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Background: The purpose was to identify the factors predictive of recurrence and survival in patients with high-risk (stage I, grade 3; stage IC, stage II, or clear cell) epithelial ovarian cancer after adjuvant therapy., Methods: Data was extracted from patients who underwent primary surgery followed by adjuvant therapy in 2 randomized trials by the Gynecologic Oncology Group (Protocols 95 and 157). Kaplan-Meier survival estimates and Cox proportional hazards model adjusted for covariates were used for analyses., Results: Of 506 patients (median age = 56.2 years), 347 (68.6%) had stage I and 159 (31.4%) had stage II cancers. The 5-year recurrence-free (RFS) and overall survivals (OS) were 75.5% and 81.7%, respectively. On multivariate analysis, older age, higher stage, higher grade, and malignant cytology were independent prognostic factors predictive for recurrence and poorer survival. The risk of recurrence was higher for those >/=60 versus < 60 years (hazards ratio [HR] = 1.57, 95% confidence interval [CI], 1.12-2.19), stage II (stage II: HR = 2.70, 95% CI, 1.41-5.16) versus stage IA or IB, grade 2 (HR = 1.84, 95% CI, 1.04-3.27) and grade 3 (HR = 2.47, 95% CI, 1.39-4.37) versus grade 1, and positive versus negative cytology (HR = 1.72, 95% CI, 1.21-2.45). By using these factors in a prognostic index, those with low-risk (no or 1 risk factor), intermediate-risk (2 factors), and high-risk (3-4 risk factors) disease had survivals of 88%, 82%, and 75%, respectively (P < .05)., Conclusions: Age, stage, grade, and cytology are important prognostic factors in high-risk early-stage epithelial ovarian cancer. This information may be used in the design of future clinical trials., ((c) 2008 American Cancer Society.)

Chemotherapy for advanced ovarian cancer remains suboptimal. Despite the improvements in objective response rates realized with cisplatin-based combination chemotherapeutic regimens, most patients still die of refractory cancer. Drug resistance has emerged as the single most important determinant of treatment outcome. Laboratory studies have provided substantial insights into the cellular mechanisms of resistance to the commonly used chemotherapeutic agents. Decreased drug accumulation, metabolic drug inactivation, and repair or tolerance to drug-induced cellular injury all contribute to resistance at the cellular level. Identification of these mechanisms has facilitated the development of specific treatment strategies, many of which are in or nearing clinical trials. These strategies include dose intensification, inhibition of P-glycoprotein function, inhibition of cellular glutathione synthesis, and inhibition of cellular DNA repair. The initial results from clinical trials that use these strategies provide reasonable grounds for optimism. In addition, efforts to identify new drugs with activity against resistant cells continue. One such drug, taxol, has significant activity in tumors refractory to conventional therapy. These approaches offer hope that intensive laboratory and clinical efforts ultimately will translate into real improvements in the efficacy of chemotherapy for ovarian cancer.

Background: The appropriate therapy for patients with localized (FIGO Stage I and II) ovarian cancer has been poorly defined for all age groups and particularly for the elderly. Few prospective randomized comparisons of adjuvant therapy after careful surgical staging have been performed. The Gynecologic Oncology Group (GOG) has performed a series of trials testing adjuvant treatment in carefully staged patients with early-stage ovarian cancer. Early trials included few elderly patients but the most recent trial (GOG 95) included 18% over the age of 65 years., Methods: Comprehensive surgical staging defined by protocol is performed before randomization. Patients with predefined stages and histologies are included and the patients are randomized prospectively to receive either intraperitoneal phosphorus-32 or three monthly cycles of cyclophosphamide and cisplatin. Assessment of the value of this adjuvant therapy will depend on survival, disease-free survival, and relapse pattern differences between the two adjuvant therapies., Results: This is an ongoing clinical trial and insufficient numbers of patients have been randomized for definitive conclusions. There have been seven recurrences on both arms of the trial with a median time to recurrence of 14 months. There currently are no significant age differences between relapsed patients and disease-free patients. At this point, 12 elderly patients have been randomized to each of the arms of therapy., Conclusions: Although no apparent survival differences exist for elderly patients in the most recent adjuvant chemotherapy trial of early ovarian cancer, the number of patients with cancer randomized and follow-up are insufficient to establish such a difference. Currently there is no evidence that elderly patients display a significant difference in relapse frequency or pattern.

