Prolonged Disease-free Interval Research Articles

Late Recurrence of Clear Cell Adenocarcinoma of the Vagina and Cervix: A Report of Three Cases

Three patients with clear cell adenocarcinomas who developed recurrent disease after a prolonged disease-free interval are presented. The first patient developed a recurrence in the lung 7 years and 3 months after wide local excision and pelvic radiotherapy for clear cell adenocarcinoma of the vagina. She then underwent thoracotomy and chemotherapy and has remained free of disease for more than 13 years after treatment of the recurrence. The second patient with clear cell adenocarcinoma of the vagina developed recurrent disease at the apex of the vagina 5 years after radical hysterectomy, bilateral pelvic lymphadenectomy, and partial vaginectomy. She then underwent exploratory laparotomy, partial vaginectomy, and vaginal irradiation and has been free of disease in follow-up for 6 months. The third patient underwent radical hysterectomy, bilateral pelvic lymphadenectomy, and total vaginectomy for clear cell adenocarcinoma of the cervix that also involved two-thirds of the vagina. Four years and 6 months after this operation, she underwent an exploratory laparotomy, with complete resection of recurrent disease in the abdomen in continuity with a left nephrectomy. Following surgery, she was treated with abdominal and pelvic radiotherapy and chemotherapy and remained clinically free of disease for 1 year, but subsequently developed an unresectable pelvic mass. Despite further chemotherapy, she died 5 years and 10 months after the initial diagnosis.

Steroid hormone receptor immunohistochemistry and amplification of c-myc protooncogene. Relationship to disease-free survival in breast cancer.

It is important to develop parameters that aid in prognosticating which patients with breast cancer are more likely to have a rapid disease course and therefore might benefit from early aggressive therapies. Specimens from two groups of women, deliberately selected because their clinical courses differed greatly, were studied to detect amplification of the protooncogenes c-myc, int-2, and C-erbB-2/neu by slot-blot assay, the estrogen receptor (ER), and the progesterone receptor (PR) by both biochemical and immunohistochemical procedures (ERICA and PRICA). One group of 50 patients had a prolonged disease-free interval after initial surgery (mean, 6.4 years); the other group of 52 women had had rapid disease recurrence (mean, 1.4 years) or progression (5 patients died of disease within 1 year of diagnosis). The patients were selected from 1700 consecutively accessioned cases if they fit the study criteria and sufficient tissue was available for oncogene hybridization studies. The two groups differed statistically by stage, number of involved axillary lymph nodes, ERICA and PRICA results (P = 0.001), and amplification of c-myc (P = 0.003). The percentage of patients with rapid disease recurrence and progression increased from 0-93% when risk factors changed from best case (ERICA and PRICA results, positive; c-myc, not amplified; and axillary nodes, not involved) to worst case (ERICA and PRICA findings, negative; c-myc, amplified; and axillary nodes, involved). Women with these worst-case parameters were more likely to have a recurrence sooner and rapidly progressive disease. They might benefit from early aggressive therapeutic measures.

Salvage carboplatin therapy for advanced ovarian cancer after first-line treatment with cisplatin.

From April 1989 to August 1990, 17 patients with Stage 3 or 4 epithelial ovarian cancer (EOC) were treated with intravenous carboplatin (160-400 mg/m2) for refractory or recurrent disease after first-line treatment with cisplatin-based combination chemotherapy. Of fifteen patients evaluable for activity, two complete responses and two partial responses were seen, for a response rate of 27%. The duration of response was 4.5, 5, 8, and 9.2 months, respectively, and responders survived longer than nonresponders. Of the nine evaluable patients receiving carboplatin as the first salvage treatment, four responses were seen. Dose selection for the first cycle of carboplatin was based on previous treatment, and adjustments were made on the basis of myelosuppression. In general, treatment was well tolerated--severe myelosuppression occurred after 6 of 73 cycles. This review confirms previous reports of anti-tumor activity of carboplatin in patients with refractory or recurrent advanced EOC who respond to first-line treatment with cisplatin. Further evaluation may help define the toxicity and efficacy of salvage treatment with carboplatin compared to cisplatin in patients who recur after a prolonged disease-free interval after first-line cisplatin-based therapy.

