High-dose Intra-arterial Cisplatin Research Articles

Protective effects of sodium thiosulfate for cisplatin-mediated ototoxicity in patients with head and neck cancer

Conclusions: Intra-arterial high-dose cisplatin chemoradiation (CRT-IA) with sodium thiosulfate (STS) causes relatively less severe cisplatin ototoxicity than intravenous cisplatin chemoradiation without STS (CRT-IV). The results of this study also suggest that early detection of ototoxicity is possible by testing the hearing loss at ultra-high frequencies. Objectives: To investigate protective effects of STS against cisplatin ototoxicity. Methods: Between 2011 and 2013, 18 patients with head and neck carcinomas were treated with intra-arterial infusions of high-dose cisplatin (range 100–180 mg/body, mean 111 mg/body; range 2–5 courses, mean 3.6 courses) and systemic administration of cisplatin (range 66–185 mg/body, mean 130 mg/body; range 1–3 courses, mean 2.6 courses) and concurrent radiation therapy (range 60–70 Gy, mean 69 Gy). Cisplatin was neutralized by STS in CRT-IA but not in CRT-IV. Results: Intra-arterial infusion in the high-dose cisplatin group caused significant hearing loss at ultra-high frequencies of 10 and 12 kHz (p = 0.028, 0.039, respectively), whereas the group receiving systemic administration of cisplatin had significant hearing loss at high frequencies of 8 and 10 kHz (p = 0.016, 0.027, respectively).

Induction chemotherapy using intra-arterial cisplatin plus systemic TS-1 for locally advanced resectable oral cancer: Preliminary experience in a single institute

This study aimed to assess the effects of induction chemotherapy (ICT) using intra-arterial high-dose cisplatin (CDDP) infusion and concurrent peroral tegafur (TS-1) for the management of locally advanced oral cancer. We analyzed 30 patients diagnosed with locally advanced oral squamous cell carcinoma who were treated at our university hospital from April 2007 to March 2011. Eleven patients were diagnosed with stage II tumors, 10 with stage III, and 9 with stage IVA. Six patients demonstrated complete response to ICT, and the overall response rate, including the partial response rate, was 77%. Definitive therapies comprised “wait and see” for 3 patients, chemoradiotherapy for 3, brachytherapy for 1, and ablation surgery for 23 (limited, standard, and extended surgeries in 9, 13, and 1 patients, respectively). Locoregional recurrence was observed in 7 patients, 4 of whom died. ICT can potentially predict good outcome in the management of locally advanced oral cancer. Definitive therapy should be determined on the basis of patients’ response to ICT. Further investigations to determine the criteria indicating the appropriate therapy to be employed after ICT are required.

超選択的動注化学放射線療法が有効であった上顎歯肉小細胞癌の1例

We describe a rare case of small cell neuroendocrine carcinoma （SNEC） arising in the maxillary gingiva that responded to high-dose intra-arterial cisplatin and concurrent radiation therapy （RADPLAT）. A 58-year-old man was referred to our clinic because of a swelling in the right maxillary gingiva. The clinical diagnosis was a malignant tumor of the upper gingiva and a biopsy was performed. The histopathological diagnosis was SNEC. Four courses of intra-arterial infusion of CDDP （50 mg） were administered into the maxillary artery via the femoral artery by the Seldinger method, with concurrent external radiation （50 Gy）. As complete response （CR） was obtained. The patient subsequently received ten courses of systemic adjuvant chemotherapy （CBDCA: 500 mg, VP-16: 180 mg） in the outpatient clinic. He has remained free of disease for 27 months after RADPLAT. However, a PET-CT scan showed multiple systemic metastases. We planned to give the patient systemic chemotherapy again, but his renal function and liver function worsened considerably. Finally, the patient died of multiple organ failure within the same month.

