Radioimmunoguided surgery after primary treatment of locally advanced breast cancer.

PURPOSE: To assess the role of radioimmunoguided surgery (RIGS) using a handheld intraoperative gamma-detecting probe (GDP) to identify neoplastic disease after primary chemotherapy in locally advanced breast cancer (LABC) patients injected with iodine 125-labeled monoclonal antibodies (MAbs). PATIENTS AND METHODS: Twenty-one patients with histologically documented LABC were treated with a combined modality approach. After three courses of primary chemotherapy and before modified radical mastectomy, the 125I-radiolabeled MAbs B72.3 (anti-TAG72) and FO23C5 (anti-carcinoembryonic antigen [CEA]) were administered to 11 patients (group A) and 10 patients (group B), respectively. At surgery, a GDP was used to locate the primary tumor and to assess possible tumor multicentricity and the presence of ipsilateral axillary metastases. Routine pathologic examination was performed in neoplastic and normal tissue specimens of all 21 patients. In addition, immunohistochemical assay for TAG72 and CEA expression was performed. RESULTS: In group A patients, RIGS identified primary tumor in seven of 11 patients (63.3%) and unpalpable multicentric tumor lesions were located in two of four (50%). Positive axillary lymph nodes were histologically documented in eight of 11 patients (72.7%) and RIGS identified three of eight (37.5%). In group B, RIGS located the primary tumor lesion in four of 10 patients (40%); in two cases, the tumor was not clinically evident. Multicentricity was observed in one of two patients and lymph node involvement in three of nine (33.3%). No false-positive results were observed in either group A or B. CONCLUSION: RIGS appears to be a safe and reliable technique. However, the MAbs used in this study are not sufficiently specific. RIGS represents a technique for which the full potential for intraoperative assessment of breast cancer lesions can be reached when more specific antibodies become readily available.

Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer.

Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.

Role of B72.3 iodine 125-labeled monoclonal antibody in colorectal cancer detection by radioimmunoguided surgery.

BACKGROUND: Radioimmunoguided surgery (RIGS) by means of radiolabeled monoclonal antibodies and a probe has been reported to be useful in recognizing subclinical tumor deposits during operation. Aim of this study was to understand the limits of this technique and to assess the potential diagnostic use of RIGS in colorectal cancer surgery. METHODS: Monoclonal antibody B72.3 reacting with TAG 72 antigen, labeled with iodine 125, was injected in 32 patients with primary tumors and in 22 patients with recurrent colorectal cancer. One hundred thirty-three suspected tumor sites were evaluated during operation by means of probe and resected with immunohistochemistry as control. RESULTS: Primary tumor sites were localized by RIGS in 60% of cases, and recurrent sites were localized in 82% of cases. There was a significant correlation both for primary (p < 0.001) and recurrent (p < 0.001) tumor sites between intraoperative RIGS findings and TAG 72 tumor antigen expression. Results obtained with the probe were instrumental in modifying the surgical approach in six (27%) of 22 patients with recurrences, allowing the removal of tumor masses that would otherwise have been overlooked. CONCLUSIONS: The results of RIGS seems to be encouraging in terms of clinical use. The potential high diagnostic resolution appears to improve surgical ablation of colorectal cancer, especially in patients with recurrent cancer or suspected recurrent tumors who have negative results for intraabdominal disease by all other roentgenographic criteria with rising carcinoembryonic antigen or TAG 72 antigen levels.

Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil.

We have recently demonstrated that continuous-infusion (CI) 5-fluorouracil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m2 per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) or FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU + LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU + LV.

Long-term femoral vein central venous access in cancer patients.

