Brain metastases from unknown primary site.

We report our experience with 32 patients presenting with brain metastasis from unknown origin. This constitutes 11.5 percent of 276 consecutive patients with brain metastasis seen over a period of eight years at the University of Mississippi Medical Center. Patients with solitary resectable lesion underwent surgery followed by irradiation. All patients with multiple metastasis were treated with whole brain radiation and dexarnethasone. The mean survival was 31.50 weeks for patients with single lesion and 19.11 weeks for multiple lesions. The investigations and treatment management of brain metastasis from unknown primary site are discussed.

The role of paclitaxel in the management of patients with carcinoma of the cervix.

The major role for systemic therapy in the management of carcinoma of the cervix is to treat those patients with advanced or recurrent disease. While 19 single agents have activity, defined as a response rate > or = 15%, the agents that have attracted the greatest attention are the platinum compounds and ifosfamide. Combinations of these two drugs have produced high response rates in phase II trials. A recent randomized trial found that a combination of ifosfamide/cisplatin yielded a superior response rate to cisplatin alone (33% v 19%), although no differences in progression-free or overall survival were observed. While ongoing randomized trials continue to explore platinum/ifosfamide combinations, current attention also is directed to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), which has demonstrated activity in a phase II trial (18% response rate). The Gynecologic Oncology Group plans to conduct a phase II trial of a platinum/paclitaxel combination and may follow it with a phase III trial of the same combination if the phase II results suggest enhanced therapeutic benefit. Randomized trials in patients with less advanced (stages IIB to IVA) disease have demonstrated superior response rates and overall survival with concomitant chemoradiation. Regimens of demonstrated efficacy in this setting include hydroxyurea plus radiation and cisplatin/5-fluorouracil plus radiation. The Gynecologic Oncology Group currently is conducting a phase I trial of concomitant paclitaxel plus radiation and may consider a paclitaxel-based regimen in future phase III trials of concomitant chemoradiation or possibly neoadjuvant chemotherapy in patients with limited disease (stages IIB to IVA).

The role of ifosfamide and systemic therapy in the management of carcinoma of the cervix.

Nineteen single agents have activity in patients with advanced or recurrent carcinoma of the cervix. The agents that have attracted the greatest attention, however, are the platinum compounds and ifosfamide. Although most phase II trials combining these agents demonstrate activity but not relative merit, a recent phase III randomized trial shows that ifosfamide/cisplatin yields a superior response rate than cisplatin alone (33% v 19%, respectively). An ongoing randomized study is evaluating cisplatin/ifosfamide with or without bleomycin on the basis of a number of phase II reports suggesting a high order of activity for the three-drug combination. Randomized trials in less advanced disease demonstrate superior response rate, progression-free interval, and overall survival for concomitant chemoradiation in patients with stage IIIB to IVA disease. Regimens with demonstrated efficacy in this setting include hydroxyurea plus radiation and cisplatin/5-fluorouracil plus radiation. Of two randomized trials of cisplatin/ifosfamide/bleomycin followed by radiation versus radiation alone, the one completed study shows no overall advantage for the combined approach but does suggest an improved 32-month survival in patients with stage IIIB disease. The other trial is ongoing, with an early observation of a superior response rate with the combined approach. Current recommendations are to use ifosfamide/cisplatin as the treatment of choice for advanced or recurrent disease and concomitant chemoradiation with either hydroxyurea or cisplatin/5-fluorouracil for stage IIIB to IVA disease.

The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix.

Endometrial carcinoma and squamous cell carcinoma of the cervix are common invasive neoplasms of the female genital tract. Early diagnosis of a majority of patients has resulted in high cure rates for both diseases. In the last two decades, a growing number of active systemic drugs have been identified. Cisplatin has been extensively studied in both neoplasms and has clear activity (20% response rate in endometrial carcinoma and 23% response rate in squamous cell carcinoma of the cervix). Recently, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be clearly active in both (35% response rate in endometrial carcinoma and 17% response rate in squamous cell carcinoma of the cervix). The apparent clinical non-cross-resistance between paclitaxel and cisplatin in other neoplasms like ovarian carcinoma makes combinations including these two agents of great interest. In endometrial carcinoma, a phase I trial of cisplatin plus doxorubicin plus escalating paclitaxel doses is being performed by the Gynecologic Oncology Group (GOG). Based on the outcome of this study, a future randomized trial will compare the current standard, doxorubicin plus cisplatin, with either a combination of cisplatin, doxorubicin, and paclitaxel or a two-drug regimen of paclitaxel plus cisplatin. In squamous cell carcinoma of the cervix, a logical approach to the incorporation of paclitaxel into front-line therapy for advanced or recurrent disease is a phase III trial of the best regimen from GOG protocol 110 (cisplatin with or without either ifosfamide or dibromodulcitol) versus the same drugs plus paclitaxel. In addition, the GOG is conducting a phase I trial of paclitaxel given concomitantly with radiation in the hope that the resulting regimen will be an arm of a future randomized study in patients with locoregionally advanced disease (stages IIB through IVA). The ultimate role of paclitaxel in the management of patients with these two neoplasms awaits the results of these efforts.

