PHOTOFRIN-mediated photodynamic therapy for treatment of early stage oral cavity and laryngeal malignancies.

BACKGROUND AND OBJECTIVE: To determine the efficacy of PHOTOFRIN-mediated photodynamic therapy (PDT) for treatment of diffuse "field cancerization" of the oral cavity and Cis-T2N0M0 squamous cell carcinoma (SqCCa) of the larynx in patients not amenable or that have failed conventional head and neck treatment. STUDY DESIGN/MATERIALS AND METHODS: Over the past 15 years 10 patients with early stage Tis-T2N0M0 SqCCa of the oral cavity and oropharynx and 10 patients with Tis-T2N0M0 SqCCa of the larynx were treated. Intravenous PHOTOFRIN (porfimer sodium) (dose 2.0 mg/kg) was administered outpatient, followed 48-60 hours later by intraoperative light photoactivation at 630 nm via fiberoptic microlens (ML) delivery (surgical light dose, 50-100 J/cm(2)) and/or cylindrical diffuser (CD) delivery (80-100 J/cm). RESULTS: Complete responses (CRs) (follow up 6 months-9 years) were achieved in eight of 10 patients with diffuse field cancerization of the oral cavity. CRs (follow up 6 months-8 years) were achieved in eight of 10 patients with superficial laryngeal cancer obviating the need for total laryngectomy in previously treated radiation therapy patients. CONCLUSION: PHOTOFRIN-mediated PDT provides a surgical oncologic modality for potentially curative treatment of early stage oral cavity and laryngeal malignancies with minimal side effects, absence of systemic toxicity, preservation of oral function and voice quality, with multiple drug administration, and laser light retreatment capability.

The prognostic value of PSA levels in radiation therapy of patients with carcinoma of the prostate: the UCLA experience 1988-1992.

BACKGROUND AND OBJECTIVES: Pretreatment prostate-specific antigen (PSA) levels may be of prognostic significance for patients with prostate cancer. Posttreatment PSA data are more limited. This study was undertaken to examine the prognostic role of pretreatment and posttreatment PSA levels in the radiation treatment of patients with carcinoma of the prostate. METHODS: One hundred one patients who received primary radiation therapy at UCLA between 1988 and 1992 for clinical stage A to D1 prostate cancer were analyzed. Included were 4 patients with stage A, 77 with stage B, 16 with stage C, and 4 with stage D. All patients had pretherapy and posttherapy PSA values. Patients received definitive radiation therapy with photons (81), neutrons (13), or interstitial implant (7). Correlations were made with other prognostic factors and treatment outcome. RESULTS: Median follow-up was 28 months. At last follow-up, 64% were without evidence of disease, 17% had rising PSA profiles or failure of PSA to normalize (chemical failure), and 19% had local recurrence and/or distant metastases. The 4-year overall survival was 85%, whereas actuarial survival free of chemical or clinical failure was only 32%. Pretreatment PSA levels and posttreatment PSA level normalization at 6 months correlated significantly with disease-free survival. On univariate analysis, pretreatment PSA levels correlated significantly with stage, high versus low Gleason score, and outcome. Posttreatment PSA level normalization at 6 and 12 months correlated with stage, pretreatment PSA level, and outcome, but not with Gleason score. Only PSA level normalization at 6 months and age were independent variables using multivariate analysis. PSA nadir values differed significantly between patients free of disease and those who failed. CONCLUSIONS: In our analysis, posttreatment PSA levels were independently predictive of outcome, whereas pretreatment PSA levels, while correlating with other prognostic factors, were not independently predictive. Given the prognostic value of posttreatment PSA levels, it is appropriate that chemical failures be included in outcome analyses, although this will lower disease-free survival.

Radiation recall dermatitis and pneumonitis in a patient treated with paclitaxel.