Subclavian percutaneous access with reservoir placement has been shown to be difficult or contraindicated in some patients. Of 465 cancer patients who required a port placement between January 1992 to January 1995, 41 (8.8%) had alternative percutaneous femoral access with a totally implantable port reservoir located in the abdomen because of the inaccessibility to subclavian or jugular veins and/or the presence of massive cutaneous metastases or severe radiodermitis in the upper part of the torso. Overall implant days was 9880, with an average of 241 days (range: 65-445). Ports were alternatively used for chemotherapy and nutritional purposes in 11 of 41 patients. Late morbidity causing the removal of the implanted ports was observed in two of 41 (4.9%) and 25 of 424 (5.9%) patients in the femoral and subclavian series, respectively (P = 0.86). The femoral percutaneous access for totally implantable port devices appears to be a safe alternative for cancer patients when subclavian and/or jugular vein catheterization and reservoir in the upper part of the torso is contraindicated.

Long-term postoperative results in 54 cases of early gastric cancer: the choice of surgical procedure.

Surgical experience on the management of early gastric carcinoma (EGC) related to a series of 54 subjects was observed from 1974 to 1984. Thirty-four patients were male, 20 were female; median age was 61.84 (range 22-79) years. Malignancy always occurred in the middle or distal third of the stomach. A partial subtotal gastrectomy (two-thirds of the stomach) with Roux en Y or Billroth II reconstruction was performed. Omentectomy and lymph node dissection of the primary and secondary groups of nodes, according to General Rules, was always performed. Age-corrected 5- and 10-year survival rates were 95.7% and 84.3%, respectively. Based on their experience, the authors discuss the surgical approach to EGC stressing the need for an accurate lymph node dissection and pointing out that results of subtotal gastrectomy are similar to that reported in the literature for total gastrectomy. The only absolute need for a total gastrectomy may be the presence of an EGC in the proximal third of the stomach. To this end the authors compare their results with 5- and 10-year series from Japanese and western countries reported in the literature.

Pseudomixoma peritonei: a case report.

Pseudomixoma peritonei is a rare neoplasm characterized by mucinous ascites and the mucinous involvement of peritoneal surfaces, omentum and bowel loops. Usually pseudomixoma peritonei is associated with benign or malignant mucinous tumor of the appendix or ovary. The diagnosis of pseudomixoma peritonei is difficult because laboratory and radiology results are frequently nondiagnostic. We report a case that was initially mistaken for carcinomatosis of unknown origin and that underwent cytoreductive procedure and omentectomy as the treatment of choice.

Intrahepatic epidoxorubicin in metastatic and primary liver tumours: a phase II study.

Primary and metastatic gastrointestinal tumours in the liver have been treated by intrahepatic artery infusion of chemotherapeutic drugs in an attempt to increase the efficacy of the administered agents. Among the several active agents, 4' epidoxorubicin, an anthracycline analogue, was selected for this study because of the therapeutic level reached in the liver by this drug. Seven patients with primary hepatic carcinoma and twenty with metastatic adenocarcinoma of the colon to the liver received intraarterial hepatic infusion of epidoxorubicin at the dosage of 30 mg weekly. No haematological or gastrointestinal grade 3-4 toxicity was recorded, only one patient experienced transient cardiac toxicity. No objective response was observed in primary hepatic carcinoma and six objective responses, 1 complete and 5 partial (30%), were achieved in metastatic colorectal cancer patients. This results is not far from those reported with FUDR, but does not justify epidoxorubicin in colorectal cancer patients as first line intraarterial treatment.

Selective lymph node dissection in patients with intermediate thickness melanoma: our experience.

The role of elective lymph node dissection (ELND) for the treatment of cutaneous melanoma has been debated for many years. Actually, the value of ELND is seriously questioned because an increasing of overall survival rates has not been demonstrated. The lymphatic mapping technique, initially performed by an intradermic injection of vital blue dye, subsequently improved by the use of radioguided surgery (RGS), proved effective for the detection of clinical occult lymph node metastasis. We performed a sentinel node biopsy on 71 patients with stage pT2/T3N0M0 melanoma. Vital blue dye mapping alone was performed on 39 patients; the remaining 32 patients had a combined lymphatic mapping with both blue dye and RGS. The sentinel node (SN) was complexively identified in 69/71 (97.2%) patients. Sixteen patients (23.2%) were found to have metastatic melanoma cells in their SN(s); all these patients underwent lymph node dissection of the affected basin. Our experience confirmed that the intraoperative detection of sentinel nodes using both blue dye and radio-guided surgery is an effective and reliable technique for selecting patients to be submitted to lymph node dissection.

