Three-dimensional conformal radiotherapy in localized carcinoma of prostate: preliminary reports of toxicity in dose-escalation treatment.

PURPOSE. Many studies confirmed the evidence of a dose-response relationship in prostate cancer. Escalation of dose using conventional techniques is however limited by rectal tolerance. IMRT and 3D-CRT have been designed to allow dose escalation while not exceeding rectal tolerance. We evaluated the acute and early late tolerance to surrounding organs upon dose escalation from 70 to 78 Gy in 3D-CRT setting, in order to introduce the IMRT process as a routine practice in prostate cancer treatment. MATERIALS AND METHODS. We compared clinical data from 35 patients with localized adenocarcinoma of the prostate, who received 70 Gy within a traditional reconstructed three-dimensional treatment planning, and data from 72 patients who received 78 Gy within a threedimensional conformal setting. In order to respect rectal tolerance in the higher dose group, limits were set for rectum doses, and simulation procedures were standardized. We evaluated radiation morbidity (acute and late gastrointestinal and genitourinary toxicity) using the Radiation Therapy Oncology Group scoring criteria (RTOG scale). RESULTS. Increasing doses from 70 Gy to 78 Gy resulted in no significant difference for acute and late effects. CONCLUSION. A procedural standardization aiming at minimizing day-by-day variation, as well as a more consistent dose distribution to critical organs may significantly reduce the risk of increased toxicity in dose-escalation setting.

Brachytherapy in the elderly.

A rapidly and constantly increasing aged population in the western countries poses a wide range of specific problems to oncologists. A different way to face medical issues should be sought for older patients with cancer, looking at the characteristics that are peculiar to the elderly from different points of view. Brachytherapy is an effective form of radiotherapy which, for its specific characteristics, may be a valid alternative to more complex modalities of treatment, thus allowing a better sparing of normal tissues and structures yet achieving a similar tumor control rate. This paper reviews the literature on the subject of cancer treatment in the elderly, focusing on radiotherapy and brachytherapy, to evaluate the current attitude toward this problem in the medical community and to see if it is possible to identify a patient population that will benefit from this technique.

Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide.

Recent studies have suggested that selective inhibition of mitogenic pathways may improve the antitumor activity of ionizing radiation. The epidermal growth factor receptor (EGFR) is overexpressed and is involved in autocrine growth control in the majority of human carcinomas. Protein kinase A type I (PKAI) plays a key role in neoplastic transformation and is overexpressed in cancer cells in which an EGFR autocrine pathway is activated. We used two specific inhibitors of EGFR and PKAI that are under clinical evaluation in cancer patients: C225, an anti-EGFR chimeric human-mouse monoclonal antibody (MAb); and a mixed-backbone antisense oligonucleotide targeting the PKAI RIalpha subunit (PKAI AS). We tested in human colon cancer (GEO) and ovarian cancer (OVCAR-3) cell lines the antiproliferative activity of MAb C225 and/or PKAI AS in combination with ionizing radiation. In vivo antitumor activity was evaluated in nude mice bearing established GEO xenografts. Dose-dependent inhibition of soft agar growth was observed in both cancer cell lines with ionizing radiation, C225, or PKAI AS oligonucleotide. A cooperative antiproliferative effect was obtained when cancer cells were treated with ionizing radiation followed by MAb C225 or PKAI AS oligonucleotide. This effect was observed at all doses tested in both GEO and OVCAR-3 cancer cell lines. A combination of the three treatments at the lowest doses produced an even greater effect than that observed when two modalities were combined. Treatment of mice bearing established human GEO colon cancer xenografts with radiotherapy (RT), MAb C225, or PKAI AS oligonucleotide produced dose-dependent tumor growth inhibition that was reversible upon treatment cessation. A potentiation of the antitumor activity was observed in all mice treated with RT in combination with MAb C225 or PKAI AS oligonucleotide. Long-term GEO tumor growth regression was obtained following treatment with ionizing radiation in combination with MAb C225 plus PKAI AS oligonucleotide, which produced a significant improvement in survival compared with controls (P < 0.001), the RT-treated group (P < 0.001), or the group treated with MAb C225 plus PKAI AS oligonucleotide (P < 0.001). All mice of the RT + MAb C225 + PKAI AS group were alive 26 weeks after tumor cell injection. Furthermore, 50% of mice in this group were alive and tumor-free after 35 weeks. This study provides a rationale for evaluating in cancer patients the combination of ionizing radiation and selective drugs that block EGFR and PKAI pathways.