Endocrine therapy for advanced breast cancer: a review.

More than 45,000 women will die of metastatic breast cancer in the United States in 1991. Endocrine therapy remains a major option for treatment of such patients, and results in complete plus partial response rates of 30% with a median duration of approximately one year. Postmenopausal status, increased age, a prolonged disease-free interval, bone and soft tissue metastases, and positive estrogen and progesterone receptors are all associated with an increased response to endocrine therapy. The use of additive hormonal therapy, specifically antiestrogens, progestins, and aromatase inhibitors, have replaced surgical ablative procedures in the majority of patients; response rates to antiestrogen therapy, progestin therapy, and aromatase inhibitors are similar, but antiestrogens have generally been associated with the most favorable therapeutic index. At present, there is no convincing evidence that either combinations of endocrine therapies or endocrine therapy combined with chemotherapy are associated with an improvement in survival for patients with metastatic disease. Future research efforts directed at defining the molecular mechanisms of endocrine activity should facilitate clinical trials of newer and potentially more effective agents. All patients with metastatic breast cancer should be considered for at least one trial of endocrine therapy provided their metastatic disease is not rapidly progressive or life-threatening.

Late Manifestations of Esthesioneuroblastomas in the Central Nervous System

Two patients with esthesioneuroblastomas that disseminated in the central nervous system (CNS) and elsewhere are reported. The latest recurrences in the CNS were 19 years after the diagnosis in patient and 9 years after the diagnosis in the other. Because the treatment of patients with such late recurrences is complicated by previous surgical procedures and radiation therapy, we review therapeutic options for these patients. The literature has not previously stressed the occurrence of late metastases, including those to the CNS, after prolonged disease-free intervals.

Late Manifestations of Esthesioneuroblastomas in the Central Nervous System

Two patients with esthesioneuroblastomas that disseminated in the central nervous system (CNS) and elsewhere are reported. The latest recurrences in the CNS were 19 years after the diagnosis in patient and 9 years after the diagnosis in the other. Because the treatment of patients with such late recurrences is complicated by previous surgical procedures and radiation therapy, we review therapeutic options for these patients. The literature has not previously stressed the occurrence of late metastases, including those to the CNS, after prolonged disease-free intervals.

The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients.

Ocular melanoma is characterized by an unpredictable clinical course, during which fulminant metastatic disease may occur after a prolonged disease-free interval. The purpose of this study was to determine the pattern of metastatic involvement in this disease. The clinical and radiologic findings in 110 patients with metastatic ocular melanoma were reviewed. The 54 men and 56 women were 24-79 years old (mean, 50 years) when the primary tumor was first diagnosed. Metastases were present in three patients at the time of first diagnosis and occurred in 107 patients 2 months to 36 years later (mean, 52 months). One hundred five patients died between 1 and 38 months after the onset of metastatic disease. Hepatic metastases developed in 101 patients (92%), and in 60 (55%) of these, the liver was the only organ involved initially. Pulmonary parenchymal metastases developed in 34 patients (31%), but in only four of them were metastases confined to the lungs. Twenty-five patients (23%) had bone involvement, mostly affecting the spine. Nineteen patients (17%) had skin or subcutaneous metastases, but in only two of them was this the initial finding. Nodal involvement was shown in 15 patients (14%), almost always associated with extensive hepatic metastases. Brain and adrenal metastases were seen in five and three patients, respectively. Hepatic involvement occurs in almost all patients who develop metastatic ocular melanoma, and the liver is the most common initial site of metastatic involvement. Metastases may develop after a long disease-free interval.

Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma.