Activity of high dose 24 hour 5-fluorouracil infusion plus L-leucovorin in advanced colorectal cancer.

BACKGROUND: Modulation of 5-fluorouracil (5-FU) by leucovorin (L-LV) in patients (pts) with advanced colorectal cancer has been demonstrated to produce a highly significant benefit over single-agent 5-FU in terms of tumor response rate, but this advantage does not translate into an evident improvement of overall survival. To improve the clinical efficacy of the 5-FU plus L-LV regimen a phase II study of weekly 24-hour high-dose 5-FU infusion with L-LV was undertaken. PATIENTS AND METHODS: Seventy advanced colorectal patients were enrolled and treated by a weekly outpatient combination regimen according to the following schedule: L-LV 100 mg/sqm by 4 hours i.v. infusion followed by 5-FU 2600 mg/sqm over a 24 hours infusion combined with a fixed dose of oral L-LV (50 mg) every 4 hours for 5 times. Forty-four pts did not receive any previous CT and 26 pts were pretreated with fluoropyrimidines. RESULTS: The overall objective response rate (OR) was 35.3%; 7 CR and 11 PR (42.8% OR) were observed in the group of untreated pts, and 6 PR (23% OR) were reported among previously treated pts. Major side effects were represented by diarrhoea (grade III: 26%, grade IV: 1%), hand-foot syndrome (grade III: 4%, grade IV: 1%) and mucositis (grade III: 4%); however, this did not significantly influence the therapeutic programme. Median 5-FU dose intensity was 100% and 80% at 4 weeks, 87% and 75% at 8 weeks in untreated and pretreated pts, respectively. CONCLUSIONS: L-Leucovorin modulation of weekly short-term continuous infusion of high-dose 5-fluorouracil appeared a well-tolerated outpatient regimen; it demonstrated a high activity in advanced colorectal cancer, both in untreated pts and in pts resistant to 5-FU-based chemotherapy.

Perilymphatic injections of recombinant interleukin-2 (rIL-2) partially correct the immunologic defects in patients with advanced head and neck squamous cell carcinoma.

Patients with advanced head and neck squamous cell carcinoma (HNSCC) are severely immunocompromised. In virtually all such patients who have been studied, reduced numbers of circulating CD3+ T-cell-receptor (TCR)alpha/beta+ T lymphocytes, a reduction of natural killer (NK) activity, and a poor induction of lymphokine-activated killer (LAK) cell activity (following in vitro treatment with recombinant interleukin-2 [rIL-2]) have been detected. Recently, however, it has been demonstrated that perilymphatic injections of low doses of rIL-2 may induce a local reduction of tumor masses in these patients. The present study, a cooperative pilot effort on the clinical effects of this route of administration, showed an activation of the lytic machinery in lymphocytes belonging to the T-cell lineage, as well as a potentiation of NK activity in the peripheral blood. These findings demonstrated that the severe immunodeficiency of HNSCC patients may be at least partially corrected by in vivo administration of rIL-2.

Treatment of esophageal anastomotic leakages after cancer resection. The role of total parenteral nutrition.

