Sentinel lymph-node biopsy after previous wide local excision for melanoma.

OBJECTIVE: To document experience with sentinel lymph-node biopsy in patients who have already undergone a wide local excision for melanoma because in many centres previous wide excision has been a contraindication for sentinel lymph-node biopsy. DESIGN: A prospective cohort study. SETTING: A tertiary care academic cancer centre. PATIENTS: One hundred patients who presented with cutaneous melanoma (depth >1 mm or Clark level IV) after having undergone wide local excision of the primary lesion that was not situated in the head or neck. The follow-up was 3 years. INTERVENTIONS: Sentinel lymph-node biopsy. Patients with truncal melanoma had preoperative lymphoscintigraphy to document the nodal basins at risk. Technetium-99m sulfur colloid (0.5-1 mCi in 0.5 mL) was injected intradermally around the scar, and the sentinel lymph node was excised with the aid of a hand-held gamma detector. OUTCOME MEASURES: Accuracy of the biopsy and false-negative rates in this setting. RESULTS: Of the 100 patients, 44 had truncal and 56 had extremity lesions. The average tumour depth was 3.47 mm and 3.07 mm respectively. Thirty-one patients had a sentinel lymph node positive for melanoma metastasis. Biopsies were positive for melanoma in 18 (41%) truncal lesions and 13 (23%) extremity lesions. There were 3 (9%) false-negative sentinel lymph-node biopsies as diagnosed by clinically evident nodal disease subsequently appearing in the nodal basin subjected to biopsy. Two occurred in patients after large rotation flap closures of truncal lesions. The third patient had a subungual melanoma of the great toe. No disease was found in the 2 nodes dissected. Two of the 3 false-negative biopsy results were obtained before serial sections and immunohistochemical staining were used to examine the sentinel lymph nodes. CONCLUSIONS: Sentinel lymph-node biopsies can successfully identify clinically occult nodal metastases in patients who have had previous wide local excision of a melanoma, but the false-negative rate in patients with rotation flap closures should be taken into consideration.

Acute Myeloblastic Leukemia: Management with High-Dose Cytosine Arabinoside, Daunorubicin and Marrow Transplantation; Malignancy; Current Clinical Practice.

Combination high-dose cytosine arabinoside (ARA-C) and daunorubicin (DNR) for primary remission induction of patients with acute myeloblastic leukemia (AML) was evaluated in a single institution study. Patients aged 55 or less with an HLA-sibling received an allogeneic bone marrow transplant (alloBMT) in first remission; other responders were offered autologous BMT (autoBMT). For remission induction 93 patients aged less than 60 received DNR 45 mg/m(2) BSA x 3 and ARA-C 2 gm/m(2) BSA every 12 hours for 12 doses; 53 aged 60 or older DNR 25 mg/m(2) daily x 3 and ARA-C 1.5-2.0 gm/m(2) BSA every 12 hours for 12 doses. Consolidation doses of DNR were the same but ARA-C 100 mg/m(2) BSA/day x 5 was given by continuous intravenous infusion. The complete remission rate for patients less than 60 years was 69.9% (95% CI: 59.5-79.0%) and 47.2% (95% CI: 33.3-61.4%) for the older patients. The median duration of first remission for the younger patients was 13.0 months and of overall survival 17.9 months; for patients over 60 years 5.6 and 10.0 months respectively. Disease-free survival and overall survival of the 19 patients receiving alloBMT and the 13 patients undergoing autoBMT aged less than 55 years and in first or second complete remission were significantly increased compared with 22 patients in remission but not having BMT (p < 0.001 and p < 0.013). The results support the effectiveness of high-dose ARA-C for remission induction, a need for intensive consolidation therapy and a role for BMT in the management of AML.

Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial.

