Radiation therapy of pancreatic cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of pancreatic tumors. Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In the adjuvant setting, the standard treatment is six months of chemotherapy with 5-fluorouracile, irinotecan and oxaliplatin. Chemoradiation may improve the survival of patients with incompletely resected tumours (R1). This remains to be confirmed by a prospective trial. Neoadjuvant chemoradiation is a promising treatment especially for patients with borderline resectable tumours. For patients with locally advanced tumours, there is no standard. An induction chemotherapy followed by chemoradiation for non progressive patients reduces the rate of local relapse. Whereas in the first trials of chemoradiation large fields were used, the treated volumes have been reduced to improve tolerance. Tumour movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique has poor evidence-based recommendation. Stereotactic body radiation therapy is also being studied, as a neoadjuvant or exclusive treatment.

[Sorafenib and radiotherapy association for hepatocellular carcinoma]. / Sorafénib et radiothérapie dans le carcinome hépatocellulaire.

Conformal radiotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC), producing local control rates above 90% within the radiation beam. However, survival after radiotherapy remains limited by the high frequency of intra- and extra-hepatic recurrences, which occurs in 40-50 and 20-30% of cases, respectively. Sorafenib (BAY43-9006, Nexavar; Bayer, West Haven, CT) is a small-molecule inhibitor that demonstrated potent activity to target v-raf murine sarcoma oncogene homolog B1 (BRAF) and VEGFR tyrosine kinases. Sorafenib is the only drug that demonstrated effectiveness to increase overall survival in advanced or metastatic hepatocellular carcinoma. The rationale to combine radiotherapy with sorafenib is the following: (1) targeting RAS-RAF-MAPK and VEGFR signaling pathways, which are specifically activated after exposure to radiation, and responsible for radio-resistance phenomenon; (2) enhancing the oxygen effect through normalization of the surviving tumor vasculature; and (3) synchronization of the cell cycle. Sorafenib and radiotherapy represent complementary strategies, as radiotherapy may be useful to prolong the effect of sorafenib through control of the macroscopic disease, when sorafenib may target latent microscopic disease. Sorafenib and radiotherapy associations are thus based on a relevant biological and clinical rationale and are being evaluated in ongoing phase I-II trials.

[Nonsurgical management of hepatocellular carcinoma]. / Prise en charge non chirurgicale du carcinome hépatocellulaire.

Most of patients with hepatocellular carcinoma (HCC) cannot benefit from surgical therapies. Among nonsurgical options, only radiofrequency can challenge surgery for small size tumours. Conformal radiotherapy is likely highly efficient on solitary tumours, but controlled studies are warranted to conclude. Other options are purely palliative. Transarterial hepatic chemoembolization is the goal-standard for multifocal hepatocellular carcinoma and sorafenib for hepatocellular carcinoma with portal vein invasion, leading to modest but significant benefit on survival rates. Yttrium-90 radioembolization is under evaluation through controlled studies, and could be of major interest for multifocal hepatocellular carcinoma with or without portal venous invasion.

Markedly effective local control of hepatocellular carcinoma with a poor prognosis by combined multimodal therapy with sorafenib as a neoadjuvant approach.

Sorafenib has recently been approved as the gold standard therapy for advanced BCLC-C hepatocellular carcinomas. Although significant improvement of survival rates was shown, objective tumor response rates remained low following RECIST criteria in phases 2 and 3 studies. We report the rare case of a patient with a large hepatocellular carcinoma tumor invading suprahepatic veins in which sorafenib led to a very significant regression by about 90% of the tumor bulk, thus allowing at sterilizing the residual tumor tissue by subsequent combination of transarterial intrahepatic chemoembolization and high dose radiotherapy.

Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.

BACKGROUND: The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain. PATIENTS AND METHODS: One hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m(2)/day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2)/day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. RESULTS: Overall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1-11.4) and 13 months (8.7-18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). CONCLUSION: This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.

[Chemoradiation for pancreatic adenocarcinoma]. / Chimioradiothérapie des adénocarcinomes pancréatiques.

Surgery remains the cornerstone treatment for pancreatic adenocarcinoma. However, 5% to 20% of tumors only are regarded as resectable, and, among them, only few benefit from an histological complete resection, major survival parameter. These data explain the overall poor prognosis of this disease, with a respectively 20% and 5% 1- and 5-year survival rates. These results justify an adjuvant or neoadjuvant therapeutic approach, mainly based on concurrent chemoradiation, with and without surgery. This paper reviews the different therapeutic approaches of non metastatic pancreatic adenocarcinoma.

[Chemoradiation in pancreatic carcinoma]. / Chimioradiothérapie des adénocarcinomes du pancréas exocrine.

Prognosis of pancreatic carcinoma remains poor, with one-year and five-year overall survival rates of 20 and 5% respectively. Only 5 to 15% of patients present with tumors amenable to resection. Long-term (5 years) survival after curative resection is less than 20%, and the median survival is about 12 months. This paper updates recent trends about concomitant chemoradiation. At first, a review of the studies on adjuvant chemoradiation after surgery is proposed. Then, indications of preoperative chemoradiation for patients with localized resectable adenocarcinoma are discussed. The last part concerns the most important and recent studies about chemoradiation in locally advanced pancreatic cancer, either with 5-fluoro-uracile or based on new drugs like gemcitabine.