Combined modality treatment in unresectable extrahepatic biliary carcinoma.

PURPOSE: Cancers of the extrahepatic biliary tract are rare. Surgical resection is considered the standard treatment, but is rarely feasible. Several reports of combined modality therapy, including external beam radiation, often combined with chemotherapy and intraluminal brachytherapy, have been published. The purpose of this study was to evaluate the effect of chemoradiation plus intraluminal brachytherapy on response, local control, survival, and symptom relief in patients with unresectable or residual extrahepatic biliary carcinoma. METHODS AND MATERIALS: From February 1991 to December 1997, 20 patients (14 male, 6 female; mean age 61 +/- 12 years; median follow-up 71 months) with unresectable (16 patients) or residual (4 patients), nonmetastatic extrahepatic bile tumors (common bile duct, 8; gallbladder, 1; Klatskin, 11) received external beam radiation (39.6-50.4 Gy); in 19 patients, 5-fluorouracil (96-h continuous infusion, days 1-4 at 1,000 mg/m(2)/day) was also administered. Twelve patients received a boost by intraluminal brachytherapy using (192)Ir wires of 30-50 Gy, prescribed 1 cm from the source axis. RESULTS: During external beam radiotherapy, 8 patients (40%) developed grade 1-2 gastrointestinal toxicity. Four patients treated with external-beam plus intraluminal brachytherapy had a clinical response (2 partial, 2 complete) after treatment. For the total patient group, the median survival and time to local progression was 21.2 and 33.1 months, respectively. Distant metastasis occurred in 10 (50%) patients. Two patients who received external beam radiation plus intraluminal brachytherapy developed late duodenal ulceration. Two patients with unresectable disease survived more than 5 years. CONCLUSION: Our data suggest that chemoradiation plus intraluminal brachytherapy was relatively well-tolerated, and resulted in reasonable local control and median survival. Further follow-up and additional research is needed to determine the ultimate efficacy of this regimen. New chemoradiation combinations and/or new treatment strategies (neoadjuvant chemoradiation) may contribute, in the future, to improve these results.

Role of intraluminal brachytherapy in extrahepatic bile duct and pancreatic cancers: is it just for palliation?

PURPOSE: To evaluate intraluminal brachytherapy (ILBT) in patients with extrahepatic bile duct or pancreatic cancers. MATERIALS AND METHODS: Thirty-one patients (aged 33-87 years) with unresectable extrahepatic bile duct (n = 18) or pancreatic (n = 13) cancer received ILBT exclusively or as part of a definitive treatment regimen. ILBT was performed with transhepatic percutaneous drainage in four patients and with endoscopic retrograde cholangiopancreatography in 27. Fourteen patients with no metastases, an Eastern Cooperative Oncology Group performance score of < or = 2, and good hematologic parameters received combined modality treatment: 30-Gy ILBT and 45-Gy external-beam radiation therapy with continuous infusion of fluorouracil. Seventeen patients underwent 50-Gy ILBT alone for palliation. RESULTS: No direct treatment-related acute toxic reactions were seen. Three patients had cholangitis early in the study. Three patients had late gastrointestinal bleeding. Jaundice was palliated in all patients (n = 29); pain, in 11 of 13 patients. The survival rate in patients with extrahepatic bile duct cancer was 62% (five of eight) at 2 years for combined modality treatment. No patient with pancreatic cancer lived for longer than 2 years. CONCLUSION: ILBT is an effective palliative treatment of unresectable extrahepatic bile duct and pancreatic cancers. Results suggest a possible "curative" role in specific clinical settings when properly integrated with other treatments.

