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PubMed2006

Molecular classification of human cancers using a 92-gene real-time quantitative polymerase chain reaction assay.

CONTEXT: Correct diagnosis of the tissue origin of a metastatic cancer is the first step in disease management, but it is frequently difficult using standard pathologic methods. Microarray-based gene expression profiling has shown great promise as a new tool to address this challenge. OBJECTIVE: Adoption of microarray technologies in the clinic remains limited. We aimed to bridge this technological gap by developing a real-time quantitative polymerase chain reaction (RT-PCR) assay. DESIGN: We constructed a microarray database of 466 frozen and 112 formalin-fixed, paraffin-embedded (FFPE) samples of both primary and metastatic tumors, measuring expression of 22,000 genes. From the microarray database, we used a genetic algorithm to search for gene combinations optimal for multitumor classification. A 92-gene RT-PCR assay was then designed and used to generate a database for 481 frozen and 119 FFPE tumor samples. RESULTS: The microarray-based K-nearest neighbor classifier demonstrated 84% accuracy in classifying 39 tumor types via cross-validation and 82% accuracy in predicting 112 independent FFPE samples. We successfully translated the microarray database to the RT-PCR platform, which allowed an overall success rate of 87% in classifying 32 different tumor classes in the validation set of 119 FFPE tumor samples. CONCLUSIONS: The RT-PCR-based expression assay involving 92 genes represents a powerful tool for accurately and objectively identifying the site of origin for metastatic tumors, especially in the cases of cancer of unknown primary. The assay uses RT-PCR and routine FFPE samples, making it suitable for rapid clinical adoption.

Algorithms↗
PubMed1990

Metastatic carcinoma in the cervical lymph nodes from an occult primary: a conservative approach to the role of radiotherapy.

This retrospective study examines the results of treatment for cervical lymph node metastases from an unknown primary epithelial cancer of squamous cell or anaplastic histology. The analysis covers a series of 87 consecutive unselected patients at the Middlesex Hospital, London, in the years between 1954 and 1986. Fifty-eight patients received radiation therapy with a view to cure, 25 patients were treated with radiotherapy to a palliative dose, 1 patient only had a radical neck dissection, and 3 patients received no treatment apart from excision biopsy. In contrast to common practice in the United States, only a single patient received prophylactic radiation to the nasopharynx as part of the initial therapy. Overall actuarial survival for all patients (87) at 2 years was 43% and at 5 years 33%, and in the radically treated group (58) it was 52% and 40%, respectively. Only 6 of the 87 patients (7%) subsequently revealed a primary tumor above the clavicles. Overall disease control above the clavicles was achieved in 53% (46/87), but was 64% (37/58) in the radically treated group. Guidelines for radiation therapy are discussed in view of these results.

Adolescent↗
PubMed2006

Disseminated Mycobacterium kansasii infection in an HIV-negative patient presenting with mimicking multiple bone metastases.

We report a patient with disseminated Mycobacterium kansasii infection, but with no underlying disease, presenting with mimicking multiple bone metastases with cancer of unknown primary site. Disseminated M. kansasii infection is rare in HIV-negative patients without underlying diseases. This patient had disseminated M. kansasii infection manifested with vertebral osteomyelitis, sacroiliitis, psoas abscess, bone marrow granuloma, liver granuloma, and possible spleen abscesses. The clinical manifestations are described and discussed in details.

Adult↗
PubMed2004

Outcomes of liver transplantation for hepatitis B: a single-center study of 35 patients.

BACKGROUND: Results of liver transplantation (LT) for hepatitis B (HBV) have improved in the past decade but recently drug resistance has been described, the clinical significance of which is unclear. The aims of this study were to evaluate outcomes of LT for HBV and describe the prevalence of drug resistance. METHODS: A retrospective chart analysis and review of the organ transplant database was performed to identify all patients transplanted for HBV between December 1982 and April 2004 who survived more than 3 months. RESULTS: Thirty-five patients were transplanted for HBV during this period: 27 men and 8 women. Median age at LT was 48.8 years (range 18.9 to 74.3). Four patients were transplanted for fulminant liver failure and 31 for decompensated cirrhosis. Intramuscular HBIG was administered to 8 patients and intravenous HBIG to 32 patients, data were unavailable for three patients. Lamivudine was prescribed for 18 patients (58%) pre-OLT and for 31 patients (88.6%) post-LT. Drug-resistant HBV developed in two patients (5.71%) receiving lamivudine and HBIG. Adefovir substitution resulted in improvement in liver function tests, in HBV DNA and in histology in both patients. Twenty-five patients are currently alive with and 1-year survival of 95% and a 5-year survival of 75%. Causes of death were respiratory failure (n = 3), metastatic cancer of unknown primary (n = 2), renal failure (n = 2), sepsis (n = 1), cerebrovascular accident (n = 1), and cerebral edema (n = 1). CONCLUSIONS: LT for HBV shows survival rates comparable to other liver transplant recipients. Lamivudine resistance was rare in this series but responded to adefovir substitution.