Selective intraarterial chemoradiation therapy for oropharyngeal carcinoma with high-dose cisplatin

Cisplatin has shown a high tumor response rate among head and neck carcinomas, and the tumor response is related to the cisplatin dosage. The purpose of this study was to evaluate the efficacy and toxicity of selective intraarterial chemoradiation therapy for oropharyngeal carcinomas with high-dose cisplatin. This retrospective study consisted of 21 patients with oropharyngeal carcinoma, stages II-IVB, in whom intraarterial chemoradiation therapy was performed between 2000 and 2008. All patients were given two courses of selective intraarterial infusions of cisplatin (300 mg/m(2)), systemic chemotherapy with 5-fluorouracil, and simultaneous radiation therapy (58-61 Gy/30 fractions), with a 1-week rest period. The 2-year overall survival rate of the 15 patients who completed the therapeutic regimen was 71.3%. The 2-year locoregional control rate and disease-free survival rate were 95.0% and 67.7%, respectively. Selective intraarterial high-dose cisplatin chemotherapy with concomitant radiation therapy shows results similar to those of original methods in terms of survival and locoregional control with a reduction in the number of procedure times.

The Influence of Intraarterial High-Dose Cisplatin With Concomitant Irradiation on Arterial Microanastomosis

In this experimental study with rabbits, the influence of intraarterial high-dose cisplatin with concomitant irradiation on arterial microanastomoses was evaluated to determine their impact on free-tissue transfers. The right and left iliac arteries of 10 rabbits were injected with 150 mg/m of cisplatin (group 1). To serve as physiological controls, the iliac arteries of 10 other rabbits were injected with the same volume of saline (group 2). Hypofractionated radiotherapy was given to the right inguinal area of all rabbits using a Co unit, 1.25 MeV, and an SSD of 80 cm for 25 Gy at 5 fractions a day for 5 days (groups 1A and 2A) and the left inguinal areas remained unirradiated (groups 1B and 2B). Both femoral arteries of all 20 rabbits were transected and anastomosed using microsurgical techniques on day 7 after the treatment. All femoral artery anastomoses were examined under anesthesia for pulsatile blood flow 14 days after the surgery. Arteries, including the anastomotic site, were harvested and fixed for histologic evaluation by light microscopy and transmission electron microscopy. Microscopic evaluation showed that all femoral artery anastomoses had good, pulsatile blood flow. Histologic examination of the femoral artery anastomotic site revealed changes of the arterial walls that varied between the groups. Evidence of intimal changes included detachment of endothelial cells in the intimal layer, edema of the endothelial cells in the intima, intimal thickening, separation of the intima from the tunica media, and collagen deposition. Evidence of damage to the tunica media included vacuolation and disarray of the smooth muscle cells, fibrinoid necrosis, and hemorrhage. The damage was most pronounced in the arteries that received both intraarterial cisplatin and radiotherapy (group 1A). The degree of damage diminished in the arteries of the radiotherapy-alone group (group 2A) and the intraarterial cisplatin-alone arteries (group 1B) compared with the control arteries (group 2B). Despite the arterial damage after irradiation and/or cisplatin, the patency rates after vascular anastomosis were 100% for every group. Although damage to the arterial walls in the group that received intraarterial high-dose cisplatin with concomitant irradiation was most obvious, there were no differences in the patency rates after vascular anastomosis between any of the groups. Thus, after intraarterial high-dose cisplatin with concomitant irradiation, the femoral arteries can be used with caution as recipient vessels for free-tissue transfer.

Ototoxicity in a Randomized Phase III Trial of Intra-Arterial Compared With Intravenous Cisplatin Chemoradiation in Patients With Locally Advanced Head and Neck Cancer

Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV). We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT-IA (150 mg/m(2), four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m(2), three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy). CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%. Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols.

