PET CT imaging in patients undergoing sentinel node biopsy for melanoma.

AIMS: Sentinel lymph node biopsy (SLNB) has been adopted in the surgical treatment of melanoma to reduce morbidity and enhance staging. Positron emission tomography with computerised tomography (PET/CT) has been utilised in the staging of patients with malignancy though the role of this imaging modality in early stage melanoma is unclear. This study examined the preoperative value of PET/CT in patients undergoing SLNB for malignant melanoma. METHODS: Patients presenting with primary melanoma without evidence of either locoregional or systemic metastasis were considered candidates for SLNB. Selected patients underwent preoperative PET/CT followed by definitive surgical therapy including SLNB with regional lymphadenectomy, where indicated. RESULTS: During a 12-month period 83 patients were identified as having undergone SLNB for melanoma, of which 37 (45%) had preoperative PET/CT. Mean melanoma thickness 1.9 mm and 2.4 mm (PET/CT vs. no PET/CT, p>0.05). 13 (15.6%) patients were found to have lymphatic metastasis at SLNB; nine of these patients underwent PET/CT, only two of these scans were suggestive of lymphatic metastasis (positive predictive value 24%, negative predictive value 76%). PET/CT revealed no unheralded metastatic disease but did identify a second occult malignancy in 4 (10.8%) patients undergoing therapy for melanoma. CONCLUSIONS: The results of this study do not support the use of PET/CT in patients undergoing SLNB for melanoma. SLNB appears to be a more sensitive staging modality in the detection of lymphatic metastasis; however PET/CT may have a future role as a screening tool for malignancy.

Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089.

PURPOSE: To determine the relationship, in patients with adenocarcinoma of the colon, between survival and the number of lymph nodes analyzed from surgical specimens. PATIENTS AND METHODS: Intergroup Trial INT-0089 is a mature trial of adjuvant chemotherapy for high-risk patients with stage II and stage III colon cancer. We performed a secondary analysis of this group with overall survival (OS) as the main end point. Cause-specific survival (CSS) and disease-free survival were secondary end points. Rates for these outcome measures were estimated using Kaplan-Meier methodology. Log-rank test was used to compare overall curves, and Cox proportional hazards regression was used to multivariately assess predictors of outcome. RESULTS: The median number of lymph nodes removed at colectomy was 11 (range, one to 87). Of the 3411 assessable patients, 648 had no evidence of lymph node metastasis. Multivariate analyses were performed on the node-positive and node-negative groups separately to ascertain the effect of lymph node removal. Survival decreased with increasing number of lymph node involvement (P =.0001 for all three survival end points). After controlling for the number of nodes involved, survival increased as more nodes were analyzed (P =.0001 for all three end points). Even when no nodes were involved, OS and CSS improved as more lymph nodes were analyzed (P =.0005 and P =.007, respectively). CONCLUSION: The number of lymph nodes analyzed for staging colon cancers is, itself, a prognostic variable on outcome. The impact of this variable is such that it may be an important variable to include in evaluating future trials.

Local recurrence of breast cancer in the stereotactic core needle biopsy site: case reports and review of the literature.

Early mammographic detection of nonpalpable breast lesions has led to the increasing use of stereotactic core biopsies for tissue diagnosis. Tumor seeding the needle tract is a theorectical concern; the incidence and clinical significance of this potential complication are unknown. We report three cases of subcutaneous breast cancer recurrence at the stereotactic biopsy site after definitive treatment of the primary breast tumor. Two cases were clinically evident and relevant; the third was detected in the preclinical, microscopic state. All three patients underwent multiple passes during stereotactic large-core biopsies (14 gauge needle) followed by modified radical mastectomy. Two patients developed a subcutaneous recurrence at the site of the previous biopsy 12 and 17 months later; one had excision of the skin and dermis at the time of mastectomy revealing tumor cells locally. In summary, clinically relevant recurrence from tumor cells seeding the needle tract is reported in two patients after definitive surgical therapy (without adjuvant radiation therapy). Often, the biopsy site is outside the boundaries of surgical resection. Since the core needle biopsy exit site represents a potential area of malignant seeding and subsequent tumor recurrence, we recommend excising the stereotactic core biopsy tract at the time of definitive surgical resection of the primary tumor.

Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation.

