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Cell growth and differentiation are processes intimately associated with carcinogenesis and regulated by tyrosine kinases and other signaling proteins. Identification of drugs that target signaling molecules is hampered by both the large number of targets and the complex nature of signaling cascades. Optimal development of chemopreventive agents must take into account affinity for the target, pharmacology, and safety profile of the agent. Validated biomarkers will allow the optimal implementation of chemopreventive trials. Directed epidemiologic studies can lead to the identification of lead compounds for chemoprevention, such as genistein. Therefore, agents targeted to pathways and molecules of known biological importance in the prostate hold the promise of clinical efficacy against prostate cancer in a chemopreventive setting.

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for “go/no go” in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the “go/no go” decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.

Ovarian Cancer Incidence and Mortality Rates. Ovarian cancer is the fourth leading cause of death from cancer in women and accounts for the highest mortality rate of all of the gynecological cancers [(1)][1] . Despite aggressive treatment via radical surgery, radiotherapy, or chemotherapy

QUESTION: A 59-year-old man is seen because of a netlike rash in the sacral area. The rash began 2 months ago and was neither pruritic nor painful. The patient has a long history of arthritis and back pain. On physical examination, a hyperpigmented reticulated rash is seen on the sacral area (figure). What additional history would help to make this diagnosis? ANSWER: Additional history revealed that the patient started using a heating pad to soothe his back pain about the same time the reticulated rash began to appear. The patient has erythema ab igne (“red from fire”), also known as toasted-skin syndrome, heat-induced circum-scribed dermal melanosis, fire stains, ephelis ignealis, or livedo reticularis e calore. Erythema ab igne is a cutaneous disorder caused by absorption of infrared radiation. Women are affected more often than men.1 Patients have a history of repeated exposures to heat at a lower level than that which causes a thermal burn. The skin is often mildly erythematous initially, but after repeated heat exposures, the classic blue, purple, or brown reticulated hyperpigmentation develops.1 Because of the general availability of central heating, erythema ab igne is less common in the United States than in countries where open fires are commonly used for heating. Historically, this condition was often seen on the inner thighs and legs of women who sat in front of a stove or open fire.1,2 Currently, it is most commonly seen in this country following repeated use of hot water bottles, infrared lamps, and heating pads. Erythema ab igne has been reported to appear on the legs following prolonged, daily exposure to a car heater. Occasionally, the first sign of splenomegaly, pancreatitis, pancreatic cancer, and other cancers is erythema ab igne resulting when patients apply external heat to relieve the underlying pain.2 Work exposure to heat (such as for bakers, silversmiths, and boiler operators) may cause this condition.1

The goal of clinical research in cancer and AIDS is either curative or palliative in intent. In cancer cure is defined as long tern disease free survival which is comparable to the survival of individuals without the disease. In cancer cure is possible, with optimal therapy, in nearly half the patients. For the other half in cancer and for all individuals with AIDS palliation is the goal. Palliation can be defined as the alleviation of symptoms and/or prolongation of survival. Inherent in all of this is the assumption that cure and palliation will have a positive impact on quality of life.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.

The inclusion of radiation therapy in multimodality clinical research has demonstrated the need for consultion and standardization of terminology and practice between participating centers. A set of guidelines has been developed to ensure that the radiotherapy section of a cooperative study is comprehensive and unambiguous, and that the techniques, fractionation and dosage used are sufficiently uniform to provide a homogeneous group of patients for comparative purposes. Procedures have been developed to facilitate the collection of pertinent information during irradiation and the collection and evaluation of completed treatment data. The quality control program is responsible for supervising all stages of radiotherapy protocol preparation and treatment evaluation. It is also responsible for ensuring adequate standards of machine accuracy and patient dosimetry at all participating facilities. An outline is given for the preparation of radiotherapy protocols including the necessary details of physical factors, localization and simulation, portal and treatment volume definition, dosimetry requirements, specification of dose, and treatment documentation.

The success of cancer chemotherapy has increased greatly the potential areas for its inclusion in clinical trials and therefore has made the experimental design considerations more complex in these trials. New drugs still go through the three classic phases of clinical study beginning with clinical pharmacology (Phase I), efficacy screening (Phase 2) and role delineation (Phase 3). The Phase 2 and 3 trials now need to be considered within the overall therapeutic strategies which are required for each of the many diseases which are called cancer. The exigencies of a disease-oriented strategy which requires a blend of therapeutic modalities many times require a modification of what would be an ideal modality-oriented strategy geared solely to effectively testing a new agent. A new drug may need many Phase 2 and 3 trials in a variety of tumors before it can be considered adequately evaluated. Essential aspects of valid clinical trials include an adequate protocol which details the study and a design which is feasible for answering the question. Historical controls are advocated by many as a valid approach to clinical trials. Unless the numbers in the historical control are large and the prognostic variables well matched this approach should be viewed cautiously by the practicing physician. Cancer 40:544–557, 1977.

