Combination cytotoxic chemotherapy with cisplatin or doxorubicin and photodynamic therapy in murine tumors.

This study was designed to evaluate the interaction of photodynamic therapy (PDT) and chemotherapy in an animal model. PDT is based on the interaction of hematoporphyrin derivative and red light of the appropriate wavelength (630 nm) and intensity. Two tumor models were utilized: C3H/Km mice bearing the RIF-1 tumor and BALB/c mice bearing the EMT-6 tumor. Tumor-bearing mice were treated with either cisplatin (DDP), doxorubicin (ADM), PDT, or a combination of drug and PDT. It was demonstrated that the RIF-1 tumor was sensitive to DDP and insensitive to both PDT and ADM. There was no additional antitumor effect when either drug was combined with PDT. The EMT-6 tumor was moderately sensitive to PDT and mildly sensitive to both DDP and ADM. Although the addition of DDP did not potentiate tumor destruction, the addition of ADM significantly enhanced the effect of PDT (P = .01). The enhanced activity of the combination of PDT and ADM appeared to be the result of increased activity of ADM alone, when illuminated with red (630 nm) light. This potentiation may be due to a photochemical process or may be secondary to the mild hyperthermia generated by illumination with the laser. This study demonstrates that PDT combined with cytotoxic chemotherapy is well tolerated in these animals and that certain combinations of PDT and chemotherapy may result in an enhanced tumoricidal effect.

Monitoring immunotherapy with Bacillus Calmette-Guérin by antibody titer.

Antibody titer to Bacillus Calmette-Guérin (BCG) was determined by complement fixation in 111 normal volunteers and 83 melanoma patients. In 43 of these melanoma patients, sequential determination of antibody titer was made and correlated with clinical course. Low titers of antibody to BCG were found frequently in normal volunteers and in melanoma patients prior to BCG immunotherapy. The typical response to BCG immunotherapy was a rapid rise of antibody titer to high levels. Six of 19 patients with recurrence had disappearance of antibody preceding clinical recurrence by up to 5 months. In 13 of 40 patients receiving BCG, serum antibody was a better indicator of the patient's response than measurement of delayed cutaneous hypersensitivity to purified protein derivative. These results suggest that measurement of the antibody response to BCG may be useful in developing an optimum mode of BCG immunotherapy as well as predicting clinical recurrence in patients with melanoma.

Pharmacokinetics of hexamethylmelamine in intralipid following hepatic regional administration in rabbits.

Hexamethylmelamine (HMM) is a cytotoxic agent demonstrated to have broad antitumor activity. Poor solubility in aqueous media has precluded significant evaluation of parenteral administration of this drug. A formulation of HMM dissolved in Intralipid has demonstrated excellent tolerance following parenteral administration. The goal of this study was to evaluate the pharmacology of HMM in Intralipid following hepatic regional administration. The routes of administration were intraarterial via the hepatic artery with and without arterial occlusion, i.v. via the portal and jugular veins, and i.p. All animals received a total dose of 10 mg HMM/kg of body weight. Hepatic extraction of HMM was most evident via the portal vein (PV) route [AUC(PV)/AUC(i.v.) = 0.5; P less than 0.05]. Lower plasma levels and areas under the curve (AUCs) were observed for the hepatic artery and hepatic artery-stop flow groups when compared to i.v., but the difference was not significant. Administration i.p. yielded low plasma levels but a very long half-life (88 min). Hepatic tissue levels were highest in the group receiving HMM by the hepatic artery-stop flow route. We conclude that the HMM-Intralipid mixture is well tolerated, that HMM is extracted to a significant degree by the liver following PV administration, and that an i.p. installation of HMM-Intralipid results in prolonged plasma drug levels. This preclinical study supports further efforts at evaluation of parenteral administration of the HMM-intralipid mixture.

Pharmacokinetics of 5-fluorouracil in rabbits in experimental regional chemotherapy.

