Metastatic carcinoid and islet cell tumours of the pancreas: a phase II trial of the efficacy of combination chemotherapy with 5-fluorouracil, doxorubicin and cisplatin.

A phase II trial of chemotherapy in carcinoid and islet cell pancreatic tumours has been conducted with the FAP protocol: 5-fluorouracil 400 mg/m2 per day (5-FU) for 3 days, 50 mg/m2 doxorubicin on day 2, and 90 mg/m2 cisplatin on day 2, repeated every 4 weeks. 24 patients, 20 non-pretreated and 4 pretreated, were included. For non-pretreated patients we observed 1 complete response and 2 partial responses. The response rate was 15% (95% confidence interval 0-31%). No response was observed in the pretreated patients. The toxicity was mainly digestive and haematological with 7 patients experiencing vomiting grade 3 and 3 patients with leucopenia grade 3. We conclude that the FAP protocol is of poor efficiency in endocrine tumours.

Prognostic value of neural invasion in rectal carcinoma: a multivariate analysis on 339 patients with curative resection.

To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.

Accelerated fractionation in esophageal cancers: a multivariate analysis on 88 patients.

PURPOSE: Accelerated fractionation was used to shorten overall treatment time to increase locoregional control and cause-specific survival. METHODS AND MATERIALS: Eighty-eight patients with cancer of the esophagus ineligible for surgery were entered in the study between 1986 and 1993. Neoadjuvant chemotherapy was given to 64% of patients. Accelerated radiotherapy using the concomitant boost technique delivered a median dose of 65 Gy in a median overall treatment time of 32 days. RESULTS: The 3-year actuarial local control rate in patients with T1, T2, and T3 tumors was 71%, 42%, and 33%, respectively. The 3-year cause-specific survival rates were 40%, 22%, and 6%, respectively. Sixteen percent of patients experienced Grade 3 esophagitis. Late toxicity included esophageal stenosis and pulmonary fibrosis in 8% and 9% of the patients, respectively. Multivariate analysis demonstrated that T stage and overall treatment time were prognostic factors for cause-specific survival. T stage and neoadjuvant chemotherapy were independent prognostic factors for locoregional control. CONCLUSION: These findings suggest that accelerated fractionation given in an overall treatment time of <35 days might be beneficial for early-stage cancer of the esophagus. Neoadjuvant chemotherapy is not recommended, as it was a significant adverse prognostic factor in the multivariate analysis for local control. Accelerated fractionation can be carried out with moderate acute and late toxicity.

Squamous cell carcinoma of the anal canal: treatment by external beam irradiation.

External beam radiation therapy alone or in combination with curietherapy is the recommended treatment for anal canal carcinoma in some countries. In others, surgery is the sole accepted treatment. The results for 64 patients treated by external radiotherapy alone show excellent survival for stage T1T2 tumors but results are poor for large tumors (stage T4). The overall 5 year crude survival rate is 46%. The 5-year results are better for stage T1T2 (72%) than for stage T3T4 (35%). The presence of inguinal node involvement at first examination is a very poor prognostic sign. Local recurrences and metastases are infrequent for stage T1T2, but are more common for stage T3 and T4. Complications follow radiotherapy more frequently in those with stage T3 and T4 tumors. The analysis of local recurrences, complications and survival shows that radiation therapy may be sufficient treatment for stage T1 and T2 and for some stage T3 tumors. The importance of anal sphincter involvement and the poor quality of life for patients who are cured but develop complications, shows the need for combined treatment with surgery and perhaps with chemotherapy. For small tumors the results obtained by external radiotherapy alone are comparable with those obtained by external radiotherapy and curietherapy in terms of survival and complications.

Esophageal squamous cell carcinoma: the specific limited place of surgery defined by a prospective multivariate study of prognostic factors after surgical approach.