BACKGROUND: Lobular carcinoma in situ (LCIS) is a known risk factor for the development of invasive breast carcinoma. However, little is known regarding the impact of LCIS in association with an invasive carcinoma on the risk of an ipsilateral breast tumor recurrence (IBTR) in patients who are treated with conservative surgery (CS) and radiation therapy (RT). The purpose of this study was to examine the influence of LCIS on the local recurrence rate in patients with early stage breast carcinoma after breast-conserving therapy. METHODS: Between 1979 and 1995, 1274 patients with Stage I or Stage II invasive breast carcinoma were treated with CS and RT. The median follow-up time was 6.3 years. RESULTS: LCIS was present in 65 of 1274 patients (5%) in the study population. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1125 patients; 2%). Ipsilateral breast tumor recurrence (IBTR) occurred in 57 of 1209 patients (5%) without LCIS compared with 10 of 65 patients (15%) with LCIS (P = 0.001). The 10-year cumulative incidence rate of IBTR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003). In both groups, the majority of recurrences were invasive. The 10-year cumulative incidence rate of IBTR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46). Subsets of patients in which the presence of LCIS was associated with an increased risk of breast recurrence included tumor size < 2 cm (T1), age < 50 years, invasive ductal carcinoma, negative lymph node status, and the absence of any adjuvant systemic treatment (chemotherapy or hormonal therapy) (P < 0.001). LCIS margin status, invasive lobular carcinoma histology, T2 tumor size, and positive axillary lymph nodes were not associated with an increased risk of breast recurrence in these women. CONCLUSIONS: The authors conclude that the presence of LCIS significantly increases the risk of an ipsilateral breast tumor recurrence in certain subsets of patients who are treated with breast-conserving therapy. The risk of local recurrence appears to be modified by the use of tamoxifen. Further studies are needed to address this issue.

Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist?

PURPOSE: The elective treatment of internal mammary lymph nodes (++IMNs) in breast cancer is controversial. Previous randomized trials have not shown a benefit to the extended radical mastectomy or elective IMN irradiation overall, but a survival benefit has been suggested by some for subgroups of patients with medial tumors and positive axillary lymph nodes. The advent of effective systemic chemotherapy and potential for serious cardiac morbidity have also been factors leading to the decreased use of IMN irradiation during the past decade. The recent publishing of positive trials testing postmastectomy radiation that had included regional IMN irradiation has renewed interest in their elective treatment. The purpose of this study is to critically review historical and new data regarding IMNs in breast cancer. METHODS AND MATERIALS: The historical incidence of occult IMN positivity in operable breast cancer is reviewed, and the new information provided by sentinel lymph node studies also discussed. The results of published randomized prospective trials testing the value of elective IMN dissection and/or radiation are analyzed. The data regarding patterns of failure following elective IMN treatment is studied to determine its impact on local-regional control, distant metastases, and survival. A conclusion is drawn regarding the merits of elective IMN treatment based on this review of the literature. RESULTS: Although controversial, the existing data from prospective, randomized trials of IMN treatment do not seem to support their elective dissection or irradiation. While it has not been shown to contribute to a survival benefit, the IMN irradiation increases the risk of cardiac toxicity that has effaced the value of radiation of the chest wall in reducing breast cancer deaths in previous randomized studies and meta-analyses. Sentinel lymph node mapping provides an opportunity to further evaluate the IMN chain in early stage breast cancer. Biopsy of "hot" nodes may be considered in the future to select patients who are most likely to benefit from additional regional therapy to these nodes. CONCLUSIONS: Irradiation of the IMN chain in conjunction with the chest wall and supraclavicular region should be considered only for those with pathologically proven IMNs with the goal of improving tumor regional control.

Management of locally advanced rectal cancer.

The treatment of rectal cancer typically involves a multidisciplinary approach. A minority of patients will have tumors that are full thickness, involve adjacent structures, or have metastatic disease to regional lymph nodes. The combination of adjuvant therapy and surgical resection is the mainstay of treatment for locally advanced carcinoma of the rectum. This article will review the role of adjuvant chemotherapy and radiotherapy in patients with high risk tumors. The operative considerations in advanced rectal cancers will be reviewed. In particular, the role of mesorectal excision and exenterative surgery will be discussed.

Importance of timing and length of administration of angiogenesis inhibitor TNP-470 in the treatment of K12/TRb colorectal hepatic metastases in BD-IX rats.