Risk Factors of Ototoxicity After Cisplatin-Based Chemo-Irradiation in Patients With Locally Advanced Head-and-Neck Cancer: A Multivariate Analysis

Cisplatin chemo-irradiation is increasingly used in locally advanced squamous cell carcinoma of the head and neck. The objective of this study is to determine risk factors of ototoxicity due to intra-arterial high-dose cisplatin chemoradiation. A prospective analysis of hearing thresholds at low and (ultra) high frequencies obtained before, during, and after treatment in 146 patients. Treatment consisted of intra-arterial infusion of high-dose cisplatin (150 mg/m(2), four courses) with sodium thiosulfate rescue and concurrent radiation therapy (70 Gy). Patient and chemoradiation variables were studied in a multivariate analysis. After treatment, 23% of the ears were under consideration for hearing aids because of therapy. Twenty-two percent of the patients developed an increase in air-bone gap >10 dB during or after therapy. In the multivariate explanatory analysis, cumulative dose of cisplatin and radiation therapy, and young age displayed a causal relationship with increased sensorineural hearing loss during and after therapy (p < 0.001). In the multivariate prediction analysis, pretreatment hearing level of the concerning ear was identified as an independent predictive factor for hearing capability after therapy (p < 0.0001). Both cisplatin and radiation therapy were proven to induce sensorineural hearing loss, in this study with short-term follow-up. Of all patient and treatment variables studied, the patients pretreatment hearing level appeared to be the main predictive factor for hearing capability after high-dose intra-arterial cisplatin chemoradiation.

Audiometric Patterns in Ototoxicity of Intra-Arterial Cisplatin Chemoradiation in Patients with Locally Advanced Head and Neck Cancer

This study describes audiometric patterns of ototoxicity in a consecutive series of patients uniformly treated with intra-arterial high-dose cisplatin chemoirradiation for advanced cancer of the head and neck. Air conduction thresholds were measured from 0.125 to 16 kHz and bone conduction thresholds were measured from 0.5 to 4 kHz. The overall audiometric pattern was characterized by maximum threshold shifts after the 2nd cisplatin infusion and a maximum total threshold shift at 8 kHz, irrespective of gender, age, pretreatment sensorineural hearing loss (SNHL) or subjective complaints during therapy. A hearing deterioration gradient was observed from (ultra-) high to low frequencies, worse with increasing pre-existent SNHL and with increasing cumulative dose of cisplatin chemoradiation. Cisplatin chemoradiation-induced hearing loss seemed to reach a plateau at higher levels (75–80 dB HL) for frequencies above 8 kHz compared to frequencies up to 8 kHz (45–60 dB HL). Recovery of SNHL was found after therapy in 27 ears characterized by extensive hearing loss at frequencies 1, 2 and 4 kHz.

Response to intraarterial induction chemotherapy: A prognostic parameter in oral and oropharyngeal cancer

Patients with head and neck cancer and good pathologic response to neoadjuvant systemic induction chemotherapy have a better prognosis for survival than do those with stable or progressive disease. Thus, induction chemotherapy could theoretically help in stratifying further treatment, but toxicity is much too high. The prognostic implication of superselective intraarterial high-dose cisplatin administered by a femoral approach, which has much less toxicity, is not yet known. One hundred eighty-seven unselected consecutive patients with previously untreated oral and oropharyngeal squamous cell carcinoma received intraarterial high-dose cisplatin for induction and were assessed for response by visual examination and palpation. This treatment was followed by surgery and adjuvant radiation with concomitant systemic chemotherapy. Omission of a modality depended on individual contraindications and not on preselection. The consequence of omissions has been the constitution of several treatment arms. The overall and disease-free survival in relation to clinical local response after intraarterial induction chemotherapy was calculated using the Kaplan-Meier method. Additional analysis excluded bias caused by stages and treatment arms. Explorative statistics using the log-rank and chi-square tests demonstrated a strong prognostic relevance of response to intraarterial chemotherapy irrespective of stage and treatment. Our results are encouraging for prospective randomized studies and molecular genetic investigations with intraarterial chemotherapy.

