Gemcitabine following radiotherapy with concurrent 5-fluorouracil for nonmetastatic adenocarcinoma of the pancreas.

Gemcitabine has been shown to be an active agent in the treatment of pancreatic cancer. This study was conducted to prospectively examine the tolerance and early efficacy of adjuvant gemcitabine following radiotherapy with concurrent 5-fluorouracil (5-FU) for nonmetastatic pancreatic adenocarcinoma. Twenty-three patients, median age 64 years, were treated with combined modality therapy. Nine patients underwent tumor resection before chemoradiation; 14 patients with locally unresectable tumors received definitive chemoradiation. Radiotherapy utilized four fields to the tumor and lymphatics to 45 Gy, plus a lateral boost to 50.4 Gy. Concurrent 5-FU 500 mg/m(2)/day was administered on days 1-3 and 29-31, followed by 4 months of gemcitabine 1,000 mg/m(2)/week for 3 weeks (fourth week break). Adjuvant gemcitabine was well tolerated. Eighty-three percent of the patients completed three to four cycles. The primary dose-limiting toxicity was leukopenia, which was observed in 10 patients (43%). Nonhematologic toxicities were reported in five patients (22%). There were no cases of gemcitabine-induced radiation recall and there have been no deaths attributed to treatment toxicity. Median follow-up for the 23 patients was 12 months (range, 5-50); the actuarial median survival was 13 months. This report confirms that adjuvant gemcitabine following radiotherapy with concurrent 5-FU for nonmetastatic pancreatic adenocarcinoma can be safely administered.

Biochemical, hematologic, and immunologic alterations following hepatic cryotherapy.

Hepatic cryosurgery causes hepatocellular damage primarily by inducing the formation of ice crystals. Cell necrosis is enhanced using two or more freeze-thaw cycles. The resultant damage to hepatocytes induces alterations in a number of biochemical and hematologic parameters, including hepatic function tests, serum bilirubin, serum and urine myoglobin, platelet count, and coagulation measures. Further, in experimental models, cryogenic surgery appears to stimulate the immune system of the host leading to an anti-tumor immune response. These perturbations in biochemical and hematologic parameters are usually transient, and long-term adverse sequelae are uncommon and preventable.

Intraoperative monitoring and postoperative imaging of hepatic cryosurgery.

Because intraoperative sonography displays segmental anatomy, allows discovery of more lesions than previously suspected from preoperative imaging, surgical inspection, or palpation, and permits more certain diagnosis of problematic masses, it facilitates surgical decision-making when liver resection or cryoablation is anticipated. Intraoperative sonography provides a guidance modality to accurately place cryosurgery probes in liver masses. More precise treatment of metastatic and primary tumors of the liver is possible with cryoablation because intraoperative sonography provides a means of monitoring the growth of the enlarging freeze zone to insure adequate surgical margins. Postoperative detection of acute complications after cryosurgery is best done with computed tomography. Normally cryosurgery defects shrink with time and lose the peripheral contrast opacification seen after surgery. Gas collections, seen as a result of tissue necrosis, must be discriminated from infection. Tumor recurrence can be detected well with computed tomography or magnetic resonance imaging following hepatic cryosurgery.

Endocrinology of melanoma.

Melanoma has a better prognosis in women than in men, may be exacerbated by pregnancy, and has been to reported to respond to hormonal manipulations. Laboratory investigations have demonstrated that both animal and human melanomas may respond to changes in the hormonal milieu. Steroid hormone binding activity has been demonstrated in some human melanomas, but only a small percentage of melanomas respond to hormonal manipulation. Randomized trials suggest a possible role for tamoxifen in combination with chemotherapy for metastatic melanoma and for megestrol acetate as an adjuvant. Nevertheless, it appears that the use of steroid hormones in the management of melanoma is limited.

Long-term results of breast conservation therapy for breast cancer.