BACKGROUND: The timing and length of administration of angiogenesis inhibitor TNP-470 was altered to evaluate the effect on disease progression in a rat model of colorectal hepatic metastases. METHODS: Pair-fed BD-IX rats, injected intrasplenically with rat colon adenocarcinoma K12/TRb cells at day 0, were randomized to receive subcutaneous injections of either placebo or 15 mg/kg TNP-470 on alternate days: for 2 weeks beginning 24 hours after tumor inoculation ("Early"), for 4 weeks beginning 24 hours after tumor inoculation ("Prolonged"), or for 2 weeks beginning at day 15 after macroscopic tumor nodules were confirmed ("Delayed"). Response to treatment was evaluated by counting tumor nodules on the surface of the liver at laparotomy on day 14 and 28 after tumor inoculation. The animals were followed for survival and cause of death. RESULTS: Maximal suppression of hepatic metastases at day 28 required 4-week rather than 2-week TNP-470 administration. Prolonged TNP-470 administration resulted in significantly fewer hepatic metastases at day 28 compared to control (P < .05). Early and prolonged TNP-470 improved survival (Wilcoxon test, P < .05) compared with delayed TNP-470 and placebo. Delayed TNP-470 administration did not increase survival or significantly diminish the number of metastases at day 28 compared with placebo. CONCLUSIONS: These data suggest that prolonged adjuvant antiangiogenic therapy may suppress colorectal hepatic micrometastases.

Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer.

PURPOSE: To determine the acute toxicity, post-operative complications, pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospective Phase I trial. MATERIALS & METHODS: To be eligible for this study, patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40% of the bowel circumference. All patients received 45 Gy pelvic radiation (1.8 Gy per fraction). Subsequent radiation was given to the region of the gross tumor with a 2 cm margin. This "boost" treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I, 57 Gy for Level II, and 61.8 Gy for Level III. 5-FU was given at 1g/m2 over 24 hours for a four day infusion during the first and sixth weeks of radiation, with the second course concurrent with the hyperfractionated radiation. Surgical resection was carried out 4-6 weeks following completion of chemoradiation (in curative cases) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery. RESULTS: Twenty-seven patients, age 40-82 (median 61), completed the initial course of chemoradiation and are included in the analysis of toxicity. The median follow-up is 27 months (range 8-68). Eleven patients were treated to a dose of 54.6 Gy, nine patients to 57 Gy, and seven patients to 61.8 Gy. Twenty-one patients had T3 tumors, and six patients T4 tumors. Grade III acute toxicity from chemoradiation included proctitis (5 patients), dermatitis (9), diarrhea (five), leukopenia (1), cardiac (1). Grade IV toxicities included one patient with diarrhea (on dose Level I) and one patient (on dose Level III) with cardiac toxicity (unrelated to radiation). Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7. Four patients did not undergo a curative resection; three initially presented with metastases and one developed metastasis during the pre-operative regimen. Post-operative complications included pelvic or perineal abscess in two (on dose Levels I & II), and delayed wound healing in two (one of whom, on dose Level III, developed perineal wound dehiscence requiring surgical reconstruction). Of the 23 patients who had a curative resection, four manifested pathologic complete responses (17.4%). Thirteen of 23 patients (57%) had evidence of pathologic downstaging and only 1/23 patients (on dose Level I) had a positive resection margin. Of these 23 patients (with a minimum follow-up of 8 months), the patient with positive margins was the only one who developed a local failure (Fisher's Exact p=.04). The 3-year actuarial OS, DFS and LC rates are 82%, 72% and 96%, respectively. Twelve of 13 patients (92% at 3 years) > or = 61 years vs. 5/10 patients (45% at 3 years) < 61 years remained disease-free (log-rank p=0.017). CONCLUSION: This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer. The vast majority of patients (96%) achieved negative margins, which appears to be a prerequisite for local control (p= 0.04). Older age (> or =61 years) was a significant predictor for improved DFS. This regimen (at dose Level III, 61.8 Gy) is currently being tested in a Phase II setting.

The presence of proliferative breast disease with atypia does not significantly influence outcome in early-stage invasive breast cancer treated with conservative surgery and radiation.

