[Research on antiemetics: an Italian model of success]
Divisione Oncologia Medica, Ospedale Policlinico, Perugia. email@example.com
At the beginning of the 80's the Italian Group for Clinical Research (G.O.I.R.C.) identified chemotherapy-induced nausea and vomiting as one of the most distressing adverse events, and decided to plan and execute clinical trials on antiemetics in order to reduce this negative impact on patients. Therefore, some consecutive double-blind randomized trials were conducted on cisplatin-treated patients. The first was a dose-finding study on four different high-doses of domperidone, followed by a study comparing two different high-doses of metoclopramide, and a study comparing the addition of a corticosteroid to high-dose metoclopramide with respect to metoclopramide alone. Finally, a study demonstrating that a combination of a higher dose of metoclopramide (3 mg/kg x 2) plus dexamethasone and diphenhydramine was significantly superior with respect to a lower dose of metoclopramide (1 mg/kg x 4) combined with methylprednisolone was carried out. With the introduction of the 5-HT3 receptor antagonists the interest for antiemetic therapy increased and other Italian gynecological and medical oncology centres became involved in the antiemetic research. The Italian Group for Antiemetic Research was formed in 90's and its first study demonstrated the superiority of a combination of a 5-HT3 receptor antagonist plus dexamethasone with respect to the standard three drug combination of high doses of metoclopramide in the prevention of cisplatin-induced acute emesis. In the following years, the Group contributed to the identification of the best antiemetic prophylaxis for acute emesis induced by moderately emetogenic chemotherapy, and for delayed emesis induced by cisplatin. Also a drug utilization review on antiemetics in clinical practice has recently been carried out. Today, the interest of the Group is concentrated in studying the optimal antiemetic prophylaxis for delayed emesis induced by moderately emetogenic chemotherapy. The rules always followed by the Italian Group for Antiemetic Research are: --complete independence of judgement on the efficacy and the tolerability of antiemetic drugs from the pharmaceutical companies; --priority of ethical problems in designing clinical trials; --strict adherence to the methodological problems of antiemetic research and--complete autonomy concerning the study planned, the data computerization and the data elaboration. In the last twelve years approximately 70 Italian centres have enrolled their patients into the studies of the Italian Group for Antiemetic Research.
[Gastroprotection in cancer patients: rational approach, pharmacologic role of antisecretory agents and eventual ulterior prospectives in oncology]
Mustacchi G. Ceccherini R.
Centro Oncologico A.S.S. n degree I Triestina, Universita di Trieste.
In view of the large number of cancer patients treated with FANS and/or corticosteroids for long periods of time. Authors discuss how the use of antisecretory drugs for gastroprotection has become common practice in spite of the lack of clear scientific evidence. The paper analyses the principal mechanisms of gastrotoxicity of FANS, essentially associated with the inhibition of prostaglandins and consequent reduction of the secretion of mucous and bicarbonate. It also discusses the numerous controlled trials evaluating the efficacy of ranitidine for gastroprotection versus placebo and versus the analogous synthetic substance, misoprostole, derived from prostaglandin E1. This analysis shows that misoprostole provides significant protection against both gastric and duodenal ulcers, whilst the antisecretory drug protects only against localised duodenal ulcer. The conclusion is that optimum protection against FANS is provided by misoprostole. In any case more than 30% of patients are destined to develop ulcerous or minor lesions for which treatment with antisecretory drugs is correct. After analysis of the available literature on the gastrotoxicity of corticosteroids, it is clear that this risk is real only for a small sub-population of patients (treated in dual therapy with FANS, for long periods, with high doses or in presence of ulcer anamnesis). It is not known in these cases whether prophylactic treatment is suitable, nor which would be the best prophylactic treatment. In other cases the problem does not arise since the number of patients developing ulcers is similar with corticosteroids treatment or with placebo. Some further interesting features of ranitidine compared to cimetidine (its better pharmacological profile due to the lack of side effects, lack of medullary depression, lack of interference with the immunological system, lack of antiandrogen effects) are also discussed. Particularly interesting is the lack of interference with cyclophosphamide metabolism, such interference having shown for cimetidine. Studies involving ranitidine treatment in association with interleukin-2 for renal carcinoma and metastatic melanoma are also of interest although no statistically significant results are available as yet.