Adult↗
PubMed1999

Antiemetic prophylaxis with ondansetron and methylprednisolone vs metoclopramide and methylprednisolone in mild and moderately emetogenic chemotherapy.

The purpose of the present study was to examine whether its is possible to successfully replace ondansetron (OND) with metoclopramide (MCP) in patients exposed to moderately emetogenic chemotherapy who did not experience severe nausea and vomiting while undergoing OND treatment during their first chemotherapy cycle. After switching to MCP, patients continued with this drug for three cycles, provided that they had adequate control of nausea and vomiting. Otherwise, they were switched back to OND. There were 76 patients, 60 women and 16 men, whose median age was 56 (mean 58) years. Karnofsky performance status score was 100 in 18 patients, 90 in 23, and 80 in 11 patients. No patient had previous chemotherapy. Thirty-four patients had breast cancer and received fluorouracil 500 mg/m2, epirubicin 100 500 mg/m2, and cyclophosphamide 500 mg/m2. Twelve patients had small cell lung cancer and received carboplatin 400 mg/m2 + etoposide 120 mg/m2 x 3 days. Twenty patients with ovarian cancer received carboplatin 350 mg/m2 and cyclophosphamide 500 mg/m2. Ten patients had cancer of unknown primary and received carboplatin 400 mg/m2, epirubicin 60 mg/m2, and etoposide 120 mg/m2 x 3 days. The OND schedule consisted of methylprednisolone 40 mg intravenous bolus followed by OND 8 mg in a 15-min infusion before chemotherapy, followed by OND 4 mg orally x 3 on the same and the next 2 days. Patients who did not experience nausea and vomiting with OND continued with an MCP schedule consisting of methylprednisolone 40 mg bolus followed by MCP 2 mg/kg in a 15-min infusion before chemotherapy, followed by MCP (20 mg x 4 on the day of therapy and the next 2 days after). Patients who failed with MCP or OND continued with OND. Considering our results as a whole, the intensity of nausea does not appear to influence the results of Gralla's scale. The results of Gralla's scale do not appear to be affected by the analysis of the antiemetic results and nausea on the next 2 days following chemotherapy administration. Overall, patients received 145 cycles with OND and 159 cycles with MCP. Of the 76 patients receiving OND-based antiemetic regimen during the first cycle, 13 (21%) experienced severe vomiting (Grade 2, 3) and the remaining 63 (79%) had mild or no vomiting (Grade 0, 1). Patients with Grade 0, 1 vomiting (63, 83%) continued with MCP in the second cycle. The final number of patients who failed on MCP, after 4 cycles of chemotherapy increased to 33 (43%); 43 (57%) were able to complete chemotherapy with MCP. Headache occurred in 15 (10%) cycles with OND and 8 (5%) with MCP. Flushing was noted in 12 (8%), and constipation occurred in 43 (30%) of OND cycles, and extrapyramidal manifestations occurred in 3 (5%) of patients receiving MCP. Diarrhea was noted in 3 (2%) of cycles with OND and in 28 (18%) with MCP. The cost ratio between MCP and OND was 1:14. If we administered OND only in patients who needed it, the overall cost decreased to 44%. Following the strategy applied in the present study, the cost decreased to 47%.

Antiemetics↗
PubMed1997

Immunohistochemical differentiation of metastases of renal carcinomas versus other carcinomas with anti-gamma GT monoclonal antibody 138H11.