PURPOSE: To evaluate the influence of the benign background breast-tissue change of atypical hyperplasia (AH) on outcome in patients with early-stage invasive breast cancer treated with conservative surgery and radiation. MATERIALS AND METHODS: Four hundred and sixty women with Stage I--II breast cancer treated with conservative surgery and radiation from 1982-1994 had pathologic assessment of their background adjacent benign breast tissue. The median follow-up was 5.6 years (range 0.1-15). The median age was 55 years (range 24-88). Of these, 23% had positive axillary nodes; 25% received adjuvant chemotherapy (CMF or CAF) with (9%) or without (17%) tamoxifen. Of the total, 24% received adjuvant tamoxifen alone. The patients were divided into 2 groups: 131 patients with atypical hyperplasia (ductal, 99 patients; lobular, 20 pts; and type not specified, 12 pts), and 329 patients with no proliferative changes or proliferative changes without atypia. RESULT: A statistically significant difference was observed between the 2 groups for method of detection, primary tumor size, presence of lobular carcinoma in situ (LCIS), pathologic nodal status, region(s) treated with radiation, and type of adjuvant therapy. Patients with atypical hyperplasia (AH) had smaller primary tumors (T1 80% vs. 70%) more often detected solely by mammography (51% vs. 36%) with negative axillary nodes (87% vs. 73%) and radiation treatment to the breast only (93% vs. 78%). LCIS was observed in 9% of the patients with AH and 3% of those without AH. Patients with AH more often received tamoxifen alone (32% vs. 21%), rather than chemotherapy (15% vs. 29%). There were no statistically significant differences between the 2 groups for race, age, menopausal status, family history, histology, histologic subtype DCIS when present, the presence or absence of an extensive intraductal component, final margin status, estrogen or progesterone receptor status, use of re-excision, or total radiation dose to the primary. The 5- and 10-year actuarial ipsilateral breast tumor recurrence rates were 2% and 12% for patients with AH and 4% and 8% for those without AH (p=0.44). Younger women or those with a positive family history of breast cancer with AH did not have an increased rate of breast failure when compared to similar patients without AH. There were no significant differences in the 5- and 10-year actuarial rates of distant metastases (AH 5- and 10-year 7% and 7%, no AH 5- and 10-year 8% and 16%,p=0.31), regional node recurrence (AH 1% and 1%, no AH 1% and 1%,p=0.71), contralateral breast cancer (AH 3% and 3%, no AH 3% and 8%,p=0.71), overall survival (AH 95% and 86%, no AH 95% and 89%, p=0.79), or cause-specific survival (AH 98% and 95%, no AH 96% and 91%,p=0.27). Subset analysis for ipsilateral breast tumor recurrence, distant metastases, overall, and cause-specific survival for T1 vs. T2 tumors and path node-negative vs. path node-positive patients revealed no significant differences between the 2 groups. CONCLUSION: AH was not associated with an increased risk of ipsilateral breast tumor recurrence or contralateral breast cancer in this study of patients with invasive breast cancer treated with conservative surgery and radiation. Therefore, the presence of proliferative changes with atypia in background benign breast tissue should not be a contraindication to breast-conservation therapy.

A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged fifty or younger.