Brachytherapy for pancreatic cancer: a review.

Brachytherapy has been used for pancreatic cancer for over eight decades. Appositional, interstitial and intraluminal applications have been employed. Data from approximately three hundred cases are summarized in this review. The most common form of brachytherapy. Although this procedure, when combined with external beam radiation therapy and systemic chemotherapy, provides the best possible local control of pancreatic cancer, it is a hazardous procedure in most hands. Hopefully, the new techniques, such as intraluminal brachytherapy and infusional brachytherapy, will less prone to serious complications and they will prove to be efficacious in the management of cancer of the pancreas.

Innovations in brachytherapy in gynecologic oncology.

With the discovery of radium by Curie in 1898, researchers recognized that this unique radionuclide had specific biologic properties that were applicable to treating patients with cancer. In the beginning, the radium sources were placed within cavities as independent sources and, when needles were available, implanted into tissues. The first combination of brachytherapy, technologies with external-beam radiation therapy was reported by Wright at the Memorial Sloan-Kettering Cancer Center in New York in 1914 in the treatment of a patient with cervical cancer. Next, there was a rapid implementation of brachytherapy in the treatment of cancer by intracavitary placement of radionuclides, interstitial implantation technologies, and systemic administrations. With the development of new radionuclides, including cesium-137, cobalt-60, iridium-192, iodine-125, palladium-103, ruthenium-109, strontium-90, iodine-131, and californium-225, which had varying types of radiation emissions appropriate when properly selected in treatment of cancer, there was a rapid development of innovative technologies to treat all malignancies, especially gynecologic cancer. The evolution of events brought forth new applicators and techniques that allowed for better distribution of the radiation dosage within the tumor being treated, safer use of radionuclides, and the development of computer programs allowing for varying source applications and dose distributions within the volume implanted.

Implantation guidelines for 169 Yb seed interstitial treatments.

The adequacy of an interstitial implant carried out with a new radioactive source, the 169 Yb seed model X1267, has been examined by computing volumetric indices based on dose-volume histograms. The comparison of these indices with the ones computed for 125I seed implantations shows that the use of ytterbium seeds presents an improvement of the dose homogeneity in interstitial implants. This is due to the significant build-up associated with 169 Yb photons that reduces the rapid dose fall-off with the distance from the source. Moreover, relative to 192Ir, the lower photon energy gives 169 Yb the advantage in clinical use of reduced radiation exposure (i) to health care workers, (ii) to relatives of treated patients and (iii) to healthy neighbouring tissues of the patients if appropriate thin shielding is used.

Carcinoma of the pancreatic head area. Therapy: intraluminal brachytherapy.

Intraluminal brachytherapy (Il-BRT) consists in the treatment of neoplasms by the positioning of radioactive sources in the lumen of cavitary organs such as the esophagus, the trachea, the bronchi and bile ducts. This procedure has been used to deliver relatively high doses of irradiation to bile duct and periampullary carcinomas while sparing the adjacent organs. Results of a number of reports appeared in the last fifteen years document the feasibility and tolerance of the procedure. Moreover these data seem to suggest that Il-BRT is able to prolong the survival of patients undergoing biliary drainage and that its use as boost dose in external beam radiotherapy (ERT) enhances the results of the latter. Combined ERT+Il-BRT is associated to an incidence of gastrointestinal ulcerations related to the total dose delivered. Better patient selection and standardization of reference dose represent prerequisites for testing this procedure in prospective randomized trials.

Intraluminal brachytherapy in the treatment of pancreas and bile duct carcinoma.