AIMS: Adenocarcinomas account for about 60% of metastatic cancers of unknown primary (CUP) site. In such a clinical CUP situation, histopathologists are challenged to differentiate renal cell carcinomas (RCC) from other adenocarcinomas with similar immunophenotypes, especially chemotherapeutically treatable mammary and ovarian carcinomas. METHODS AND RESULTS: Recently, we produced a monoclonal antibody (mAb), designated 138H11, against human gamma-glutamyl-transferase (gamma GT), which stained over 98% primary clear cell and chromophilic RCC on frozen sections. The 138H11 epitope could not be stained using conventional techniques in most paraffin-embedded sections of the same origin, due to destruction by formalin fixation below the detection level. Here, we demonstrate that mAb 138H11 can specifically stain gamma GT in paraffin-embedded primary and metastatic RCC after enhancement with an ultrasensitive immunohistochemical method. We analysed a selected subgroup of adenocarcinomas with immunophenotypes which would not allow a differentiation from RCC in a CUP situation. We found a predominantly membranous expression of the 138H11 target antigen in 26/51 primary RCC and 15/ 34 metastatic RCC. In contrast, all 43/43 primary ovarian and bronchial carcinomas as well as 54/54 metastases of ovarian, mammary, bronchial and gastric carcinomas were negative for mAb 138H11. CONCLUSIONS: The data suggest that mAb 138H11 is useful for the immunohistochemical differentiation of RCC from other metastatic adenocarcinomas if the primary site of the tumour is not known.

Antibodies, Monoclonal↗
PubMed2000

Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.

A phase I study was designed to evaluate the toxicity of escalating doses of gemcitabine along with fixed-dose paclitaxel in patients heavily pretreated with chemotherapy or radiotherapy. All patients had no prior therapy with the study drugs and possessed both adequate performance and end organ function. Eighteen patients were entered in the study. Characteristics included a median age of 66 years (range, 41 to 77) and stage IV disease in all patients; there were six patients with colon cancer, two with bladder cancer, three with non-small-cell lung cancer, two with esophageal cancer, three with pancreatic cancer, and two with cancer of unknown primary. Paclitaxel (150 mg/m2 over 3 hours) was given on day 1 and gemcitabine (800, 900, and 1,000 mg/m2 over 15 minutes) was given in three separate dose-escalating cohorts (1-3) on days 1 and 8. The treatment cycled every 21 days. The dose-limiting toxicity (DLT) proved to be neutropenia. All nonhematologic toxicities were mild and included gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash), and neurologic (paresthesias) disturbances along with transient elevations of liver function tests. The combination of gemcitabine and paclitaxel seems to be well tolerated, and the recommended starting dose for a phase II study, in pretreated patients using a day 1/day 8 treatment schedule, should be 900 mg/m2 for gemcitabine (days 1 and 8) along with 150 mg/m2 for paclitaxel (day 1).

Adult↗
PubMed2005

An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin.

Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR-based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.

Gene Expression Profiling↗
PubMed2005

Phase I trial of intravenous cisplatin-topotecan chemotherapy for three consecutive days in patients with advanced solid tumors: parallel topotecan escalation in two fixed platinum dosing schemes.

PURPOSE: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. EXPERIMENTAL DESIGN: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. RESULTS: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. CONCLUSIONS: The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Adolescent↗
PubMed1983

Effects of cloned human leukocyte interferons in the human tumor stem cell assay.

Clonogenic tumor cells from fresh biopsies of human cancers were cultivated in vitro and tested for sensitivity by continuous exposure to pharmacologically achievable concentrations of either of two highly purified human leukocyte interferon subtypes (IFN-alpha A and IFN-alpha D) prepared by recombinant DNA methods. The interferons were compared on a weight basis at concentrations of 0.4 and 4.0 ng/ml (equivalent to 80 and 800 units of interferon activity for IFN-alpha A and 2.0 and 20 units for IFN-alpha D). Inhibition of tumor colony-forming units (50% of control or less) was observed in 38.1% of the 273 tumors tested against IFN-alpha A, and in 16% of the 71 tumors tested against IFN-alpha D. Of the tumor types with at least ten samples tested against IFN-alpha A, the percentage of cases exhibiting inhibition was as follows: melanoma (51.7%), lung cancer (50%), myeloma (33.4%), ovarian cancer (33.9%), sarcoma (33.3%), adenocarcinoma of unknown primary (30.4%), breast cancer (28%), acute leukemia (30.8%), and renal cancer (23%). More marked inhibition (30% of control or less) was observed in 18.7% of all tumors tested against IFN-alpha A. Of 60 melanomas tested, 18 (30%) exhibited marked in vitro inhibition of growth with IFN-alpha A. Although a smaller number of tumors (71) were tested against IFN-alpha D on a weight basis, it appeared, in general, to be slightly less active than IFN-alpha A (p less than 0.01), and only 8% of tumors tested exhibited marked inhibition over the same dosage range of interferon. Comparison of the dose-response curves for the 68 tumors tested simultaneously against both interferons did not reveal marked interpatient differences in the inhibition curves, although IFN-alpha D was slightly less active overall. Tumors exhibiting at least 50% inhibition of tumor colony formation also proved to be sensitive to a significantly larger number of cytotoxic drugs (tested simultaneously) than the tumors not inhibited with interferon (p less than 0.0001 for IFN-alpha A). We conclude that the in vitro clonogenic assay may aid in targeting tumor types most likely to exhibit interferon sensitivity and assist in case selection for entry into clinical trials with cloned interferons.