Syndrome of inappropriate ADH secretion and diplopia: oat cell (small cell) rectal carcinoma metastatic to the central nervous system.

Extrapulmonary small cell carcinoma is being increasingly recognized as a distinct clinical entity. We report a patient with small cell carcinoma of the rectum metastatic to the brain, presenting with diplopia and inappropriate antidiuretic hormone syndrome.

Report of a prospective trial--split course versus conventional radiotherapy in the treatment of non small cell lung cancer.

A prospective randomized trial was started in January 1982, to compare morbidity and survival of two different radiation regimens for the treatment of non-small cell lung cancer (NSCLC). The trial was closed in December 1988. One group of patients was treated by conventional daily radiation therapy, and the other group by split course therapy. To maintain uniformity, a single physician staged and treated all patients and noted morbidity during treatment. Two hundred seventy-three consecutive lung cancer patients were treated. Only patients who completed the full radiation therapy course were included in this study. One hundred fourteen patients were treated with split course therapy, and 159 patients were treated by conventional daily radiation therapy. A few patients did not return for the second course of treatment, which accounts for the different number of patients in the two arms of the study. There was no statistically significant difference in survival between the two arms. Median survival for the split course and the continuous fraction therapy regimens was 11.6 months and 10.9 months, respectively. Split course radiation was associated with less morbidity.

Chemotherapy as a palliative treatment in carcinoma of the uterine cervix.

The vast majority of patients with cervix carcinoma present with either preinvasive or minimally invasive (stage IA) disease and are cured with surgery alone. The remaining patients can be classified into two groups: those with disseminated (extrapelvic) disease at the time of presentation or recurrence after initial treatment and those with advanced pelvic disease. In the first group, the goal of therapy is palliative and the principal modality is chemotherapy. A number of single agents have significant activity (> or = 15% response rate): the platinum compounds, certain alkylating agents, the anthracyclines, bleomycin, the vinca alkaloids, certain antifols, 5-fluorouracil, 5'-floxuridine, ICRF-159, hexamethylmelamine, and CPT-11. Although uncontrolled trials report high response rates with combination regimens, no such regimen has been shown to be superior to single-agent therapy. The current standard of care for initial treatment is single-agent cisplatin 50 to 100 mg/m2 every 3 weeks, with an expected 23% response rate. In the second group, palliation takes the form of prevention of recurrence. Patients who have stage IIIB or IVA disease benefit from the addition of concomitant chemotherapy to radiation. The current standard of care is hydroxyurea 80 mg/kg orally twice weekly during radiotherapy. For patients with stage IB or II disease, surgery and/or radiotherapy remains the standard of care. Although concomitant or neoadjuvant chemotherapy followed by either surgery or radiotherapy has been evaluated, no conclusive evidence proves the value of the addition of chemotherapy to the management of these patients. Ongoing phase III trials are evaluating both approaches.

Predictors of depression among male cancer patients.

The diagnosis of cancer is often associated with a host of negative emotional responses, including depressed mood. Social support and quality of life were used to predict depression in a sample of older male cancer patients. Depression was found to be a common, but not universal, reaction to the diagnosis and treatment of cancer. Almost 40% of subjects reported symptoms of moderate depression and nearly one fifth produced scores indicative of clinical depression. A stepwise multiple regression analysis revealed that our social support and quality of life measures accounted for 31.5% of the variance in total Beck Depression Inventory scores. Quality of life accounted for more of the variance in depression than did social support.

Cisplatin and 5-fluorouracil for metastatic squamous cell carcinoma from unknown primary.