OBJECTIVE: This study was done to determine the long-term outcome of breast conservation therapy (BCT) for patients with early-stage breast cancer during a period of treatment evolution at a single institution. SUMMARY BACKGROUND DATA: Breast cancer treatment has evolved from extensive surgical extirpation of the breast to treatment options that conserve the breast. Prospective and retrospective studies have confirmed the efficacy of BCT and justify its use for many patients with early breast cancer, but there is no universally accepted consensus as to who benefits from more aggressive application of surgery or radiotherapy in BCT. Prognostic variables for breast cancer and information on factors that contribute to local recurrence help predict BCT results. Continued analysis of BCT still is necessary to improve patient outcome. METHODS: Eighty-five patients treated with BCT (lumpectomy with adjuvant radiation therapy) at the Medical College of Virginia from 1980 to 1990 were identified. Clinicopathologic parameters and treatment details were analyzed for relationship to development of local recurrence, distant metastasis, and survival. Fisher's exact test was used for comparisons. Actuarial survival curves were plotted. The earlier treatment period (1980-1985) was compared with the later treatment period (1985-1990). RESULTS: Median follow-up was 5 years. Actuarial overall survival was 83% at 5 years (69% at 10 years), and 5-year distant metastasis-free survival was 79%. The 5-year actuarial local recurrence rate was 6.6% (crude rate 10.6%, 9/85). Young patients (age < 40 years) were found to be at increased risk for local recurrence (24% < 40 years vs. 6% > or = 40 years, p < 0.05). Tumor margins < or = 3 mm were more frequently found, and lumpectomy site radiation boost was used increasingly from 1986 to 1990. Almost half of all local recurrences occurred after 5 years. CONCLUSIONS: Survival and local recurrence rates were comparable to other series. Young patients were found to be at increased risk for local recurrence. Negative microscopic margins, even when close, can provide low local recurrence rates when adjuvant radiation therapy is administered.

Complications of mastectomy and their relationship to biopsy technique.

BACKGROUND: Wound complication rates after mastectomy are associated with several factors, but little information is available correlating biopsy technique with the development of postmastectomy wound complications. Fine-needle aspiration (FNA) biopsy is an accurate method to establish a diagnosis, but it is unknown whether this approach has an impact on complications after mastectomy. METHODS: Charts of 283 patients undergoing 289 mastectomies were reviewed to investigate any association between biopsy technique and postmastectomy complications. RESULTS: The diagnosis of breast cancer was made by FNA biopsy in 50%, open biopsy in 49.7%, and core needle biopsy in 0.3%. The overall wound infection rate was 5.3% (14 of 266), but only 1.6% when FNA biopsy was used compared with 6.9% with open biopsy (p = 0.06). Among 43 patients undergoing breast reconstruction concomitantly with mastectomy, the infection rate was 7.1% (0% after FNA, 12% after open biopsy). Neither the development of a postoperative seroma (9.8%) nor skin flap necrosis (5.6%) was influenced by the biopsy technique used. CONCLUSIONS: These data suggest that wound infections after mastectomy may be reduced when the diagnosis of breast cancer is established by FNA biopsy.

Postoperative radiotherapy improves survival in squamous cell carcinoma of the hypopharynx.

BACKGROUND: Postoperative radiation is considered to be "standard of care" therapy for advanced, resectable squamous cell carcinoma of the head and neck. This approach has been supported by retrospective data but has not been validated in randomized clinical trials. PATIENTS AND METHODS: The present analysis examined the clinical course of 110 patients with squamous cell cancer of the hypopharynx treated with surgery alone (n = 65) and postoperative radiotherapy alone (n = 45) between 1966 and 1990. Staging of patients was performed using the 1988 American Joint Committee on Cancer criteria. Cox regression analyses identified clinical and pathologic factors that were significant for disease-free and overall survival. Crude and adjusted cancer-specific survival rates were calculated. RESULTS: The postoperative radiotherapy group presented with more advanced disease than the surgery alone group (stage III and IV combined, 96% versus 77%, P = 0.015). Crude 5-year cancer-specific survival probabilities were 43% for the postoperative therapy group and 27% for the surgery alone group (P = NS). Adjusted 5-year survival rates, correcting for differences in significant prognostic variables between groups, were 18% and 48%, respectively, for the surgery and postoperative radiotherapy groups (P = 0.029). CONCLUSIONS: The addition of postoperative radiotherapy was associated with improved disease-free and adjusted overall cancer-specific survival in patients with advanced hypopharyngeal squamous cancer. The potential survival benefit of postoperative radiotherapy should be addressed in a randomized clinical trial.

p53 tumor suppressor oncogene expression in squamous cell carcinoma of the hypopharynx.

