Maurizio Cosimelli

Preoperative Chemoradiation for Extraperitoneal T3 Rectal Cancer: Acute Toxicity, Tumor Response, and Sphincter Preservation

PURPOSE To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control. METHODS AND MATERIALS Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m2, Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m2, Days 1-4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4-6 weeks after the end of chemoradiation. RESULTS Total Grade 3-4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% (7) of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a sphincter-saving surgical procedure. In 12 (44%) of 27 patients candidate for an APR, the sphincter was preserved, as it was in 19 (95%) of 20 probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > 20 mm was observed in 21 patients (26%). Of 63 patients, 4 (6%) had moderate soilage after the sphincter-saving procedure. CONCLUSION Preoperative combined modality therapy seems to afford some potential advantages in nonrandomized trials: patients are able to tolerate higher chemotherapy doses and they experience a lower acute toxicity. Tumor downstaging and resectability rates are high; sphincter preservation is feasible. Larger T3 tumors remained less influenced by this treatment; thus, taking into account the low toxicity rate recorded, a more aggressive schedule should be applied in these resectable tumors.

Ten years of preoperative chemoradiation for extraperitoneal T3 rectal cancer : Acute toxicity, tumor response, and sphincter preservation in three consecutive studies

PURPOSE To compare acute toxicity, tumor response, and sphincter preservation in three schedules of concurrent chemoradiation in resectable transmural and/or node-positive extraperitoneal rectal cancer. PATIENTS AND METHODS Between 1990 and 1999, 163 consecutive patients were treated according to the following combined modalities: FUMIR: between 1990 and 1995, 83 patients were treated with bolus i.v. mitomycin C (MMC), 10 mg/m(2) day 1, plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1,000 mg/m(2) days 1-4, and concurrent external beam radiotherapy (37.8 Gy). PLAFUR-4: between 1995 and 1998, 40 patients were treated with cisplatin (c-DDP) 60 mg/m(2) given as slow infusion (1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-4 and 29-32 with concurrent external-beam radiotherapy (50.4 Gy). PLAFUR-5: between 1998 and 1999, 40 patients were treated with c-DDP 60 mg/m(2) given as slow infusion (during 1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-5 and 29-33 with concurrent external-beam radiotherapy (50.4 Gy). RESULTS Grade > or = 3 acute toxicity occurred in 14%, 5%, and 17% of patients treated in the FUMIR, PLAFUR-4, and PLAFUR-5 studies, respectively (p = 0.201). In the FUMIR, PLAFUR-4, and PLAFUR-5 studies, clinical response rate was 77%, 70%, and 83%, respectively. Tumor downstaging occurred in 57%, 68%, and 58% of patients, respectively. Pathologic complete response was recorded in 9% (FUMIR), 23% (PLAFUR-4), and 20% (PLAFUR-5) of patients. Sphincter-preserving surgery was feasible in 44% (FUMIR), 40% (PLAFUR-4), and 61% (PLAFUR-5) of patients having a distance between the anal-rectal ring and the lower pole of the tumor of 0-30 mm, and in 95%, 100%, and 100%, respectively, in those having a distance of 31-50 mm. Comparing FUMIR vs. PLAFUR, the clinical response rate was similar in the two series: a partial response was observed in 62/81 (77%) patients with FUMIR treatment, and in 61/80 (76%) patients with PLAFUR treatment. Tumor downstaging was observed in 46/81 (57%) patients and in 50/80 (68%) patients, respectively. The pathologic complete response rate was statistically higher in the PLAFUR series: 7/81 (9%) patients with FUMIR treatment and 17/80 (21%) patients with PLAFUR treatment (p = 0.04). Major downstaging (pT0+ pTmic+ pT1) in the FUMIR group was reported in 12/81 (15%) patients versus 31/80 (39%) patients in the PLAFUR group (p = 0.0006). The anal sphincter was preserved in 63/81 (78%) patients with FUMIR treatment and in 69/80 (86%) patients with PLAFUR treatment. The perioperative morbidity was statistically lower with PLAFUR: a perioperative morbidity was experienced by 20/81 (25%) patients with FUMIR treatment and by 9/80 (11%) patients with PLAFUR treatment (p = 0.042). CONCLUSION In our experience, higher radiation dose (50.4 Gy vs. 37.8 Gy), a second course of concurrent 5-FU, and the use of c-DDP instead of MMC improved the pathologic response rate without increasing acute toxicity and perioperative morbidity. The use of 5-FU 5-day infusion (PLAFUR-5) resulted in higher toxicity with a similar response rate compared to 4-day infusion (PLAFUR-4).

Diagnostic and prognostic value of peritoneal immunocytology in gastric cancer.