Although many effective anti-cancer agents are now available, their curative potential is compromised by a variety of problems related to tumor sensitivity, drug access, and pharmacokinetics. Central to the problem of inadequate chemotherapy is drug resistance. Drug resistance may be intrinsic, acquired, or induced, and it may develop to one drug or it may occur simultaneously to multiple agents (pleiotropic). Substantial progress has been made in our understanding of the mechanisms of drug resistance and techniques for overcoming that resistance. New evidence has emerged that highlights the importance of dose intensity in achieving successful drug treatment outcomes. Retrospective analysis of studies in breast, ovarian, colon cancer, and lymphoma suggest that new studies designed to optimize dose intensity may yield improved results. Several prospective trials have now corroborated the retrospectively derived importance of dose intensity as an independent factor in achieving improved survival. Finally, new techniques for drug delivery offer considerable promise. Chemotherapy by regional infusion and perfusion, implantable drug delivery systems, and continuous infusion of chemotherapy are unique novel techniques that may improve the efficacy of presently available chemotherapeutic agents even as new agents are developed.

Thirty-nine patients with Stage III nonseminomatous testicular cancer were treated in a prospective randomized trial comparing cytoreductive surgery followed by a cis-platinum containing combination chemotherapy regimen versus chemotherapy alone. All patients had one or more of the following poor prognostic signs: palpable retroperitoneal disease, liver involvement, invasion or obstruction of the inferior vena cava, or lung metastases larger than 2 cm in diameter. Cytoreductive surgery was technically feasible in this group of patients as assessed radiographically (70-90% reduction in tumor mass) and by the decline in serum levels of alpha-fetoprotein and human chorionic gonadotropin in 75% of the patients following surgery. However, there was no statistically significant improvement in overall response rate (75% versus 84%), complete response rate (50 versus 37%) or in survival between the patients treated with surgery prior to chemotherapy or with chemotherapy as the initial treatment. It is unlikely (P less than 0.028) that any true beneficial effect of surgery was missed due to the relatively small number of patients in each treatment arm. The authors of this study conclude that cytoreductive surgery prior to chemotherapy in patients with poor prognosis Stage III testicular carcinoma is not routinely indicated. Since the overall complete response rate to chemotherapy in these 39 patients with bulky Stage III disease was only 43%, alternate approaches, other than cytoreductive surgery, are necessary to improve the prognosis for this group of patients.

Four of 13 patients receiving intermittent high-dose methotrexate therapy experienced recurrent symptoms of ocular irritation (burning, pruritus, "dry eyes") two to seven days after chemotherapy. Ophthalmic examination was unremarkable in symptomatic individuals except for decreased reflex production of tears in some patients. Pharmacokinetic studies of a group of these patients revealed concentrations of methotrexate in tears equivalent to those in plasma at 24 and 48 hours after treatment; these concentrations reached 1 X 10(-5) M during the infusion of methotrexate. The occurrence of acidic lacrimal secretions, pH 6.5 in one symptomatic patient, may have contributed to decreased solubility of methotrexate in the fluid of the conjunctival sac.

A retrospective study of 66 cases of undifferentiated non-Hodgkin's lymphomas at the National Cancer Institute over a 22-year period suggests that the histologic distinction between Burkitt's and non-Burkitt's types is clinicopathologically meaningful. Thirty-nine patients with Burkitt's lymphoma had a median age at presentation of ten years. The primary site of disease in these patients was more commonly extranodal; at the time of diagnosis 26 (66%) of these cases revealed intra-abdominal involvement; 25 (64%) of the cases were Stage IV. The 27 patients with non-Burkitt's lymphomas had a median age at presentation of 34 years; the primary site of disease was more commonly nodal (peripheral adenopathy was often present at the time of diagnosis); only nine (33%) of the cases were Stage IV. Median survival was essentially equivalent in the two groups, 9.5 months for Burkitt's lymphoma and 10.0 months for the non-Burkitt's lymphoma. Overall, survival was not significantly different among the two patient populations; however, patients with Burkitt's lymphoma had a longer survival than those with non-Burkitt's lymphoma. Estimates of five-year survival (with 95% confidence) are 42% for Burkitt's lymphoma and 11% for non-Burkitt's lymphoma, respectively, which are significantly different (P = 0.01).