BACKGROUND: Radiation recall refers to a tissue reaction produced by a chemotherapeutic agent in a previously irradiated field that would not occur in a nonirradiated field. A number of agents have been reported to cause radiation recall. Recently, there have been case reports of recall dermatitis from paclitaxel treatment. METHODS: A patient with metastatic lung cancer received palliative radiation to her mediastinum and ribs. Because of disease progression, she subsequently received paclitaxel. RESULTS: After paclitaxel administration, the patient became acutely dyspneic. A subsequent chest X-ray revealed a parenchymal opacity in a region that corresponded with the patient's radiation portal. She also developed a severe skin reaction in the previously treated electron field. CONCLUSIONS: This is one of few reported cases of recall dermatitis from paclitaxel and is also suggestive of recall pneumonitis, a phenomenon previously unreported to the authors' knowledge. Given paclitaxel's ability to function as a radiosensitizer, this response is not unexpected. As the frequency of paclitaxel administration increases, its potential as a radiation sensitizer and radiation recall should be considered.

Ototoxicity of chemotherapeutic agents.

This chapter summarizes the reported ototoxicity data on the most clinically important ototoxic chemotherapeutic agents, notably emphasizing the oto(neuro)toxicities of the more commonly administered platinum compounds, cisplatin and carboplatin. Currently, in the United States, the only other marketed ototoxic chemotherapeutic agents are nitrogen mustard, alpha-difluoromethyl ornithine (DFMO), and the vinca alkaloids (vincristine and vinblastine sulfate); for these groups, animal ototoxicity data is sparse, and audiovestibular records of human ototoxicity are not available from most prospective, randomized controlled clinical trials. Future phase I, II, and III clinical oncologic trials of "experimental" chemotherapeutic agents should include methodology for audiovestibular monitoring, just as present FDA-approved cancer protocols with either monotherapy or combined therapy of known "ototoxic" agents should include standardized audiovestibular assessment in the database. Finally, continued clinical application of cisplatin alone or in combination with other chemotherapeutic agents in the successful treatment of solid tumors mandates decreasing or eliminating specifically the dose-dependent sensorineural hearing loss (partially in cases of complete or long-term partial remission) in addition to other common antiproliferation-induced side effects (nephritis, peripheral neuropathy, intractable nausea and vomiting, electrolyte imbalance, anaphylactic-like reactions, and myelosuppression). Because of the chemotherapeutic superiority of cisplatin, it is essential to continue to investigate methods of altering the dose-limiting oto(neuro)toxicity without causing a "counterproductive" reduction of the antitumor activity of cisplatin (or other second- or third-generation ototoxic platinum agents).

Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents.

Cis-diamminedichloroplatinum II (cisplatin), a divalent platinum compound and potent cell-cycle nonspecific chemotherapeutic agent, produces a dose-limiting, permanent, high-frequency sensori-neural hearing loss and peripheral neuropathy, and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. The exact mechanism(s) of ototoxicity and/or nephrotoxicity are still unknown. Continued aggressive high-dose cisplatin chemotherapy necessitates the investigation of ways to decrease the dose-limiting side effects that inhibit the administration of cisplatin at therapeutic and tumoricidal doses. This multifaceted project investigates two categories of potential inhibitors of cisplatin toxicity that, when coadministered with a known tumoricidal and ototoxic dose of cisplatin, will decrease or inhibit the ototoxicity: 1. phosphonic acid antibiotics (fosfomycin; 1,2 epoxypropylphosphonic acid); 2. nonglucocorticoid 21-aminosteroids, which are free oxygen radical scavengers (LAZAROIDS: U74006F and U78517F). This project also investigates the role of pigmentation as a variable affecting the evaluation of platinum-induced ototoxicity in the guinea pig animal model. Identification of an optimal animal model for future cisplatin toxicity research should be based on previously established species-specific differences in total drug dose, systemic toxicity, and morphological and functional evidence of cochlear toxicity, as affected by differences in pigmentation and drug tolerance. Cytocochleography, brainstem auditory evoked response (BSER), scanning and transmission electron microscopy of organ of Corti and the stria vascularis, double-blind light microscopy of renal, small intestine, and peripheral nerve tissue, and gamma-emission analysis of 195Mplatinum localization in inner ear neuroepithelium and the stria vascularis are used in the global evaluation of the ototoxic effects of cisplatin in both the adult albino and pigmented guinea pig.