PURPOSE Among the clinical factors with a pivotal role in the prediction of outcome for patients with gastric cancer, intraperitoneal (i.p.) microscopic dissemination may represent an important cause of recurrences, even in the early stages of the disease. In this context, the cytologic examination of intraoperative peritoneal washings may be essential to identify metastatic free cells, although a number of false-negative cases may be encountered. PATIENTS AND METHODS To determine whether immunocytochemical (ICC) methods that used a panel of three monoclonal antibodies (MoAbs), B72.3, AR3, and BD5, directed to gastric cancer-associated antigens can improve peritoneal cytology by providing more accurate prognostic indications, we immunocytochemically and morphologically evaluated 144 peritoneal washings sampled from patients surgically treated for gastric cancer. RESULTS The ICC analysis allowed the identification of metastatic free peritoneal cells in 35% of the patients, with a 14% improvement over routine cytopathology (P < .0001). Furthermore, a 54-month survival analysis by Kaplan-Meier curves showed a statistically significant decrease in overall survival (OS) in patients with stages I through III disease with peritoneal microscopic disease detected morphologically and/or by ICC at the time of the primary surgery. CONCLUSION Our data indicate that the use of a combination of selected MoAbs may allow the identification of cytologically false-negative cases that provide valuable prognostic information. This may be useful to stratify patients on more adequate therapeutic trials.

Treatment of peritoneal carcinomatosis with intent to cure.

Low‐grade malignant tumors arise in the abdomen, do not infiltrate, and “redistribute” on the peritoneum with no extraregional spreading. In these cases, aggressive surgery combined with localized chemotherapy may provide cure.

Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, sphincter preservation ☆

PURPOSE To evaluate the impact of preoperative external radiation therapy intensified by systemic chemotherapy including bolus cisplatin (c-DDP) and 4-day infusional 5-fluorouracil (PLAFUR-4) on tumor response and sphincter preservation in patients with extraperitoneal T3 rectal cancer with acceptable toxicity, and to compare the results to our previous experience with bolus mitomycin c (MMC) and 4-day infusion 5-FU (FUMIR). METHODS AND MATERIALS Between October 1995 and March 1998, 40 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: slow infusion i.v. c-DDP, 60 mg/m2, day 1 and 29 plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1000 mg/m2, days 1-4 and 29-32, and concurrent external beam radiotherapy (45 Gy whole pelvis followed by 5.4 Gy boost). All but 3 patients had T3 disease. Surgery was performed 6-8 weeks after the end of chemoradiation. RESULTS No patient had Grade 4 acute toxicity. Grade 3 hematological toxicity was observed only in 2 (5%) patients. No patient had major gastrointestinal, skin, or urological acute toxicity. All patients had radical surgery. There was no perioperative mortality; perioperative morbidity rate was 12%. Overall, 23% (9 of 40) of patients had a complete pathological response and 10% (4 of 40) of patients had rare isolated residual cancer cells (Tmic). Comparing the stage at the diagnostic workup with the pathological stage, tumor downstaging was observed in 27 (68%) patients; nodal status downstaging was detected in 24 (60%) patients. Thirty-four (85%) patients had a sphincter-saving surgical procedure. In 4 of 10 (40%) patients who were definitive candidates for an abdominoperineal resection (APR), the sphincter was preserved, as it was in 13 of 13 (100%) probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > or =20 mm was observed in 9 (23%) patients. None of the patients had soilage after the sphincter-saving procedure. In our previous experience with FUMIR the complete pathological response was 9%, the sphincter-saving surgical procedure was performed in 66% cases, and the Grade 3+ toxicity was observed in 13% of patients. CONCLUSIONS The addition of c-DDP to 5-FU (PLAFUR-4) in a neoadjuvant radiochemotherapy schedule improved the pathological response rate in comparison with our previous experience. Toxicity was low indeed, thus we commenced another study adding one more day of 5-FU infusion (PLAFUR-5) to further improve our results.

Coloanal anastomosis for rectal cancer

PURPOSE: This study was designed to determine functional outcomes and rates of survival and recurrence of coloanal anastomosis in rectal cancer patients. METHODS: Between 1981 and 1991, 117 patients underwent coloanal anastomosis. Fifteen percent of the patients had a J-pouch; the rest had a straight coloanal anastomosis. Thirty-eight percent had no diverting stoma. Median distance of the tumor from the anal verge was 6.7 cm. RESULTS: Local recurrence rate was 7 percent. Five-year survival was fully 69 percent. Satisfactory fecal continence was achieved by 78 percent of patients; no J-pouch patient had frequent incontinence. Sixty-two percent of the patients had major (anastomotic leak = 18 percent) or minor complications; complications were not mitigated by a diverting stoma or worsened by adjuvant therapy. CONCLUSION: Although coloanal anastomosis is associated with a high chance of complications, the long-term outcome, in terms of disease-free survival and satisfactory function, is excellent.