The pathology and medical records of 515 patients with malignant lymphomas treated at the National Cancer Institute have been reviewed to determine the frequency and natural history of patients who have different histologic diagnoses in various tissue sites at their initial staging evaluation. Of the 101 patients who had multiple tissue sites biopsied, 33 patients had different histologic diagnoses. Eighteen patients had a nodular pattern in one site and a diffuse pattern in another. The final stage and treatment of these 18 patients were similar to that of the 27 patients with multiple identical nodular biopsies and 41 patients with multiple identical diffuse biopsies. However, the 56% complete response rate for patients with both a nodular pattern and a diffuse pattern was intermediate between that achieved in patients with identical nodular biopsies (70%) and identical diffuse biopsies (30%). Median survival for these three groups was as follows: identical nodular biopsies, 53 months; both a nodular and a diffuse pattern, 37 months; and identical diffuse biopsies, 12 months. These results demonstrate that patients with different histologic diagnoses in various sites at staging evaluation are not uncommon and have a unique natural history that should be considered in planning treatment.

Approximately 33% of women with invasive ovarian tumors present with what appears to be early epithelial ovarian cancer (FIGO Stages I and II) accounting for approximately 6000 new ovarian cancer cases each year in the United States. A better understanding of the natural history and patterns of spread of this disease has led to an increased awareness of the importance of thorough operative staging, cytoreductive surgery, and accurate determination of the extent of residual disease. These staging studies have documented frequent understaging of such patients. Results from such surgical staging studies indicate that only about 25% of women operated on in the United States have an initial surgical incision adequate to allow evaluation of the entire pelvis and abdominal cavity. As a result about 33% of patients thought to be free of disease at initial surgery have residual disease and in 75% the disease has spread intraabdominally. These studies have important implications for the design of future adjuvant trials. Fortunately, these accurate staging studies have defined groups of patients who require adjuvant treatment as well as those who do not. It is now apparent that certain groups of patients with Stage II and high-risk Stage I disease are at risk for failure throughout the abdominal cavity. Any form of adjuvant therapy, if it is to succeed, must obviously encompass this entire area. With this in mind, several prospective clinical trials have tested a variety of adjuvant approaches. Present evidence would suggest that systemic chemotherapy, intraperitoneal radioisotopes (32P) or whole abdominal irradiation have the potential to eradicate micrometastases throughout the area at risk. The need for adjuvant therapy is dependent upon the accuracy of initial surgical staging. If initial surgical evaluation was incomplete, the five year survival rates for Stage I (70%) and Stage II (40% to 50%) disease are poor enough that most investigators would advocate some sort of adjuvant therapy. However, comprehensive and accurate surgical staging will define subsets of ovarian cancer patients with such good prognoses (five year survival of 90% to 95%) that no adjuvant treatment is required. With the known risk of late second malignancies in ovarian cancer patients treated with long-term adjuvant chemotherapy, the identification of patients who do not require further treatment represents an advance. Accurate surgical staging coupled with proper adjuvant therapy designed to treat areas of high risk have improved the survival rate of patients with early ovarian cancer.

Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. Care must be exercised in associating previous therapy and a subsequent malignancy. "Naturally" occurring second cancers must be separated from those which are iatrogenic. Associations in the literature have been made involving malignancies as a sequelae of prior gynecologic therapy. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. Irradiation therapy, however, has not yet been shown to be related to leukemia in cervical cancer patients. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified.

Twenty-one patients with advanced ovarian cancer proven resistant to standard alkylating chemotherapy were evaluated in a prospective study of Hexamethylmelamine. All but three patients received 8 mg/kg daily with dose modifications appropriate to the degree of toxicity; the latter three patients were treated on an intermittent 14 day course of 8 mg/kg daily. Six patients (28%) experienced an objective response with a median duration of 2.5 months (range 1--5 months). The toxic effects requiring dose modification were gastrointestinal in 57%, hematologic in 62%, and neurologic in 28.5%. An average of 60.5% of the total projected dose was tolerated for a median of 44 days (range 7--113). Twelve patients (57%) experienced severe toxicity requiring discontinuation of therapy. It is apparent from this study that Hexamethylmelamine is an active agent in ovarian cancer and is not invariably cross-resistant to conventional alkylating agent therapy. These two characteristics make it an attractive agent for use in combination. Its toxicity in previously treated patients in the schedules used here, however, is substantial.