PURPOSE: A new method of palliation of malignant obstructive jaundice is presented. METHODS AND MATERIALS: Twelve patients with carcinoma of the extrahepatic bile ducts (EHBD-five patients) or pancreatic head (PH-seven patients) received radiation therapy between 1988 and 1991. Percutaneous transhepatic biliary drainage was performed in four EHBD patients and an endoprosthesis was placed during endoscopic retrograde cholangiopancreatography (ERCP) in the other eight patients. All 12 received intraluminal brachytherapy (ILBT): 20-50 Gy calculated at 1 cm from the Iridium-192 (192Ir) wire. In four PH patients the source was placed in the duct of Wirsung; in the other eight patients ILBT was performed via the common bile duct. Five of the seven PH patients and one of the five EHBD patients received External Beam Radiation Therapy (EBRT): 26-50 Gy, alone or with concomitant 5-Fluorouracil (5-FU). RESULTS: Cholangitis occurred in six patients. Three PH patients treated with EBRT+ILBT developed gastrointestinal toxicities. With a minimum follow-up of 18 months, median survival times were 14 months (EHBD) and 11.5 months (PH); one of the seven PH patients is alive (29 months) and two of the EHBD patients are alive (18 and 43 months). All patients had satisfactory control of jaundice. CONCLUSIONS: The results in the EHBD patients suggest that the addition of ILBT after biliary drainage prolongs survival. Further experience is necessary to determine whether ILBT in the common bile duct and/or in the duct of Wirsung may be, in PH patients, an alternative boost technique to Interstitial Brachy-therapy (IBT) or Intraoperative Electron Beam Radiation Therapy (IOEBRT).

Interstitial brachytherapy for low-grade cerebral gliomas: analysis of results in a series of 36 cases.

The results obtained with interstitial brachytherapy in thirty-six low-grade cerebral gliomas (2 pilocytic astrocytomas, 23 astrocytomas and 11 oligodendrogliomas) are reported (mean follow-up: 75 months, range 37-159). All tumours were situated in locations which did not call for surgical removal as the treatment of choice. Their volume ranged from 4 to 82 cc (m = 32); the Karnofsky performance status (KPS) of the treated patients lay between 0.60 and 0.90. The sources utilized (Iridium-192 in 32 cases and Iodine-125 in 4) were implanted permanently in 22 patients and temporarily in 14, using the Talairach stereotactic apparatus. The mean peripheral dose was 89.7 Gy for the permanent implants and and 42.8 Gy with a rate of 32.05 cGy/h for the temporary implants. External beam irradiation was added for tumour volumes greater than 35 cc (19 cases) on a second target volume extending 2 cm beyond the tumoural borders treated with interstitial irradiation. The survival estimates for the entire group showed a probability of 82.9% at 60 months, of 56.8% at 96, 39.4% at 120 (m.s.t.: 112 months). The quality of life in the treated patients was satisfactory, KPS never falling below a mean score of 0.70. The extent of the target volume turned out to be the most significant factor influencing survival at the multivariate analysis. Severe neurological impairment due to radionecrosis occurred in 4 patients (11%), three of them requiring surgical decompression.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic and therapeutic integration in ductal carcinoma of the head of the pancreas. Preliminary note]. / Esperienza di integrazione diagnostica e terapeutica del carcinoma duttale della testa del pancreas. Nota preliminare.

The diagnosis and treatment of pancreatic ductal carcinoma are managed, in our hospital, by a team of radiologist, surgeons, radiotherapists and pathologists. In periodic meetings they discuss the clinical cases before and after clinico-radiologic staging. Patients are entered one of three different treatment routes, based on their general status, on disease stage, tumor size and its arrangement around common bile duct and main pancreatic duct. Thirty-eight patients were studied: 23 of them, considered as resectable on the basis of imaging (CT, US) findings, were submitted to radical surgery and intraoperative radiotherapy (route I); of 11 unresectable cases, 8 had a bilio-digestive bypass and interstitial brachitherapy with 125I seeds (tumor size < 3 cm). Eleven patients unresectable by imaging and 1 by surgery followed treatment route II, characterized by radio-chemotherapy followed by intraluminal radiotherapy with 192Ir wires, relative to residual tumor size and to lesion arrangement around access ways. Four patients with metastases and "adequate" tumor size entered treatment route III-i.e., merely palliative luminal radiotherapy. This preliminary note stresses the importance of polyspecialistic team work in the diagnosis and treatment of pancreatic ductal carcinomas.

