Role of surgery in treatment of advanced differentiated thyroid carcinomas.

Well-differentiated thyroid carcinomas are characterized by a long natural history. The evolution of the reconstructive techniques and the improvement of the peri-operative anaestesiologist management of the patient have contributed, over the last few years, to a progressive widening of demolitive surgery. The aims of enlarged surgical treatment in differentiated advanced thyroid carcinomas are to guarantee respiratory and alimentary functions as well as symptomatic benefits, to obtain local control of the disease and the recovery of adjuvant therapeutic options, such as metabolic and conventional radiation. In the present study, 27 patients who underwent enlarged surgery for differentiated thyroid carcinoma involving the superior digestive-aerial ways (SDAW) were treated between January 1992 and December 2002. The following results were achieved: Group 1 (7 patients): partial resection of the trachea and larynx: 57% of patients are Not Evidence Disease (NED) at a mean follow-up of 7 years; the other 43% are Alive With Disease (AWD). Group 2 (4 patients): total laryngectomy associated with emi-pharyngectomy or oesophagectomy of whom 50% are NED at a mean follow-up of 6 years. Group 3 (4 patients): mediastinum dissection in sternotomy of whom 3 patients NED at 7, 8 and 12 years of follow-up, respectively (75%). Group 4 (12 patients): latero-cervical, retro-clavear and subclavear dissection, of whom 75% of cases are NED at a mean follow-up of 5.1 years. Enlarged surgery is justified by the long natural history of the differentiated histotypes and the advantages it offers to adjuvant therapies. An essential principle, in the case of enlarged thyroid resections, is the modularity. With respect to the loco-regional spread of the disease, the surgeon has to study a treatment plan with a surgical procedure that involves the various elective districts of spreading, planning each surgical step with the entity of demolition and reconstruction being modulated according to the demand.

Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma.

BACKGROUND: The addition of cytokines to chemotherapy (CT) has obtained encouraging but contradictory results in metastatic melanoma. In this phase III trial, we compared the effects of CT [cisplatin, vindesine and dacarbazine (CVD)] with those of concurrent biochemotherapy (bioCT) consisting of CVD plus interleukin-2 and interferon-alpha2b. PATIENTS AND METHODS: A total of 151 untreated metastatic melanoma patients were randomized, 75 on arm A (cisplatin 30 mg/m2 on days 1-3, vindesine 2.5 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 1-3), and 76 on arm B (same CVD scheme plus interferon-alpha2b on days 1-5 and interleukin-2 on days 1-5 and 8-15, both administered subcutaneously), either recycled every 3 weeks. Response was assessed every two cycles. RESULTS: Ten percent of the patients were alive at a median of 52 months from start of therapy. We observed a response rate (RR) of 21% on arm A versus 33% on arm B; three patients (4%) given bioCT had complete responses (CRs). Median time to progression (TTP) was identical; median overall survival (OS) time was 12 months on arm A and 11 months on arm B. CONCLUSIONS: BioCT is not better than CT alone; the trend in favor of the bioCT in terms of RR did not translate into better TTP or OS. Therefore, bioCT cannot be recommended as standard first-line therapy for metastatic melanoma.

[Impact of sentinel lymph node biopsy on the treatment of melanoma]. / Impatto della biopsia del linfonodo sentinella sul trattamento del melanoma.

In the National Cancer Institute and S Pio X Hospital series we registered 981 patients with primary cutaneous melanoma and no evidence of clinically detectable regional node metastases underwent sentinel node (SN) dissection to microscopically define the tumor status of the regional lymph nodes. In 62.2% of cases, only one SN was detected; 26.4% of patients had two SNs and 11.4% had three or more SNs. A positive SNB was demonstrated in 18.1%. Analysis of survival indicated that the tumor status of the nodes was the most important prognostic factor. Breslow's thickness had a significant impact on survival in tumors of 4 mm or thicker, and ulceration dropped to a borderline significant P-value. To assess the tumor burden in positive SNB, all slides (148 SN pos) were reviewed. Twenty per cent of these patients had evidence of metastasis in other nodes. Of the remaining 80% with a single tumor-involved SN, 62% had a single metastatic deposit. Preliminary data from this study indicate that several subgroups may be identified among patients with 1 positive node, but adequate analysis of survival requires a larger number of patients and a multicentric study.