From 1982 to 1990, 181 patients underwent surgery for esophageal squamous cell carcinoma, for which 14 prognostic parameters were prospectively recorded in order to perform a multivariate study. A squamous cell head and neck cancer was associated with the esophageal tumor in 40% of the cases (synchronous 18% and metachronous 22%). Resection was curative (i.e. macroscopically complete) in 128 cases, palliative (i.e. with residual tumor) in 24 cases and not possible in 29 cases. There were 21 deaths in hospital (hospital mortality was 11.7%). One hundred and twenty-two patients received preoperative chemotherapy and 77 received postoperative radiotherapy according to different phase II prospective studies. The 5-year survival rate according to the Kaplan-Meier method was 15.8% (+/- 3.4) for all patients and 23.5% (+/- 4.8) for the patients who had a curative resection. A palliative resection or the invasion of a neighbouring organ was synonymous with incurability, but positive lymph nodes were not considered proof of incurability. The multifactorial study concerning all the patients highlighted two main prognostic parameters: the histological staging according to the Japanese classification (P = 0.0006) and the type of resection (curative or not) (P = 0.006). An objective response to preoperative chemotherapy was the third and last parameter revealed by Cox's model. The multivariate study, which was limited to the 112 patients who were alive after a curative resection, showed that only the stage was an important prognostic factor (P = 0.003), with stages 2 and 3 carrying a worse prognosis. We propose a therapeutic scheme, based on these prognostic data and on the usual pre-therapeutic workup with three additional exams: CT scan measurement of tumor diameter, ultrasound examination +/- fine needle aspiration cytology of supra-clavicular lymph nodes and echo-endoscopy. The aim of this scheme is to limit surgery to the subgroup of patients for whom this modality is really beneficial.

Neoadjuvant chemotherapy in multiple synchronous head and neck and esophagus squamous cell carcinomas.

A consecutive series of 22 patients with multiple synchronous squamous cell carcinomas of the upper aerodigestive tract was retrospectively reviewed. These patients were treated initially with cis-platinum combination chemotherapy before definitive locoregional therapy (surgery and/or radiation therapy). Sixteen of 21 patients had simultaneous head and neck and esophageal primaries, 3 patients had multiple synchronous head and neck primaries, 2 patients had head and neck (HN) and a bronchial epidermoid cancer, and 1 patient had simultaneous esophageal and bronchial carcinomas of epidermoid lineage. Sixteen (77%) of the 21 patients responded to chemotherapy in all the tumor sites evaluated, and a clinically complete response was obtained in 6 (29%). After definitive locoregional treatment, the complete local control rate was 68%, with 34 complete responses for 50 primary tumor sites in 21 patients. Twelve patients were free of disease after locoregional treatment. Six patients are still alive 27 to 57 months after complementary definitive locoregional treatment and a minimum follow-up of 27 months. Median survival for the overall group is 17 months. The response to chemotherapy is remarkable, which may be due to the small tumoral volume present in many of the cases (T1 to T2). Nevertheless, the present report stresses the importance of an aggressive combined therapeutic approach in this difficult clinical situation.

[Epidermoid cancers of the esophagus: combined chemotherapy, surgery and radiotherapy. Preliminary results in 50 cases]. / Cancers épidermoïdes de l'oesophage: association chimiothérapie, chirurgie et radiothérapie. Résultats préliminaires sur 50 cas.

Fifty operable epidermoid esophageal carcinomas were treated by combined chemotherapy, surgery and radiotherapy. The post-operative mortality was 5.4% and the severe post-operative morbidity was 29%. The vindesine-5FU-platinum association and the vindesine-endoxan-platinum association gave respectively 55% and 35% objective responses (OR) after two preoperative courses without increasing the operative mortality. The patients who showed an OR had a less important tumoral extension. Thus, an objective response to the pre-operative chemotherapy is in fact a new prognostic factor. Survival without recurrence seems to be increased when chemotherapy is efficient in the curative resection group. These findings incite to promote prospective randomized studies with this kind of combined therapy.

[Synchronous cancers of the esophagus and of the ORL area: results of combined treatments with esophagectomy (28 cases)]. / Cancers synchrones de l'oesophage et de la sphère ORL: résultats des traitements combinés avec oesophagectomie (28 cas).

