Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments.

BACKGROUND: In cancer therapy, molecularly targeted agents have the potential to maximize antitumor efficacy while minimizing treatment-related toxicity. However, these agents may only be effective in specific tumor subtypes with defined genomic profiles. This emphasizes the importance of developing personalized cancer therapeutic strategies (i.e. through the use of companion diagnostic tests) to appropriately select and treat patients who are likely to benefit from specific targeted therapies, thus leading to improvements in clinical and safety outcomes. A potential biological target is the folate receptor (FR), which has been shown to be overexpressed on the surface of many cancers, including tumors of the lungs and ovaries. DESIGN: We carried out a literature search to identify how the FR can be a potential target for selected tumors, and how the FR expression can be exploited by targeted therapies. RESULTS: The two main therapeutic strategies for targeting the FR are based on the use of: (i) an anti-FR antibody (e.g. farletuzumab) and (ii) folate conjugates of folate-targeted chemotherapies and companion radiodiagnostic imaging agents (e.g. vintafolide and (99m)technetium-etarfolatide). Both of these strategies are being assessed in phase III trials. CONCLUSIONS: The important role that the FR plays in cancer development and progression has led to the development of FR-targeted therapeutic approaches. To date, the promising data observed in phase II clinical trials have not been confirmed in phase III studies. Accordingly, there is a need for further research in the refinement of patient selection and identification of new therapeutic combinations. In particular, the development of these targeted therapies requires reliable methods to be developed to detect FR-positive tumors in order to help select patients who may benefit from treatment.

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

PURPOSE: In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. PATIENTS AND METHODS: Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. RESULTS: Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). CONCLUSION: Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

Mitral valve prolapse in sickle cell disease. Presumptive evidence for a linked connective tissue disorder.

To determine the prevalence of mitral valve prolapse in sickle cell disease, M-mode echocardiography was performed on 57 patients with sickle cell disease and 35 patients with chronic anemia of end-stage renal disease (anemic control group). In 25% (14/57) of patients with sickle cell disease, unequivocal mitral valve prolapse was diagnosed by echocardiography; all these patients had a mobile systolic click and/or late systolic murmur. This figure was significantly greater than the reported 5% to 6% prevalence in the general adult population, the 1% to 3% prevalence in the black population, and the 3.0% prevalence (1/35) in the anemic control group. The association of mitral valve prolapse and sickle cell disease cannot be explained on the basis of left ventricular size, systolic function, ischemic left ventricular or papillary muscle dysfunction, or chronic anemia. Therefore, a linked connective tissue defect in these two diseases is a hypothesis worthy of further investigation.

Current therapy of ovarian carcinoma: an overview.

Significant advances in the management of ovarian carcinoma have been developed over the last decade of research. The advanced nature of the disease in a majority of the patients has underlined the importance of systemic therapy in the treatment of patients with ovarian carcinoma. The last decade has seen the identification of cisplatin-based combinations of drugs as superior to single alkylating agents in the treatment of advanced disease. The importance of aggressive surgical bulk reduction in terms of improved response to chemotherapy and survival has been demonstrated, and the necessity for careful surgical staging of disease both before chemotherapy and at the completion of treatment has been emphasized. A number of exciting new alternative therapies are currently being investigated: intraperitoneal chemotherapy, whole abdominal radiotherapy, biologic response modifiers, and in vitro drug sensitivity testing with the human tumor stem cell assay. The role of these various alternatives is not clear at this time, but their potential for significant contributions to the treatment of ovarian carcinoma holds major promise. For the present, the essentials of management of these patients include careful staging including laparotomy, aggressive surgical bulk reduction, and cisplatin-based combination chemotherapy.

The role of ifosfamide in gynecologic cancer.

Ifosfamide exhibits promising activity in a variety of gynecologic neoplasms. In carcinoma of the ovary, the drug shows clear-cut activity, effecting responses in patients who have proven clinically resistant to cisplatin-based combination chemotherapy. In carcinoma of the cervix, the drug also appears to be highly active, both as a single agent and in combination with other agents, such as the platinum compounds. The drug is active in uterine sarcomas and appears to be the most active agent studied to date in mixed mesodermal sarcomas of the uterus. The drug's role in combination with other agents in the treatment of all of these neoplasms is under study, but cannot be determined from currently available data on combination therapy. Its activity in other gynecologic tumors, such as endometrial carcinoma and ovarian germ cell tumors, is also indeterminate at present. Although further studies are needed, current evidence supports the contention that ifosfamide is a major new active drug in the management of gynecologic cancers.

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.

Ifosfamide in the management of gynecologic cancers.