Summary Surgery, radiotherapy, chemotherapy and immunotherapy of glioblastoma multiforme have been briefly reviewed. It is quite clear that, with the exception of immunotherapy as it is presently understood, each therapeutic modality has something to add to the preceding one. New approaches in the therapy of glioblastoma must make use of all these modalities because none of them alone can do more than add a few months to survival. The review of surgical studies indicates that extensive surgery, whenever possible, provides a longer survival than more limited surgery or none at all. The median survival for non-irradiated patients is between 3 and 6 months. Undoubtedly, a complete removal of tumor is almost never accomplished by surgery alone and, consequently, long-term survivors are virtually negligible in this disease. The techniques of neurosurgery are now sophisticated enough to state that in the future this modality will not be able to add much more than it presently does to the survival statistics. The review of radiotherapy studies indicates that in combination with surgery it is superior to surgery alone. There is no survival data on radiotherapy alone without surgery. It appears that the benefits of radiotherapy accrue only within the first 12 months and are no longer evident by 18 months and, in addition, the response to radiotherapy is dose related at least up to 3000 rads. Radiotherapy may have more to offer through the use of high energy particles, although, like surgery, it probably will not improve significantly on what it currently adds to survival. Neither X-ray nor surgery appear to influence the ultimate course of glioblastomas and, from a pragmatic point of view, this leaves to chemotherapy the task of arriving at fresh approaches to the disease. At present, the nitrosoureas are essentially the only drugs having significant activity against this malignancy. These agents alone or in combinationtion with radiotherapy produce a more prolonged survival than either modality alone. Evaluation of chemotherapeutic efficacy is difficult, at best, and the future design of studies must include careful forethought if useful data is to be obtained for new agents. The future short-term approaches should be based on current leads, i.e. lipid-soluble drugs, drugs capitalizing on biochemical abnormalities of gliomas, and new previously untested structures known to be active in other malignancies. In the chemotherapy of this disease, we are far from the degree of sophistication that has been reached in the drug therapy of hematologic malignancies and some of the solid tumors. This review has considered the approaches that seem promising but the major advances to be made in long-term approaches must probably await concomitant strides in basic research concerning the unique physical and biochemical characteristics of the central nervous system and the glioblastoma multiforme.

While carcinomas of the stomach is decreasing in incidence in the Dnited States, it is still a major cause of cancer death. But gastric neoplasms are not decreasing in some other geographic areas. According to some studies, 30% of all cancer in the U.S.S.R. originates in the stomach. The rate of gastric neoplasms is greatest in Japan, and over 54% of all cancer in the male population arises in the stomach. The peak age for development of stomach cancer is between 70 and 80 years; over 60% of all stomach cancer is diagnosed in patients between the ages of 60 and 70, while more than 10% is found in those over 80. The main hope for cure at this time rests with surgical treatment. However, despite increased use of surgery, the 5-year survival rate of approximately 13% for patients diagnosed during 1955-59 has not improved to any degree since that time. The major drugs commonly used to treat gastric cancer are 5-fluorouracil (5-FU) and mitomycin C. Controversy still exists concerning the optimum method for administering 5-FU, the most frequently used drug in the United States. The standard loading-course method was attended by a high risk of severe toxicity and drug-related deaths. Several variations of the loading course have evolved. Currently, the Mayo Clinic group uses a 5-day course of 13.5 mg 5-FU/kg repeated every 5 weeks, with therapy interrupted if stomatitis or diarrhea develops; with this regimen the drug-related mortality rate was reported to be less than 1%. Studies have shown that 5-FU plus radiotherapy can enhance survival in patients with locally unresectable diseases. The overall objective with 5-FU is 20-25% with an average of 4-5 months' duration of response. Despite the many patients treated with 5-FU, rarely has a systematic analysis been done of factors such as age, sex, disease-free interval, histologic grade of the tumor, or sites or metastases, which might predispose to a favourable or unfavorable response. In Japan the most commonly used drug for treatment of gastric cancer is mitomycin C, the second most frequently used drug in the United States. The overall objective response rate with mitomycin C is between 20 and 30%, with the higher response rates being reported in the Japanese data. The average duration of response ranges from 1 to 3 months. The nitrosoureas [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1,3-cis(2-chloroethyl)-1-nitrosourea (CCNU), and methyl CCNU (MeCCNU)] have shown some evidence of activity against gastric cancer. BCNU has yielded an objective response rate of 18% (6/33) and an average duration of response of 4.5 months in gastric cancer patients, most of whom had no prior therapy. Adriamycin recently has been shown to have some antitumor activity, with an approximate response rate of 25%. Combination approaches have been more successful in stomach cancer than in any other gastrointestinal neoplasm. The Japanese have reported higher response rates with a combination of 5-FU, mitomycin C, and cytosine arabinoside...

