Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

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.

Preoperative, single-fraction irradiation for prophylaxis of heterotopic ossification after total hip arthroplasty.

We gave a single fraction of 750 cGy preoperatively (within 16 h of surgery) to 143 patients prior to total hip arthroplasty. The patients were evaluated for heterotopic ossification at 1, 3 and 6 months. The preoperative radiation did not affect the surgical procedure. After a median follow-up of 12 (6-24) months we encountered six patients with heterotopic ossifications of Brooker grade I-II. Potential late risks from ionising radiation should be considered when treating younger patients.

Radiotherapy for non-small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival.

For patients with advanced, inoperable non-small cell lung cancer (NSCLC), increasing age seems to be the primary reason of receiving no treatment. The elderly aged 75 years and over are more likely to be given only supportive care (irrespective of symptoms) or no therapy at all. We evaluated the outcome of 48 patients, aged 75 years and over, treated with radiation therapy for advanced (stage IIIA-B), inoperable, symptomatic NSCLC. A median dose of 50 Gy was delivered to the primary site and mediastinum with standard fractionation. Based on WHO criteria, of 47 assessable patients, 21 had partial remission, 17 stable disease, and nine had progressive disease. Most symptoms were successfully palliated. Toxicity was negligible and mainly consisted of WHO grade I-II esophagitis. Despite the overall median survival being short (5 months), dose-related survival was much better in patients given at least 50 Gy than in those treated with lower doses: 52% versus 35% at 6 months, and 28% versus 4% at 13 months. These results confirm that radiation therapy may be safely delivered to very aged patients with advanced NSCLC at not merely palliative doses, both to achieve better local control and to give likely survival benefits. Adequate pretreatment evaluation should be always performed to exclude any comorbidity unfit to chest radiation and to individualize treatment to the single patient requirements. Because a large amount of literature data now concurs with the feasibility and safety of high-dose radiotherapy in the elderly, specifically designed, age-oriented trials are needed to settle definitively the issue of survival advantage from curative radiotherapy in these patients.

A practical technique for conformal simulation in radiation therapy of pelvic tumors.

PURPOSE: A radiological procedure, based on straightforward conventional methods, was used for a demonstration of pelvic anatomy during simulation to precisely delineate the target volume and increase the probabilities of pelvic tumor control. METHODS AND MATERIALS: Between 1990 and 1993, 450 patients with primary pelvic malignancies underwent external radiotherapy by means of photons, 6-10 MeV, with multiple-field techniques. The simulation was carried out immediately following a pelvic organs opacification (POO) by standard methods. This procedure used a minimal quantity of contrast media (barium sulphate, iodine contrast) and metallic markers to locate directly and simultaneously: (a) small intestine, (b) bladder, (c) rectum, (d) anal canal, (e) bulbous male urethra, and (f) vagina. When all these structures were clearly visualized, the procedure was scored as successfully performed. RESULTS: The sensitivity of procedure was defined as the percentage of successful pelvic organs opacification (POO) carried out in the patients. It was 98% in both women and men. Indirectly, the procedure helped us to locate the prostate, the perineum, and the uterus cervix in the same percentage of patients. Pelvic organs opacification allowed us to document not only the normal position of the pelvic organs tested, but also any variations (ranging from 5% to 40% of cases, after pelvic surgery). Furthermore, POO revealed previously not-reported abnormalities in patients undergoing surgery, mostly rectal stenosis, urinary or anal incontinence, and bladder luxation. The cost of the materials used was $10-15 for each POO, and the time required 5-7 min. The side effects were 7% and not significant. CONCLUSION: In the simulation phase for multiple-field irradiation technique, the simultaneous visualization of pelvic organs obtained by POO procedure allows an exact positioning of the isocenter, an accurate shielding of structures, and finally, a reliable conformal therapy. Due to the low cost, the short length, and the insignificant side effects, POO can be carried out more than once during pelvic treatments for localization and verification of target.

Definitive irradiation of nasopharyngeal carcinoma: analysis of results and failures in 103 cases.

During the period 1975-1984, 103 patients were treated for nasopharyngeal carcinoma. Most of them presented with an advanced stage: 64 stage IV and 26 stage III. Sixty-one patients presented with neck nodes, which was the most frequent symptom of presentation. The histologic subtypes included 64 squamous cell carcinoma and 39 undifferentiated carcinoma. All patients were treated by high energy sources with portals encompassing the primary and the whole neck. Doses ranged from 50-55 Gy in T1 patients to 65-70 Gy in T4 patients. The mean survival was 58.5 months, and 31 patients were alive and disease free at 60 months from treatment. A clear difference in survival emerged among T1, T2-3, and T4 patients (p greater than 0.01), whereas there was no significant difference between T2 and T3 patients. Also, N0 and N1 showed no significant difference in 5-year disease-free survival (38% and 41%, respectively); only 20% of N2 and 7% of N3 patients survived for more than 5 years. As regards histology, 25% of patients with a squamous cell carcinoma and 36% of those with an undifferentiated carcinoma were alive at 5 years. The presence of distant metastases (in 20 patients) was not correlated with T stage but was strongly correlated with N stage; histology did not affect the development of metastases. There clearly was no correlation between T and N stage, a behavior which probably constitutes a characteristic of these tumors. From our analysis we can affirm that N stage has a greater influence on prognosis and final outcome than T stage, at least using the UICC staging criteria.