Twenty-eight patients with synchronous esophageal and head and neck epidermoid cancers have been treated by a combined protocol including esophagectomy. Seventy-nine percent received pre-operative chemotherapy, 50% had resection of the head and neck lesion at the same time as the esophagectomy and 79% received post-operative irradiation. Two patients died during the post-operative period (7%), and 1, 2 and 3-yr survival rate (Kaplan-Meier) was respectively 64, 32 and 27%. Contrary to our initial assumption, there was no significant decrease in survival compared to patients operated on for an isolated esophageal cancer. The patients were divided into 4 very simple prognostic groups based on the T and N stages of the clinical pre-therapeutic TNM classification: T1 or T2 for esophageal lesions and different T or N stages according to the prognosis for head and neck lesions. A study of each group tended to show that esophagectomy was beneficial except in cases of synchronous T2 esophageal cancer and locally advanced head and neck cancer (there was 2-yr survival in this group). The 28 patients studied represent a particular population which presented 91 cancerous localisations during the duration of the study (mean: 3.25 localisations per patient).

[Combination vindesine, cyclophosphamide, cis-platinum and CCNU in esophageal epidermoid cancer. Preliminary analysis of 64 cases]. / Association vindésine, cyclophosphamide, cis-platinum et CCNU dans les cancers epidermoïdes de l'oesophage. Analyse préliminaire de 64 cas.

We have treated 64 patients with esophageal squamous cell carcinoma using a combination of Vindesine 1.4 mg/m2 on day 1-2, Cyclophosphamide 200 mg/m2 on day 2-3-4, Cis-Platin 100 mg/m2 on day 3 and CCNU. 28 of the 37 patients considered to be inoperable were evaluable. We observed three complete responses and three partial responses in this group (overall response rate 21,5%). Twenty seven patients considered to be operable received the same chemotherapy without CCNU, owing to the risk of thrombopenia. 23 of these patients were evaluable in whom we observed 35% partial responses and no complete responses. No severe toxicity related to the chemotherapy protocol was observed. The mediocre results among the group of inoperable patients suggest that other chemotherapy protocols need to be tested. On the other hand, in the group of operable patients, the preliminary results encourage us to continue this study.

[Epidermoid cancer of the esophagus: is the combination of chemotherapy then surgery beneficial?]. / Cancers épidermoïdes de l'oesophage: l'association chimiothérapie puis chirurgie est-elle bénéfique?

Ninety-two patients with carcinoma of the esophagus were treated with pre-operative chemotherapy (2 courses) before undergoing surgery. Chemotherapy and/or radiation were carried out after surgery depending on the tumor response to chemotherapy and extent of the tumor found at surgery. Tumor response before surgery (according to OMS criteria) was determined in 84 patients. Forty-four percent of patients showed a tumor regression of over 50%. Curative surgery was more frequently performed in patients with good tumor regression (greater than 50%) than in patients with less satisfactory tumor regression (less than 50%) (76 versus 57.5% respectively) (P = 0.08). Patients who underwent curative surgery had a lower pathologic staging when tumor regression was over 50%. However, the number of patients is too limited for any definite conclusions to be made. Survival rate at 3 years was similar in both groups of patients with curative surgery. Survival was not influenced by the extent of tumor regression before surgery. This study also suggests that the pre-operative chemotherapy did not increase the survival rate of patients who underwent curative surgery. Therefore it does not seem advisable to undertake a phase III randomized study on pre-operative chemotherapy patients.

[Importance of a multidisciplinary approach to metastatic cancer of the rectum]. / Intérêt d'une approache multidisciplinaire des cancers du rectum initialement métastatiques.

Management of rectal cancers with synchronous metastasis is difficult. We evaluated in 23 patients a combination of pelvic radiotherapy at the dose of 45 Gy in 5 weeks and 25 fractions with chemotherapy by 5-fluorouracil (350 mg/m2/day) and folinic acid (20 mg/m2/day) for 5 days at the time of the first and the fifth week of the irradiation. Surgery was indicated firstly in cases of stricture or secondarily for resection of the primary location and, when possible, of the metastasis. General state of health of the patients improved in 35%, symptomatology in 86% and comfort in 72% of the cases. Response rates for the primary tumor were 41% of partial response and 50% of stable disease. For the metastatic lesions, they were 9% and 59% respectively. Sixty-one per cent of patients were secondarily operated with resection of the primary tumor in 12 cases and of hepatic metastases in 2 cases. The median survival and the median survival without progression were respectively 13 and 9 months. Radiochemotherapy combination as the first treatment was beneficial in 4/5 of the patients presenting a rectal cancer with synchronous metastasis and allowed us to select those that would secondarily benefit from a surgical resection.