Two separate studies have been reported comparing Corynebacterium parvum and bacille Calmette-Guérin (BCG) as adjuvant immunotherapy for stage II melanoma patients (The Milton S. Hershey Medical Center, 48 patients; Southeastern Cancer Study Group [SECSG], 162 patients). As the criteria for patient selection and drugs used were similar, we have pooled the data to analyze the effects of these two treatments. Both studies used BCG (Tice, Chicago, IL) 3 x 10(8) live organisms per treatment by Tine technique and C parvum (Burroughs-Wellcome, Triangle Park, NC) subcutaneous at a dose of 4 mg/m2 (SECSG) or 5 micrograms/m2 (Hershey) per treatment. The only difference in these studies was the frequency of immunization, with patients in Hershey receiving 22 doses and the SECSG patients receiving 55 doses during the 2-year period of treatment. Kaplan-Meier life-table analysis for the 210 patients shows a prolonged disease-free interval for patients treated with C parvum (P = .02, two-sided Mantel procedure). In similar fashion, patients treated with C parvum had an improved survival rate (from all causes) when compared with BCG-treated patients (P = .012). An analysis of the results for the 170 patients for which the number of positive nodes was available was performed using Cox's model, with nodes as a stratification variable and with covariates of place, treatment, age, and sex. In this analysis, an observed benefit for C parvum on the disease-free interval had a P value of .37 while the benefit of C parvum on the survival times (from all causes) had a P value of .04. When the same analysis was performed using only patients aged younger than 60 years, the observed benefit of C parvum on disease-free interval had a P value of .08 and the benefit of C parvum on survival times (from all causes) had a P value of .008.

Primary central nervous system lymphoma as a secondary malignancy

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, but it is occurring with increased frequency even among apparently immunocompetent patients. Although secondary malignancies frequently involve the lymphoreticular system, PCNSL has been reported as a second neoplasm only once previously. Seven patients are discussed who developed PCNSL after successful treatment for a prior neoplasm. The original cancer was colon (one), breast (one), thyroid (one), Hodgkin's disease (two), and non-Hodgkin's lymphoma (two). Patients with systemic non-Hodgkin's lymphoma were thought to have a separate cerebral lymphoma on the basis of a prolonged disease-free interval from their systemic lymphoma, and the absence of systemic disease, when PCNSL was diagnosed and through subsequent follow-up. The PCNSL developed a median of 10 years after the diagnosis of the first tumor and 6 years after the last evidence of systemic disease. The diagnosis of PCNSL was often delayed because of confusion with brain metastases, and initial shrinkage or disappearance of the lesion after corticosteroids. Formation of PCNSL may be a consequence of treatment for the first malignancy, reflect an unidentified inherent predisposition to neoplastic transformation, or result from the changing epidemiology of PCNSL in the general population. These mechanisms are not mutually exclusive, and a single hypothesis cannot account for all these cases.

An Unusual Case of Wegener's Granulomatosis

A 58-year-old male developed extensive multisystem Wegener's granulomatosis eight years after pneumonectomy for a large solitary granuloma of the lung. Follow up following pneumonectomy had indicated a very prolonged disease free interval.

Photochemotherapy of Generalized Granuloma Annulare

Various forms of treatment for generalized granuloma annulare have been employed with little success. The results of treatment with topical and intralesional corticosteroids, as well as systemic therapy with corticosteroids, salicylates, aspirin, niacinamide, and chloroquine, have been generally disappointing. We describe five patients with generalized granuloma annulare of several years' duration who were treated with oral psoralen plus ultraviolet A irradiation. Lesions were present on the extremities, buttocks, and trunk in the form of macules, papules, and plaques. One patient also had perforating lesions on her thighs. Flattening of the lesions with decreased erythema and pigmentation was noted as early as 1 month after initiation of treatment. Complete clearance was achieved in all patients. Maintenance therapy has been required, resulting in prolonged disease-free intervals. Although the mechanism of action of oral psoralen plus ultraviolet A irradiation in granuloma annulare is unclear, one possibility is selective elimination of the cells that are responsible for initiating the disease.

Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormonal treatment in advanced breast cancer.