The goal of this study was to identify the mode(s) of regional administration of 5-fluorouracil (5-FUra) with the greatest pharmacological advantage in an animal model. Parameters examined were the amount of systemic exposure to 5-FUra and plasma and tissue levels of 5-FUra. Anesthetized New Zealand white rabbits bearing a VX-2 carcinoma in the thigh received 5-FUra (20 mg/kg body weight) by the following routes: i.v., intraarterial (i.a.), i.a. with stopflow, i.a. with outflow occlusion, and isolation perfusion (IP). Serial venous blood samples were obtained prior to and after drug administration for a total of 45 min. A similar sampling of the perfusion circuit was conducted in those animals undergoing IP. At the end of the sampling period tumor and adjacent normal muscle were obtained. Plasma and tissue levels of 5-FUra were determined by a high pressure liquid chromatographic method. It was observed that systemic exposure to 5-FUra was identical for the i.v., i.a., i.a. with stopflow, and i.a. with outflow occlusion groups. Systemic exposure to 5-FUra in the IP group was only 0.30 of that observed for the i.a. group. Tissue 5-FUra levels in the i.v., i.a., and i.a. with stopflow groups were low and comparable to one another. Tissue levels of the 5-FUra were significantly higher in the i.a. with outflow occlusion and IP groups. We conclude that only selected forms of regional administration of 5-FUra offer pharmacological advantage when compared to systemic administration.

Laser photoradiation therapy of cancer.

We conducted a trial of photoradiation therapy of cancer at the University of California at Irvine. The basis of this technique is a photochemical reaction between an i.v.-injected material, hematoporphyrin derivative, and red light (wavelength, 630 nm). Hematoporphyrin derivative localized in malignant tissue, resulting in selective destruction of cancer cells upon illumination with red light. One hundred twenty-eight sites of recurrent cancer or premalignant lesions were treated in 37 patients. Of this group, 35 patients had recurrent cancer refractory to conventional therapy, and two had premalignant lesions. Favorable responses were achieved in 67% of the sites treated. The dose of hematoporphyrin derivative used in this study ranged from 2 to 5 mg/kg with the majority of patients receiving 3 mg/kg. Total light dose administered appeared to be the most critical parameter evaluated. Light doses in excess of 20 J/sq cm generally resulted in blistering and necrosis of intact skin, while no appreciable increase in response was observed. Photoradiation therapy has demonstrable efficacy in cancer therapy and avoids much of the morbidity of current conventional techniques.

Experimental hyperthermic isolation-perfusion using cis-diamminedichloroplatinum(II).

The intent of this study was to determine whether or not local control and/or cure of rabbits bearing the VX-2 carcinoma could be achieved with regional hyperthermia and chemotherapy. A model of isolation-perfusion used cis-diamminedichloroplatinum(II) (DDP). Five different experimental groups were studied, each group receiving progressively smaller tumor inocula and shorter treatment intervals. Although local control and cure improved as the tumor inocula became smaller and treatment interval became shorter, there was no benefit demonstrated when compared to sham-operated animals. DDP appeared to be well tolerated in animals perfused as normothermic temperatures. However, animals perfused at hyperthermic temperature with DDP experienced necrosis of normal as well as neoplastic tissue, resulting in early demise of the animal. This final observation suggests that the amount of DDP utilized in clinical isolation-perfusion should be approached with caution.

Pharmacokinetics of 5-fluorouracil during hyperthermic pelvic isolation-perfusion.

The pharmacokinetics of 5-fluorouracil (5-FU) injected into a surgically isolated pelvic circuit during hyperthermic perfusion was studied in five patients with local recurrence of anorectal cancer. 5-FU doses ranged from 11 to 23 mg/kg. The geometric mean ratio of peak plasma 5-FU in the isolated to systemic circuits was 10, the ratio at the end of the 45-minute perfusion was 12.5. The mean half-life of 5-FU in the isolated circuit was 18.5 minutes. Total drug exposure for the isolated circuit was 7.8-fold greater than for the systemic compartment. These results demonstrate a large pharmacologic advantage for the use of the isolation-perfusion technique.

Hematoporphyrin phototherapy of cancer.

