Gianpiero Romano

Should we continue to study high-dose chemotherapy in metastatic breast cancer patients? A critical review of the published data

Summary:Data from eight randomised trials on high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) have been published, but only seven studies are evaluable after the Bezwoda trial was discredited. Moreover, overall survival (OS) has been evaluated in only four out of seven studies since three had a crossover design. OS was similar for the HDC and standard-dose chemotherapy (SDC) group in the four evaluable trials, while disease-free survival (DFS) was improved in the HDC group in six of the seven trials. The delay in relapse for patients with metastatic disease represents an important clinical outcome; furthermore, since none of the reported studies randomised more than 220 patients, their statistical power may have been too limited to detect meaningful survival differences. Finally, preliminary experiences have shown that HDC seems to be the ideal platform upon which to build novel therapies. In conclusion, HDC remains an important field of clinical research for breast cancer patients with stage IV disease and, from the studies reported in this article, there is some evidence for offering this therapeutic modality to selected patients who are interested in a medically aggressive approach.

Prevention of high-dose melphalan-induced mucositis by cryotherapy.

Oral mucositis is a frequent and significant sideeffect of both chemotherapy and radiation treatment. It is an especially severe problem in the setting of patients undergoing high-dose chemotherapy (HDC) followed by peripheral blood progenitor cell transplantation. In fact, in the presence of neutropenia, severe mucositis predisposes patients to infections. Rapaport et al. [1] reported that a higher peak of oral mucositis and the duration of parenteral nutrition support are correlated with the occurrence of bacteremias and transplant-related mortality; a relationship between oral mucositis and hepatic veno-occlusive disease has been reported by Wingard et al. [2]. Furthermore, the management of infectious complications and mucositis-related pain result in increased hospitalization and increased cost [3]. There are many grading scales for diagnosing oral mucositis and assessing its severity. The most commonly used is that of the World Health Organization, which is similar to that of the National Cancer Institute and the Eastern Cooperative Oncology Group [4 – 6]. Recently, a new scoring system, the Oral Mucosal Assessment Score, was developed and validated in a large study [3]. Considering that once mucositis has occurred the main treatment consists of measures to palliate symptoms, the need for prevention or early intervention is obvious. Recommendations that can be made include oral decontamination, oral cryotherapy, the administration of amifostine and agents directed to the epithelial mucosa, such as mitogens and epithelial growth factors. Oral cryotherapy, through vasoconstriction, can decrease the mucosal damage induced by agents with short half-lives, such as 5-fluorouracil (5-FU) or melphalan (L-PAM) [7]. Here we report our experience regarding the prevention of high-dose L-PAM-induced mucositis by cryotherapy. From December 2001 22 patients (5 with multiple myeloma, 9 with non-Hodgkin’s lymphoma, 7 with breast cancer, 1 with ovarian cancer) underwent HDC including L-PAM; 5 patients received L-PAM (140 – 160 mg/m) alone and 17 patients a L-PAM including regimen. All these patients were asked to suck on ice chips for 30 min, starting 5 min prior to the L-PAM infusion. These patients also received anti-mycotic and antibiotic prophylaxis with fluconazole 200 mg/ day and ciprofloxacin 500 mg 6 2/day, respectively. We observed oral mucositis (NCI-CTC) G0 in 2/22 patients (9%), G1 in 12/22 patients (55%), G2 in 3/22 patients (13%) and G3 in 5/22 patients (23%). In our experience, the incidence of severe mucositis was significantly lower with respect to data reported in the literature. Therefore, we suggest that prophylaxis with cryotherapy should be considered in patients receiving HDC including L-PAM.

Role of parenteral nutrition in cancer patients undergoing high-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation.

High-dose chemotherapy followed by autologous bone marrow or peripheral blood progenitor cell transplantation represents a recognized option in the treatment of solid tumors and hematologic diseases. Patients receiving high-dose chemotherapy are traditionally supported with parenteral nutrition with the aim to prevent malnutrition secondary to gastrointestinal toxicity and metabolic alterations induced by the conditioning regimens. Nevertheless, well-defined guidelines for its use in this clinical setting are lacking and there are several areas of controversy.

Primary gastric lymphoma for stage I/II1 E: Operative and conservative management in retrospective data from 71 cases