In order to determine the prognostic and therapeutic importance of histologic grade for patients with advanced ovarian cancer, the pathologic specimens from 82 patients with Stage III-IV disease (as defined by the International Federation of Gynecologists and Obstetricians (F.I.G.O.)) were reviewed and graded by two methods. A system based on cytologic detail using both the degree of anaplasia and the number of undifferentiated cells, (modified Broders' Grades 1--4) was found to be particularly useful because it identified four groups with different survival outcomes as well as an apparent differential response to chemotherapy. Specifically, the overall improvement of survival in patients with Stage III-IV disease observed in a prospective study of combination chemotherapy was related primarily to an increased survival of patients with Grade 2 and 3 lesions. Survival in Grade 1 patients was markedly better than for Grade 4 patients, but in neither case did survival appear to be influenced by the choice of chemotherapy. These observations suggest that prospective clinical trials assessing the efficacy of chemotherapy should employ cytologic grades as a separate stratification factor since chemotherapy for advanced disease may have to be tailored, in part, to the histologic grade.

The age adjusted death rate for ovarian cancer has remained unchanged for the past 20 years. Recent data obtained by staging ovarian cancer patients with lymphangiography and peritoneoscopy demonstrated that many patients with apparently localized disease actually have occult dissemination within the abdomen. These new staging techniques plus the determination of the histologic grade of anaplasia may permit a more precise determination of a patient's prognosis and therefore better design of therapeutic stategy. Radiotherapeutic techniques are being adapted to attempt to treat some areas of occult disease. Numerous single chemotherapeutic agents are capable of producing objective tumor responses. Preliminary data suggest that combination chemotherapy can increase the objective response rate above that seen with single agents. Longer follow-up is necessary to determine whether combination chemotherapy can prolong survival.

A retrospective review was performed of 473 consecutive patients with malignant lymphoma referred to the National Cancer Institute. All patients had their clinical and pathologic material reviewed and where necessary reclassified. Using a modification of the Rappaport system, 180 (38.1%) patients had a nodular lymphoma, 293 (61.9%) had a diffuse lymphoma. Nodular lymphoma patients usually presented with lymphadenopathy; diffuse lymphoma patients often presented with extranodal disease, particularly those patients with poorly differentiated lymphocytic, "histiocytic", and Burkitt's lymphoma. Median age for all patients was 46 years, but was lower for diffuse poorly differentiated lymphocytic, diffuse undifferentiated, and Burkitt's lymphoma patients. Women were more likely to have a nodular rather than diffuse lymphoma. P less than 0.05. Analyzed by clinical staging, most nodular lymphoma patients had CS III (66.1%) disease, while most diffuse lymphoma patients had either CS III (31.1%) or CS IV (38.9%) disease. Analyzed by pathologic staging, most nodular lymphoma patients had PS III (34.8%) or PS IV (49.4%) disease, most diffuse lymphoma patients had PS IV (56.3%) disease. Only 7% of all lymphoma patients had PS I disease, only 14.9% were PS II. Systemic symptoms were more likely to be found in diffuse lymphoma and/or advanced stage patients.