Ifosfamide, an alkylating agent chemically similar to cyclophosphamide, has been tested both as a single agent and in combination therapy for a variety of gynecologic cancers. In celomic epithelial carcinoma of the ovary, single agent ifosfamide yields response rates ranging from 19% to 79% and, most significantly, responses in patients who are refractory to cisplatin. Use in combination with both cisplatin and carboplatin has been reported, but the relative merits of these two combinations are indeterminate at present. In carcinoma of the cervix, response rates for ifosfamide alone range from 20% to 40% in patients who have not received prior chemotherapy. Very high response rates from 67% to 86% have been reported with ifosfamide in combination with platinum compounds with or without other agents such as doxorubicin and bleomycin. No studies have yet demonstrated superiority of combination therapy. Data from the Gynecologic Oncology Group demonstrate activity for ifosfamide alone in mixed mesodermal sarcomas of the uterus. Finally, anecdotal data note responses in endometrial carcinoma and germ cell carcinomas of the ovary. Thus, it appears that ifosfamide has significant activity in a variety of gynecologic cancers and deserves further testing as a part of combination chemotherapy in at least celomic epithelial carcinomas of the ovary, cervix carcinomas, and mixed mesodermal sarcomas of the uterus.

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.

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.

The role of paclitaxel in the management of coelomic epithelial carcinoma of the ovary: a review with emphasis on the Gynecologic Oncology Group experience.

Coelomic epithelial carcinoma of the ovary, the most common cause of death from cancer of the female genital tract in the United States, presents most commonly as advanced (stage III or IV) disease. Management consists of aggressive surgical cytoreduction followed by combination chemotherapy, until recently, a platinum compound plus an alkylating agent. The recent identification of the activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) offers the potential to improve further the management of patients with advanced disease. That this agent might enhance current front-line therapy is supported by its unique mechanism of action and by the significant numbers of responses reported in patients clinically resistant to the platinum compounds: more than 20% of these patients responded to paclitaxel as salvage therapy in four different phase II trials. These observations led to a phase I Gynecologic Oncology Group trial that showed that paclitaxel 135 mg/m2 over 24 hours followed by cisplatin 75 mg/m2 could be given every 3 weeks. This group then compared six cycles of the identified regimen with six cycles of standard cisplatin/cyclophosphamide chemotherapy given every 3 weeks in a phase III trial in 388 previously untreated patients with large-volume (residual nodules > 1 cm after surgery) disease. The results show the superiority of the paclitaxel/cisplatin regimen: overall response rate 77% versus 62%, clinical complete response 54% versus 33%, frequency of achieving a grossly disease-free state at second-look laparotomy 40% versus 22%, progression-free survival 18 versus 13 months, and overall survival 38 versus 24 months. Thus, paclitaxel/cisplatin is the new standard of care for patients with advanced ovarian carcinoma. Current phase III studies explore further the role of paclitaxel in front-line therapy: the relative merits of single-agent versus combination chemotherapy, the role of interval surgical cytoreduction combined with paclitaxel/cisplatin, the value of carboplatin-based versus cisplatin-based combinations with paclitaxel, the significance of the paclitaxel infusion length (3 v 24 v 96 hours), and the value of more dose-intense combinations.

Dilatation of bronchial stenoses due to sarcoidosis using a flexible fiberoptic bronchoscope.

Stenosis of the trachea and bronchi can complicate many diseases and lead to significant pulmonary complaints. Unfortunately, steroids rarely yield satisfactory results in reversing symptoms. We describe six patients with symptomatic airway stenosis from sarcoidosis, all of whom were refractory to steroid therapy. By using a Fogarty embolectomy catheter inserted through the inner channel of a flexible bronchoscope, we were able to dilate the stenotic areas under direct vision. Patients had significant subjective improvement following dilatation and no significant complications occurred. We believe this technique represents an improvement on previously described methods because it can easily access the upper lobes and more distal segments and can be performed at the bedside.

Abnormal septal Q waves in sickle cell disease. Prevalence and causative factors.

Electrocardiograms and M-mode echocardiograms were obtained prospectively from 72 patients with hemoglobin SS (n = 55) or SC (n = 17) disease to assess the prevalence of abnormal Q waves in sickle cell disease and to determine if such Q waves could be explained by, or related to, echocardiographically determined anatomic or functional abnormalities. The mean age (+/- SD) of the population under study was 28 +/- 9 years, and the mean hematocrit reading was 28 +/- 5 percent; 43 male and 29 female patients were evaluated. No patient had a history of systemic arterial hypertension, valvular heart disease, or congestive heart failure. Abnormal septal Q waves (amplitude greater than or equal to 0.30 mV; duration less than or equal to 29 msec) were noted in leads V4, V5, or V6 in 15 of 72 patients, and 50 percent (36) of the population under study demonstrated electrocardiographic voltage changes consistent with left ventricular hypertrophy. M-mode echocardiography showed that 29 of 72 patients had a thickened interventricular septum (greater than or equal to 1.2 cm), 16 of 72 had an abnormally thickened left ventricular posterior wall (greater than or equal to 1.2 cm), and 31 of 72 had increased left ventricular mass (greater than 215 g). The prevalence of electrocardiographic and echocardiographic abnormalities was not significantly different between patients with hemoglobin SS and SC disease. Septal excursion was decreased in 11 of the patients, and global left ventricular function (percent fractional shortening) was slightly decreased in three patients. Regional wall motion was normal in all 72 patients. Six percent (four) of the patients met echocardiographic criteria for asymmetric septal hypertrophy. Linear regression analysis yielded significant positive correlations between septal dimension (r = 0.38; p less than 0.001) and left ventricular mass (r = 0.37; p less than 0.005) when each was compared with Q-wave amplitude. A significant negative correlation (r = 0.40; p less than 0.001) was noted between hematocrit reading and Q-wave amplitude. We conclude that abnormal septal Q waves are common in sickle cell disease and are related, in part, to septal thickness, as well as left ventricular mass and degree of anemia.