Primary non-Hodgkin lymphomas of the gastrointestinal tract: analysis of 41 cases.

Forty-one patients suffering from primary non-Hodgkin lymphomas of the digestive tract have been observed over a period of 15 years. The primary sites were: the stomach in 27 cases, the small bowel in 8, the ileocecal region in 5, and the mesentery in 1. Patients were staged according to the modified Ann Arbor staging system proposed by Mushoff (20). Four kinds of management were employed: 1) surgery alone; 2) surgery and radiotherapy; 3) surgery, radiotherapy and chemotherapy; 4) surgery and chemotherapy. One patient was treated by chemotherapy alone. Radiotherapy was administered postoperatively and chemotherapy after or during radiotherapy. Generally, 2 opposed fields largely encompassing the tumor area and lomboaortic nodes if necessary, up to 25-30 Gy to the midline, were employed, with a booster dose up to 40-45 Gy to the involved area. Total abdominal irradiation was never employed. No clear difference emerged in survival rate nor in relapse-free survival among the four subgroups, but patients who underwent complete resection fared better than incompletely resected patients. However, these two subgroups were not homogeneous. A clear difference in survival rate did not emerge between patients treated or not with postoperative chemotherapy, whereas patients who relapsed after complete remission or those who never had complete remission had a poor prognosis.

External radiotherapy in the treatment of tonsillar carcinomas. Analysis of 183 cases.

A retrospective analysis of 183 consecutive patients with tonsillar carcinoma observed from 1970 through 1984 and treated by external radiotherapy was carried out. The data were analyzed retrospectively to determine the factors affecting prognosis. Tumor size (T) and lymph node involvement (N) were found to be predominant prognostic factors. The difference in 5 year survival rate between T2 and T3 tumors was significant, and that between N1 and N3 was highly significant, whereas difference in survival could be found between N0 and N1 groups. The primary tumor was controlled by radiotherapy alone in 90% of cases of T1 lesions, 58% of T2, 37% of T3 and 11% of T4, and lymph node metastases was controlled in 70% of N1 cases, 0 of N2 and 15.5% of N3. Twenty-three patients underwent salvage surgery after radiotherapy had failed and the actuarial 5 year survival rate was 75% for stage I, 40% for stage II, 30% for stage III and 13% for stage IV.

[The problem of false positives in bone scintigraphy in patients with breast neoplasms. A follow-up at 10 years]. / Il problema dei falsi positivi ala scintigrafia ossea in pazienti con neoplasia mammaria. Verifica a 10 anni.

Bone scanning plays a pre-eminent role in tumor staging procedures, but its reliability is often questioned because of the high incidence of false positive results; not even bone biopsy can always clarify these questionable findings. To verify what actually becomes of the pathological hot spots lacking radiological evidence, we studied 49 patients with this discrepancy and followed them for an average period of 10 years (range: 8-11). The patients were divided into 3 subgroups: 1) 13 N+ patients with multiple hot spots (greater than 2) (N+ IM); 2) 24 N+ patients with single hot spots (less than or equal to 2) (N+ IS); 3) 12 N- patients with single hot spots (less than or equal to 2) (N- IS). Bone metastasis-free survival rate (SLMO) was calculated, which was confirmed by radiology, and overall survival rate (SG). SLMO was considered to coincide with the percentage of "true" false positives. At 10 years SLMO was 7%, 65%, and 83%, whereas SG was 15%, 70%, and 90%, respectively, in the 3 subgroups N+ IM, N+ IS, and N- IS. The Log-rank test demonstrated a highly significant difference (p less than 0.001) between SLMO and SG in these subgroups, due to the poor prognosis of N+ IM patients. The cumulative examination of all N+ N- patients with single hot spots (36 patients) demonstrated 75% probability of "true" false positives at 10 years. Moreover, the risk of bone metastases resulted higher in the hot spots of the spine than in those of the skull and ribs. The possible role is discussed of microfractures and bone traumatisms in the genesis of "true" false positives.

The role of radiotherapy in the management of choroid plexus neoplasms.

Choroid plexus papillomas are very rarely reported neoplasms in both the surgical and radiological literature. The authors present their series of 7 papillomas and 1 carcinoma. They review the recent and former literature with the aim of demonstrating the role and usefulness of radiotherapy.

Non-Hodgkin lymphomas presenting with spinal epidural involvement.