Optical imaging and automated melanoma detection: questions and answers.

Early detection and prompt excision of cutaneous melanoma is of paramount importance to improve patient survival, and the clinician should be aware of the clinical features that suggest the presence of a malignant lesion. The clinical diagnosis is mainly based on observation of the colour and shape of a given skin lesion. Unfortunately, evaluation of a pigmented lesion is to a large extent subjective and is closely related to the experience of the clinician. To overcome this problem, optical imaging techniques using different instrumentation (i.e. colour video camera, epiluminescence microscopy, reflectance spectrophotometry) and computer image analysis have been proposed in an attempt to provide quantitative measurements in an objective and reproducible fashion. The different procedures employed to perform the diagnosis automatically all have a common denominator: mimicking the eye and the brain of the clinician by image processing and computerized analysis programs, respectively. Sensitivity and specificity data reported in the literature suggest that the computer-based diagnosis of melanoma does not greatly differ from the diagnostic capability of an expert clinician, and is independent of the optical acquisition method employed to analyse the lesions. Most of the computer-processed morphometric variables useful in automated diagnosis are not recognizable nor can be objectively evaluated by the human eye, except that of lesion dimension. However, several questions should be answered before assessing the actual usefulness, including the potential and limitations, of computer-based diagnostic procedures. The purpose of this study was to briefly review the different kinds of instrumentation being used to diagnose melanoma, and to raise questions and whenever possible provide answers in an attempt to establish whether there will be a future for these computerized systems.

A feasibility study using polychemotherapy (cisplatin + vindesine + dacarbazine) plus interferon-alpha or monochemotherapy with dacarbazine plus interferon-alpha in metastatic melanoma.

AIMS AND BACKGROUND: This trial evaluated the feasibility and tolerability of an immunochemotherapeutic approach that uses cisplatin, vindesine, and dacarbazine (DTIC), or only DTIC, in combination with interferon alpha-2a (IFN-alpha), in patients with metastatic melanoma, considering the significant toxicity of several different regimens used up to now. METHODS: Between May 1995 and September 1997, 51 melanoma patients (50 of whom were assessable) entered a multicentric trial and were randomized to receive cisplatin (30 mg/m2 daily for 3 days) + vindesine (2.5 mg/m2 only day 1) + DTIC (250 mg/m2 daily for 3 consecutive days) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (CVD arm) versus DTIC (800 mg/m2 day 1) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (DTIC arm). The chemotherapy was recycled every 21 days. Patient reevaluation was performed every two cycles, and the treatment was continued in case of objective response or stabilization of disease. RESULTS: We observed 3 complete responses, 2 partial responses and 5 stable diseases in the CVD arm, and 2 partial responses and 4 stabilizations of disease in the DTIC arm. CONCLUSIONS: We conclude that these chemotherapeutic regimens are well tolerated regimens with modest toxicity. Future trials will be conducted associating the CVD regimen with biological response modifiers (IFN, IL-2) in order to improve the results.

Surgical treatment of gastric metastases from cutaneous melanoma: experience of the National Cancer Institute of Milan.

AIM: To evaluate the role of a surgical approach in patients affected with gastric metastases from cutaneous melanoma. METHODS: A retrospective review of our local melanoma database of 2100 patients identified 31 cases with gastric metastatic deposits. Nine of them were considered candidates for surgical resection. RESULTS: Median overall survival of the 9 patients who underwent surgery was 14.2 months. Six (67%) underwent a local radical resection of disease, and 3 (33%) had a simple exploratory laparotomy. The median survival was 21.6 months (range, 4-32 months) for the subset receiving radical surgery and 3.6 months (range, 2-6 months) for the patients who had no resection. Median follow-up was 14.2 months. No specific correlation of serologic LDH levels and final outcome, as documented elsewhere, was observed. A marked decreased or substantial remission of symptoms with an improvement in quality of life was observed in all radically resected patients. CONCLUSIONS: Patients with gastric metastases from melanoma may benefit from surgery if all macroscopic disease can be removed. In addition, gastric resection in patients with symptomatic melanoma spread to the stomach provides important symptomatic palliation.

Do patients with tumor-positive sentinel nodes constitute a homogeneous group?