Initial clinical trial of substernal epicardial echocardiography: SEEing a new window to the postoperative heart.

BACKGROUND: Postoperative echocardiography windows are often of poor quality because of intervening air spaces around the heart and great vessels. We assessed the utility of a new commercially available adult chest drainage tube that has been modified with the addition of a sterile sleeve to accommodate the introduction of a nonsterile pediatric transesophageal echocardiography (TEE) probe. The TEE probe lies in a substernal epicardial position on the postoperative heart allowing one to perform substernal epicardial echocardiography (SEE). METHODS: Informed consent was obtained from 21 consecutive adult cardiac operation patients. At the completion of the operation the SEE drainage tube was inserted through the rectus muscle and into the pericardium. After chest closure, all patients underwent a full echo examination using an Acuson pediatric biplane probe in the SEE position. Views obtained and ease of insertion were judged on a 1 to 10 (worst to best) scale. RESULTS: Full SEE examinations were completed in an average of 12 minutes. Ease of probe entry and manipulation was excellent (ratings of 9.3 and 9.6, respectively). The quality of the anatomic images was also excellent. Substernal epicardial echocardiography tube positioning was integral to the orientation of the images obtained. There were no complications related to the placement of the SEE tubes or TEE probes. In 4 of 21 patients (19%) the SEE methodology was used serially in the intensive care unit to accurately assess ventricular function and filling during weaning of an intraaortic balloon and inotropic agents. CONCLUSIONS: Substernal epicardial echocardiography is a safe and highly effective methodology for the serial echocardiographic assessment of the postoperative heart.

Evaluation of bone scan as a screening work-up in primary and local-regional recurrence of breast cancer.

To evaluate the use of radionuclide bone scan in staging patients with primary and local-regional recurrence of breast cancer, we reviewed the results in 265 patients with primary breast cancer who had the scan either preoperatively or within 6 weeks of surgery, and in 39 patients presenting with their first local-regional recurrence. All patients were clinically staged according to the revised 1983 criteria of the American Joint Committee for Cancer Staging and End-Results Reporting. None of the 92 with stage I and four of 95 patients with stage II had a positive scan. Eleven of 41 with stage IIIA and 13 of 37 with stage IIIB had a positive bone scan. In patients with their first local-regional recurrence, 12 of 39 had a positive scan. Follow-up scans were available in 61 patients with clinical stage I and II breast cancer who had adjuvant chemotherapy for pathological involvement of axillary node. There were six conversions observed in 61 scans obtained during the first year. Seven converted in follow-up scans in 47 patients in the second year. We conclude that although bone scans have a low positive yield in stage I and II breast cancer, their use in the preoperative setting and in the follow-up of patients with axillary node involvement detects early converters. Bone scans are justified in stage IIIA and IIIB breast cancer and in patients being evaluated for local-regional recurrence.

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.

Phase II evaluation of dianhydrogalactitol in lung cancer: a Southwest Oncology Group Study.

A phase II study of dianhydrogalactitol in patients with advanced lung cancer yielded responses in three of 33 patients with adenocarcinoma and in one of 11 patients with large cell anaplastic carcinoma. Small cell and squamous cell carcinomas were unresponsive. Toxic effects were acceptable and were related to serum creatinine values.

Local pulmonary immunity in pigeon breeder's disease. A case study.

We studied pulmonary and systemic aspects of the immune response in a patient with pigeon breeder's disease before and after an inhalation challenge with pigeon serum. Macrophage migration inhibition was induced with bronchoalveolar wash cells exposed to both pigeon serum and pigeon dropping extract before but not after challenge. Peripheral blood lymphocytes exposed to these antigens did not induce inhibition of guinea pig peritoneal macrophage migration before challenge. However, after challenge peripheral blood lymphocytes did cause macrophage migration inhibition when exposed to pigeon serum. Both systemic and bronchoalveolar lymphocytes proliferated when exposed to these pigeon antigens in vitro. Our patient represents the first reported case of lymphokine production by pulmonary as well as systemic lymphocytes in hypersensitivity pneumonitis.