Spinal cord compression was the presenting symptom in 9 out of 299 previously undiagnosed non-Hodgkin lymphomas observed between 1972 and 1987. All patients had unfavourable histologic diagnosis and 4 had stage I E, 2 stage II E and 2 were staged as IV; one patient did not undergo a staging procedure. All patients were treated with surgery and radiotherapy, whereas chemotherapy was employed in 3 cases only. Only 2 patients are still alive and disease-free after 3 and 8 years respectively; the remaining 7 died with progression of disease, even if in 2 cases a complete clinical remission was obtained. The recent literature has been reviewed. Non-Hodgkin lymphoma with spinal epidural presentation is usually an aggressive disease. An intensive treatment combining surgery, radiotherapy and chemotherapy is finally suggested to achieve better local and long-term results. Surgery can as a rule be limited to laminectomy plus biopsy.

Postoperative management of primary spinal cord ependymomas.

Treatment and final outcome of 11 patients with primary spinal cord ependymomas admitted between 1967 and 1983 have been reviewed. All patients had undergone surgery once or twice before radiation treatment. Six of them are alive and disease-free 78 months to more than 180 months after radiation therapy. A short analysis of the recent literature is presented with special emphasis on the most frequent treatment techniques, extension of radiation fields and doses. The value of postoperative radiation therapy and the complications of both surgery and radiotherapy are analyzed. Some guidelines for treatment are finally discussed and proposed.

Postoperative irradiation of brain ependymomas. Analysis of 33 cases.

Treatment and final outcome of 33 patients with brain ependymoma were reviewed. All patients had been operated, but the surgical removal was incomplete in the great majority of cases. Radiation therapy was subsequently performed using one of the following techniques; a) partial brain irradiation against the primary involved areas in 17 cases, b) whole brain irradiation plus boost against primary involved sites in 6 cases and c) total craniospinal irradiation in 7 cases. Three patients were not eligible for the present study because of underdosage. Five- and 10-year survival rates were 48 and 38% respectively. A short survey of recent literature is presented. The possible causes of failure and the methods for postoperative irradiation are discussed against the background of literature and our own cases.

The role of radiation therapy in the management of primary non-Hodgkin lymphomas of the central nervous system: clinical study of 10 cases.

A series of 10 patients with a primary non-Hodgkin lymphoma of the central nervous system were observed and treated by the authors. All were diagnosed after a pathologic examination of the surgical material; the lesions were supratentorial in all cases and unifocal in 9. In every case radiation therapy improved clinical conditions and in most cases even radiologic features of the patients. Four patients were alive and without evidence of disease many months after therapy. Four patients died with a relapse in the central nervous system; 3 of them had disseminated disease at the time of death. Two patients died for an unknown cause. Radiation therapy was performed with 60Co source with 2 opposed portals and the whole brain irradiation technique in all cases but 2. Doses ranged from 35 to 54 Gy. The recent literature on this uncommon disease and the most adequate therapeutic possibilities of radiation therapy and chemotherapy, or both, are discussed.

[Radiotherapy of brain metastases. Presentation of 104 cases examined by computerized axial tomography]. / Radioterapie delle metastasi cerebrali. Presentazione di 104 casi studiati con tomografia assiale computerizzata.

104 patients suffering from brain metastases and treated by whole brain irradiation have been studied with computerized tomography before and after radiation therapy. Brain computerized tomography is increasingly helpful and reliable in determining the location of metastases and regression of disease; it is too a more reliable source of information than neurologic examination in the evaluation of prognosis. Results of our study show that radiation therapy achieves an effective palliation and may be considered the most helpful therapeutic method of such patients; it really relieves symptoms relating to brain metastases and allows a longer survival in a fairly good number of patients.

[Extracranial metastases from medulloblastoma: report of four cases (author's transl)]. / Metastasi extracraniche da medulloblastoma. Presentazione di 4 casi.

Four cases of bone and pulmonary metastases of medulloblastoma histologically diagnosed and with an exhaustive clinical-radiological and scintigraphic documentation, are described. In three patients, one of which non operated, the metastases of the osteolytic and osteoblastic type affected diffusely the skeleton; in the fourth patient the bone lesions were associated with a single pulmonary metastasis. The modality of metastatic spread and the clinical course of the illness in the diagnostic and therapeutic aspects are discussed.

Ovulation induced by LH-RH in rats made anovulatory by various experimental procedures.

The injection of LH-RH induced ovulation in constant estrous rats (CEA), made anovulatory either by frontal hypothalamic deafferentation (FHD), or by exposure to continuous light (CL), or by neonatal androgenization (NA) with 0.500 mg testosterone propionate (NA500). Rats neonatally treated with 1.250 mg testosterone (NA1250) were almost unable to ovulate. 100% of FHD-CEA rats ovulated in response to 10 ng LH-RH, which is 1/3 of the lowest dose able to determine 100% of full ovulation in control proestrous rats. NA500-CEA rats, on the other hand, ovulated in response to doses comparable to those effective in the controls, whereas in CL-CEA rats the doses required for full ovulation were 2-3 times higher than in the controls. The results of these experiments demonstrate that the pituitary glands of CEA rats respond to the stimulation by the specific hypothalamic releasing factor. The pituitary response, however, appears enhanced in FHD-CEA rats and markedly depressed in CL-CEA animals.