Gynecologic cancers present unusual opportunities to explore the fruits of well-designed clinical trials to assess the value of existing treatment using a combined modality approach soon after diagnosis. Cancers of the ovary and uterus have well-defined, familiar natural histories. Pathways of spread are clear and reasons for treatment failure are often blatantly obvious. In the case of ovarian cancer, regional treatment with surgery and radiotherapy has been relatively ineffective and generally has not improved the survival statistics in the last two decades. Spread of tumor cells widely throughout the abdominal cavity outside radiation or surgical fields, even in patients with apparently early disease, is the obvious reason. Studies are underway to assess the impact of long-term postoperative adjuvant chemotherapy with L-phenylalanine mustard, an alkylating agent effective in patients with advanced disease, in early stages of ovarian cancer following surgery and or x-irradiation. The search is on for more effective drugs, or combinations of drugs, that could subsequently serve as more effective adjuvant treatments. In carcinoma of the uterine cervix, chemotherapy as an adjunct to surgery and/or radiotherapy in patients with localized, or locally inoperable disease has been poorly evaluated; little data are available and the value of many established drugs in patients with metastatic cervical cancer is undermined. Some recent evidence suggests the use of hydroxyurea, a drug that by itself is not effective in controlling tumor, may enhance the effect of radiotherapy in patients with Stage II disease. Uterine fundal cancer is often successfully treated by surgery alone. The data for the use of pre- or postoperative radiotherapy are open to considerable question. While the relative nontoxic progesterone compounds are effective in a small but significant fraction of patients with advanced uterine cancer, no properly designed clinical trial has truly evaluated their role as postoperative adjuncts in patients who have resectable tumor but a definite high risk of recurrence. Systemic chemotherapy has been rarely used with any consistency against this tumor but, even so, some chemotherapeutic leads, such as the use of adriamycin, are worthy of exploration. The absence of useful information on systemic treatment of gynecologic malignancies can be traced to the excessive rigid compartmentalization of medical practice. Only recently have investigators of all persuasions begun to explore and exploit some of the therapeutic opportunities, which have been available for some time.

In a period of a little over 20 years, chemotherapy of cancer has evolved from a period of empiricism with little impact on the cancer problem to become part of a sound medical discipline with firm scientific underpinning playing an increasingly important role in the control of cancer. This progress has come from an increasing knowledge of cancer biology and pharmacology and the application of this knowledge to improved design of clinical trials, with due consideration to the intricacies of the natural history of each disease in question. Now that the chemotherapeutic tools are sharpened, their use in combinations with other modalities in the previously unfamiliar setting of the patient with early stages of the disease promises to lead to an even more exciting chapter in clinical cancer research in the next decade.

One hundred sixty-one patients with advanced Hodgkin's disease achieved complete remission after combination chemotherapy. Of these, 52 (32%) have subsequently relapsed and the patterns of relapse have been studied. The probability of relapse increases with increasing stage and particularly with the presence of systemic symptoms. Patients with Nodular Sclerosis histology are more likely to relapse than those with other histologies. Patients relapse primarily (92%) in sites of previous disease and particularly in nodal sites (75%). Nodal sites most frequently involved at relapse are the central nodal areas and the left supraclavicular area. When patients relapse in new sites they tend to be either adjacent to sites of previous disease which relapse or to be contiguous with previously involved sites of disease. In the small number of patients who received prophylactic radiation therapy to sites of nodal disease after complete remission, the pattern of relapse was not significantly altered.

Thirty-nine untreated patients with either lymphocytic or nodular mixed/nodular histiocytic non-Hodgkin's lymphoma, stage II--IV, were randomized to treatment with total body irradiation (TBI), 100 rads in 10 fractions over 12 days, plus combination chemotherapy with either cyclophosphamide, vincristine and prednisone (CVP) or cyclophosphamide, vincristine, procarbazine and prednisone (C-MOPP) or to treatment with combination chemotherapy (CVP or C-MOPP) alone. Remission rate and duration was comparable for both treatment groups; thus the use of both treatment modalities ab initio provides no therapeutic advantage.

The results of staging and treatment of 18 patients with diffuse histiocytic lymphoma involving the gastrointestinal tract are summarized. Widespread disease (Stage IV) was found in the majority (72%) of patients after rigorous staging, indicating the relative rarity of localized gastrointestinal lymphoma and the resulting need for systemic therapy in most of these patients. Chemotherapy combined with surgical resection and/or radiation therapy produced complete remissions in only 5 of 18 patients (28%). Patients failed to achieve complete remission due to 1) tumor resistance to drug therapy (46% of treatment failures), and 2) massive intestinal hemorrhage or bowel perforation secondary to tumor necrosis (38% of treatment failures). These findings indicate the need for more active chemotherapeutic regimens and for measures aimed at preventing complications such as bowel perforation or hemorrhage, possibly by combining surgical resection of bowel lesions with systemic chemotherapy.