Trends of colorectal cancer incidence and prevalence in Italian regions.
De Angelis R. Valente F. Frova L. Verdecchia A. Gatta G. Chessa E. Berrino F.
Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanita, Rome, Italy.
Incidence and prevalence of tumors of colon and rectum, estimated from mortality and survival data, are presented for Italian regions and for the period 1970-1990. Projected rates to the year 2000 are also given. Age-standardized incidence rates have increased during the considered period. The increase has been higher for southern regions, which had, during the 70's, the lowest incidence and mortality levels. Geographic heterogeneity of colorectal cancer occurrence across Italian regions is therefore decreasing. The phenomenon parallels a tendency towards the homogenization of dietary habits observed in the Italian population. Estimated incidence levels increased less for the younger generation and appear stable for people born after 1940. More than 150,000 prevalent cases were estimated by the year 1990. The number is likely to increase owing to the simultaneous increasing tendency in incidence and survival rates.
Gastrointestinal stromal tumors: a benign tumor with hepatic metastasis after 11 years.
Ballarini C. Intra M. Ceretti AP. Prestipino F. Bianchi FM. Sparacio F. Berti E. Perrone S. Silva F.
Seconda Divisione di Chirurgia, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milan, Italy.
Gastrointestinal stromal tumors (GIST) constitue the largest category of primary non-epithelial neoplasms of the stomach and small bowel. They are characterized by a remarkable cellular variability and their malignant potential is sometimes difficult to predict. Very recent studies, using mitotic count and tumor size as the best determinants of biological behavior, divide GISTs into three groups: benign, borderline and malignant tumors. We report on a male patient who underwent a right hepatectomy for a large metastasis 11 years after the surgical treatment of an antral-pyloric gastric neoplasm, histologically defined as leiomyoblastoma and with clinical, morphological and immunohistochemical features of benignity (low mitotic count, tumor size < 5 cm, low cellular proliferation index). Histological and immunohistochemical analysis of the hepatic metastasis showed the cellular proliferation index (Ki-67) to be positive in 25% of neoplastic cells, as opposed to the primary gastric tumor in which Ki-67 was positive in only 5% of neoplastic cells. In conclusion, although modern immunohistochemical techniques are now available to obtain useful prognostic information, the malignant potential of GISTs is sometimes difficult to predict: neoplasms clinically and histologically defined as benign could metastasize a long time after oncologically correct surgical treatment. Therefore, benign GISTs also require consistent, long-term follow-up.
Bone lesion in a patient with transplanted liver for a metastatic carcinoid. The role of somatostatin receptor scintigraphy.
Savelli G. Chiti A. Spinelli A. Regalia E. Mazzaferro V. Castellani MR. Balzarini L. Musumeci R. Bombardieri E.
Nuclear Medicine Department, Istituto Nazionale per la Cura e lo Studio dei Tumori, Milan, Italy.
A patient who had previously undergone ileal resection and liver transplantation for a gastroenteropancreatic (GEP) tumor was evaluated with somatostatin receptor scintigraphy (SRS) using 111In-DTPA-D-Phe1-pentetreotide. Eighteen months after surgery, during follow-up procedures, conventional imaging techniques (ultrasound, computed tomography, magnetic resonance imaging) only showed a relapse in the gastropancreatic lymph nodes, while SRS demonstrated skeletal spread. This case report emphasizes the clinical impact of SRS on the management of patients affected by neuroendocrine gastroenteropancreatic tumors.
Supportive care in radiotherapy: a review.
Ausili-Cefaro G. Marmiroli L.