Hematoporphyrin phototherapy of cancer is a new modality for cancer diagnosis and treatment that is currently undergoing clinical trials worldwide. A variety of tumors have been studied, e.g., breast (mostly recurrent skin), lung, bladder, eye, head and neck, gynecological and brain. The most success to date has been with lung and the gynecological tract. Cell and animal studies are being conducted to elucidate the basic photobiological mechanisms involved, as well as the histopathological events associated with tumor destruction. Although major questions remain to be resolved, hematoporphyrin phototherapy is an exciting new therapeutic modality for the treatment of cancer, especially in sites where the unique features of lasers and fiber optics are advantageous.

Immunology and adjuvant chemoimmunotherapy of breast cancer.

Antibody against a breast carcinoma antigen was present in patients with breast carcinoma and other cancer more often (P less than .05) than in normal women. The incidence of antibody in women with breast carcinoma correlated with the presence or absence of gross tumor, and the titer of antibody paralleled the clinical course. These results suggest importance of a host-immune response to breast carcinoma. Fifty-seven patients with stage II carcinoma of the breast were entered into a prospective randomized adjuvant chemoimmunotherapy program of cyclophosphamide, methotrexate, and fluorouracil, and BCG vaccine +/- an irradiated allogeneic tumor cell vaccine. After 24 months of study, metastases occurred in two patients (3.5%) and a new primary carcinoma developed in the contralateral breast in two others, for an overall treatment failure rate of 7%. Adjuvant chemoimmunotherapy can delay early recurrence. Long-term follow-up is needed to assess the significance of these results.

Technique for placement of an implantable venous access system.

Increasingly complex programs of cancer chemotherapy have necessitated a system of reliable venous access that is relatively free of infectious complications. These criteria are met by the Porta-Cath, a totally implantable system consisting of an injection port and Silastic catheter. A technique for implantation of this device has been presented. It focuses on patient safety and comfort, ease of placement, and minimization of time and expense in the operating room.

Hormones and breast cancer.

Patients with successfully managed breast cancer have generally been denied subsequent exposure to increased levels of estrogen (endogenous or exogenous) based on the belief that exacerbation of the cancer would occur. The advent of oral contraceptives, the trend toward childbearing later in life, and the demonstration of the protective value of menopausal estrogen replacement therapy against osteoporosis and cardiovascular disease requires that this issue be reexamined. New information bearing on this subject includes the recognition of estrogen receptors, the isolation of youth rather than pregnancy as the factor resulting in poor prognosis, epidemiologic studies showing no increased risk of breast cancer in women using oral contraceptives or taking hormonal replacement therapy, the beneficial effect of pregnancy subsequent to successfully managed breast cancer, and the absence of an adverse effect of oral contraceptives upon established breast cancer. In view of the lack of evidence relating estrogen to exacerbation of existing breast cancer, it may be in the best interest of our patients to liberalize our attitude to renewed hormonal exposure in patients with successfully managed breast cancer.

PIP: This review raises the issue whether endogenous or exogenous estrogens, such as those circulating during pregnancy, oral contraception or hormonal replacement therapy, have an adverse effect on the course of breast cancer. Breast cancer has traditionally been managed by terminating pregnancy and contraindicating estrogen therapy. Breast cancer is difficult to detect in pregnancy, even by mammography. It is now recognized that pregnant women without axillary lymph node cancer have a favorable prognosis, that most breast cancers arising during pregnancy are not estrogen-receptor positive, and that youth, not pregnancy, is the independent risk factor for poor prognosis. Women whose cancer was successfully managed often do better if they subsequently become pregnant than do those who do not. Furthermore, additive hormonal therapy, and therapy using tamoxifen, a estrogen- antagonist, are effective. The U.S. Food and Drug Administration stated in 1984 that there is no increased risk of breast cancer in users of oral contraceptives. Possibly the improved surveillance and earlier diagnosis of pill users, who see doctors regularly, contribute toward better prognosis of those who do develop cancer. So far there is no evidence that women on hormonal replacement therapy are at increased risk for breast cancer.

Hormone replacement therapy in previously treated breast cancer patients.