INTRODUCTION: Indications for postmastectomy radiation include primary tumor size > or = 5 cm and/or > or = 4 positive axillary nodes. In clinical practice, patients with a close or positive margin after mastectomy are also often treated with postmastectomy radiation. However, there is little data regarding the risk of a chest wall recurrence in patients with close or positive margins who otherwise would be considered low risk (tumor size <5 cm and/or 0-3 positive nodes). To address this issue, we assessed the risk of a chest wall recurrence in women with Stage I-II breast cancer who underwent mastectomy and were found to have primary tumor size <5 cm and 0-3 positive nodes with a close or positive deep margin. METHODS AND MATERIALS: The pathologic reports from 789 patients treated by mastectomy between 1985 and 1994 at our institution were retrospectively reviewed. Of these, 136 (17%) had tumor within 1 cm of the deep resection margin. The study population consists of 34 of these patients with close or positive margins whose primary tumor size was <5 cm with 0-3 positive axillary nodes and who received no postoperative radiation. The median age was 43 years (range 29-76). Of these, 44% had T1 tumors and 56% T2 tumors. Pathologic axillary nodal status was negative in 65% and positive in 35%. The median number of positive nodes was 1. The deep margin was positive in 2 patients, < or = 2 mm in 17 patients, 2.1-4 mm in 7 patients and 4.1-6 mm in 8 patients. Of the 34 patients, 67% received adjuvant chemotherapy +/- tamoxifen and 21% received tamoxifen alone. The median follow-up was 59 months (range 7-143). RESULTS: There were 5 chest wall recurrences at a median interval of 26 months (range 7-127). One was an isolated first failure, one occurred concurrent with an axillary recurrence, and three were associated with distant metastases. The 5- and 8-year cumulative incidences of a chest wall recurrence were 9% and 18%. Patient age correlated with the cumulative incidence of chest wall recurrence at 8 years; age < or = 50 years had a rate of 28% vs. 0% for age >50 (p = 0.04). There was no correlation with chest wall failure and number of positive nodes, ER status, lymphovascular invasion, location of primary, grade, family history, or type of tumor close to the margin. Of 5 chest wall failures, 4 were in patients who had received adjuvant systemic chemotherapy +/- tamoxifen. Chest wall failures occurred in 1 patient with a positive deep margin, 3 patients with margins within 2 mm, and 1 patient with a margin of 5 mm. The estimated cumulative incidence probability of chest wall recurrence at 8 years by margin proximity was 24% < or = 2 mm vs. 7% 2.1-6 mm (p = 0.36), and by clinical size 24% for T2 tumors vs. 7% for T1 (p = 0.98). CONCLUSIONS: A close or positive margin is uncommon (< or = 5%) after mastectomy in patients with tumor size <5 cm and 0-3 positive axillary nodes but, when present, it appears to be in a younger patient population. The subgroup of patients aged 50 or younger with clinical T1-T2 tumor size and 0-3 positive nodes who have a close (< or = 5 mm) or positive mastectomy margin are at high risk (28% at 8 years) for chest wall recurrence regardless of adjuvant systemic therapy and, therefore, should be considered for postmastectomy radiation.

Use of saline-filled tissue expanders to protect the small bowel from radiation.

Over the past 7 years, 58 saline-filled tissues expanders (TEs) have been temporarily placed in 57 patients. The indications for TE placement were: small bowel exclusion from external-beam radiation therapy (N = 25), interstitial RT (N = 16), or both (N = 13) when there was insufficient omentum to provide adequate exclusion. Of the 57 patients, 24 had primary tumors (4 colon, 4 endometrial, and 11 rectal cancer; 3 sarcomas, 1 schwannoma; and 1 vaginal cancer). The remaining 33 patients (58%) had recurrent cancers (3 anal, 8 colon, and 16 rectal cancers; and 6 sarcomas), of whom 26 (79%) had received prior RT. Of the 58 TEs, 15 were placed superior to the iliac vessels and 43 were placed in the pelvis. Complications included post-withdrawal enterocutaneous fistulae in four patients, TE deflation in three patients, and TE extrusion in one patient. Improvements in TE design and removal techniques have reduced the incidence of these complications. When no native tissue is available for small bowel exclusion, the saline-filled TE is a safe, effective substitute.

Results of conservative surgery and radiation for mammographically detected ductal carcinoma in situ (DCIS).

PURPOSE: The role of conservative surgery and radiation for mammographically detected ductal carcinoma in situ (DCIS) is controversial. In particular, there is little data for outcome with radiation in a group of patients comparable to those treated with local excision and surveillance (mammographic calcifications < or = 2.5 cm, negative resection margins, negative postbiopsy mammogram). This study reports outcome of conservative surgery and radiation for mammographically detected DCIS with an emphasis on results in patients considered candidates for excision alone. METHODS AND MATERIALS: From 1983 to 1992, 110 women with mammographically detected DCIS (77% calcifications +/- mass) and no prior history of breast cancer underwent needle localization and biopsy with (55%) or without a reexcision and radiation. Final margins of resection were negative in 62%, positive 7%, close 11%, and unknown 20%. The median patient age was 56 years. The most common histologic subtype was comedo (54%), followed by cribriform (22%). The median pathologic tumor size was 8 mm (range 2 mm to 5 cm). Forty-seven percent of patients with calcifications only had a negative postbiopsy mammogram prior to radiation. Radiation consisted of treatment to the entire breast (median 50.00 Gy) and a boost to the primary site (97%) for a median total dose of 60.40 Gy. RESULTS: With a median follow-up of 5.3 years, three patients developed a recurrence in the treated breast. The median interval to recurrence was 8.8 years and all were invasive cancers. Two (67%) occurred outside the initial quadrant. The 5- and 10-year actuarial rates of recurrence were 1 and 15%. Cause-specific survival was 100% at 5 and 10 years. Contralateral breast cancer developed in two patients. There were too few failures for statistical significance to be achieved with any of the following factors: patient age, family history, race, mammographic findings, location primary, pathologic size, histologic subtype, reexcision, or final margin status. However, young age, positive or close margins, and the presence of a mass without calcifications had a trend for an increased risk of recurrence. There were no recurrences in the subset of 16 patients who would be candidates for surveillance by Lagios' criteria. CONCLUSION: For selected patients, conservative surgery and radiation for mammographically detected DCIS results in a low risk of recurrence in the treated breast and 100% 5- and 10-year cause-specific survival. Improved mammographic and pathologic evaluation results in better patient selection and reduces the risk of the subsequent appearance of DCIS in the biopsy site. The identification of risk factors for an ipsilateral invasive breast recurrence is evolving.