BACKGROUND: Although abnormalities of the p53 tumor suppressor oncogene system are being detected in many human cancers, the frequency and prognostic significance of such events in squamous cell cancer of the head and neck remain unknown. METHODS: Immunohistochemical studies were performed on archival tumor tissue taken from 43 patients with squamous cell carcinoma of the hypopharynx. Statistical analyses examining potential associations between p53 oncoprotein accumulation and various clinicopathologic parameters (including survival) were conducted. RESULTS: Sixteen (37%) tumors demonstrated strong specific staining for p53. Patients whose tumors stained strongly for p53 were significantly younger, presented at a more advanced clinical disease stage, and tended to have increased expression of epidermal growth factor receptor (P = 0.056). There was no correlation between p53 expression and the incidence of multiple primary cancers, tumor grade, DNA ploidy, or percent of S-phase. Median survival times were 11.6 months and 18.0 months for the p53-positive and p53-negative groups (NS). A Cox regression analysis confirmed the lack of significance of p53 in overall survival. CONCLUSIONS: These data suggest that although abnormalities of the p53 oncoprotein are common in this cancer, this finding is of little clinical significance.

Epidermal growth factor receptor expression in squamous cell carcinoma of the hypopharynx.

Expression of the epidermal growth factor receptor (EGFR) has been demonstrated in normal and malignant squamous epithelia. Its presence has been suggested to be important in the pathophysiology and prognosis of epithelial cancers. Archival tumour specimens from 57 patients with squamous cell carcinoma of the hypopharynx were studied using OM-11-951, a new murine anti-EGFR monoclonal antibody which recognizes the receptor on deparaffinized tissue. By visual inspection, 28 (49%) tumours were EGFR negative; 29 (51%) tumours were EGFR positive. While patients whose tumours were EGFR positive were younger, there was no significant correlation with other clinical or pathological variables (including grade and stage). Patients whose tumours were EGFR negative had a median survival of 21 (95% CI 4.3-37.7) months compared with a median survival of 17 (95% CI 11.4-22) months for patients whose tumours were EGFR positive. The difference was not statistically significant. A multiple regression analysis did not demonstrate EGFR status to be important in predicting survival. These data cast doubt on the prognostic significance of EGFR expression in this neoplasm.

Incompletely resected advanced squamous cell carcinoma of the head and neck: the effectiveness of adjuvant vs. salvage radiotherapy.

Between 1982 and 1988, 441 patients were treated at the Medical College of Virginia for AJC Stage III and IV squamous cell carcinoma of the head and neck. We report here on 84 patients whose tumors were incompletely resected based on histopathological margins of 1 mm or less. Of these 84 patients, 49 were treated with surgery alone and 35 received immediate postoperative irradiation to doses of 50-70 Gy. The two patient groups are comparable with respect to stage of disease, age, male/female and racial ratios. This retrospective analysis, based on follow-up of 24-110 months, gives actuarial locoregional tumor control and survival data. The local control and disease-free survival rates in the combined modality group are significantly superior at the p = 0.0006 and p = 0.0003 levels, respectively, relative to the group treated with surgery alone. Patients in the combined modality group also experienced a significantly improved adjusted and overall survival, p = 0.005 and p = 0.01, respectively. The administration of postoperative irradiation was not associated with an increased rate of complications. The benefit of radiotherapy on survival was only seen when given as postoperative treatment but was lost in patients treated for salvage after tumor recurrence.

Formal hepatic resection of colorectal liver metastases. Ploidy and prognosis.