[Efficacy of a daily application of mesalazine (Pentasa) suppository with progressive release, in the treatment of ulcerative proctitis. A double-blind versus placebo randomized trial]. / Efficacité d'une application quotidienne d'un suppositoire de mésalazine (Pentasa) à libération progressive, dans le traitement des poussées de rectite ulcéro-hémorragique. Essai randomisé en double aveugle contre placebo.

Therapeutic efficacy of mesalazine controlled-release suppository 1 g once daily was compared with that of a placebo during 2 weeks in 50 patients (26 in the mesalazine group, 24 in the placebo group) with ulcerative proctitis, in a double-blind randomized trial. Endoscopic and clinical remission was seen in 69 and 65% of mesalazine-treated patients and in 33 and 25% of placebo-treated patients respectively (P < or = 0.01). No side effects were seen. It is concluded that a once-a-day administration of 1 g mesalazine controlled-release suppository is effective for topical treatment of patients with ulcerative proctitis.

[A multivariate prospective study of prognostic factors in 200 operated epidermoid cancers of the esophagus. Definition of patients for whom surgical resection was of benefit]. / Etude multifactorielle prospective des facteurs pronostiques de 200 cancers épidermoïdes de l'oesophage opérés. Définition des malades tirant bénéfice de l'exérèse chirurgicale.

From 1982 to 1991, 200 patients with squamous-cell esophageal cancers underwent operation. Sixteen prognostic parameters were prospectively collected and analyzed. The main aim of this study was to define the best preoperative criteria for selection for curative surgery and which patients would benefit most from radical resection. Squamous-cell head and neck carcinoma was associated in 43.5% of cases. Of these, 24% preceded the esophageal carcinoma while 19.5% were synchronous. Resection was curative (i.e. grossly complete) in 144 cases, palliative (leaving gross tumor behind) in 25 cases, and judged impossible in 31 cases. Twenty-one patients died during their hospitalization. Five-year survival, according to the Kaplan-Meier method, was 18 +/- 3.6% for all patients, and 27 +/- 4.8% for patients undergoing curative resection (including postoperative mortality). Palliative resections or invasion of adjacent organs, but not resection with positive lymph nodes, was thought to be synonymous with incurability. Multivariate analysis showed that the two principal statistically significant characteristics were the stage as determined by roentgenological and endoscopic evaluation (P = 0.003) (clearly assessable during initial work-up) and type of resection (complete or not) (P = 0.04). Tumor diameter, as determined on CT-scan (< or > than 30 mm), was at the limit of statistical significance (P = 0.09). A second multivariate analysis of prognostic factors was conducted in 128 patients undergoing resection with curative intent and who survived the initial postoperative period. Roentgenologic/endoscopic staging alone emerged as being statistically significant (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Gastroduodenal complications of hepatic intra-arterial chemotherapy of hepatic metastases of colorectal origin]. / Complications gastroduodénales de la chimiothérapie intra-artérielle hépatique pour métastases hépatiques d'origine colorectale.

Fifty-eight patients with colorectal liver metastases were treated by intra-arterial hepatic chemotherapy (IAHC) containing 5 FU (n = 42) or FUDR (n = 16). Twenty-three patients (39.6 p. 100) complained of abdominal pain. In three of these patients, the course was complicated by digestive hemorrhage. Endoscopic explorations and angioscintigraphy were normal in 4, showed oesophagitis in 3, superficial gastritis or duodenitis in 8 (34.7 p. 100) and gastric (2) or duodenal ulceration (6) in 8 (34.7 p. 100). The duodenal ulceration was extensive and considered to be cause of hemorrhage in two cases. Duodenal perforation due to the catheter was discovered in two other cases, one of which was secondary to tumoral extension revealed by forceps biopsy. This patient died 3 months later. Surgical treatment was mandatory in the other case due to digestive hemorrhage but did not prevent death. Angioscintigraphy performed in 15 patients with gastroduodenal inflammation or ulceration was normal in 7 patients, revealed arterial thrombosis in 5 and an extra-hepatic perfusion in the gastroduodenal area in 3 : this was related to a small pyloric artery which was occluded secondarily. IAHC was continued there after. This experience underlines the importance of exploring patients with digestive symptoms during IAHC so that it may be temporarily discontinued while an inadequately positioned infusion catheter may be corrected should gastroduodenal ulceration occur.