Identification of women with T1-T2 breast cancer at low risk of positive axillary nodes.

BACKGROUND AND OBJECTIVES: The diagnostic and therapeutic significance of axillary dissection has been questioned. We sought to define a subgroup of patients with early-stage breast cancer who are at low risk for positive axillary nodes. METHODS: Between 1970 and 1995, 1,598 women with stage I and II breast cancer underwent level I-II axillary dissection with a minimum of 10 nodes removed. The following factors were examined in univariate analysis for predicting positive nodes: race, method of detection, location of the primary tumor, age, menopausal status, obesity, ER status, PR status, pathologic tumor size, lymphatic vascular invasion, tumor grade, and histology. RESULTS: Four hundred and forty-five of the 1,598 patients (27.8%) had histologically positive axillary nodes. Significant factors in univariate analysis for positive nodes included: tumor size, lymphatic vascular invasion, grade, method of detection, primary tumor location, and age. The only group of women with a 0% risk of axillary nodes were those in whom the pathologic tumor size was < or = 5 mm and mammographically detected. A 5-10% risk of positive axillary nodes was identified in women with (1) pathologic tumor size 6-10 mm, mammographically detected, and age < or = 40 years, and (2) tubular carcinoma < or = 10 mm. Tumors detected on physical examination with or without mammography and women < or = 40 years had a significantly increased risk of nodes. In multivariate analysis lymphatic vascular invasion (P < 0.001), method of detection (P = 0.026), location (P = 0.01), and pathologic tumor size (P = 0.002) were significant predictors of positive axillary lymphadenopathy. CONCLUSIONS: The decision to forego an axillary dissection should be considered in (1) tumors mammographically detected and < or = 5 mm (2) mammographically detected, pathologic size 6-10 mm, age > 40 and (3) tubular carcinoma < or = 10 mm. All other groups had a > 10% risk of nodes and may benefit from axillary dissection.

Primary combined malignant melanoma and ductal carcinoma of the breast. A report of two cases.

BACKGROUND: Tumors consisting of a combination of malignant melanoma and carcinoma are very rare. The authors report two such cases occurring as primary breast tumors. METHODS: The breast tumors were analyzed by histologic, immunohistochemical, and ultrastructural techniques. RESULTS: Histologically, the tumors were composed of a closely related admixture of ductal adenocarcinoma and malignant melanoma with abundant melanin pigment. Ductal carcinoma in situ was identified in both cases, confirming their origin in the breast. In both tumors, double-labeling immunohistochemistry showed that the epithelial component was immunoreactive for cytokeratin, the melanoma component was immunoreactive for HMB45, and both components were immunoreactive for S-100 protein. Immunostains for estrogen and progesterone receptors were negative in both tumors. Electron microscopy demonstrated glandular lumens and junctional complexes in the epithelial component and melanosomes and premelanosomes in the melanoma component. In one of the cases, rare tumor cells contained both premelanosomes and desmosomes. CONCLUSIONS: Combined malignant melanoma and carcinoma is a rare tumor. Only a handful of cases have been reported. The authors report two such cases occurring as primary tumors of the breast. The histology of the tumors revealed a closely related admixture of pigmented malignant melanoma and ductal carcinoma. Double-labeling immunohistochemistry showed that cytokeratin and HMB45 were expressed in the tumors, but not within the same cells. The authors propose describing this type of lesion as a single tumor of breast origin with bidirectional differentiation.

The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer.