A new immunohistochemical assay using a monoclonal estrogen receptor (ER) antibody (H222, Abbott Laboratories, North Chicago) for determination of ER in formalin-fixed paraffin-embedded tissue was applied to evaluate its clinical value in a group of 145 previously untreated patients with advanced breast cancer. Suitable histologic material was accessible in 137 of these patients, of whom 70% had ER-positive tumors. The ER-positive patients had a significantly longer median overall survival than ER-negative patients (67 versus 32 months, P much less than 0.001) and this was an effect of both a prolonged disease-free interval (27 versus 17 months, P less than 0.05) and a prolonged survival after recurrence (41 versus 15 months, P much less than 0.001). Response to endocrine therapy was obtained in 49% of the patients with ER-positive tumors and in 7% with ER-negative tumors (P much less than 0.001). Relationship between response and semiquantified individual staining features could not be established. It is concluded that ER analysis in formalin-fixed paraffin-embedded tissue offers clinically useful information for allocation of patients to endocrine therapy.

Treatment of stage III breast cancer. A panel discussion.

A major question in oncology today concerns the most appropriate therapy for locally advanced breast cancer. Realistic goals include effective local treatment and a prolonged disease-free interval for these patients, most of whom have incurable disease. Here, our panel discusses the roles of surgery, radiation therapy, chemotherapy, and hormonal therapy, and the proper sequencing of these modalities.

Neuroendocrine neoplasms of the lung: A clinicopathologic update

One hundred forty-six cases of pulmonary neuroendocrine tumors are assessed according to the classification of Gould and associates and are evaluated for their clinical presentation and subsequent clinical course. Bronchial carcinoids are characteristically found to be central tumors often occurring in comparatively young patients; surgical resection with minimal but clear margins is usually curative. The long-term prognosis is excellent in the majority of patients, although rarely regional nodal and distant metastases develop. Well-differentiated neuroendocrine carcinomas are most frequently peripheral tumors. In stage I and II disease, surgical resection alone is curative and patients with locally advanced tumors may have a prolonged disease-free interval. The overall prognosis is less favorable than that of bronchial carcinoids but considerably better than that of small cell neuroendocrine carcinomas, with which they are still at times confused. Intermediate-sized cell neuroendocrine carcinomas are often wrongly categorized as large cell undifferentiated carcinoma. They have a distinctly aggressive clinical course comparable with that of small cell neuroendocrine carcinoma and should be treated similarly. Small cell neuroendocrine carcinomas are aggressive, rapidly disseminating neoplasms. Even in clinical stage I tumors, patients must be considered to have disseminated metastases. The role of surgical therapy in these two latter tumor types is adjuvant to aggressive systemic chemotherapy.

Malignant parotid gland tumors: a retrospective study.

This is a comprehensive retrospective study (1965-1984) of 130 patients with malignant parotid gland tumors. Patients were studied by comparison of presenting symptoms, histopathologies, treatments, disease-free intervals, and ultimate intervals. Facial paralysis was noted on presentation in 23% of the cases and regional neck node metastases were noted in 13%. Both findings correlated with prognosis. Seventy patients underwent surgery alone and 30 patients received combined therapy. The remaining patients were excluded from the study. The overall 5-year survival rate was 50%, with a 44% risk of recurrence. Fifty-six percent of the patients whose conditions subsequently recurred had their facial nerves sacrificed at time of surgery. Selected patients who received combined therapy experienced better local regional control and a prolonged disease-free interval as compared with those who underwent surgery alone. Combined therapy, however, provided no survival benefit for this group of patients. Adjuvant radiation therapy is recommended in the treatment planning of selected malignant tumors of the parotid gland.

Solitary pulmonary metastasis: an enigma.

Lung metastases, which are an expression of the new phase of the underlying neoplastic disorder, have been treated in the recent years by multiple disciplinary approach. When the metastases to the lungs are multiple, it is indicative of extensive tumor burden, and the organ plays an insignificant role in the distribution of the metastases in the different lobes of the lungs. However, when the pulmonary metastases appear after a prolonged disease-free interval it becomes an enigma; when the metastases are solitary, the majority (over 80% in this series) are located in the upper zone of the lungs. This study of 28 patients with solitary lung metastases explores the possible etiology of this clinical observation and proposes that the pattern of perfusion and anatomopathological features of the upper lobes are the main reasons why these lobes are prevalently the sites for solitary lung metastases.