Systemic cancer therapy can be used to achieve cure or palliation depending upon the tumor of origin and its stage. Curative treatment can be accomplished in clinically evident disease or as adjuvant treatment after surgery and/or irradiation when there is no clinically evident disease remaining. Palliation, which is still the major role for systemic therapy, can be defined as prolongation of survival and the alleviation of symptoms resulting in an improved quality of life. All cancer therapy is toxic and must be evaluated within the context of a therapeutic index (Table 1). The efficacy of the treatment must be balanced against the toxicity, arriving at a cost-benefit analysis. The therapeutic index can be evaluated in a research orientated manner or in a practice orientated manner. The literature reporting of clinical trials tends to be dominated by the research orientated perspective. It is distinctly uncommon to find any part of the discussion section of papers devoted to community practice recommendations based upon a patient care oriented therapeutic index analysis of the results being reported. The efficacy parameters for the use of cancer chemotherapy against clinically evident disseminated malignant disease are varied. The most commonly used criteria are objective response and its duration, measured either from the initiation of therapy, or from when response is first achieved. Objective response is an excellent research orientated parameter in that it is reflective, albeit imperfectly, of cell kill and can be measured in a relatively reproducible manner, utilizing generally accepted, although somewhat variable, criteria. While objective shrinkage of tumor is gratifying to the physician, and, therefore, to the patient as well, it does not benefit the patient per se. What benefits the patient is alleviation of symptoms and living longer. Objective regression without a quality of life improvement, or survival prolongation is of little practical benefit. Therefore, in a patient care orientated sense, overall survival, and time to progressive disease, are the more critical efficacy criteria. Toxicity can be reported in a variety of ways. The major focus in the toxicity reporting of cancer chemotherapy trials is on acute toxicity. This acute toxicity can be reported as laboratory results (leukopenia, thrombocytopenia , creatinine, liver function enzymes, etc.), clinical signs (alopecia, stomatitis, skin rash) and symptoms (anorexia, nausea, vomiting, diarrhea, fatigue). Each of these have varying impacts on quality of life, with symptoms carrying the greatest weight and laboratory parameter changes per se, the least. In the research reporting of chemotherapy side effects, the manifold signs, symptoms and laboratory changes are usually listed in tabular form, or objectively described in mathematical terms, with little if any attempt at a holistic integration of the toxicity

Despite its successes cancer chemotherapy fails to cure the great majority of patients treated (2). This failure is due to the overgrowth of resistant cells. The final common pathway of all chemotherapy strategies is to overcome the resistance of tumor cells to eradication at dose levels which are tolerable by the host. The concept of resistance is as old as cytotoxic chemotherapy itself. The views on resistance mechanisms, however, have been changing over the years as it has become obvious that the older hypotheses were not resulting in new successful treatment strategies. In the early days of chemotherapy the major postulated mechanism of resistance was viewed to be kinetic. Drugs were viewed as being optimally effective against actively proliferating cells. Drugs were classified according to their preferential killing within the cell cycle based on cell culture kinetic studies. The most resistant cell was viewed to be the nonproliferating cell and such cells were labelled as Go to separate them from cells that were moving through the actively proliferating phases of the cell cycle (M --) G, --) S -+ G, + M). Solid tumors were viewed as being more resistant than hematological malignancies because they had a large percentage of cells in the Go phase and reciprocally their growth fraction was low and their doubling time long. New drugs were sought which would be able to kill Go cells. This search was hampered by the fact that the in viva screening systems in common use had very high growth fractions and short doubling times in comparison to human solid tumors. A second view ofresistance which began to evolve relatively early in the history of cancer chemotherapy was the biochemical view. A significant number of the early effective cytotoxic drugs were anti-metabolites. The early chemotherapists developed elegant biochemical paradigms for the mechanisms of action of drugs such as methotrexate, 6-mercaptopurine and 5-Fluorouracil. These paradigms enabled elegant hypothesis of biochemical resistance to be developed which to a great degree were testable, and seemingly validated, in cell culture studies. This early love of postulated biochemical patterns for mechanisms of action and resistance can still be found today in the chemotherapy literature. The biochemical view of drugs action led to the concept of ‘rational’ drug design which was set up in opposition to the empirically based approach of

The results of trials testing combined surgery and chemotherapy in lung cancer are reviewed. Fifteen adjuvant trials using various chemotherapeutic agents were analyzed to determine reasons for their lack of success. Current trials with adjuvant therapy in lung cancer are briefly outlined. In addition, analysis of the activity of chemotherapeutic agents in advanced lung cancer and its implications in the design of future adjuvant studies are detailed.