We conducted a phase 1 trial of direct injection of an E1, E3-deleted adenovirus encoding interleukin-2 (AdCAIL-2) into subcutaneous deposits of melanoma or breast cancer. Twenty-three patients were injected at seven dose levels (10(7)-10(10) p.f.u). Local inflammation was observed at the site of injection in 60% of patients, but side-effects were otherwise minor. Incomplete local tumor regression occurred at the site of injection in 24% of patients, but no conventional clinical responses were seen. Circulating CD4 and CD8 counts fell significantly 24 h after injection. Post-injection biopsies demonstrated tumor necrosis and lymphocytic infiltration with the predominant tumor-infiltrating cells both CD3- and CD8-positive. Vector-derived sequences were detected in 14 of 18 biopsies examined 7 days after injection and vector-derived hIL-2 mRNA was detected in 80% of 7-day biopsies processed after injection of 10(8) p.f.u. of AdCAIL-2 or higher. While IL-2 was detectable by ELISA in tumor biopsies at 48 h, no protein was detectable in injected tumors after 7 days and no circulating IL-2 was detectable at any time-point. No Ad5E1 sequences were detected either before or after injection indicating absence of replication-competent virus or endogenous E1-like sequence; furthermore, only rare vector shedding was detected. Anti-adenovirus and neutralizing antibody titers were elevated 1 month after injection in all patients. This trial therefore confirms the safety of use of adenoviral vectors for gene delivery in humans and demonstrates successful transgene expression even in the face of pre-existing immunity to adenovirus.

Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma.

Escalated as compared with standard doses of doxorubicin in BACOP therapy for patients with non-Hodgkin's lymphoma.

BACKGROUND AND METHODS: In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkin's lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (< 1000 cells per cubic millimeter) had not developed during the first cycle. RESULTS: The 119 patients assigned to the esc-BACOP regimen received doxorubicin at a significantly higher mean weekly dose intensity (13.5 vs. 10.4 mg per square meter per week, P < 0.001) and mean total dose (296 vs. 231 mg per square meter, P < 0.001). Because of granulocytopenia during the first cycle of therapy, only 56 of these patients (47 percent) received the escalated doses of doxorubicin. During a median follow-up of 65 months, there were no differences between the s-BACOP and esc-BACOP groups in response rate, overall survival, or survival without disease progression. When the patients who actually received the escalated doses of doxorubicin were compared with the patients in the s-BACOP group in whom neutropenia did not develop during the first treatment cycle, no difference between their outcomes was observed. Toxicity was greater in the esc-BACOP group. CONCLUSIONS: In patients with advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma, escalating the dose of doxorubicin in the BACOP regimen increases toxicity but does not improve the rate of response or survival.

A phase II study of weekly edatrexate (10-EDAM) in metastatic melanoma. A National Cancer Institute of Canada Clinical Trials Group study.

BACKGROUND: Phase I and II clinical trials have demonstrated acceptable toxicity and promising activity of Edatrexate (10-EDAM). The objective of this multicentre phase II study was to determine the efficacy and toxicity of this agent in patients with metastatic melanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanoma received 10-EDAM, 80 mg/m2/week intravenously. Patients were evaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensity of 10-EDAM actually delivered was 56.25 mg/m2/week (70% of projected). Mucositis of any degree was encountered in 93.8% of patients. Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia, thrombocytopenia, anemia and hyperbilirubinemia each were encountered in 1-2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

Neurologic disorders in patients with small cell lung cancer.

In a series of 641 patients with small cell lung cancer, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the cancer. The total number of neurologic disorders was 210, which included brain metastases (75.7%), meningeal carcinomatosis (6.7%), intramedullary metastases (2.4%), epidural metastases (11.0%), hyponatremia producing CNS symptoms (3.3%), and Eaton-Lambert syndrome (1.0%). The most common signs and symptoms were motor dysfunction and confusion. The overall survival of patients with any neurologic disorder was compared to that of patients without neurologic problems. There was no difference between the survival curves for the first year and a half, but patients without neurologic complications had a greater probability of long-term survival (log-rank P = 0.03). There were no statistically significant differences when this comparison was made according to stage of disease. When a neurologic disorder related to cancer occurred, the survival time from the date of that diagnosis was usually short. The neurologic disorder was the immediate cause of death in the majority of cases. In patients who achieved a complete remission, the administration of prophylactic cranial irradiation (PCI) significantly reduced the risk of developing brain metastases as the initial site of the relapse (log-rank P = 0.0034). After adjustment for performance status and extent of disease, the survival of complete responders treated with and without PCI was not significantly different. We conclude that neurologic complications are a frequent and serious problem in patients with SCLC.

Poor prognosis metastatic gestational trophoblastic disease: experience with moderate dose methotrexate plus folinic acid rescue as initial therapy.