Divisione di Radioterapia II, Cattedra di Radioterapia, Universita Cattolica del Sacro Cuore, Roma, Italy. firstname.lastname@example.org
The normal tissue tolerance and the related early side effects represent the main constraint on the total radiation dose which can be administered to the target volume. The most common disorders during radiotherapy or chemo-radiotherapy are summarized in this review. Since in the recent years great advances have been made towards the improvement of acute tolerance, practically every adverse symptoms can be controlled or lowered with an adequate treatment. Some suggestions are reported in order to prevent or lower the degree and the incidence of major complications, specifically mucositis-related symptoms like stomatitis, diarrhea, cystitis. Possibly, a multicenter effort is to be made in order to optimize the quality of supportive care for irradiated patients in all radiation therapy centers.
Radiotherapy combined with other treatments in rectal cancer.
Cattedra di Radioterapia, Universita Cattolica S. Cuore, Rome, Italy. email@example.com
Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.
Radio-chemotherapy of anal cancer.
Zucali R. Doci R. Kenda R. Lozza L. Tana S. Valvo F.
Divisione di Radioterapia A, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Conventional treatment of anal cancer has been the demolitive Miles operation for decades. Radiotherapy has been utilized in a limited number of centers for early cancers only. Radio-chemotherapy has become the treatment of choice for all stages of anal cancer after the first experiences by the group of Detroit and after the confirmation of successful results by many other centers. Infusional chemotherapy (5-FU and Mitomycin C or CDDP) and concurrent irradiation are able to achieve local control in more than 80% of patients. Surgery currently represents a rescue treatment for partial responders or in relapsing patients. A brief review of the literature and the experience at the Istituto Tumori in Milano are presented.
Combined modality treatment for esophageal cancer.
Tordiglione M. Kalli M. Vavassori V. Luraghi R.
Divisione di Radioterapia, Ospedale di Circolo, Varese, Italy.
This paper describes the mechanisms of action of ionizing radiations combined with antineoplastic drugs. Some relevant drugs for the combined modality treatments of locally advanced lung cancer are reported. The meta-analyses including randomized trials comparing single agent (radiotherapy or chemotherapy) versus combined chemotherapy and radiotherapy in patients with unresectable non small cell lung cancer and limited small cell lung cancer are then reviewed. The clinical outcome in relation to different schedules of chemoradiotherapy (sequential, alternating and concurrent) is also focussed.
Prevention of radiotherapy-induced emesis.
Roila F. Ciccarese G. Palladino MA. De Angelis V.
Medical Oncology Division, Policlinico Hospital, Perugia, Italy. firstname.lastname@example.org
The severity of nausea and vomiting in patients undergoing radiotherapy is lower than that associated with chemotherapy regimens, but its duration may be considerably longer. Total body irradiation and irradiation of the upper part of the abdomen or whole abdomen are considered the most emetogenic regimens in radiotherapy. Instead, the emetogenic potential is considered moderate in radiotherapy of the thorax, pelvis and lower half-body irradiation, and low in radiotherapy of head and neck, extremities, brain and skin. In contrast to the very extensive literature on the prevention of chemotherapy-induced emesis, relatively few studies have been published on patients submitted to radiotherapy. Metoclopramide, prochlorperazine and cannabinoids offer only limited symptom control in patients undergoing radiotherapy of moderate to severe emetogenic potential. Double-blind randomized studies showed the superior antiemetic efficacy of the 5-HT3 antagonists with respect to placebo and to the older antiemetic drugs in patients submitted to single dose or fractionated doses of radiotherapy to the upper abdomen, to lower hemibody radiotherapy and to total body irradiation. In all these cases the 5-HT3 antagonists should be considered the antiemetic treatment of choice and should be administered as prophylactic agents. The optimal duration of antiemetic therapy with the 5-HT3 antagonists is unknown. Whether corticosteroids added to the 5-HT3 antagonists will increase their antiemetic efficacy, as in chemotherapy-treated patients, remains to be demonstrated in double-blind controlled trials. Patients submitted to radiotherapy of low emetogenic risk do not require any antiemetic prophylaxis. In this case a rescue antiemetic treatment can be administered if patients present vomiting or moderate to severe nausea.