Antineoplastic Agents↗
PubMed1991

Limited sampling models for doxorubicin pharmacokinetics.

Although doxorubicin is one of the most commonly used antineoplastics, no studies to date have clearly related the area under the concentration-time curve (AUC) to toxicity or response. The limited sampling model has recently been shown to be a feasible method for estimating the AUC to facilitate pharmacodynamic studies. Data from two previous studies of doxorubicin pharmacokinetics were used, including 26 patients with sarcoma and five patients with breast cancer or unknown primary. The former were divided into a training data set of 15 patients and a test datum set of 11 patients, and the latter patients formed a second test data set. The model was developed by stepwise multiple regression on the training data set: AUC (nanogram hour per milliliter) = 17.39 C2 + 163 C48-111.0 [dose/(50 mg/m2)], where C2 and C48 are the concentrations at 2 and 48 hours after bolus dose. The model was subsequently validated on both test data sets: first test data set--mean predictive error (MPE), 4.7%; root mean square error (RMSE), 12.4%; second test data set--MPE, 4.5%, RMSE, 9.2%. An additional model was also generated using a simulated time point to estimate the total AUC for a daily x 3-day schedule: AUC (nanogram hour per milliliter) = 44.79 C2 + 175.65 C48 + 47.25 [dose/(25 mg/m2/d)], where the C48 is obtained just prior to the third dose. We conclude that the AUC of doxorubicin after bolus administration can be adequately estimated from two timed plasma concentrations.

Doxorubicin↗
PubMed1997

Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach.

The objective of our study was to delineate clinical features and specific diagnostic and therapeutic implications of spinal epidural metastasis (SEM) occurring as the initial manifestation of malignancy (IMM)-a less common event than SEM in the setting of previously established malignancy (PEM). We performed a retrospective review of the clinical histories of 337 patients seen at Mayo Clinic with a radiographically verified diagnosis of SEM between January 1, 1985, and December 31, 1993. Twenty percent of all cases of SEM occurred as SEM-IMM. Carcinoma of the lung, cancer of unknown primary site, multiple myeloma, and non-Hodgkin's lymphoma were disproportionately represented in SEM-IMM, together accounting for 78% of SEM-IMM patients and only 26% of SEM-PEM patients. Inversely, breast and prostate carcinoma contributed only 12% of SEM-IMM patients but 51% of SEM-PEM patients. Only 27% of patients with SEM-IMM had nonspecific symptoms suggesting malignancy, and in only 24% did the history or physical examination suggest the primary site of malignancy. Percutaneous needle biopsy of the vertebral lesion was diagnostic of malignancy in 18 of 19 patients (95%), and no complications ensued. Fifteen patients underwent diagnostic laminectomy with biopsy, and one had a fatal complication. Survival after the diagnosis of SEM did not differ between patients with SEM-IMM and those with SEM-PEM; the median survival was 6.6 months. SEM not uncommonly occurs as the presentation of malignancy, and often it produces the only symptoms or signs of malignancy. The great majority of neoplasms presenting with SEM are carcinomas of the lung, unknown primary lesions, and hematologic malignancies. Computed tomography-guided needle biopsy is a safe, efficacious means of diagnosing malignancy, allowing for rational diagnostic workup and staging. In most patients it obviates a diagnostic spinal surgical procedure.

Adolescent↗
PubMed2005

[Therapy of brain metastasis based on the RPA classification].