The protective effects of allopurinol and superoxide dismutase-polyethylene glycol on ischemic and reperfusion-induced cochlear damage.

The purpose of this study was to assess the protective effects of allopurinol, a blocker of free oxygen radical (FOR) formation, and superoxide dismutase-polyethylene glycol (SOD-PEG), a scavenger of FORs, on ischemic and reperfusion-induced cochlear damage. Fifteen Wistar Kyoto rats (WKY) were randomly assigned to three groups: (1) a control group (5 animals) that was exposed to 15 minutes of cochlear ischemia by clamping the anterior inferior cerebellar artery (AICA), followed by 15 minutes of reperfusion as documented by laser Doppler flowmetry; (2) a drug-treated group (5 animals) that received allopurinol before ischemia/reperfusion; and (3) a drug-treated group (5 animals) that received SOD-PEG before ischemia/reperfusion. In the control group, the tone burst-evoked compound action potential (CAP) recorded from the round window (RW) of the cochlea was abolished, and the cochlear microphonic (CM) was reduced after ischemia. In contrast, both allopurinol and SOD-PEG-treated animals showed post-reperfusion sensitivity in CAP and CM measures. We interpret these results to indicate that damage to the cochlear from ischemia and subsequent reperfusion can be attenuated by pretreatment with allopurinol or SOD-PEG. This provides indirect evidence that FORs may be partially responsible for cochlear damage resulting from ischemic conditions.

Perilymphatic fistula: analysis of free amino acids in middle ear microaspirates.

High-performance liquid chromatography was used to determine 19 free amino acid concentrations in perilymph, serum/plasma, and red blood cell intracellular fluid. Significant differences were found between perilymph and these fluids. Free amino acid analysis was then used to quantitatively analyze middle ear microaspirates in order to test the hypothesis that perilymph is a potential source of clear fluid in perilymphatic fistulas (PLF). Fourteen unknown samples from patients with visually identified PLF, including patients with no identifiable otic capsule defect, were studied. Six samples on amino acid pattern analysis were correlated most similarly with perilymph (rrho greater than 0.95). Four of these six samples were scored on the basis of quantitative amino acid values as similar to perilymph. However, three samples of clear fluid were more similar to serum/plasma than to perilymph on both amino acid pattern and quantitative amino acid score analysis. These results objectively suggest perilymph as a potential source of clear fluid in some patients with a diagnosis of PLF. Not all clear fluid observed in the middle ear, however, is potentially perilymph.

Cochlear implant flap necrosis: adjunct hyperbaric oxygen therapy for prevention of explantation.

The most common complication resulting from cochlear implant surgery involves the skin flap: scalp breakdown, flap necrosis, and implant exposure requiring explantation. A 5.4 percent flap complication rate has been reported with the C-shaped postauricular flap (anteriorly-based on the superficial temporal and occipital arteries) in contrast to a 0 percent flap complication rate with the Australian inverted U-flap (inferiorly-based on the occipital artery). The literature is scant concerning detailed management of flap necrosis in order to obviate cochlear implant removal. Presented is an illustrative case of full thickness C-shaped flap necrosis with resultant exposure of a Nucleus multichannel implant. Successful wound management required pre- and postoperative hyperbaric oxygen in conjunction with a transposition flap closure of the scalp defect. Cochlear explantation was not necessary and rehabilitation and implant function were excellent 18 months postoperatively.

Free amino acid analysis of guinea pig perilymph: a possible clinical assay for the PLF enigma?

