R. Cavaliere

Sentinel lymph node biopsy in cutaneous melanoma: the WHO Melanoma Program experience.

Background: We report the experience of the World Health Organization (WHO) Melanoma Program concerning sentinel lymph node (SLN) biopsy for detecting patients with occult regional nodal metastases to submit to selective regional node dissection.Methods: From February 1994 to August 1998, in 12 centers of the WHO Melanoma Program, 892 SLN biopsies were performed in 829 patients with clinical stage I melanoma (male: 370; female: 459; median age: 50 years old). The location of the primary melanoma was as follows: trunk, 35%; lower limbs, 45%; upper limbs, 18%; and head and neck, 2%. Blue dye injection for SLN identification was performed in all cases; preoperative lymphoscintigraphy was one in 440 patients, and an intra-operative probe for a radio-guided biopsy was used in 141 cases. Overall, the SLN identification rate was 88%. In 68% of the patients, only one SLN was identified, whereas two and three or more SLN were detected in 24% and 8% of the remaining cases, respectively.Results: Overall SLN positivity rate was 18%. Intra-operative frozen section examination was performed in 39% of the cases and was helpful in detecting occult localizations only in 47% of the positive SLNs. Distribution of positive cases by primary thickness was as follows:,1mm: 2%; 1–1.99 mm: 7%; 2–2.99 mm: 13%; and 3 mm: 31%. Positive nonsentinel lymph nodes were found in 22% of cases with positive SLN submitted for selective dissection. No complications due to the procedure were registered. Of 710 patients who were evaluated, 40 (6%) presented a regional nodal relapse after a negative SLN biopsy and underwent a delayed therapeutic dissection. From the 710 enrolled cases, 638 (88.5%) were alive without evidence of disease at the time of this writing. A multivariate analysis showed SLN status as one of the most significant prognostic factors (P 5 .000) along with thickness (P 5 .001) and ulceration (P 5 .015) of primary tumor.Conclusions: These data confirm the feasibility and safety of the SLN technique for selecting patients to submit to a radical node dissection. The data represent the basis for a future trial by the WHO Melanoma Program in this field to evaluate the most appropriate surgical approach for treating patients with occult regional nodal metastases.

Prognostic variables in recurrent limb melanoma treated with hyperthermic antiblastic perfusion

Between October 1969 and December 1986, 136 patients with recurrent limb melanoma were treated with hyperthermic antiblastic perfusion (HAP). This retrospective analysis is aimed at identifying tumor‐related and treatment‐related variables likely to influence tumor response, locoregional control, disease‐free survival, and overall survival. Independent factors predicting a complete response (CR) were the number of lesions (P < 0.0001) and the minimum tumor temperature (minT) (P = 0.03). Only a positive trend was observed for the drug dose (P = 0.08). However, the proportion of CR was significantly higher (57.7%; P = 0.02) in patients who had a minT of 41.5°C or greater and who were given a dose equal to or greater than the standard dose than in patients treated with lower temperatures and/or lower drug doses. The occurrence of a CR significantly increased the rates of locoregional control (77%; P = 0.007), disease‐free survival (55.6%; P = 0.006), and overall survival (68.6%; P = 0.03). Treatment optimization may provide further therapeutic improvements by increasing the incidence of CR. However, the overall survival rates also were influenced by the number of lesions (P = 0.0014), sex (P = 0.04), and the number of previous relapses (P = 0.01). Therefore, tumor aggressiveness also is crucial in determining the outcome of the disease, and only early treatment with HAP can reduce the risk of distant metastases.

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.

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.

Hyperthermic antiblastic perfusion with alpha tumor necrosis factor and doxorubicin for the treatment of soft tissue limb sarcoma in candidates for amputation: results of a phase I study.

To improve the therapeutic effectiveness of hyperthermic antiblastic perfusion (HAP), the association of recombinant tumor necrosis factor alpha (rTNF alpha), doxorubicin, and true hyperthermia (41 degrees C) was employed for the treatment of soft tissue limb sarcoma. A dose-escalation study according to Fibonaccis modified scheme was conducted, starting with a rTNF alpha dose of 0.5-3.3 mg. The doxorubicin doses (0.7 and 1.4 mg for the upper and lower limbs, respectively) and temperature level (41 degrees C) remained unchanged. Eighteen patients have been treated thus far: 9 males and 9 females of a mean age of 33 years (range: 24-71 years). The tumor was located in the upper limb in one patient and in the lower limbs in seventeen. Only 16 patients were evaluable, as 2 refused further treatment after the perfusion. In terms of local toxicity, a grade I limb reaction was observed in 3 patients, a grade II or III in 10 patients, and a grade IV in 5 patients, showing a strict correlation between the TNF dose and the grade of limb reaction. In fact, a grade III-IV limb reaction was observed in 66.6% of the patients treated with > 1 mg of rTNF alpha. The maximum tolerable dose in association with doxorubicin and true hyperthermia (41 degrees C) was 2.4 mg. Eleven patients showed a good pathological response (> 75%) and five patients showed a partial response (> 25%-< 75%). In no case was stable or progressive disease observed. The postperfusional tumor shrinkage permitted limb-sparing surgery in 75% of the patients, all of whom were candidates for amputation before HAP. No recurrences have been observed thus far. Two patients developed regional disease: one presented with a skip femur metastasis that disappeared after radiotherapy and systemic chemotherapy; the second developed regional node involvement, requiring a radical node dissection. Another patient had pulmonary metastases, 2 months after the HAP, which were resected. At a median follow-up of 12 months, all the patients are living without disease. The results of this phase I study suggest that the association of rTNF alpha, doxorubicin, and true HAP (41 degrees C) by regional perfusion is feasible and safe at a maximum tolerable rTNF alpha dose of 2.4 mg. However, because no correlation was found between the amount of rTNF alpha and the tumor response, 1 mg is recommended as the dose able to provide a high tumor necrosis rate and low local and systemic toxicity. This association appears to play an important role in the neoadjuvant treatment of soft tissue limb sarcoma.