A series of 16 cases of esophageal anastomotic leakages after cancer resection observed from 1978 to 1982 is analyzed in a retrospective manner. Eight patients related to the period 1978 to 1980 (series A) were treated with emergency surgery while the remaining eight patients observed from 1980 to 1982 (series B) were treated conservatively with total parenteral nutrition (TPN) and complete fasting. Seven patients from series A eventually died postoperatively and one patient had a good recovery after emergency reintervention. In the series B six patients left the hospital with complete healing of the anastomotic leaks after 27.2 +/- 13.5 days of TPN and complete fasting, while failure of the treatment was observed in two patients who died from septic mediastinitis and acute respiratory failure. Different incidence of positive clinical results in Series A and B was statistically significant (p less than 0.01). The role of TPN and complete fasting will be discussed as the primary approach for the management of this severe complication, taking in consideration the suture line drainage and the control of infection.

Sentinel lymph node mapping and biopsy for breast cancer: a review of the literature relative to 4791 procedures.

The status of axillary nodes is the most important prognostic factor in breast cancer to select patient subgroups for adjuvant chemotherapy; the current standard of care for surgical management of invasive breast cancer is complete removal of the tumor by either mastectomy or lumpectomy followed by axillary lymph node dissection (ALND). The recent introduction of intraoperative lymphatic mapping and sentinel lymph node biopsy (SLND) represents a major new opportunity for appropriate and less invasive surgical management of many tumors. There is an almost uniformly enthusiasm concerning the potential of this technique in breast carcinoma management, shown by published data. A peculiar attention to the so-called "sentinel node debate" in breast cancer surgery is a constant in the last years issues of the major medical journals. Even patients have become more aware about medical enthusiasm and their request of concise information on the topic and the possibilities of this approach is an increasing reality in medical practice. The aim of this paper is to review recent literature to offer an overview about the main controversial methodological aspects and a wide analysis of reported results. The most significative international literature papers from Medline were retrieved from 1993 to September 1999, and 4782 procedures were analysed. This extensive review of the literature has confirmed accuracy, feasibility and reliability of the SN detecting technique in axillary mapping. Provided a good proficiency in SN localisation and pathological evaluation, human resources and efforts should be mainly focused on its clinical validation as an alternative to ALND instead of on further phase I-lI clinical studies.

[Current status of the classification and clinical staging of primary and secondary tumors of the liver]. / Considerazioni sullo stato attuale della classificazione e stadiazione clinica dei tumori primitivi e secondari del fegato.

Over the past few decades there has been outstanding expansion in the surgical exeresis of primary and metastatic liver tumours and particularly hepatic metastases of colorectal carcinomas. With the advance in surgical technique it becomes increasingly necessary to codify the system for the classification and clinical staging of these conditions for the purposes of correct programming of treatment and assessment of the clinical results obtained. The most commonly used systems of classification and clinical staging are analysed, in particular the classifications proposed by the American Joint Committee on Cancer and D. Manfredi for primary liver tumours and those proposed by Gennari et al and Sugerbaker et al for hepatic metastases of colorectal carcinomas. The selection criteria adopted in each system are analysed as the basis for a more thorough discussion of the problem that is felt to be fundamental for the standardisation of classification and clinical staging systems in the future. Such standardisation is essential for the assessment of the value and limitations of liver surgery in cancer.

[Evaluation of the delayed hypersensitivity response by the Multitest-IMC. Multicenter study for the definition of reference values in a sample population]. / Valutazione della risposta di ipersensibilità ritardata mediante Multitest-IMC. Studio multicentrico per la definizione di valori di riferimento in una popolazione campione.

The latest investigations in the field of clinical immunology have proposed ways of assessing immunological efficiency that have also been used to identify patients most susceptible to infectious complications. The assessment of delayed hypersensitivity response (DHR) using anamnestic antigens is currently the most common method. The results of a polycentric study are presented. The study was conducted on a group of healthy subjects from various Italian regions divided into three age classes. Positive responses to the MT were noted in 96.4% of the population studied. The incidence of energy was statistically higher among females than males, while the mean response to the MT expressed in millimetres was statistically higher in males. Though 7 antigens were administered, the responsive population reacted on average to 3. The highest incidence of positive responses was to Candida, with Trichophyton responsible for the fewest.