RPA classification of patients suffering from brain metastases is not widely used in Hungary. The authors reviewed the RPA disposition-based therapeutic recommendations in the literature. Retrospective analysis of their 123 brain metastatic cases showed 3.8 months median, 34.1% 1-year and 7.9% 2-year overall survival. Patient number and median survival in subgroups: RPA 1: 42/14 months, RPA 2: 38/6,2 months, RPA 3a: 6/3.1 months, 3b: 13/2 months, 3c: 10/0.7 months. Median survival of patients with brain metastases from cancer of unknown primary (CUP) was 3 months. In RPA class 1 and 2, 10% undertreatment has been found for solid brain metastases, and all of the 3c patients were over-treated according to literature recommendations. The authors strongly recommend the use of RPA classification in the management of brain metastases and in contemplation of the capacity of radiotherapy/neurosurgery and oncology.

Adult↗
PubMed2000

[Meningeal carcinomatosis as first manifestation of carcinoma of the bladder: report of 2 cases].

Meningeal carcinomatosis may occur in 0.8-8% of patients with solid tumors. The most common tumors associated with that condition are breast and small cell lung cancer. Meningeal carcinomatosis from urothelial cancer is rare, and it appears described in advanced stages of disease, generally, after chemotherapy. Two cases of meningeal carcinomatosis as the first manifestation of bladder cancer were reported. In the first case, a 46-year-old man presented signs and symptoms indicative of involvement of the spinal roots, subsequently neurologic dysfunction of the brain and cranial nerves appeared. In the second case, a 68-year-old man was admitted to our hospital with a history compatible with panhypopituitarism and pulmonary lymphangitic carcinomatosis from cancer of unknown primary site. Follow-up revealed a transitional cell carcinoma of the bladder and hydrocephalus due to cerebrospinal fluid outflow obstruction. We emphasize in the polymorphic presentation of meningeal carcinomatosis and the necessity to consider the bladder as primary tumor localization.

Aged↗
PubMedDate not supplied

[Breast metastases of an ovarian adenocarcinoma].

INTRODUCTION: Breast metastases are rare. Primary tumors are cutaneous, pulmonary, digestive and prostatic. A malignant tumor of the ovary is rarely responsible. OBSERVATION: A 69-year-old women presented a voluminous unilateral mastitis in a poly-metastatic context 3 years after the discovery of an ovarian adenocarcinoma. The anatomo-pathological examination confirmed the ovarian origin of the breast nodules observed. Progression was poor and the patient died 8 months after the first clinical signs in the breast. COMMENTS: The difficulty in differentiating a primary from a secondary carcinomatous mastitis is enhanced when the primary cancer is unknown. In our patient, the immunohistochemical study did not discriminate between the breast and ovarian origin. The diagnosis was finally made on the basis of standard histology and the anatomoclinical correlation. Since immunohistochemical examinations may not be specific enough, such as was the case in our patient, the anatomoclinical confrontation is essential.

Aged↗
PubMed1992

[Diagnostic and therapeutic management in malignant neck tumors of unknown origin. Our experience in the last 5 years].

The AA. analyzed 37 cases of metastatic neck cancer from unknown primary sites treated at the Oncologic Unit from 1986 to October 1991. This group account for 7 percent of total cervicofacial tumors seen. Factors that affected survival include the symptoms of consult, the control of cervical disease after treatment and surgery. The survival was 50 percent at two years and the rate of neck disease control amounted to 57.7 percent.

Adenocarcinoma↗
PubMedDate not supplied

Positron emission tomography imaging in evaluation of cancer patients.

Positron emission tomography (PET) is a diagnostic imaging technique that has progressed rapidly from being a research technique in laboratories to a routine clinical imaging modality. The most widely used radiotracer in PET is Fluorine18-fluorodeoxyglucose (F18-FDG), which is an analogue of glucose. The FDG uptake in cells is directly proportional to glucose metabolism of cells. Since glucose metabolism is increased many fold in malignant tumors PET has a high sensitivity and a high negative predictive value. PET with FDG is now the standard of care in initial staging, monitoring the response to the therapy, and management of lung cancer, colonic cancer, lymphoma, melanoma, esophageal cancer, head and neck cancer and breast cancer. Other indications of PET like bone tumor, ovarian cancer and cancer of unknown primary (CUP) has also been discussed in brief. The aim of this review article is to review the clinical applications of PET in various malignancies and only limited number of important studies will be discussed for this effort.

Fluorodeoxyglucose F18↗
PubMed1995

Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer.

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.

Adenocarcinoma↗