Fifty consecutive patients who underwent 52 formal hepatic resections (excluding isolated wedge resections) for metastatic colorectal cancer were analyzed to determine whether DNA content was of prognostic significance. The Dukes' stages of the colorectal primaries were: A (10%), B (20%), C (40%), D (28%), and unknown in 2%. Four patients whose liver metastases were discovered at the time of resection of the primary bowel cancer underwent concomitant liver resection, and the remaining patients underwent delayed resections. The hepatic resections performed were right lobectomy (50%), extended right lobectomy (19%), left lobectomy (13%), left lateral segmentectomy (6%), left lobectomy and right wedge (6%), extended left lobectomy (4%), and right lobectomy and left wedge (2%). The overall morbidity rate was 29%. The in-hospital mortality rate was 9%. As of November 1991, 36 patients have recurred. The 5-year actuarial survival was 28%. Flow cytometry could be performed on 37 archival specimens, 15 of which were found to be diploid whereas 22 were aneuploid. All metastases from Dukes A colorectal primaries demonstrated a diploid DNA content. In addition, there was no difference in actuarial survival between diploid and aneuploid tumors. These data suggest that in selected patients, formal hepatic resection of colorectal liver metastases can be performed with an acceptable morbidity rate, mortality rate, and survival, but ploidy of the resected tumor is not of prognostic significance.

Diagnosis and management of sacrococcygeal chordoma.

Chordoma is a rare, slow-growing but locally aggressive malignant tumor derived from the primitive notochord and located along the axial skeleton. Between 1973 and 1991, of 15 patients with chordomas treated at the Medical College of Virginia, eight originated in the sacrococcygeal area. There was a median one year interval between the onset of symptoms and diagnosis (range of four months to six years) for this latter group. Two patients had undergone coccygectomies and one patient a lumbar discectomy prior to establishing the correct diagnosis of sacral chordoma. Seven patients underwent resection and one refused therapy. The four patients who had an initial wide radical resection had a longer disease-free survival than the three who underwent local excision. Three of four patients had metastatic disease at the time of death. Early diagnosis and aggressive initial surgical resection are necessary for long-term survival.

Closure of craniofacial defects after cancer resection.

Resection of malignancies of the upper face and skull base may result in complex bone and soft tissue defects. To better define the optimal management of these defects, we conducted a retrospective review of 75 consecutive patients who underwent closure of 76 craniofacial defects after malignant tumor excision from 1966 to 1990. Wound complications requiring further surgery occurred in 30% of the defects (23 of 76). Wound complications at anterior, temporal, or combined sites were correlated with each method of reconstruction (scalp flap or split thickness skin graft, pedicled myocutaneous flap, and free flap). The presence of a large combined defect involving both frontal and temporal areas was the only significant risk factor for development of a wound complication requiring secondary surgery. These data suggest that anterior or temporal craniofacial defects may be closed with either scalp flaps and split thickness skin grafts or pedicled myocutaneous flaps with reasonable wound complication rates of 16% to 22%. Large combined defects have high wound complication rates (90%) when local tissue is used; therefore, other methods of closure such as free tissue transfer should be strongly considered in these patients.

Benign cartilaginous tumors of the upper airway.

Benign cartilaginous neoplasms of the laryngotracheal apparatus are uncommon clinical entities. Two cases of cartilaginous lesions of the upper airway are reported. Resection with maintenance of upper airway structural integrity is the preferred treatment. Temporary tracheostomy is often necessary and can provide access for stenting of the tracheal repair.

Soft tissue sarcomas.

Soft tissue sarcomas in infants and children differ from those in adults in clinical presentation, histology, and response to therapy. For rhabdomyosarcoma, the most common sarcoma in children, each primary site has special characteristics that affect both treatment programs and survival rates. Some results are so good, from the standpoint of survival data, that studies are now in progress to evaluate means of reducing treatment morbidity. Other ongoing studies focus on improved protocols for metastatic or recurrent rhabdomyosarcoma. Results thus far in the IRS trials have proven the value of cooperative clinical trials in the management of patients with this disease.

The potential of hormone receptors in the treatment of various cancers.

Breast cancer, prostate cancer, endometrial cancer, and lymphocytic leukemias may possess steroid hormone receptors that can predict a high probability of response to the appropriate hormone when the receptor is present. The presence or absence of receptor may also be an important prognostic variable and may aid in the selection of patients for appropriate adjuvant therapy. Although putative receptors have been described in many other tumors, their clinical significance is questionable because these tumors generally do not respond to hormonal therapy. In the future, steroid receptors may enable us to target drugs, radioisotopes, or other molecules to tumors by linking these drugs to steroid hormones.