An analysis of patterns of relapse from complete remission in patients with non-Hodgkin's lymphoma treated with combination chemotherapy has demonstrated differences between histologic subgroups. Patients with diffuse histiocytic lymphoma who achieved a histologically proven complete remission after 6 months of treatment without maintenance have remained disease-free whereas those with nodular poorly differentiated lymphocytic and diffuse well-differentiated lymphocytic lymphomas have demonstrated a pattern of continuous late recurrence. The initial sites of relapse from complete remission in lymphocytic lymphoma were lymph nodes and bone marrow which were involved prior to treatment. Aggressive attempts at remission induction appear warranted in patients with diffuse histiocytic lymphoma because of the potential for extended disease-free survival. Patients with nodular poorly differentiated lymphocytic lymphoma may benefit from the use of maintenance chemotherapy, or radiotherapy to regions of previously known involvement after initiation of remission with chemotherapy.

The results of clinical and surgical staging in a series of 170 patients with non-Hodgkin's lymphoma are reviewed. Advanced disease (Stage IV) was established without laparotomy in 95 patients (56%), primarily through bone marrow biopsy, closed liver biopsy, and peritoneoscopy. Laparotomy revealed a high incidence of liver involvement and involvement of lymph nodes outside of conventional abdominal irradiation portals only in patients with nodular types of pathology and in patients with positive lymphangiograms. The limitations and indications for staging laparotomy are discussed in the context of these findings.

Histologic slides were reviewed from 192 autopsies of patients with non-Hodgkin's lymphomas admitted to the National Cancer Institute (NCI) from 1953 to 1975. Each autopsy was classified according to the systems of Rappaport and Lukes-Collins. Comparisons with the initial diagnosis were made. The initial histologic diagnoses of the autopsied population were similar in distribution to other published series of non-Hodgkin's lymphomas. Of the 56 cases which initially demonstrated nodular patterns of growth, the following distribution was found at autopsy: 25%, no lymphoma; 6%, nodular lymphoma; 32%, diffuse histiocytic (large cell) lymphoma (DHL); 21%, diffuse undifferentiated (non-Burkitt's) lymphoma (DUL); and 16%, the remaining diffuse morphologies. Of the 136 patients with initial diagnosis of diffuse lymphoma, the following distributions were observed at autopsy: 20%, no lymphoma; 0%, nodular lymphoma; 31%, diffuse histiocytic (large cell) lymphoma; 12%, diffuse undifferentiated (non-Burkitt's) lymphoma; 9%, Burkitt's tumor; 14%, diffuse poorly differentiated lymphocytic lymphoma; and 14%, the remaining diffuse morphologic types. One hundred and thirty-four cases which were initially diagnosed as follicular center cell type within the Lukes-Collins classification gave the following distribution at autopsy: 21%, no lymphoma; 25%, small noncleaved type; 17%, large noncleaved type; 23%, non-follicular center cell lymphomas (17% immunoblastic B); and the remaining 13% were distributed among the other follicular center cell types. This autopsy review demonstrates the rarity of nodular (follicular) lymphomas at autopsy, and the predominance of the diffuse histiocytic or "transformed" type. This study provides a comparison of the rate of histologic progression of lymphomas in the same patient population at autopsy with a previously published study of progression during life.

Treatment results were reviewed in 473 consecutively staged and treated patients at the National Cancer Institute over a 22-year period from 1953 to 1975. Responses correlated with histologic pattern and stage of disease. Complete responses to radiotherapy were frequent in CS I (86%) or PS I (91%). CS II (70%) or PS II (69%) nodular lymphoma patients. Similar treatment regimens were less effective in diffuse lymphoma patients, CS I (53%) or PS I (57%) and CS II (50%) or PS II (51%). Using chemotherapy or combined modality approaches, complete responses were obtained in a high proportion of advanced nodular disease patients, CS III (51%) or PS (59%), CS IV (44%), or PS IV (46%). With the introduction of combination chemotherapy and/or modern radiotherapeutic techniques, 52% CS III and 63% PS III, and 47% CS IV and 46% PS IV patients achieved a complete response. Patients with nodular lymphoma tend to have higher complete response rates and longer survivals than their counterparts with diffuse histologic types (P less than 0.05). Patients with nodular lymphocytic lymphoma had a better survival than those with mixed or "histiocytic" histologic types (P less than 0.03). Patients with diffuse well differentiated lymphocytic lymphoma survived significantly longer than patients with other diffuse histologic types (P less than 0.05). Percentage and prominence of nodularity were not of prognostic significance in those patients with combined nodular and diffuse patterns of disease. When compared by histologic type, patient sex did not appear to be an important prognostic factor. The presence of B-symptoms was associated with a poorer survival in patients with nodular disease (P less than 0.05) and in patients with diffuse disease (P less than 0.001). Over the years of this study, survival appears to have improved in each histologic subtype except DPDL.