Immunoprophylaxis in "septic risk" patients undergoing surgery for gastrointestinal cancer. Results of a randomized, multicenter clinical trial.

The results of a randomized, multicenter clinical trial of immunoprophylaxis of post-operative infections with intravenous Immunoglobulins (IVIG) (Sandoglobulin) in "septic-risk" patients undergoing surgery for gastrointestinal cancer are presented. "Septic-risk" patients were selected by an original multiparametric test based on delayed hypersensitivity skin testing and serum protein electrophoretic sub-fractions. This screening test had shown 76% positive predictivity in a previous validation assessment. In the present study, 159 "septic-risk" patients were selected prospectively from 369 patients undergoing colo-rectal (colon) and other kinds of gastrointestinal (non-colon) oncologic surgery: 80 "septic-risk" patients were included in the colon and 79 in the non-colon group. Immunoprophylaxis with IVIG (15 g on the day prior to operation, on the 1st and 5th postoperative days) was randomly associated with antibiotic prophylaxis (cefoxitin: 2 g one hour prior to, followed by 2 g at the end of operation plus 2 g every six hours for 24 hours) in colon surgery while the prophylactic schedule in non-colon surgery was only based on random administration of IVIG, at the same dosage as in the colon group. There was a clear-cut reduction of post-operative infections both in colon and non-colon "septic-risk" patients who had IVIG prophylaxis; in the colon group, 37 and 21 infections (P < 0.004) in antibiotic (A) versus IVIG plus antibiotic (IVIG + A) subset, respectively; in the non-colon group, 33 and 19 infections (P < 0.01) in control (C) versus (IVIG) subset, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[The diagnosis and therapy of recurrent tumor of the rectum]. / Considerazioni sulla diagnosi e terapia del tumore recidivo del retto.

The authors review the pathogenesis of locoregional recurrences of rectal cancer, pointing out clues for the diagnosis and staging of the disease which are valuable for the definition of a treatment strategy. Surgery is the mainstay of any attempt to cure those recurrences that are amenable to radical resection; over and above the diagnostic role of second-look laparotomy in suspected cases, surgery must include those measures able to reduce actinic damage whenever postoperative radiotherapy is required. On the other hand, palliative surgery is necessary to resolve the presence of intestinal obstruction, fistulous tract, or the removal of abscess and necrotic tissue. In these cases, the quality of life seems to be the prime factor in the choice of therapy (radiotherapy, loco-regional or systemic chemotherapy, hyperthermia).

[Long-term central venous access in oncology. Review of a caseload of 750 cases]. / Accessi venosi centrali a lungo termine in oncologia. Revisione di una casistica relativa a 750 casi.

Totally implantable central venous accesses systems are presently widely used in cancer patients. Perioperative and long-term morbidity of 750 consecutive implants performed from 1985 to 1994 were retrospectively reviewed. Our Series consisted in 616 (82.1%). Ports and 134 (17.9%) external tunnelled catheters with subcutaneous Dacron cuff (Hickmann or similar catheters) implanted by percutaneous access route in local anesthesia. Subclavian vein was the elective access route in 700 (93.3%) patients while in the remaining 50 (6.7%) the access was performed in the femoral vein, due to peculiar clinical conditions. One-day surgery was only required for 19 (2.6%) patients while outpatient surgery was the routine in 731 (97.4%) patients. Perioperative morbidity was at all similar both for Port and external catheters Series (p > 0.07). Late morbidity requiring the removal of the device occurred in 27/134 patients (18.7%) and in 40/616 (6.5%) for external catheters and Port Series, respectively (p < 0.002). The rate of infection, 2.3% for ports (p < 0.002). Patient's compliance was higher for Ports compared to external catheters. Apart from peculiar clinical conditions such as hematologic cancers, bone marrow transplantation or short life expectancy, Ports seem to guarantee for a lower morbidity coupled with better long-term results.