDT is primarily indicated for the treatment of superficial or early-stage lesions. At the Department of Radiotherapy and the First Institute of Surgery in Padova (Italy) more than 150 cases of tumours of different types have been treated using this technique. This paper briefly describes 21 cases of superficial oesophageal cancer. A complete response was observed in 11 of 21 cases. Radiation therapy appeared to be very effective as a salvage treatment of non-response patients.

[Intraoperative radiotherapy in the combined treatment of pancreatic cancers]. / La radioterapia intraoperatoria nel trattamento integrato del carcinoma pancreatico.

Pancreatic cancer is a highly lethal disease either for the high incidence of distant metastases or for the frequent local recidive also after potentially curative resection. For this reason new multimodality approaches have to be investigated. Intraoperative radiotherapy (IORT) permits to administer a high dose to the tumor or to the retropancreatic tissues and to the regional lymph nodes. Literature data suggest it is possible a better local control and perhaps a better survival than the surgery alone or the palliative treatments by the use of schedules with IORT. Anyway they are retrospective data and IORT is an investigational method which has to be indagate in the combined modality approaches to this disease.

Time dependence of hematoporphyrin distribution in selected tissues of normal rats and in ascites hepatoma.

The distribution of hematoporphyrin was determined in normal rats and in rats bearing ascites hepatoma as a function of time after i.p. injection of 10-20 mg/kg of dye. In both cases, hematoporphyrin displayed a high affinity for the tumor cells. At 20 mg/kg, the maximum difference between the amount of hematoporphyrin accumulated in the tumor and in the liver was obtained at 12 h after injection (tumor/liver ratio = 28). Our results suggest that hematoporphyrin is almost exclusively metabolized in the liver and excreted via the biliary tract, whereas only minor amounts are metabolized in the tumor cells. Moreover, the binding between the porphyrin and tumor cells is competitive with serum protein binding.

Choroidal metastasis from carcinoma of the hypopharynx: a case report.

Choroidal metastasis from primaries other than breast or lung cancer is a rare event. There is no documented case in the literature of choroidal metastases in patients with hypopharynx carcinoma. Early treatment with radiation therapy provides effective palliation by preserving visual function and preventing the need for enucleation. Chemotherapy alone does not seem to be as effective as radiation therapy for patients with choroidal metastases. In this paper a case of choroidal metastasis arising from a primary hypopharynx carcinoma is presented.

[Study of the efficacy of neuramide in the treatment of pain in cancer patients]. / Studio dell'efficacia della neuramide nel trattamento del dolore su pazienti neoplastici.

The effectiveness of neuramide as an analgesic was assessed in 71 patients with neuritic pain in an oncological radiotherapy ward. 1-2 vials i.m. twice a day for results in 54%, poor results in 13%, and nil results in 21%. The degree of analgesia was that the drug is useful as an analgesic, anti-inflammatory, cell membrane stabilising, and neurotrophic preparation in certain well-defined pain syndromes, especially those of a secondary nature. Attention is also drawn to its excellent tolerance and the complete absence of side-effects.