Cancer of the bladder ranks seventh among the causes of dcath due to cancer in males and thirteenth in females (42). Estimates of new cancer cases in the United States show that bladder cancer is the fifth most prevalent malignancy in males and the eleventh ranking cause of cancer among females (43). I t is a disease ofelderly men and the incidence in men is about three times higher than in women; over 60% of the patienls are between the ages of 50 and 70 years ( 1 t). Cancer of the bladder is not a single disease but one that covers a spectrum of' neoplasia ranging from benign papillary growth of slow, recurrent course to highly invasive and aggressive tumors of short duration and rapid lethality. There are two main clinicopathologi c types of tumor, i.e., transitional cell and squamous cell carcinomas. The transitional cell carcinomas are papillary lesions tending to occur in multiple sites (multicentric origin), often with an increasing degree of malignancy. During the natural course of the disease they may become sessile and infiltrative. Squamous metaplasia is often present in addition to the multiple papillary tumors, which means that the entire bladder mucosa is potentially malignant or precancerous. Ninety-seven per cent of the tumors of the bladder arc epithelial in origin. There are, however, no generally accepted criteria for diagnosis (32). Staging is particularly critical in a tumor with as many variable lesions as those found in bladder cancer. The major classifications used are those of Jewett and Strong (20) and the Union Internationale Contre le Cancrum (UICC) (26). In both, the depth of penetration or infiltration into and through the bladder wall is critical (40). The incidence of metastases is related to the depth of infiltration in the bladder wall. Cooling (8) found no evidence of spread in 67~/o of patients with superficial muscle infiltration but did report evidence of metastases in all patients in whom the bladder wall had been deeply invaded. Jewett and Eversole (22) have reported that among 63 tumors infiltrating less than half-way through the bladder wall, 60 had not metastasized or extended to a deeper level. In 58~/o of tumors studied by Jewett (21) perlvcsieal fat was invaded and these tumors had already metastasized.

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.

The nitrosourea group of antitumor agents was developed by the Division of Cancer Treatment of the National Cancer Institute. Three nitrosoureas (BCNU, CCNU, MeCCNU) have undergone extensive clinical trials, and two of them (BCNU, CCNU) will soon become commercially available. This paper briefly considers the preclinical development of the nitrosoureas and provides an overview and comparison of the extensive clinical data. Information is given regarding any clinical differences. We discuss general conclusions drawn from the nitrosourea development.

A tentative evaluation is proposed for the clinical status of 15 early and investigational drugs in human solid tumors.

Nafoxidine is a nonsteroidal antiestrogen available as an investigational agent from the Investigational Drug Branch of the National Cancer Institute. It has been used effectively in the treatment of breast cancer patients. A cumulative response rate of 31% is reported for a total of 200 patients treated with this drug. Most patients have been treated with a dose of 60 mg three times a day. Side effects include dryness of skin, photosensitivity reactions and, less commonly, partial hair loss. There is a strong correlation of response to nafoxidine with the presence of estrogen receptor in the tumor and also with the response to previous hormonal treatment. Nafoxidine is a useful addition to the list of hormonal treatments in the therapy of breast cancer.

The therapeutic cure of breast cancer involves local and metastatic control. In the past they have been conceptually separated with local control being considered the focus for primary therapy and metastatic control an issue only at the time of relapse. With new understanding of tumor cell biology and the natural history of breast cancer, it has been recognized that the two issues cannot be easily separated. The emotionalism that has accompanied breast cancer research, and its results, both within the oncologic community, and in the public mind, have made the design, interpretation, and analysis of breast cancer trials a difficult area. The author reviews the existing clinical trial literature base in primary therapy and attempts to develop its therapeutic implications.

The quality of participation in the performance of clinical trials of university members and community affiliates of the Northern California Oncology Group is evaluated and compared. The data, based on 738 patients on 33 protocols, were collected during a one year period, July 1, 1980--June 30, 1981. The comparisons are made on three types of criteria: accrual distribution, with respect to study phase and modality multiplicity; data quality, generally reflecting protocol adherence; and data completeness. The performance of the community affiliates was found to equal or surpass that of the university members in most measures. Therefore, it is concluded that the community affiliates are functioning as full and valuable participants in the Northern California Oncology Group.