Histologically proven infection of the heart by Candida organisms occurred in 17 (10%) of 168 cancer patients with candidiasis studied at necropsy. All 17 patients were among the 85 patients with disseminated Candida infection; none of the 83 patients with localized candidiasis had involvement of the heart. Abscesses in the myocardium were present by histologic examination in all 17 patients and in 8 were evident on gross inspection as well. The mural endocardium was also affected in 5 patients from direct extension of a myocardial abscess. The valves were uninvolved. Pericardial infection was detected in 2 patients. The 17 patients with cardiac Candida infection had a higher frequency of positive premortem blood and cerebrospinal fluid cultures and of presence of Candida in the heart's blood than did the 68 patients with disseminated candidiasis but without involvement of the heart. Symptoms or signs of cardiac dysfunction resulting from the cardiac Candida infection were not readily detected in any patient. The clinical and pathologic features of cardiac candidiasis in cancer patients are distinct from those observed in Candida endocarditis.

The development of acquired resistance has limited the effectiveness of chemotherapy in the treatment of ovarian cancer. Experimental model systems were developed to study the mechanisms associated with primary resistance to chemotherapeutic agents and broad cross-resistance (multidrug resistance) which is characteristic of human ovarian cancer. Doxorubicin-resistant cell lines developed in vitro by exposure of a sensitive cell line to increasing concentrations of doxorubicin develop resistance on the basis of a decrease in drug accumulation and have increased expression of the mdr-1 gene. This gene encodes for a membrane glycoprotein and leads to a decreased drug accumulation in drug resistant cell lines. Cell lines established from patients refractory to doxorubicin-containing combinations, however, do not demonstrate a decrease in drug accumulation. Studies are in progress on the measurement of mdr-1 levels in tumors of patients undergoing treatment to determine whether agents, such as verapamil may be useful in the treatment of drug resistant gynecologic cancers. Human ovarian cancer cell lines from drug resistant patients also has been demonstrated to increase levels of glutathione. Lowering of glutathione levels with buthionine sulfoximine (BSO), which irreversibly inhibits the enzyme gamma-glutamyl cysteine synthetase, leads to a marked potentiation of the cytotoxicity of melphalan both in vitro and in vivo in a nude mouse model of human ovarian cancer. Based on those studies, BSO is undergoing toxicologic evaluation before initiation of clinical trials in drug resistant patients. Our studies demonstrate that drug resistance in human ovarian cancer is likely due to interaction of multiple factors. However, biochemical intervention in some of the key steps leading to drug resistance has been demonstrated experimentally feasible and indicates that pharmacologic reversal of drug resistance is a clinical possibility.

A new intensive four drug combination chemotherapy regimen, termed PVeBV, consisting of cis-platinum, vinblastine, bleomycin, and VP-16, was administered to six previously untreated patients with poor prognosis advanced nonseminomatous testicular cancer and to four patients who had relapsed on primary platinum based regimens. The cis-platinum was administered in 250 ml of 3% saline at twice the dose (40 mg/m2 IV days 1-5 every three weeks) used in other treatment schedules. All six previously untreated patients achieved a complete remission. Four achieved a complete remission with three cycles of PVeBV while the other two patients achieved a complete remission with an additional cycle of cisplatinum and VP-16 at 200 mg/m2 IV X five followed by autologous bone marrow infusion. All four relapsed patients responded to PVeBV (two complete remissions and two partial remissions). There were no deaths associated with PVeBV therapy; however, myelosuppression was severe. There has been no renal toxicity (other than hypomagnesemia) observed with 35 cycles of high-dose platinum therapy in previously untreated patients. These results indicate that PVeBV is a promising chemotherapy regimen for the treatment of poor prognosis testicular cancer patients. Furthermore, it appears that cis-platinum can be administered at higher doses than previously used without an increase in renal toxicity if administered in hypertonic saline. The high-dose cis-platinum schedule, as used in PVeBV, warrants evaluation in other tumors which respond to standard-dose platinum therapy.