Natural history and treatment of mucosal melanoma.

Forty-three patients with primary mucosal melanomas seen between 1960 and 1987 were reviewed. There were 17 patients with tumors arising from the head and neck, 17 from the vulva and/or vagina, 8 from the anorectum, and 1 from the esophagus. Twenty-one patients were resected with curative intent. In patients with head and neck tumors, local recurrence was the initial cause of failure in the majority of cases, whereas with tumors arising from the anorectum, vulva, and vagina, systemic recurrence was more common. There were four long-term survivors, and three of these had melanomas less than 1 mm thick with negative regional lymph nodes; no patients with mucosal melanoma less than 1 mm thick developed recurrent disease. Overall, actuarial survival was 64% after 1 year and 23% after 5 years. Mucosal melanoma has a poor prognosis, and adequate resectional surgery affords the only chance of long-term survival.

Management of desmoid tumors.

Desmoid tumors are rare, being less than 0.03 per cent of all neoplasms. Because of scarcity of data and relatively small numbers of patients, optimal treatment remains controversial. In this report, our experience with 36 patients evaluated and treated from 1960 to 1987 is analyzed. The most common primary site was the wall of the chest (ten); eight tumors originated in the abdominal wall. Nine patients had a history of previous trauma, and eight of these were women. Thirty-two patients had wide local excision and two had amputations. Clear margins were obtained in only 22 patients despite an attempt at wide resection in all instances. With a mean follow-up period of 41 months and a median of 24 months, only one of 22 patients with negative histologic margins had recurrence of tumor. Among the 11 patients with positive margins, four received postoperative radiation therapy and two remain disease-free; of the seven remaining patients with positive margins, three had recurrences. One patient with unresectable disease was treated with tamoxifen with regression of tumor and remains alive 15 months later. These data suggest that the best treatment of desmoid tumors remains resection with a clear margin of normal tissue surrounding the tumor. Adjuvant radiotherapy did not appear to decrease the rate of local recurrence.

Intraoperative ultrasound of the liver affects operative decision making.

The surgeon operating upon patients with primary or metastatic hepatic cancers must determine if resection is feasible and, if it is, the magnitude of required resection. In an attempt to determine which tests best aid the surgeon in these determinations, the authors prospectively compared preoperative computed tomography (CT) of the liver and intraoperative ultrasound (IOU) in 42 patients with liver tumors who underwent 45 exploratory operations. The primary diseases included colorectal cancer metastases in 27 patients, hepatoma in 11 patients, and metastatic cancers of other origins in 4 patients. In the 42 patients there were 89 identified hepatic lesions that were confirmed to be malignant by resection, biopsy, or continued growth on follow-up CT. The sensitivity of either test for detecting these lesions was 69/89 (77%) for CT and 87/89 (98%) for IOU. Resection was not feasible in 13 patients. Five had extrahepatic disease, 4 had more nodules discovered by IOU, 3 were found by IOU to have involvement of all three hepatic veins by tumor and 1 patient had portal-vein invasion. Alternatively, in four patients tumors thought to involve all three hepatic veins by CT were shown to be free of at least one hepatic vein, thereby permitting resection. In one patient who had been previously operated upon, a tumor thought to involve the remaining right hepatic vein was seen to be free of the vein, also permitting resection. Regarding the extent of resection, IOU was also helpful. Lesser procedures than anticipated were proved possible by IOU in seven patients. A more extensive resection was shown to be necessary by IOU in two patients. Thus, IOU affected the operative management in 22 of 45 operative episodes (49%). It was conclude that IOU is superior to both preoperative CT and surgical exploration in assessing both the feasibility and the extent of resection required for primary and secondary hepatic cancers. In the authors' experience, IOU is the most sensitive indicator of number of lesions present in the liver. In addition, the ability of IOU to determine hepatic venous anatomy is a helpful adjunct in determining resectability of liver tumors.