The standard management of primary gastric lymphoma (PGL) has not been established despite the use of various treatment modalities [1]. In fact, in patients with PGL both surgery and combined modality including radio and chemotherapy have been widely performed. However, in the last decade a trend toward a conservative approach is emerging although it is not supported by randomised studies [2]. Our aim was to retrospectively analyse the survival of patients with PGL according to the treatment type. From November 1980 to February 1999 different treatments were used in 71 consecutive (37 Females, 34 Males) patients with PGL limited stage I/II1 E, according to the Lugano staging system for gastro-intestinal lymphomas [3]: surgery and chemotherapy combined treatment (CMT), only surgery, only chemotherapy or only Helicobacter pylori eradication therapy [4]. The procedures of staging included gastroscopy with several biopsies with a middle number of six specimens (range 3– 12), small bowel radiograph with contrast, colonscopy, chest–abdomen or total body TC or bone marrow biopsy and otorhinolaryngologist evaluation. Table I shows the main clinical features of our patients. Median age was 58 years (range: 22–81 years) with 25% of patients older than 65 years, median performance status (WHO) was 1; the stage of disease was I E in 38 patients and II1E in 33. At onset, patients experienced more frequently epigastric pain, weight loss more than 5 kg, nausea, vomiting, rare episodes of light hematemesis and gastric bleeding without anaemia; only 7 patients had levels of hemoglobin , 10 g/dl and 1 patient, with levels of hemoglobin 7.4 g/dl, had recurrent episodes of gastric bleeding needing packed red cell transfusions. Histologic evaluation according to WHO criteria gave the following results: 48 patients had an aggressive lymphoma and 23 patients had an indolent lymphoma; 15 (21%) patients were found to have MALT lymphoma [5]. All patients had B-cell phenotype and were diagnosed by gastric biopsy or gastric surgery. Total or partial gastrectomy was performed in 41 (58%) patients and 30 of them subsequently received 4–6 courses of chemotherapy. In contrast, 24 patients were treated only with chemotherapy, while 6 patients received antibiotic therapy with metronidazole (2 £ 550 mg/d), clarythromicin (2 £ 500 mg/d) and omeprazole (2 £ 20 mg/d) by oral therapy for 10 days for their HPrelated low-grade MALT lymphoma [6]. The treatment with an inhibitor of the protonic pump was extended for the whole duration of chemotherapy in order to reduce the risk of bleeding. Chemotherapy given either as primary treatment or following surgery consisted of CVP regimen (intravenous cyclophosphamide 400 mg/m 1–5 days, vincristine 1.4 mg/m 1 day and prednisone 100 mg/m 1–5 days) for patients with indolent histology or older than 65 years, or of anthracycline-containing regimen (CHOP/CHOP-like and ProMECE Cyta-BOM) for those younger or with aggressive histology patients. In our experience we have not submitted any patient to radiotherapic treatment [7]. The antiemetic prophylaxis with antagonists of the receptor 5-HT3 was routinely administered. Including criteria to start therapy were left ventricular ejection fraction .50%, white blood cell count .3500/ml, platelet count .100,000/ml, and normal parameters of liver and renal function as well. After 4 cycles of therapy a response evaluation was done by gastroscopy and biopsies, TAC scan of chest and abdomen and ETG abdomen. Response to treatment was classified on the basis of the standard WHO criteria.

Loss of p27Kip1 expression correlates with tumor grade and with reduced disease-free survival in primary superficial bladder cancers

p27Kip1 is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. We previously reported a deregulated expression of p27Kip1 in a series of human cancer cell lines and in primary breast and colon cancers. Moreover, p27Kip1 has been reported as an important prognostic factor in primary lung, breast, colon, and prostate cancers. In this study, we evaluated the prognostic value of p27Kip1 in a series of 96 superficial (pTa-1) human bladder carcinomas. High (>50% positive cells), moderate (25-50%), and low (<25%) p27Kip1 staining was observed in 39 (41%), 19 (20%), and 38 (39%) of the 96 primary superficial bladder cancers, respectively. No significant association was found between the expression level of p27Kip1 and tumor stage. Decreased p27Kip1 staining correlated with higher tumor grade (P = 0.001). Interestingly, a significant association was observed between increased expression of p27Kip1 and positivity for p53 (>20% positive cells; P < 0.001). A significant correlation was also observed between low expression of p27Kip1 and decreased disease-free survival (P = 0.0003 by log-rank test) and overall survival (P = 0.01 by log-rank test). Furthermore, on multivariate analysis, low p27Kip1 protein expression was an independent predictor of reduced disease-free survival (P = 0.018; relative risk = 1.95) second only to tumor stage. These data indicate that p27Kip1 protein is frequently expressed at low level in poorly differentiated tumors and suggest that this protein might represent a useful prognostic marker for disease recurrence and overall survival in superficial bladder carcinomas.

Prevention of high dose melphalan-induced mucositis by cryotherapy in transplanted patients

8174 Background: Oral mucositis is a severe problem for patients (pts) undergoing high dose chemotherapy (HDC) followed by peripheral blood progenitor cells transplantation. Once mucositis has occurred, treatment consists of measures to palliate symptoms. Multiple agents have been used prophylactically to reduce this toxicity with discordant results. Oral cryotherapy, through vasoconstriction, can decrease the mucosal damage induced by agents with short half-lives, such as melphalan (L-PAM). Aim of this study was to evaluate the effect of local cryotherapy on oral mucositis in pts treated with high-dose (HD) L-PAM Methods: From December 2001, 23 pts (5 with multiple myeloma, 9 with non Hodgkins Lymphoma, 7 with breast cancer, 1 with ovarian cancer) underwent HDC including L-PAM; in particular, 5 pts received HD L-PAM (140-160 mg/m2) alone and 17 pts a L-PAM including conditioning regimen. All these pts were asked to suck on ice chips for 30 minutes, starting 5 minutes prior to the L-PAM infusion. These pts received also antimycotic and antibiotical prophylaxis with fluconazole 200 mg/d and ciprofloxacin 500 mgx2/d, respectively. RESULTS We observed oral mucositis (NCI-CTC) G0 2/22 pts (9%), G1 12/22 pts (55%), G2 3/22 pts (13%), G3 5/22 (23%) pts. CONCLUSIONS In our experience, the incidence of severe mucositis was significantly lower respect to historical data; so, the prophylaxis with cryotherapy should be considered in pts receiving high dose L-PAM. No significant financial relationships to disclose.