Quantitative analysis of CEA expression in colorectal adenocarcinoma and serum: Lack of correlation

Tissues and sera from 110 patients diagnosed with colorectal primary carcinoma, 20 patients with benign colorectal diseases and 31 healthy donors were subjected to quantitative CEA analysis. Multiple samples from tumor lesions and autologous histologically normal mucosa (10 cm from the tumor) were obtained at the time of surgery (cancer patients) or endoscopy (benign patients and healthy volunteers). CEA content was measured in protein extracts obtained from these tissues using a quantitative RIA method. A limit of normality for CEA content was established as 300 ng/mg of protein. When this was taken as cut‐off, 104 of 110 (94.5%) tumor lesions and 51 of 110 (46.4%) autologous histologically normal colonic mucosa from cancer patients had elevated CEA levels. No correlation with stage of disease was found, while a correlation was observed with degree of tumor differentiation. A statistically significant difference between CEA content in tumor lesions and in histologically normal mucosa from cancer patients was observed (p = −0.001). Moreover, CEA content was statistically higher in the normal mucosa from cancer patients than in that from healthy donors (p = 0.005). CEA content in tissue specimens from benign lesions differed significantly from that in tissue from healthy donors (p = 0.005) and in carcinoma lesions (p < 0.001). The highest CEA content was observed in benign lesions with severe dysplasia. No statistical correlation between CEA content in carcinoma tissues and serum CEA levels (r = 0.195, p = .13) was found. Therefore, in considering diagnosis or therapy with anti‐CEA MAbs for colorectal‐carcinoma patients, or potential therapies with anti‐CEA recombinant vaccines, serum CEA levels should not be taken as indicating CEA expression in tumor lesions. Int. J. Cancer 72:949–954, 1997.

Nerve-sparing surgery in 302 resectable rectosigmoid cancer patients: Genitourinary morbidity and 10-year survival

PURPOSE: The aim of this study was to evaluate 5-year and 10-year disease-free survival, urinary dysfunction, and sexual activity after nerve-sparing radical surgery, including lumboaortic lymphadenectomy for rectosigmoid cancer. METHODS: Since 1980 to 1992, 302 consecutive patients affected with rectal (188) or sigmoid (114) resectable cancer underwent radical surgery. Lumboaortic lymphadenectomy was routinely performed and total mesorectal dissection was always accomplished in rectal cancer. Splanchnic nerves, superior hypogastric plexus, hypogastric nerves, and sacral parasympathetic nerves were sought, identified, and preserved or, when necessary, unilaterally sacrificed. Fifty-three (17.6 percent) patients were classified Dukes A, 145 (48.0 percent) B, 46 (15.2 percent) C1, and 17 (5.6 percent) C2. Thirtynine (12.9 percent) patients were Dukes D. In 85 rectal cancer patients, tumor was located at the lower third. Eighty-six of 210 Dukes B and C patients were submitted to systemic chemotherapy and/or high-dose pelvic radiotherapy. RESULTS: The actuarial 5-year disease-free survival was 58.5 percent in rectal and 65.7 percent in sigmoid cancer patients, median follow-up time was 47 months. During the follow-up, each patient was interviewed about sexual activity and urinary dysfunction and a questionnaire was filled out. Urinary dysfunction was not frequently observed, while a definitive sexual impotence was reported in 27.6 percent of the patients. The age under 60 years and sphincter-saving surgery were demonstrated as significantly contributing to retaining a satisfactory sexual activity. CONCLUSIONS: Unexpectedly high disease-free survival was observed in the Dukes C2 subgroup. It allows us to hypothesize that lumboaortic lymphadenectomy could remove neoplastic microfoci present at this level in those patients, enhancing surgical chances of cure. The majority of male patients under 60 years old can retain a satisfactory sexual activity after undergoing a nerve-sparing sphincter-saving cancer surgery.

TAG-72 (CA 72-4 assay) as a complementary serum tumor antigen to carcinoembryonic antigen in monitoring patients with colorectal cancer

Background. Serum carcinoembryonic antigen (CEA) is the most frequently chosen tumor marker in the clinical diagnosis of colorectal carcinoma and in the long‐term monitoring of patients after tumor resection. In recent years, monoclonal antibody technology has identified several new markers of neoplasia, two of which, TAG‐72 and CA 19‐9, are found in the sera of patients with adenocarcinoma. Serum CEA, TAG‐72, and CA 19‐9 were evaluated in 300 patients with either malignant (n = 200) or benign (n = 100) colorectal disease.

CA 72-4 Serum Marker–A New Tool in the Management of Carcinoma Patients

Among the new tumor markers that have been recently proposed, CA 72-4 is of particular interest, not only for its capabilities in diagnosing and monitoring certain neoplastic diseases, but also for its excellent specificity. Several studies focused on the potential clinical usefulness of CA 72-4 in gastrointestinal (GI) and gynecological cancer, showing a sensitivity of approximately 40% in colorectal and gastric cancer and 50% in ovarian cancer, with an overall specificity of more than 95%. Longitudinal evaluations of patients with either GI or gynecological malignant diseases demonstrated that significant elevations of CA 72-4 serum levels may be predictive of recurrent disease. Moreover, the combination of CA 72-4 with other known serum markers, such as CEA and CA 19-9 for GI cancer or CA 125 for ovarian cancer, indicated that an increase in the sensitivity can be achieved without substantial changes in the overall specificity, improving the possibility of monitoring these patients. In conclusion, these results provide a strong argument for the use of CA 72-4 in the management of these neoplastic diseases.