From 1971 to 1981, twenty patients with poor-prognosis metastatic gestational trophoblastic neoplasia (GTN) were treated with moderate-dose methotrexate (1 g) and folinic-acid rescue (MD-MTX-FAR) as initial therapy. Seven (35%) were cured with MD-MTX-FAR, and salvage chemotherapy was successful in an additional seven, for a total cure rate of 70%. The ultimate outcome is similar to that reported for MAC triple therapy during this era. Hematologic and mucosal toxicity were negligible and no serious complications were encountered. We now use combination chemotherapy in patients with poor-prognosis GTN as first-line treatment. However, these results suggest that there may be advantages to the incorporation of MD-MTX-FAR in combination regimens in place of low-dose methotrexate, because of reduced toxicity and potential benefits for the prophylaxis and treatment of cerebral metastases.

Superior vena caval obstruction syndrome in small cell lung cancer.

In a series of 643 patients with small cell lung cancer (SCLC), 55 patients (8.6%) had signs or symptoms of superior vena caval obstruction syndrome (SVCO). Relatively long intervals from the onset of the first symptoms of SVCO to the start of therapy were observed, and invasive diagnostic procedures were safely performed in most patients. The pretreatment characteristics of patients with SVCO were not significantly different from those of patients without signs of the syndrome, and survival was similar in both groups. Patients with SVCO were usually treated first with induction chemotherapy, and prompt resolution of signs and symptoms occurred in the majority. Radiation was effective in controlling SVCO at relapse or after failure of initial chemotherapy. It was concluded that SVCO in patients with SCLC should be treated initially with systemic chemotherapy, as for other presentations of this disease. The current data do not support the commonly held view that SVCO in SCLC should be approached as an oncologic emergency.

Ewing's sarcoma: a trial of adjuvant chemotherapy and sequential half-body irradiation.

The results of a pilot study using adjuvant chemotherapy and sequential half-body irradiation (HBI) for nonmetastatic Ewing's sarcoma are presented. Seventeen patients received Cyclophosphamide, Vincristine, and Adriamycin (8 cycles), followed by sequential radiation treatment of the upper (500 cGy) and lower (600 cGy) half body. Survival at 3 years was 49%. These results are contrasted with those for 18 concurrently treated patients who received standard adjuvant therapy. Overall 5-year survival and relapse-free survival for these 35 consecutive patients was 61 and 53%. The pilot protocol was given on an out-patient basis with limited and acceptable acute toxicology. Further study is necessary to determine the value of the pilot protocol.

The value of staging and serial follow-up investigations in patients with completely resected, primary, cutaneous malignant melanoma.

The purpose of this study was to determine the value of staging and serial follow-up investigations in newly diagnosed patients with completely excised primary cutaneous malignant melanoma. We reviewed the records of the 393 patients with completely excised primary malignant melanoma who were referred to the Ontario Cancer Institute and the Toronto-Bayview Regional Cancer Centre between 1 January 1978 and 31 March 1982. Initial investigations included history and physical examination in all 393 patients, complete blood count (199 patients), liver function tests (198 patients), urinary melanins (159 patients), chest X-rays (345 patients), whole lung tomography (182 patients), radionuclide liver-spleen scans (207 patients), and bone scans (116 patients), bipedal lymphangiograms (78 patients), CT scans of the chest (59 patients), and CT brain scans (51 patients). The clinical stage of ten patients was changed as a result of history and physical examination or lymphangiogram. All other investigations failed to detect metastatic melanoma. Follow-up investigations included history and physical examinations, complete blood counts, liver function tests, radionuclide liver spleen and bone scans. History and physical examinations, chest X-rays and patients' awareness of abnormalities were responsible for detection of subsequent melanoma recurrences. All other tests failed to identify metastatic melanoma at the time of its occurrence. Therefore, we recommend that initial staging investigations be limited to history and physical examination with clinical photographs, and baseline chest X-ray. We recommend that subsequent follow-up include only history and physical examinations and chest X-rays.

Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.

One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.

Results of radical radiation for chondrosarcoma of bone.