From January 1993 to May 2000, 1062 patients with primary cutaneous melanoma and no evidence of clinically detectable regional node metastases underwent sentinel node (SN) dissection to microscopically define the tumor status of the regional lymph nodes. A total of 1165 biopsies were performed. The SN identification rate was 89.6%. In 62.2% of the cases, only one SN was detected; 26.4% of patients had two SNs; and 11.4% had three or more SNs. Analysis of survival indicated that the tumor status of the nodes was the most important prognostic factor. Breslow's thickness had a significant impact on survival in tumors 4 mm or thicker, and ulceration dropped to a borderline-significant P value. To assess the tumor burden in positive SNs, all slides for patients at the Istituto Nazionale Tumori and S. Pio X Hospital were reviewed. Of 658 patients in this series, 90 had positive SNs. Eighteen of these patients had evidence of metastasis in other nodes. Of the remaining 72 with a single tumor-involved SN, 62% had a single metastatic deposit. Preliminary data from this study indicate that several subgroups may be identified among patients with positive nodes, but adequate analysis of survival requires a larger number of patients and a multicenter study.

Impact of clinical trials on the treatment of melanoma.

Today the role of clinical trials is being challenged and it seems that this investigative tool does not keep in step with the rhythms imposed by the progress of scientific knowledge and the expectations of the public and media. From the 1970's to the 1990's, however, clinical trials have been the most important way for clinical researchers to find answers to therapeutic questions.

Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial.

BACKGROUND: Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients. METHODS: 444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse. FINDINGS: 424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27.5% (95% CI 21.7-33.6); for those who received surgery alone, survival was 28.4% (22.5-34.6) (p=0.50). Neither Kaplan-Meier cumulative survival rates, nor multivariate analysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% CI 29-42) and those who had surgery alone (37%, 31-44). INTERPRETATION: Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

Axillary lymph node staging in breast cancer by 2-fluoro-2-deoxy-D-glucose-positron emission tomography: clinical evaluation and alternative management.

BACKGROUND: Surgical removal of axillary lymph node and histologic examination for metastases are used to determine whether adjuvant treatment is necessary for patients with breast cancer. Axillary lymph node dissection (ALND) is a costly procedure associated with various side effects, and 80% or more of patients with tumors of 20 mm or less are lymph node negative and might avoid ALND. In this study, we evaluated whether an alternative, noninvasive method--i.e., positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-- could be used to determine axillary lymph node status in patients with breast cancer. METHODS: One hundred sixty-seven consecutive patients with breast cancers of 50 mm or less (range = 5-50 mm; mean = 21 mm) scheduled for complete ALND were studied preoperatively with FDG-PET, and then PET and pathology results from ALND were compared. All statistical tests were two-sided. RESULTS: The overall sensitivity, specificity, and accuracy of lymph node staging with PET were 94.4% (PET detected 68 of 72 patients with axillary involvement; 95% confidence interval [CI] = 86.0% to 98.2%), 86.3% (82 of 95 patients without axillary involvement; 95% CI = 77.8% to 91.9%), and 89.8% (150 of 167 patients with breast cancer; 95% CI = 84.2% to 93.6%), respectively. Positive- and negative-predictive values were 84.0% (68 patients with histologically positive lymph nodes of 81 patients with positive FDG-PET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with negative FDG-PET scan; 95% CI = 88.2% to 98.5%), respectively. When PET results for axillary metastasis were analyzed by tumor size, the diagnostic accuracy was similar for all groups (86.0%-94.2%), with higher sensitivity for tumors of 21-50 mm (98.0%) and higher specificity for tumors of 10 mm or less (87.8%), and the range was 93.5%-97.3% for negative-predictive values and 54.5%-94.1% for positive-predictive values. Among the 72 patients with axillary involvement, PET detected three or fewer metastatic lymph nodes in 27 (37.5%) patients, about 80% of whom had no clinically palpable axillary lymph nodes. CONCLUSIONS: Noninvasive FDG-PET appears to be an accurate technique to predict axillary status in patients with breast cancer and thus to identify patients who might avoid ALND. These results should be confirmed in large multicenter studies.

Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.

What is the most promising strategy for the treatment of metastasizing melanoma?