PURPOSE: To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. METHODS AND MATERIALS: From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Re-excision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. RESULTS: There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of re-excision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p = 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5-year actuarial breast recurrence rate (21 vs. 4%; p = 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all patients or pathologic node-negative patients. Pathologically node-positive patients had a significant decrease in distant metastasis (35 vs. 11%; p = 0.02). There were no significant differences in cause-specific survival for patients receiving tamoxifen when compared to observation (95% no tamoxifen vs. 89% tamoxifen; p = 0.24). Similar findings were noted for pathologically node-negative patients. However, axillary node-positive patients receiving tamoxifen had an improvement in 5-year actuarial cause-specific survival (90% tamoxifen vs. 70% no tamoxifen; p = 0.10). Cosmesis (physician assessment) was good to excellent in 85% of the tamoxifen patients compared to 88% of the patients who did not receive tamoxifen. CONCLUSION: The addition of tamoxifen to conservative surgery and radiation in women with Stage I-II breast cancer and estrogen receptor positive tumors resulted in a modest but not statistically significant decrease in the 5-year actuarial risk of a breast recurrence. Tamoxifen significantly decreased the 5-year actuarial risk of distant metastasis in axillary node-positive patients and there was a trend towards improvement in cause-specific survival that was not statistically significant. Tamoxifen did not decrease the 5-year actuarial rate of distant metastasis in axillary node negative, patients and in this group, there was no improvement in cause-specific survival. Tamoxifen did not have an adverse effect on cosmesis or complications.

Does the placement of surgical clips within the excision cavity influence local control for patients treated with breast-conserving surgery and irradiation.

PURPOSE: A number of authors have demonstrated the importance of using surgical clips to define the tumor bed in the treatment planning of early-stage breast cancer. The clips have been useful in delineating the borders of the tangential fields, especially for very medial and very lateral lesions as the boost volume. If surgical clips better define the tumor bed, then a reduction in true or marginal recurrences should be appreciated. We sought to compare the incidence of breast recurrence in women with and without surgical clips, controlling for other recognized prognostic factors. METHODS AND MATERIALS: Between 1980 and 1992, 1364 women with clinical Stage I or II invasive breast cancer underwent excisional biopsy, axillary dissection, and definitive irradiation. Median follow-up was 60 months. Median age was 55 years. Seventy-one percent of patients were path NO, 22% had one to three nodes, and 7% had > than four nodes. Sixty-one percent were ER positive and 44% PR positive. Margin status was negative in 62%, positive in 10%, close in 9%, and unknown in 19%. Fifty-seven percent of women underwent a reexcision. Adjuvant chemotherapy + tamoxifen was administered in 29%, and tamoxifen alone in 17%. Surgical clips were placed in the excision cavity in 556 patients, while the other 808 did not have clips placed. All patients had a boost of the tumor bed. Patients had their boost planned with CT scanning or stereo shift radiographs. No significant differences between the two groups were noted for median age, T stage, nodal status, race, ER/PR receptor status, region irradiated, or tumor location. Patients without clips had negative margins less often, a higher rate of unknown or positive margins and more often received no adjuvant therapy compared to patients with surgical clips. RESULTS: Twenty-five and 27 patients with and without surgical clips, respectively, developed a true or marginal recurrence in the treated breast. The actuarial probability of a breast recurrence was 2% at 5 years and 5% at 10 years for patients without clips compared to 5 and 11%, respectively, for patients with clips (p=0.01). Comparing the breast recurrence rates for patients with and without clips there was no significant difference for the following factors: chemotherapy, tamoxifen, negative, positive or close margins, reexcision, N1, and central or inner primary. Increased rates of breast recurrence were noted for patients with clips for the following variables: no adjuvant treatment (p < 0.001), unknown margins (p < 0.001), a single excision (p = 0.003), path NO (p = 0.001), and outer location (p= 0.02). A forward stepwise multivariate analysis for all 1364 patients was performed using the aforementioned variables as well as the presence or absence of surgical clips and the primary surgeon. The surgeon (p = 0.03) and no adjuvant treatment (p = 0.01) significantly influenced breast recurrence. For patients with surgical clips the 10 year isolated breast recurrence rate was 21% for a single surgeon vs. 6% in the remainder of the group (p = 0.01). For patients with clips, this surgeon had unknown margins in 48% of cases compared to 10% overall (p = 0.001). Excluding this surgeon from analysis the isolated breast recurrence for patients with clips was 6 vs. 5% for patients without clips (p = 0.18). CONCLUSIONS: Overall, there was a significant difference in the 10-year breast recurrence rate favoring women without clips despite more adverse prognostic factors. There was no difference in the breast recurrence rate for patients with or without surgical clips if careful attention to margin status was addressed. Failure to ink the surgical specimen resulting in unknown margins cannot be compensated for with the placement of .