A retrospective analysis has been made of 38 radically treated patients with chondrosarcoma of bone treated with irradiation alone or with concurrent chemotherapy (nine patients) at the Princess Margaret Hospital (P.M.H.) between 1958 and 1981. This includes updated data on previously reported patients. No patient had complete surgery. Tumours in axial sites (25/38 patients) and presenting with pain (25/38 patients) predominate; both well known poor prognostic factors. There is also a greater proportion with unfavourable histology (mesenchymal, poorly differentiated, dedifferentiated) (13/38 patients) compared to other series. The 5 and 10 year actuarial survival rate was 41% and 36% respectively with a median survival of 46 months. The best results were obtained in the group with favourable histology (well and moderately differentiated) with 48% 5 year actuarial survival versus 22% in the unfavourable subgroup. The progression-free survival of the favourable group was 13/25 patients versus 2/13 for the unfavourable group (p less than 0.01). Distant metastasis were rare in the patients with favourable histology (1/24) compared to 5/13 of the unfavourable group. Nine patients were given concurrent chemotherapy and irradiation. To date, only 1/7 patients with favourable histology and combined treatment have had progressive disease (follow-up 8-83 months). Only two patients with unfavourable histology received combined chemotherapy and irradiation and both have relapsed. In conclusion, there is evidence to suggest chondrosarcoma is not radioresistant and irradiation should be considered when surgery would cause major unacceptable morbidity or be technically impossible. Early evidence suggests there may be a role for chemotherapy to supplement the effects of irradiation.

Upper half body irradiation (UHBI) for extensive small cell carcinoma of the lung.

Upper half body irradiation (UHBI) was given to 41 of 121 patients with extensive small cell carcinoma of the lung. All patients were treated with 6 courses of cyclophosphamide, doxorubicin, and vincristine (CAV). Responding patients also received prophylactic cranial irradiation and local irradiation to prechemotherapy intrathoracic disease. Among the 70% (85/121) of patients who responded to chemotherapy, 41 have received UHBI, given one to two months later. The single fraction midline dose given has been increased in successive patients from 300 to 720 cGy (uncorrected for inhomogeneities). Actual lung doses were higher by 9-22%, (determined in 31 patients by CT scanning and lung density measurements). Adverse effects seen were vomiting, fever, drowsiness, myelosuppression, liver dysfunction and dry mouth. All were transient, and no pneumonitis or treatment deaths occurred. Adverse effect rates were similar at all dose levels. UHBI is well tolerated in patients who have received chemotherapy and merits further study.

Cyclophosphamide, doxorubicin, and cisplatin in the treatment of non-small cell bronchogenic carcinoma.

One hundred and forty-three patients with unresectable non-small cell bronchogenic carcinoma were treated with combination chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin (CAP). Objective responses were seen in 27.5% of 131 evaluable patients. Response rates for squamous cell carcinoma, adenocarcinoma, and large cell anaplastic carcinoma were 30.2% (13 of 43 patients), 28.0% (14 of 50), and 32.1% (nine of 28), respectively. The median survival time for responders with extensive disease was 33.0 weeks compared with 29.3 weeks for patients with stable disease and only 9.6 weeks for patients with disease progression. The survival advantage of patients responding to CAP relative to those who had disease progression during treatment is highly significant statistically (P = 0.0005). However, patients whose disease remained stable also had longer survival than those who had disease progression (P = 0.001), and their survival was not significantly different from that of responders (P = 0.19). The CAP chemotherapy regimen was generally well-tolerated, although acute gastrointestinal symptoms were common. Our results indicate that CAP chemotherapy can cause tumor regression in patients with non-small cell bronchogenic carcinoma and may extend the survival of responding patients.

Combined modality treatment of small cell carcinoma of the lung.

Ninety patients with extensive and 61 with limited small cell carcinoma of the lung were treated with three courses of intravenous chemotherapy (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) followed by radiotherapy to intrathoracic disease, and a second three-drug oral combination consisting of lomustine, procarbazine, and methotrexate for one year. Among the 147 patients who were evaluated, 55 of 66 (83%) with limited disease and 53 of 81 (65%) with extensive disease showed response after three courses of chemotherapy. The complete response rate in patients with limited disease prior to radiotherapy was 24%, but increased to 58% when evaluated following radiotherapy. The median survival was 47 weeks for patients with limited disease and 36 weeks for those with extensive disease. A 24% two-year survival is projected for complete responders. Important prognostic factors for survival are performance status, extent of disease, and sex, with female subjects doing somewhat better than male subjects. Among patients with limited disease, 45% failed within the CNS despite the use of chemotherapeutic agents that cross the blood-brain barrier. The initial induction regimen and radiotherapy were well tolerated; the oral three-drug combination was more toxic and did not prevent CNS metastases.