[Curative treatment of non-metastatic esophageal cancer: concomitant chemoradiotherapy and high-dose-rate endoluminal curietherapy boost]. / Traitement à visée curative du cancer de l'oesophage non métastatique: chimio-radiothérapie concomitante et surdosage par curiethérapie endoluminale à haut débit de dose.

OBJECTIVES: The aim of this study was to evaluate the feasibility, toxicity, and efficacy of a curative combination of chemo-radiotherapy with high-dose-rate brachytherapy (HDRB) in patients with non metastatic esophageal cancer. PATIENTS AND METHODS: Fifty-two patients with esophageal carcinoma were treated with > 50 Gy external irradiation, concomitant chemotherapy (5FU-CDDP) followed by HDRB delivering 12.5 Gy (6-20) as a boost. Twelve patients were stage I, 20 stage IIa, 5 stage IIb, and 13 stage III, 1 Tis, 1 stage N unknown. Surgery was not indicated for medical reasons. RESULTS: The response rate was 96%, with complete response rate 85%. The 1-, 3-, 5-year overall survival rates were 78%, 33%, and 22% respectively. A local failure occurred in 32%, and distant metastasis in 16%. Severe (grade 3, 4) acute toxicity occurred in 6 cases, severe late toxicity in 2 cases and there was 1 toxic death. Tumoral length > or = 5 cm and stage IIa, IIb and III versus stage 1 indicated poor prognosis. CONCLUSION: This regimen is feasible and well tolerated. The 5-year overall survival is 22%, but the local failure rate is still very high. These results are encouraging and will be prospectively evaluated with currently ongoing randomized trial.

Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.

PURPOSE: To evaluate the long-term results of the treatment of anal canal carcinoma (ACC) with a combined concomitant radiochemotherapy (CCRT) treatment using fluorouracil (5 FU) and cisplatinum (CDDP) with a high dose of radiation therapy. PATIENTS AND METHODS: Between 1982 and 1993 a series of 95 patients were treated. Staging showed a majority of advanced squamous ACC, i.e. 6 T1, 47 T2, 28 T3, 14 T4, 53 NO, 32 N1, 6 N2 and 4 N3. Irradiation was done with high dose external beam radiation therapy (EBRT) followed by a boost with 192 Iridium implant. During EBRT all patients received one course of 5 FU continuous infusion (1 g/m2/day, days 1-4) and CDDP (25 mg/m2/day, bolus days 1-4). RESULTS: The median follow-up time was 64 months. At 5 and 8 years the overall survival was 84 and 77%, the cancer specific survival was 90 and 86% and the colostomy-free survival was 71 and 67%, respectively. The stage and the response of the tumor after EBRT were of prognostic significance. Patients with pararectal lymph nodes had an overall 5-year survival of 76% (versus 88% for non-N1). Among 78 patients who preserved their anus, the anal sphincter function was excellent or good in 72 (92%). CONCLUSION: According to these results and recent randomized trials, CCRT appears as the standard treatment of ACC. Radical surgery should be reserved for local recurrence or persisting disease after irradiation. High dose irradiation in a small volume with concomitant 5 FU-CDDP appears to give a high rate of long-term local control and survival. Careful evaluation of pararectal nodes is essential for a good staging of the disease.

Radioimmunotherapy of athymic mice bearing human colon carcinomas with monoclonal antibody B72.3: histological and autoradiographic study of effects on tumors and normal organs.

Monoclonal antibody (MAb) B72.3 has been linked successfully to several radionuclides forming stable complexes and analyzed in vitro and in vivo without significant loss of its immunoreactivity. Previous studies have demonstrated that radioiodinated B72.3 can selectively bind to human colorectal carcinomas grown in athymic mice. The same successful localization has been obtained more recently in clinical trials in patients with metastatic colorectal carcinomas. The high degree of selective binding of this MAb has led us to investigate its potential as a radioimmunotherapeutic agent. Athymic mice bearing human colon carcinoma xenografts were injected with either 300 or 500 microCi of 131I-B72.3 IgG to assess the effect o the radiolabeled MAb on the tumor growth as well as potential toxic side effects in vital organs. In mice treated with the 131I-B72.3 IgG, a marked inhibition of the growth of the human colon carcinoma xenografts was noticed in comparison with control mice injected with PBS or control mice that received unlabeled B72.3 IgG. The tumors from these control mice weighed 2.7 to 3.7 times more than the tumors from the treated mice at 17 days post-inoculation of the radiolabeled MAb. Autoradiographic studies demonstrated a heterogeneous distribution of radioactivity throughout the tumor mass at 11 days post-administration of MAb. With time, the periphery of the tumor contained significantly less radioactivity than the medial areas composed of predominantly nonviable tissue; these findings suggest that the more biologically active peripheral tumor zones, with higher mitotic rates, could have partially escaped the radiation effect of the single dose administered. The tumor cells could have continued dividing when the levels of circulating radiolabeled monoclonal antibody had decreased. Toxicity was readily evident in the mice injected with the high-dose regimen (500 microCi), with confirmed bone marrow aplasia that proved lethal for 2 of 10 animals. The lower dose (300 microCi) resulted in a bone marrow suppression of approx. 50% of the cells, which proved to be non-lethal. The tumors in the treated mice showed extensive necrosis caused by the lethal dose of 131I-B72.3 that irreversibly damaged the cells. Radiation-induced terminal differentiation of cells was also found as manifested by the drastically decreased mitotic count (0-2 vs. 12-14 per 10 high power fields seen in control tumors) in treated animals.