Concomitant preoperative radiochemotherapy in operable locally advanced rectal cancer

PURPOSE: The aim of this study was to examine the effectiveness of a combination of preoperative radiotherapy and chemotherapy for operable locally advanced rectal cancer (Stages II and III). METHODS: Chemotherapy and radiotherapy are started jointly on day one of the therapy. 5-Fluorouracil is given in a dosage of 1000 mg/ m2/day as a continuous 24-hour infusion for 4 days. Mitomycin C is given as a bolus intravenous at a dosage of 10 mg/m2 the first day. The radiation therapy is given to a total dosage of 37.8 Gy. Surgery is generally performed four to five weeks following completion of the radiation therapy. From March 1990 to April 1993, 34 patients with histologically documented adenocarcinoma of the rectum have been treated. Twenty-one lesions were located in the lower third of the rectum. Twenty-nine neoplasms were judged by initial clinical staging as Stage III. RESULTS: Patients compliance to the treatment have been 97 percent. Toxicity of treatment has been low (15 percent). Tumor sizes decreased 50 percent or more in about 80 percent of patients. Distance of the tumor from the anal canal increased in all but seven cases. Twenty-two anterior resections have been performed. The morbidity rate has been 24 percent. No postoperative mortality has been reported. Histologic examination of surgical specimens after integrated treatment showed in 10 cases a tumor confined to the rectal wall (T2), in 3 patients only a residual tumor limited to submucosa (T1), and in 5 (15 percent) patients no evidence of neoplastic cells (T0). CONCLUSIONS: We conclude that preoperative radiochemotherapy was generally well tolerated; in all cases we had a reduction of tumor sizes, surgery presented no technical difficulties, and there was the effect of stage reduction.

The application of hyperthermia in regional chemotherapy

To evaluate the role of hyperthermia combined with chemotherapy in the loco-regional treatment of tumors, a retrospective analysis was done with 228 limb melanoma patients treated with hyperthermic antiblastic perfusion (HAP). A series of treatment- and tumor-related prognostic factors was analyzed to establish their influence on tumor response, loco-regional control, and survival. Concerning tumor response, the logistic model showed that the number of lesions and the minimal tumor temperature (min T) maintained their individual predictive values (P < 0.000001 and P = 0.04, respectively). For loco-regional control, only the number of lesions had a significant predictive value. No direct correlation was found between the treatment-related variables and loco-regional control. However, the 5-year survival rate was significantly higher for patients who achieved a complete response (CR) (51.5%, P = 0.0033) as compared to those who did not (33.3%), providing indirect evidence of the role of the treatment. Multivariate analysis showed that both disease-free and overall survival are strongly influenced by numerous clinical variables and the min T always maintained its significance. When analyzing the subgroup of 119 patients evaluable for tumor response, the Cox model selected the tumor response as the dominant factor for both disease-free and overall survival. These data seem to demonstrate that the optimization of treatment parameters is crucial in determining the CR rate, which, in turn, positively affects the disease outcome. HAP is the treatment of choice for recurrent limb melanoma, and hyperthermia plays an important role in exploiting the efficacy of this technique.

S-100 and NSE as serum markers in melanoma.

S-100 protein and neuron-specific enolase (NSE) have recently been proposed as serum markers for melanoma. In this study NSE and S-100 serum levels were assayed by commercial IRMA methods in 53 patients with melanoma. The overall prevalence of abnormal marker levels was similar for NSE (26%) and S-100 (30%). The 24 patients in stages I and II had uniformly normal S-100 levels, but abnormal NSE levels were observed in 3 out of the 12 patients in stage II (33%) and in 1 out of 12 in stage I. NSE appears thus to be the marker of choice in the early stages, where its increase points to disease progression. In patients in stages III and IV the prevalence of abnormal values was 34% for NSE and 55% for S-100 (p = < 0.05). In the latter group diagnostic sensitivity increased to 62% if isolated elevation of each marker was considered. In patients with advanced stage disease, both NSE and S-100 should be assayed.

The role of hyperthermic perfusion in the treatment of tumors of the extremities.

Approximately 60% of all soft tissue and osteogenic sarcomas and 50% of all melanomas arise in the extremities. Treatment of these tumors has traditionally been limited to local surgical procedures, often resulting in a non-functioning limb or amputation, particularly in the case of sarcoma and in a local recurrence rate Primarily related to the biological tumor aggressiveness. A higi incidence of micrometastatic nodules has been found in most high-grade sarcomas and in high-risk melanomas in the form of “skip” or “in transit” metastases. This suggests that these tumors cannot be managed as locally confined neoplasms, being a regional disease “ab initio” and requiring loco-regional treatment.

Lonidamine and hyperthermia: Clinical experience in melanoma. Preliminary results

Lonidamine alone or in combination with hyperthermic perfusion, with or without melphalan, was investigated in 12 patients with stage II, III, and IV malignant melanoma. The authors evaluated the most effective methods and sequence of Lonidamine administration. Preliminary results suggest that the highest effectiveness is obtained with the simultaneous administration of Lonidamine and hyperthermia.