Regional chemotherapy for colorectal hepatic metastases: evidence for improved survival with new drug combinations.

BACKGROUND: In patients with colorectal hepatic metastases, response rates with hepatic arterial infusion (HAI) FUdR (5-Fluoro-2-deoxyuridine) are significantly higher than with systemic fluoropyrimidines. We report a novel animal model of intrahepatic therapy for hepatic metastasis for the study of methods to increase response rates and improve survival. METHODS. BD-IX rats are injected intrasplenically with K12/TRb cells. When hepatic metastases are established, animals are treated with hepatic or systemic chemotherapy, and the response to treatment, survival, and cause of death is determined. RESULTS: Significant responses were observed with low- and high-dose HAI FUdR (p = 0.03 and 0.001, respectively). Only high-dose FUdR controlled hepatic disease. HAI FUdR alone did not prolong survival compared with control, but combination systemic FUdR and HAI FUdR did (p = 0.04). Continuous HAI of either 5-fluorouridine or mitomycin C has not previously been reported. There was no significant difference in response to FUdR, 5-fluorouridine, or mitomycin C. However, combination HA bolus mitomycin C plus either HAI 5-fluorouridine or HAI mitomycin C showed synergy with improved survival compared with all treatment groups (p < 0.0001). CONCLUSIONS: The combination of bolus hepatic artery mitomycin C with either HAI mitomycin C or HAI 5-fluorouridine yields significant response rates, and survival is improved by this novel combination therapy.

Long-term follow-up of local excision and radiation therapy for invasive rectal cancer.

PURPOSE: Little is known regarding the long-term outcome of patients with rectal cancer treated by local excision and radiation therapy. We updated our institutional experience with this approach. METHODS: From January 1986 to December 1991, 23 patients (median age, 64 (range, 30-80) years) with mobile, moderately differentiated adenocarcinoma of the rectum were offered transanal excision. Two patients with large T3 tumors, who were judged intraoperatively to be unsuited for a local procedure, received radical resection and were excluded from analysis. Twenty-one patients underwent transanal excision en bloc (14) or piece-meal (7) through a resectoscope. Seven patients (74 percent) had either extensive medical problems or refused a colostomy. Patients received a median of 5,040 cGy postoperatively, and 15 also received 500 cGy preoperatively on protocol. Two patients received concomitant chemotherapy. Median follow-up is 56 months for all patients and 67 months for survivors (range, 27-92 months). RESULTS: There were 2 T1, 15 T2, and 4 T3 tumors. The distance from the anal verge was a median of 4 (range, 1-7) cm. The median tumor size was 3 (range, 2-7) cm. Sixteen patients had more than one-third of the wall involved. Four patients (19 percent) developed a local recurrence at 26, 30, 33, and 48 (median, 31.5) months. Three were salvaged (abdominoperineal resection = 2; low anterior resection = 1) and remain disease-free 18, 36, and 37 months postoperatively. Four patients (19 percent) developed metastases (lung = 3; liver = 1) at 3, 22, 25 and 44 months after initial treatment (median, 23.5 months). The actuarial five-year overall, disease-free and recurrence-free survival are 77, 75, and 58 percent, respectively. Twelve patients (57 percent) have no evidence of disease while retaining their rectum. There was one postoperative death. CONCLUSIONS: Long-term follow-up confirms that local excision and radiation therapy is of value in patients with mobile tumors of the rectum. It suggests that this treatment can be offered to those patients who refuse a colostomy or are medically compromised and may be an acceptable option for selected patients with T2 or T3, mobile adenocarcinomas of the rectum.

Surgical palliation of colorectal cancer.

After curative resection of primary colorectal cancer, some tumors will recur in the local or regional area or metastasize to sites amenable to surgical extirpation: the liver, lung, abdominal wall, peritoneum, bone, brain, ovaries, or penis. The local recurrence or metastasis may be resected with curative intent. Frequently, however, that is not possible, and an approach to control symptoms is necessary. The role of surgical extirpation of disease without an expectation of cure is warranted in many instances.