Chemotherapy for squamous cell carcinoma with unknown primary (SCUP) has not been prospectively studied. To evaluate the efficacy of cis-diaminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) in advanced SCUP, we treated 15 patients with measurable disease. A prospective trial was conducted of cisplatin and 5-FU in patients presenting with SCUP. All patients had evaluation in search for primary disease with computed tomographic scan of the head, neck, and chest and endoscopic evaluation of the nasopharynx, larynx, esophagus, and tracheobronchial passages with negative blind biopsies. Chemotherapy consisted of cisplatin 100 mg/m2 on day 1 and 5-FU 1000 mg/m2 continuous infusion over 24 hr for 4 days. The regimen was repeated every 21 days. Responses were seen in 8 of 15 patients [1 complete response (CR) and 7 partial responses (PR)], for an overall response rate of 53%. These results suggest that cisplatin-5-FU combination has efficacy in advanced SCUP and deserves further trials both in advanced disease and in combined modality programs with surgery and radiation therapy.

5-Fluorouracil, adriamycin, and mitomycin C in adenocarcinoma of the esophagus or gastroesophageal junction tumors.

We reviewed our results with chemotherapy for adenocarcinoma of the esophagus or gastroesophageal junction tumors in patients treated with 5-fluorouracil, Adriamycin, and mitomycin C (FAM) regimen as developed by MacDonald and colleagues for adenocarcinoma of the stomach. Sixteen patients were treated, 12 with metastatic and 4 with locoregional disease. Responses were seen in 6 of 16 patients (all partial responses), for an overall response rate of 37.5%. The sites of response include liver (3), lung (1), bone (1), and lymph nodes (1). Median duration of response was 7 months. These results with FAM in adenocarcinoma of the esophagus suggest activity similar to that seen in gastric carcinoma. The second-generation chemotherapy combinations effective in gastric carcinoma merit evaluation in this tumor to see if the remission rates could be further improved.

Chemotherapy in advanced ovarian carcinoma: current standards of care based on randomized trials.

The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the standard chemotherapy for advanced ovarian carcinoma should be considered a combination of taxol plus a platinum compound.

Management of brain metastases: past, present, and future.

Brain metastasis is an important cause of morbidity and mortality in cancer patients. Because most of these patients die of systemic disease, the primary therapeutic goal is to improve the quality of life. Conventional therapy for brain metastases is usually whole-brain irradiation. Chemotherapy often results in regression of brain metastases in chemosensitive tumors. We review our institutional experience in the treatment of brain metastasis with both radiation and chemotherapy. In the future, improvement in the management of brain metastases will depend on improved chemotherapy, radiosensitizers, and radiotherapy techniques such as stereotactic radiosurgery.

Carcinoma of the uterine cervix: current status and future directions.

Based on rigorous interpretation of current evidence, systemic therapy has two roles in the management of carcinoma of the uterine cervix. In patients with advanced or recurrent disease, single-agent chemotherapy constitutes the treatment of choice. The most extensively studied agents are the platinum compounds. Either cisplatin or carboplatin represents a reasonable choice for first-line treatment. There appears to be no significant influence of either dose or schedule on patient benefit. Other agents with clear-cut activity include ifosfamide, dibromodulcitol, and doxorubicin. At this time, there is no scientific basis for the use of combination chemotherapy in advanced or recurrent carcinoma of the cervix. In patients with locoregionally advanced disease (stages IIIB or IVA), radiation plus either hydroxyurea or a combination of cisplatin plus 5-fluorouracil offers an advantage over radiation alone in terms of progression-free interval and survival. In patients with more limited disease, there is no defined role for systemic therapy at the present time. Three goals constitute the focus for current investigational efforts: (1) continued efforts to identify additional highly active drugs are needed; (2) the development of effective combination chemotherapy depends on the use of logically designed combinations of active drugs in well-designed phase III trials with single-agent therapy as the control; and (3) phase III trials seeking more effective combinations of systemic therapy with surgery and/or radiotherapy should continue for not only locoregionally advanced disease but also for more limited carcinoma of the cervix.

Second-line chemotherapy for recurrent carcinoma of the ovary.