The treatment of patients with metastasizing melanoma, still one of the most deadly diseases in modern medicine, ranks among the greatest challenges that a clinician has to face. Metastatic melanoma also is one of the most profound sources of clinical frustration, since it provides far more ultimately defeating experiences than clinical victories. At the same time, the fascinating biology of melanoma has invited the study of this neuroectodermal tumor as a model system for dissecting many of the key problems of modern oncology, ranging from molecular oncogenesis via the controls of tumor proliferation, apoptosis, invasion, metastasis, and angiogenesis to tumor immunosurveillance and tumor drug resistance. Together with the dire need to develop more effective treatment modalities for improving both life expectancy and quality of life of affected patients, this has made metastatic melanoma a favorite model for the exploration of innovative strategies for tumor management. Encouragingly, many of these have already generated very promising results in animal models. However, this impressive level of research progress in conquering melanoma in the animal room contrasts rather pitifully with the actual progress made on the ward. This CONTROVERSIES feature, therefore, critically and soberly reviews the state of the art of treating metastatic melanoma today (distinguishing between nodal and distant metastases), and sharply defines unresolved or comparatively neglected key problems. In addition, this feature highlights several novel, provocative, hitherto underappreciated, yet potentially promising treatment approaches that deserve systematic exploration. Hopefully, this will offer further inspiration for the design and pursuit of innovative anti-melanoma strategies off-the-beaten-track.

Sentinel node biopsy in patients with cutaneous melanoma of the head and neck.

Biopsy of head and neck sentinel nodes (SNs) can be technically problematic due to the unpredictable and variable drainage patterns of this anatomic region. The aim of the present study was to evaluate the feasibility of SN biopsy for cutaneous melanoma of the head and neck. We performed SN biopsy in 17 patients affected by stage I cutaneous melanoma of the head and neck on the basis of lymphoscintigraphy, blue dye and gamma probe. A total of 24 procedures were performed. Drainage to more than one lymphatic basin was observed in five patients (two basins in three cases and three basins in two cases) and in all cases SN biopsy was performed in all basins. The biopsy distribution by site was: six cervical nodes, five parotid nodes, four supraclavicular and submandibular nodes, three auricular and axillary nodes. The SN identification rate was 87.5% (21/24); metastases were discovered in four cases, with a positivity rate of 23.6%. At the time of writing, 1 patient is alive with local disease, 3 patients are dead and 13 are alive and free of disease with a follow-up ranging from 1 to 40 months (median, 21 months) following SN biopsy. In our opinion preoperative lymphoscintigraphy and the intraoperative use of a gamma probe are useful for the identification of lymphatic drainage of cutaneous melanoma of the head and neck.

Unusual association between cutaneous melanoma and axillary metastasis from occult breast cancer detected by sentinel node biopsy.

We report a case of cutaneous Stage I melanoma associated with occult breast cancer detected incidentally during a sentinel node biopsy. A brief review of the literature is presented with particular emphasis on this association and on an examination of the theoretical link which may exist between melanoma and breast cancer.

Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma.

UNLABELLED: The purposes of this study were to establish the diagnostic accuracy of FDG PET for lymph node metastases and to determine the smallest detectable volume of disease. METHODS: Using FDG PET, we preoperatively studied 56 lymph node basins in 38 patients with a clinical or instrumental diagnosis of lymph node metastases from melanoma. All lymph node basins underwent node dissection. The FDG PET results were compared with the postoperative histopathology results. PET images were obtained using a GE 4096 WB scanner, after injection of a mean activity of 496 MBq (range, 366-699 MBq) of FDG. RESULTS: The efficacy of FDG PET in the diagnosis of involved lymph node basins was good. Sensitivity was 95% (35/37); specificity, 84% (16/19); accuracy, 91% (51/56); positive predictive value, 92% (35/38); and negative predicative value, 89% (16/18). Metastases were shown histologically in 114 of 647 surgically removed lymph nodes. FDG PET detected 100% of metastases > or = 10 mm, 83% of metastases 6-10 mm, and 23% of metastases < or = 5 mm. Moreover, FDG PET had high sensitivity (> or = 93%) only for metastases with more than 50% lymph node involvement or with capsular infiltration. CONCLUSION: Our study shows that FDG PET has a reasonable sensitivity and specificity for detecting the presence or absence of lymph node metastases in patients with melanoma. However, even if able to detect small volumes of subclinical macroscopic disease, FDG PET cannot detect subclinical microscopic disease with acceptable sensitivity. The specificity of FDG PET is good, but some false-positive results may occur.