Anti-genotoxic activity of the mushroom Lactarius vellereus extract in bacteria and in mammalian cells in vitro.

In a previous study we screened a range of mushroom species growing in Slovenia for their anti-genotoxic potential and found Lactarius vellereus to be the most effective. In this study genotoxic and anti-genotoxic activities of methanol extracts of Lactarius vellereus (Fr.: Fr.) Fr. were evaluated in the bacterial reverse mutation test with Salmonella typhimurium TA98 and, in the mammalian cell test with human hepatoma (HepG2) cells, using the comet assay to measure DNA damage. The extract induced no mutations in S. typhimurium TA98 and no DNA damage in HepG2 cells. Against the indirect acting mutagen 2-amino-3-methylimidazo(4,5-f)quinoline (IQ) the extract showed significant, dose dependent antimutagenic activity, while it did not counteract the direct acting mutagen 4-nitroquinoline oxide (4-NQO). The extract also exerted a protective effect against IQ induced genotoxicity in mammalian cells of human origin. Treatment of HepG2 cells with the L. vellereus extract (125-500 microg/ml) together with IQ, reduced the genotoxic effect of the latter in a dose dependent manner. Our findings show that a methanol extract of L. vellereus is highly protective against IQ induced DNA damage in human derived cells and L. vellereus can be considered as a natural source of antimutagens with potential pharmacological applications in cancer prevention.

[Esophagectomy for epidermoid cancer discovered during evaluation of ENT cancer]. / Oesophagectomie pour cancer épidermoïde découvert lors du bilan d'un cancer ORL.

UNLABELLED: The treatment of synchronous esophageal and head and neck carcinomas is difficult. MATERIAL AND METHOD: Retrospective study of 33 patients treated with esophagectomy for an intrathoracic squamous cells carcinoma discovered during pan-endoscopy for a synchronous head and neck cancer. RESULTS: In 7 cases (21%) it was advanced (pT3-4) esophageal cancers. The hospital mortality was 9%. Five year survival was 18% without stabilization of the survival curve, 60% of patients died of recurrence of tumor. CONCLUSION: Esophagectomy is suitable for usT1-2 tumors if surgery is also indicated for the head and neck tumor. Radiochemotherapy is indicated for advanced usT3-4 esophageal tumors or when the treatment of the head and neck tumor is not surgery.

[Epidermoid cancer of the esophagus. Does the efficacy of chemoradiotherapy justify surgical abstention?]. / Cancers épidermoïdes de l'oesophage. L'efficacité des traitements chimio-radiothérapiques autorise-t-elle l'abstention chirurgicale?

Nine inoperable patients with squamous esophageal cancer were selected from 112 patients treated with combination chemo-radiotherapy. The criteria of selection were: 1) localized cancer (T1 or T2 of the TNM classification), 2) complete response after neoadjuvant chemotherapy suggesting the possibility of a good survival, 3) and 65 Gy-irradiation in the previous tumor bed. Eight of these 9 carcinomas recurred locally after a median delay of 12.6 months after the end of the treatment (extremes: 2 and 30 months). Only one patient is free of disease 24 months after the end of the treatment. These results point out that this chemo-radiotherapeutic association is disappointing in the long term in terms of loco-regional tumoral control and survival, but appeared to be good palliative treatment. This is an argument against the attitude of physicians who currently recommended a non-surgical strategy and deny the value of surgery. The carcinologic surgical excision of esophageal cancers is still the best treatment today. It must be performed whenever it is feasible, possibly associated with complementary treatments (evaluated in prospective studies).

[Epidermoid cancers of the operated esophagus. High incidence of associated neoplasia]. / Cancers épidermoïdes de l'oesophage opéré. Incidence élevée des néoplasies associées.