We report our experience with 25 women previously treated for breast cancer who subsequently received hormone replacement therapy (HRT) for the relief of menopausal symptoms and the prevention of postmenopausal cardiovascular disease and osteoporosis. Two patients had in situ disease, 13 had stage I disease, 7 had stage II disease, 1 had stage III disease, and 2 had invasive cancer of undetermined stage. Seventeen patients (group I) began HRT less than 24 months after primary breast cancer therapy, and 8 patients (group II) began HRT more than 24 months after breast cancer therapy. The HRT-free interval for group I patients averaged 7.9 months and for group II patients averaged 64.5 months. The average period of observation while receiving HRT for the entire group was 35.2 months (range: 24 to 82 months). Three of 25 patients have had a recurrence, all in group I. One patient developed local recurrence after breast conservation treatment, and her condition was salvaged by further wide excision. Two patients developed recurrence after mastectomy, and one patient ultimately died of systemic disease. The overall survival rate for the entire group was 96%. Overall survival of high-risk group I patients, with a mean follow-up of 30.4 months, was 94%. We recognize that this report of HRT in a small group of patients does not have the power to demonstrate an adverse effect of HRT on breast cancer. However, the lack of an obvious adverse effect of HRT in this group of breast cancer patients and the known beneficial effect of HRT on postmenopausal cardiovascular disease and osteoporosis warrant formal prospective trials of HRT in such patients.

Photoradiation therapy of head and neck cancer.

We have embarked upon a pilot study of photoradiation therapy (PRT) in the treatment of persistent or recurrent cancer of the head and neck, utilizing the photosensitizing agent, hematoporphyrin derivative (HPD). This treatment is based upon selective concentration of HPD within malignant tissue, with resultant necrosis upon illumination with light of the appropriate wavelength (640 nm). Patients entered in this trial have failed all forms of conventional therapy. Twenty-one patients with local recurrence were treated. Sites of recurrence were: tongue (9); nasopharynx (3); floor of mouth (2); soft palate (2); oropharynx (1); buccal mucosa (1); maxilla (1); larynx (1); and basal cell nevus (1). There were six complete responses and twelve partial responses (greater than 50% reduction). These responses are clinically significant, with some complete responses lasting over 1 year after a single course of therapy. Ten patients with cutaneous metastases from head and neck primary tumors were also treated. There were two complete responses and three partial responses. However, these patients rapidly developed new tumors in areas adjacent to those previously treated. Less than complete responses could be augmented by repeated applications of this technique. The success of this pilot study combined with the accessibility of head and neck primaries suggest that there should be a clinical trial of HPD-PRT in early mucosal cancer of the head and neck region.

The contributions of patient factors, physician delay, and tumor biology to the outcome of gastric cancer.

Patients with gastric cancer were presenting at advanced stage to our hospital. We were concerned that patient or physician controlled factors might have been responsible. A retrospective review of 49 analytic gastric cancer cases presenting to UCIMC between 1984 and 1989 was conducted. Twenty-four patients were determined to have gastric cancer as outpatients, with a median duration of symptoms of 4 months. The other 25 patients had initial physician contact in the emergency room, with a median duration of symptoms of only 1.5 months (P = 0.007). Minority ethnic groups were urgently admitted more frequently than Caucasians (P = 0.004). Multivariate analysis revealed that the worst prognostic factors for gastric cancer were urgent admission of Caucasians and Asians (P = 0.0013) and distant metastases (P = 0.005). Age, gender, duration of symptoms, and physician delay, could not be shown to have any effect on survival. This study demonstrates that the aggressive nature of gastric cancer, particularly in certain minority ethnic groups, is the overriding prognostic feature.

Surgical management of breast masses in pregnant women.