Interstitial irradiation for newly diagnosed or recurrent malignant gliomas: preliminary results.

The preliminary results obtained in 19 patients treated with interstitial irradiation for malignant gliomas are reported. Three different groups are included in the study: I Newly diagnosed tumours not suitable for surgery: 13 cases (10 anaplastic astrocytomas (AA) and 3 glioblastomas (GBM), mean volume 46.56 cc, source Ir 192) were implanted permanently (n = 11, mean peripheral dose 93.54 Gy) or temporarily (n = 2, 50 Gy = 0.5 Gy/hr). External beam irradiation was additionally applied in all cases. II Residual or recurrent tumours: 5 patients (2 AA and 3 GBM, mean volume 7.2 cc, source Ir 192) received temporary implants (150 Gy peripheral dose = 1.5 Gy/hr) after surgery and conventional radiotherapy. III Newly diagnosed surgically removable tumours: only one patient with AA (15 cc volume, source Ir 192) received temporary implantation with the same dose regimen used in Group II before surgery and external beam irradiation. A median survival time of 26.75 mos (34.62 mos for AA, with 3 long-term survivors) was observed in the patients of Group I. Three patients of Group II are still alive after 8, 12 and 12 mos after brachytherapy, the other 2 (GBM) survived 7 and 12 mos. The single patient so far included in Group III is still alive after 6 mos. Although the study is still in progress, these preliminary data seem to indicate that interstitial radiotherapy can be effective in prolonging survival of patients with malignant gliomas.

Carcinoma of the pancreas: a personal experience with 100 cases.

One hundred patients with pancreatic cancer were evaluated between March 1981 and December 1989. This study showed that 61 were not candidates for definitive surgery because of nonoperability (28 patients) or nonresectability (33 patients). An additional 25 patients had cancers that were unresectable because of metastases (13 patients) or local spread of disease (12 patients) discovered at laparotomy. Fourteen patients had resectable cancers. Ten were treated by total pancreatectomy, three by distal pancreatectomy and one by pancreatoduodenectomy (Whipple). There were two operative mortalities. The median patient survival time was 20.5 months. Two patients survived 5 years. Five patients are alive at 3, 14, 18, and 47 months. Palliative surgical procedures performed in 18 patients included 10 biliary bypasses, 9 gastrojejunostomies, and 6 T-tube placements. This was associated with an operative mortality rate of 11%. The median survival time was 5 months. Other palliative measures included endoscopic placement of biliary and pancreatic stents (47 patients, 2.7% mortality rate), endoluminal radiation therapy, interstitial radiation therapy and external beam radiation therapy. The median survival time of patients so treated was 4.5 months.

Interstitial brachytherapy for pancreatic cancer: report of seven cases treated with 125I and a review of the literature.

Since 1975, seven groups of investigators have reported clinical results of interstitial brachytherapy (IBT) for pancreatic cancer. The reports are comprised of data from 254 patients, 21 of whom died in the postoperative period for an overall operative mortality rate of 8.7%. Operative mortality rate range from 0% to 32% in individual reports. Most patients have been treated with 125I, although 25 patients were treated with 198Au seeds. Most investigators report combining IBT with external beam radiation therapy (EBRT) +/- adjuvant chemotherapy. In general, IBT has been associated with considerable morbidity. Median patient survival time has not exceeded 15 months. This report describes an additional seven patients with locally unresectable pancreatic cancer, without distant metastases, treated primarily with 60 to 100 Gy matched peripheral dose (MPD) by 125I IBT. One patient died postoperatively of a pulmonary embolus. Four of the remaining six patients were also treated with modest doses (10.5 to 30 Gy) of EBRT late in the course of the disease for local tumor progression. One developed a pancreaticocutaneous fistula, and one developed exacerbation of pre-existing diabetes mellitus. The median patient survival time from the date of IBT was 7 months (range: 0 to 21 months). One patient is alive without clinical evidence of cancer 9 months after IBT.