In a retrospective study we counted the number of neoplasias associated with oesophageal epidermoid cancer, as we thought that their frequency and influence on treatment had been underestimated. Between 1982 and 1990, 181 patients underwent surgery of oesophageal epidermoid cancer. The global actuarial 5-year survival rate was 20.7 percent (28.8 percent after complete excision of the tumour). The mean follow-up period was 4.2 +/- 2.6 years. These 181 patients had a total of 324 cancers, 97 percent of which were cancers of the upper respiratory and digestive tracts. The frequency of associated cancers was 56 percent (102 out of 181), and 50 percent of the patients presented with at least one associated head and neck cancer. Twenty-two percent of the patients had been treated for another cancer before the oesophageal epidermoid cancer, and in 19 percent of the cases this was a head and neck cancer. Thirty-five percent had a malignancy that was contemporary with the oesophageal cancer (this malignancy affected the head and neck in 18 percent of the cases and consisted of multiple lesions in 25 percent). During the short period under study, in only 10 percent of the patients did a cancer develop after the oesophageal one, and 6 percent of these affected the head and neck. This high incidence of associated neoplasia was due to tobacco and alcohol abuse. The presence of multiple cancers should alter as least as possible the treatment required by each associated cancer in order to optimize the chances of complete cure. Close surveillance of the high-risk population may result in the early discovery of a 2nd cancer at a curable stage. For the time being, the prevention of such associated cancers relies more on daily administration of retinoids than on alcohol and tobacco abstinence which is difficult to obtain.

[Value of endorectal ultrasonography in the treatment of rectal tumors]. / Intérêt de l'échographie endorectale pour le traitement des tumeurs rectales.

OBJECTIVES: To determine the diagnostic accuracy of endosonography and to appreciate its influence on the therapeutic strategy. METHODS: Sixty-two patients referred to the gastroenterology unit between April 1990 and February 1995 for a rectal tumor. Thirty-two patients did not receive any preoperative treatment (group A) and 30 were treated by radiotherapy or chemoradiotherapy before surgery (group B). Transrectal ultrasonography was performed with a Bruel and Kjaer device. RESULTS: Diagnostic accuracy for parietal infiltration was 84% for the entire series, 94% for group A and 73% for group B. Diagnostic accuracy of lymph node invasion was 71% for the entire series, 81% and 60% for groups A and B, respectively. It is highly probable that a histopathologic down-staging due to preoperative treatment explained the results in the group B. Using a pragmatic approach which combined the results for parietal infiltration and for lymph node invasion, transrectal ultrasonography would have correctly selected 20 among the 25 patients who could have been treated by local excision. The use of this same pragmatic approach in patients with high risk of local recurrence enabled correct selection of 26 among the 32 exposed patients. CONCLUSION: We conclude that transrectal ultrasonography: 1. is a reliable technique for the pretherapeutic staging of rectal cancer, especially for the assessment of parietal infiltration. Progress is needed for the diagnosis of lymph node invasion; 2. selects well the patients who can be treated by local excision; 3. is a reliable technique for the selection of patients who need preoperative treatment.

[Retrospective study of 88 cases of cancer of the cervical esophagus and definition of a new therapeutic approach]. / Etude rétrospective de 88 cas de cancers de l'oesophage cervical et définition d'une nouvelle approche thérapeutique.

Eighty-eight cases of cancers of the cervical esophagus were treated at the Institut Gustave-Roussy (France) between 1968 and 1980. They included 67 epitheliomas of the esophageal opening excluding those of the hypopharynx extending into the esophagus, and 21 epitheliomas of the actual cervical portion of the esophagus. Whenever possible, basic therapy was by radiotherapy (64 cases). There were no survivors after 2 years, possible explanations for this poor result being the selection criteria for treatment, the choice of radiotherapy as basic treatment, and the doses employed. A new therapeutic approach is suggested following a pathological study and an analysis of the different therapeutic possibilities available. Pre-operative chemotherapy is followed by total laryngopharyngectomy with total esophagectomy without opening of the thorax, performed under certain well defined conditions. Continuity is reestablished by gastropharyngostomy and postoperative radiotherapy is applied systematically. This therapeutic approach involving major surgery is applicable only for selected patients, others having to be treated by combined radiotherapy and chemotherapy alone.