Despite relatively high response rates to chemotherapy for ovarian carcinoma, most patients eventually will have progressive disease that will require additional therapy. Most efforts to study such second-line or "salvage" chemotherapy have been single-arm trials of small numbers of patients, which report widely variable response rates, relatively short response durations, and short survival times. Only recently have certain critical patient characteristics been recognized as important in determining appropriate therapy as follows: (1) the extent and volume of disease at recurrence and (2) the type and duration of response to prior chemotherapy. Patients with small-volume disease confined to the peritoneal cavity have a far better chance of achieving a response to second-line chemotherapy with subsequent prolonged survival than do those with bulky disease or disease outside the abdomen. Perhaps even more critical is the distinction between those patients whose neoplasm is still "clinically sensitive" to the platinum-containing compounds (initial response to platinum-based therapy and relapse more than 6 months after cessation of treatment) and those with "clinically resistant" disease (progression during or within 6 months of front-line platinum-based therapy). Those considered clinically sensitive to platinum-based therapy should be retreated with a platinum-containing regimen at the time of recurrence. Those with evidence for resistance should receive alternative treatment with one or more drugs capable of inducing responses in such patients. These drugs currently include: taxol, ifosfamide, and hexamethylmelamine.

Case report: cisplatin-induced hemolytic uremic syndrome.

Two patients developed noncardiogenic pulmonary edema (NCPE), following red blood cell transfusion in a setting of acute cisplatin nephropathy. One manifested the full picture of hemolytic uremic syndrome, the other had transient features following blood transfusion. We further reviewed the clinical records on blood transfusion for all patients with cisplatin nephropathy. A third case of (NCPE) was identified in a patient with acute renal dysfunction. However, none of the 16 patients with cisplatin-induced, mild stable chronic renal impairment had pulmonary dysfunction or other laboratory evidence for microangiopathy following transfusion. Hemolytic uremic syndrome may be a rare manifestation of cisplatin toxicity. Caution is indicated in transfusing patients with acute platinum nephropathy even in the absence of overt microangiopathy. The pathogenesis of this syndrome and the cause for NCPE is unclear. The literature is reviewed and discussed.

Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin.

Seven patients with advanced locoregional or metastatic squamous cell carcinoma of the skin were treated with cis-daimminedichloroplatin (cisplatin) and 5-fluorouracil (5-FU). Responses were seen in six of seven patients (three partial responses [PR] and three complete responses [CR]). One patient is alive and disease-free at 2 years. These results indicate that cisplatin and 5-FU is an effective combination regimen that should be used in future clinical trials in squamous cell carcinoma of the skin.

Evaluation of staging workup in malignant melanoma.

To evaluate the role of staging workup in primary and recurrent malignant melanoma, we reviewed the results in 115 patients with primary melanoma and in 28 patients with recurrent disease who underwent evaluation with chest roentgenograms, radionuclide bone and liver scans, and either a radionuclide brain scan or computed tomography of the brain. Upper gastrointestinal tract series with small-bowel follow-through were obtained in 42 patients. Metastatic disease was documented in nine of 143 chest roentgenograms, seven of 137 liver-spleen scans, three of 141 bone scans, two of 85 brain scans, two of 43 brain computed tomographic scans, and two of 42 upper gastrointestinal tract series. All documented metastasis was in stage II and recurrent melanoma. Postoperatively determined serum lactate dehydrogenase levels showed greater than 300 U/L in all patients with documented metastasis except in two with bone and one with brain metastases. We conclude that, in view of low yield, there is no role for routine metastatic workup to detect silent metastasis in malignant melanoma. Elevated postoperative serum lactate dehydrogenase levels indicate need for metastatic workup.

Prostate cancer: a model of cancer in the elderly.

Prostate cancer is the most common malignancy in men over 70. Chronic course of the disease and multiple therapeutic options allow a customized management of the patient's individual problems. Prognostic factors are stage, size of primary tumors, serum acid phosphatase levels, number of metastases, ureteral obstruction and patient's age. In localized disease, surgery and radiation therapy are equally effective for patients with a life expectancy less than or equal to 10 years. Surgery may be superior to radiation if longer survival is expected. In locally advanced disease radiation therapy is preferred to surgery, due to a lower rate of complications. Management of metastatic disease requires offsetting androgen effects by castration or by antiandrogens. Orchiectomy, the safest way to produce castration, is unacceptable to 50% of patients. LHRH analogs are safer than estrogens, but more expensive; the risk of tumor flare up controindicates these compounds in life-threatening situations. The use of ketoconazole is limited by long-term toxicity, but may be life-saving in life-threatening situations, due to a rapid onset of action. Antiandrogens are as effective as castration, but are not commercially available in the USA. Alternative treatments include Estracyt, intermittent estrogentherapy, progesterone derivative and aminogluthetimide. Radical prostatectomy and radiation therapy to the prostate cause erectile impotence with persistence of orgasmic sensations. These patients are ideal candidates for erection-restoring interventions, such as intrapenile injections or penile implants.