Controversy prevails regarding the accuracy of the clinical diagnosis of perilymphatic fistula (PLF). The diagnosis of PLF has been based on the subjective evaluation of vestibular function tests and the intraoperative macroscopic visualization of "clear fluid" from the oval/round windows at the time of exploratory tympanotomy. However, the subjective visual characterization of PLF varies among observing surgeons. Furthermore, perilymph can be "contaminated" with serum, blood, cerebrospinal fluid (CSF), and local anesthesia. This article presents a scientific biochemical microassay for the free amino acid profile of perilymph. Microaliquots of uncontaminated perilymph were sampled from the bilateral round windows (scala tympani) of 20 guinea pigs and analyzed for 19 free amino acid concentrations (FAAC) by high-performance liquid chromatography (HPLC). These samples were compared with the FAAC of guinea pig serum samples. Perfect predictor value ranges were nonoverlapping for 12 of 19 free amino acids in perilymph vs. plasma. Amino acid microassay of middle ear fluid for verification of "true" perilymph vs. nonperilymph fluids by the identification of nonoverlapping FAA markers may allow scientific verification of the existence of PLF in "suspected" patients.

Hyperbaric oxygen management of chronic staphylococcal osteomyelitis of the temporal bone.

Hyperbaric oxygen (HBO) has proven efficacious in the adjunct management of selected otolaryngologic problems: radiation therapy-induced osteoradionecrosis of the temporal bone, malignant external otitis, mandibular osteoradionecrosis and refractory osteomyelitis, soft tissue head and neck necrotizing fasciitis, compromised skin flaps and grafts, acute air or gas embolism, and otologic barotrauma. Herein is described the management of an insidious Staphylococcus aureus osteomyelitis of the temporal bone by pre- and postoperative HBO in conjunction with surgical debridement. The possible application of angiogenic agents and tetracycline bone-labeling in combination with hyperbaric oxygen therapy in the management of refractory neurotologic disease will be discussed.

Photodynamic therapy for treatment of AIDS-related oral Kaposi's sarcoma.

Since 1975, Phase I and II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts at cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions; (2) a tumor-specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; and (4) the potential for retreatment without increasing side effects. Herein we present five cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular oral lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

Angioedema related to angiotensin-converting enzyme inhibitors.

Angioedema is a disorder characterized by well-demarcated nonpitting edema involving the tongue, floor of the mouth, larynx, lips, and face. This condition can progress to upper airway obstruction and death. Angiotensin-converting enzyme inhibitors (ACEIs), relatively new antihypertensive agents, act by blocking the formation of angiotensin II, a potent vasoconstrictor and stimulator of aldosterone formation. ACEIs also retard the breakdown of bradykinin, a potent vasodilator, which may lead to the edema seen in nonhereditary angioedema. These ACEIs include enalapril, captopril, lisinopril, saralasin acetate, and a combination of ACEI with diuretics (for example, Capozide). From August 1987 to January 1989, we treated six patients with a nonhereditary form of angioedema related to ingestion of angiotensin-converting enzyme inhibitors. Symptoms developed in all patients within 12 hours after their initial dose of an ACEI. They presented with shortness of breath and dysphagia associated with tongue and floor of the mouth edema. Two of the six required intubation and monitoring in the surgical intensive care unit for 36 to 48 hours. Three required supportive treatment and observation in an intermediate care unit, and one received supportive care in the clinic and was discharged the same day. Specifically, treatment consisted of cessation of inciting agent, steroids, antihistamines, and epinephrine, if not otherwise contraindicated. Assays of C1 esterase inhibitor levels and C4 were normal in all six patients; this was important in order to rule out hereditary forms of angioedema. These cases will be discussed, including a review of the literature, methods of diagnosis, pathophysiology, and treatment of angioedema.

Photodynamic therapy for treatment of head and neck cancer.

Since 1975, photodynamic therapy has reportedly been effective in a variety of head and neck malignancies that failed traditional (conventional) therapy, including surgery, cryotherapy, chemotherapy, hyperthermia, and radiation therapy. Photodynamic therapy consists of the intravenous administration of (di)hematoporphyrin ether, a chemosensitizing drug selectively retained by neoplastic and reticuloendothelial tissues which, when exposed to a 630-nm argon laser, catalyzes a photochemical reaction to release free oxygen radicals, "the cytotoxic" agents responsible for cell death and tumor necrosis. Preliminary investigations have assessed the efficacy of photodynamic therapy in treatment of: (1) superficial "condemned mucosa" or "field cancerization" of the oral cavity and (2) stage III and IV head and neck carcinomas that had unsuccessful conventional therapy. Complete and/or partial remissions were obtained in 11 of 12 patients (16 treatments) with a variety of carcinomas of the nasopharynx, palate and uvula, retromolar trigone, temporal bone, cervical esophagus, and AIDS-related Kaposi's sarcoma of the oral cavity.