OBJECTIVE: The goal of this study was to review the outcomes of breast biopsies in pregnant women in order to plan optimum management strategies for pregnant women with breast masses. STUDY DESIGN: From January 1990 to October 1992, 17 pregnant women underwent breast biopsy at a university hospital. Parameters evaluated were (1) trimester at presentation, (2) timing of biopsy, (3) mode of anesthesia, (4) requirements for tocolytics, and (5) histology of the lesion. RESULTS: Antepartum biopsy was performed on all 11 patients who presented in the first or second trimester. Biopsy was accomplished postpartum in four of five patients presenting in the third trimester. Only one patient required tocolysis (associated with biopsy followed by immediate mastectomy). Histologic diagnosis was predominantly lactating adenoma (13 of 17 patients). CONCLUSION: These results demonstrate that breast biopsy can be safely performed on pregnant women. We recommend that women presenting with breast masses in the first or second trimester undergo antepartum biopsy. We recommend postpartum excision for masses presenting in the latter half of the third trimester. For those presenting in the first half of the third trimester, fine needle aspiration biopsy may be a suitable alternative, particularly for the mass suspicious for cancer.

Effect of dose, route, and schedule of BCG on antibody titer and survival of murine skin grafts across a weak histocompatibility barrier.

Skin was transplanted from male to female C57BL/6JRC mice. Bacillus Calmette-Guérin (BCG) was administered once subcutaneously, intramuscularly, or intraperitoneally either 14 days prior to grafting or on the day of grafting in a dose of 5 X 10(5), 5 X 10(6), or 5 X 10(7) microorganisms. Serum antibody to BCG was assayed using complement fixation. There was a linear inverse relation between skin graft rejection and dose of BCG (p less than .01) such that the lowest dose of BCG was the most effective. The IM and SQ routes were more effective than the IP route. Schedule did not have significant effect on skin graft survival. Time to appearance of antibody correlated directly with dose. The prolonged survival of skin grafts combined with early appearance of antibody to BCG suggested that high doses of BCG could result in antigenic competition.

Plasma ultrafiltration as successful therapy of rabbit VX-2 carcinoma.

It has been demonstrated that tumor-bearing animals elaborate a low molecular weight (less than 10,000 daltons) factor capable of inhibiting in vitro lymphocyte function. It was postulated that removal of this factor would have a favorable effect on host immune response that would translate into improved tumor control. A study was conducted in rabbits bearing the VX-2 carcinoma. Ultrafiltration (UF) was performed 10 days following IV tumor inoculation. UF was achieved by passing blood through an Amicon Diafilter (molecular weight cutoff 10 kD) positioned between the arterial and venous cannulae after heparinization. Two plasma volumes of ultrafiltrate were removed with continuous saline replacement. Two groups of animals received the nonspecific immunoadjuvant, Detox, at time of therapy. Survival in the UF group (N = 9) was compared to untreated tumor-bearing animals (N = 10), sham-operated animals (N = 6), animals receiving Detox (N = 7), and animals receiving UF plus Detox (N = 6). UF imparted a survival advantage when compared to controls (mean 35 days vs. 25 days, P less than .01). The sham group had survival identical to controls. Detox alone conferred minimal survival advantage (mean 29 days, P greater than .05). However, UF + Detox demonstrated maximal survival benefit (mean 40 days, P less than .01). We conclude that UF is an effective anticancer modality in this preclinical model. This study suggests that efforts aimed at eliminating suppressor molecules in cancer patients may be of benefit, especially when combined with biological response modifiers such as Detox.

The pharmacology of hepatic regional administration of cisplatin in a rabbit model.

The pharmacology of hepatic regional administration of CisplatinR (DDP) was examined in a rabbit model. Routes and modes of administration were: IV, hepatic arterial infusion (HAI), HAI with stopflow, HAI with microembolic material [collagen for embolization (CFE)], and portal vein (PV). DDP was rapidly administered, blood samples were drawn over 45 minutes, and hepatic tissue was obtained. Filterable plasma DDP levels were measured by HPLC. Hepatic DDP levels were determined by atomic absorption spectroscopy. All modes of regional administration yielded significantly higher hepatic DDP levels when compared to tissue levels following IV administration. Only the PV and HACFE routes resulted in significantly less systemic drug exposure (AUC) when compared to IV administration. These data indicate a relative pharmacologic advantage of 1.8 for HAI, 3.4 for PV, 1.8 for HAI stopflow, and 4.3 for HACFE compared to IV DDP administration. This pre-clinical study demonstrates substantial pharmacologic advantage for PV and HACFE routes of DDP administration and suggests that clinical trials based on this information be considered.