Adjuvant radiation therapy in stages C and D 1 prostatic adenocarcinoma: Preliminary results

Twenty patients with adenocarcinoma of the prostate underwent postradical prostatectomy adjuvant external beam megavoltage radiation therapy because of periprostatic disease in histologic evaluation of the resected specimen. Fourteen of these patients had pathologic Stage C and 6 pathologic Stage D 1 disease. Treatment in most patients consisted of 5,000 rad delivered to the true pelvis. The five-year recurrence free survival was 75 per cent for pathologic Stage C and 41 per cent for Stage D 1 disease. The median time to first evidence of treatment failure was fifty months for D 1 patients and has not been reached by the C group. Minor complications occurred in 85 per cent of patients and major complications in 5 per cent. In 1 patient with mild, postoperative stress incontinence total urinary incontinence developed after radiation therapy. These preliminary observations suggest a prolonged disease free interval with an acceptable morbidity is obtained utilizing this regimen.

Small cell bronchogenic carcinoma

We have attempted to highlight the most important aspects of SCBC in this review. The significant strides made in a variety of areas have been associated with increased response rates and survival as well as with a prolonged disease-free interval in a fraction of patients. The consensus is that 50% or more of patients with LD can achieve a CR, with an overall objective response rate of 80% or greater and a median overall survival of 14 months or longer. Furthermore, 15% to 20% of such patients may expect a disease-free interval of at least three years that appears to be associated with cure in at least some of these patients. Patients with ED may experience a 20% or greater CR, an 80% or greater objective response, and have a median overall survival of at least seven months. Extensive research is ongoing in a variety of areas. Further refinements in developing more effective chemotherapeutic regimens are likely, as is obtaining new information concerning the intensity, duration, and selection of chemotherapeutic agents and their role in relationship to radiotherapy. Improvement in radiotherapy techniques may lead to improved therapeutic results. Only recently has a reevaluation of the role of surgery in SCBC begun to take place. Also, several new areas of investigation are on the horizon, ranging from improved staging with thoracic and abdominal computed tomography to the role of warfarin, monoclonal tumor antibodies, and several currently investigational chemotherapeutic and biologic response modifier agents.

NIH conference. Recent advances in chronic granulomatous disease.

Chronic granulomatous disease represents a group of disorders of phagocytic cell oxidative metabolism involving recurrent infections with catalase-positive microorganisms and chronic inflammation. Genetic heterogeneity and phagocyte abnormalities, including enzyme deficiencies, abnormal elicited membrane potential changes, abnormal acidification of the phagocytic vacuole, and deficiencies of an electron transport cascade, have been associated with its pathogenesis. In addition, recently we have shown abnormal neutrophil C3b-receptor expression, antibody-dependent cellular cytotoxicity, and abnormal microtubule metabolism (tyrosinolation of the alpha-chain of tubulin). Fourteen patients with the disease who were followed at the National Institutes of Health had life-threatening infections, on average, once every 9.6 months. In most of the 119 febrile episodes seen in these patients, no infectious agent was found. Retrospective studies indicated that prophylactic antibiotic therapy, particularly with trimethoprim-sulfamethoxazole, significantly prolonged disease-free intervals to greater than 40 months (p less than 0.05). In serious, life-threatening infections, leukocyte transfusions have been used in therapy. Transfused leukocytes localize and persist at infectious sites, and the clinical efficacy of leukocyte transfusions has been suggested.

In situ lobular carcinoma of the breast.

Nineteen patients who did not have mastectomy for in situ lobular carcinoma that was diagnosed by excisional biopsy were followed up for a period of seven to 21 years. In two patients, infiltrating carcinoma developed; each had mastectomies. They were followed up for 20 and 21 years. A third patient who previously had a mastectomy for infiltrating lobular carcinoma and who was being followed up for in situ lobular carcinoma in the contralateral breast died of metastatic disease. The remaining patients were found to be free of disease. These data support the concept that a small percentage (11%) of in situ lesions will progress to invasive tumors. Although mastectomy would seem to be the most prudent course, prolonged disease-free intervals were seen in patients who did not have mastectomy, suggesting close observation to be an alternative approach to this problem.