Management of chronic staphylococcal osteomyelitis of the temporal bone: the use of hyperbaric oxygen.

Hyperbaric oxygen (HBO) is an effective adjunct in the management of selected otolaryngologic problems including radiation-induced necrosis of the temporal bone, malignant external otitis, mandibular osteoradionecrosis and refractory osteomyelitis, soft tissue head and necrotizing fasciitis, compromised skin flaps and grafts, acute air or gas embolism, and otologic barotrauma. We describe the management of a patient with insidious Staphylococcus aureus osteomyelitis of the temporal bone by the use of HBO preoperatively and postoperatively in conjunction with surgical debridement. The possible application of angiogenic agents and tetracycline bone-labeling in combination with HBO therapy in the management of refractory neurotologic disease is discussed.

Covalent binding of platinum to renal protein from sensitive and resistant guinea pigs treated with cisplatin: possible role in nephrotoxicity.

Covalent binding of platinum from the anticancer drug cisplatin has been determined in subcellular organelles from kidney and liver of guinea pig strains sensitive and resistant to the systemic toxicity of cisplatin. Organ distribution of platinum was similar between the two strains, but the sensitive animals (pigmented) excreted only half as much platinum in 24 hr as did the resistent animals (albino). Subcellular distribution of platinum in mitochondria, microsomes, and cytosol was approximately equal for both strains, but the sensitive animals had twice as much platinum bound covalently to cytosolic acid-insoluble protein as did the resistant animals. In the albino guinea pigs, concentrations of total platinum and of covalently bound platinum were greater in kidney subcellular organelles than in either liver or lung organelles, which may help explain the sensitivity of the kidney to the toxic effects of cisplatin.

Amelioration of cisplatin-induced ototoxicity by fosfomycin.

The continued chemotherapeutic application of cisplatin (cis-diamminedichloroplatinum [II]) necessitates reduction of its dose-limiting toxicity without decreasing its tumoricidal effect. This research project evaluated the efficacy of fosfomycin, a phosphonic acid antibiotic, in decreasing or ameliorating the ototoxicity (high frequency sensorineural hearing loss) and nephrotoxicity (renal tubular necrosis and interstitial nephritis) of cisplatin. Experimentally, fosfomycin effectively inhibits aminoglycoside-induced ototoxicity and nephrotoxicity in animals and humans. The efficacy of fosfomycin in blocking platinum-induced toxicity in the guinea pig was evaluated histologically and functionally using cytocochleography and light microscopy of the organ of Corti and the auditory brain stem evoked response (ABR), and light microscopy of renal corticomedullary tissues, small bowel, liver, lung, and peripheral nerve. The results demonstrate that fosfomycin ameliorates the acute renal tubular necrosis and interstitial nephritis and markedly inhibits the elevation of ABR thresholds and simultaneous outer hair cell loss that can result from cisplatinum administration. Fosfomycin should be considered a potential antidote for the dose-limiting ototoxicity and nephrotoxicity of cisplatin chemotherapy.

Vestibular morphological analysis of the effects of cisplatin vs. platinum analogs, CBDCA (JM-8) and CHIP (JM-9).

Synthetic second generation chemotherapeutic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objective of this study was to analyze potential vestibular effects of cisplatin and of the two platinum analogs, CBDCA (cis-diammine 1,1-cyclobutane dicarboxylato [2]-0,0(1) platinum or JM-8) and CHIP (cis-dichlorotrans-dihydroxy-bis(isopropylamine) platinum [IV] or JM-9) using scanning and transmission electron microscopy of vestibular neuroepithelium from the albino guinea pig. Vestibular neuroepithelial damage was not demonstrated in either cisplatin- or the analog-treated animals when administered at equitoxic doses.