Long‐term results of hyperfractionated radiation and high‐dose intraarterial cisplatin for unresectable oropharyngeal carcinoma

In this report, the authors present the results from a study of patients with unresectable oropharyngeal squamous cell carcinomas who were treated on a protocol of hyperfractionated radiation and high-dose intraarterial cisplatin (HYPERRADPLAT) at the University of Kentucky. The study was designed as a prospective, single-armed case series that was conducted in the setting of a single, academic, tertiary referral center. The patient cohort consisted of 24 previously untreated patients who were diagnosed with unresectable oropharyngeal carcinoma and were treated on the HYPERRADPLAT regimen, which included hyperfractionated external beam radiotherapy (1.2 grays [Gy] twice daily) was given for 5 weeks (60 Gy) followed by high-dose intraarterial cisplatin (150 mg/m2) and sodium thiosulfate. Shrinking "large-field" portals were started on Week 6 and finished on Week 7 with a cumulative dose of 76.8-81.6 Gy. The main outcome measures of the study were the primary and neck response rates, the 2-year and 5-year overall survival and disease-specific survival rates, and acute and late treatment morbidity. The median follow-up was 77 months. Complete response rates at the primary and regional lymph nodes were both 88%. The 2-year overall survival and disease-specific survival rates were 57% and 68%, respectively; whereas the 5-year overall survival and disease-specific survival rates were 33% and 42%, respectively. Two patients had Grade 4 mucosal toxicity, and no patient experienced neurologic or significant hematologic toxicities. Within 1 year of treatment, 58% of patients had used a feeding tube. The HYPERRADPLAT regimen produced excellent response rates and overall survival rates comparable to those achieved by patients who had unresectable oropharyngeal carcinomas. Tolerance of the therapy was good, and further studies using HYPERRADPLAT with induction therapy may improve outcomes further in this subset of patients with unfavorable disease.

Is high‐dose intensity intraarterial cisplatin chemoradiotherapy for head and neck carcinoma feasible?

The author outlines his personal experience treating hundreds of patients with head and neck carcinoma using combined high‐dose intraarterial cisplatin chemotherapy and concomitant, radiation therapy, and he also highlights the published experience of other investigators, all of whom concluded that the high‐dose intensity approach is feasible and highly efficacious. This differs from the results reported in this issue by a group of investigators from the Mayo Clinic.See referenced original article on pages 559–68, this issue.

A pilot study of high‐dose intraarterial cisplatin chemotherapy with concomitant accelerated radiotherapy for patients with previously untreated T4 and selected patients with T3N0–N3M0 squamous cell carcinoma of the upper aerodigestive tract

This Phase I clinical trial was developed to assess the feasibility of combining high-dose intraarterial cisplatin chemotherapy with concurrent, concomitant boost accelerated radiation therapy for patients with previously untreated T4 and select patients with T3N0-N3M0 squamous cell carcinoma of the upper aerodigestive tract. Between July 1999, and February 2002, 19 patients were treated with 3 or 4 weekly cycles of intraarterial Cisplatin chemotherapy (150 mg/m(2)) with concurrent, concomitant boost accelerated radiation therapy (72 grays in 42 fractions over 6 weeks). Two patient deaths occurred among the first 15 patients enrolled. Both patients presented with febrile neutropenia, and both died of complications related to infection. The number of cycles of intraarterial cisplatin was reduced from four cycles to three cycles, and an additional four patients were treated. The fourth patient treated on the modified protocol developed febrile neutropenia, sepsis, and a thromboembolic event, which resulted in lower extremity amputations. The maximum acute toxicity experienced was Grade 2 in 6 patients, Grade 3 in 5 patients, Grade 4 in 6 patients, and Grade 5 in 2 patients. With a median follow-up of 21 months (range, 6.2-34.6 months), the overall survival at 1 year was 89.5% (95% confidence interval [95%CI], 76.7-100%). At 1 year, 92.9% of the patients were free from disease progression (95%CI, 80.3-100%). The results of this study suggest that concurrent intraarterial cisplatin chemotherapy at a dose of 150 mg/m(2) with concomitant boost accelerated radiation therapy is not feasible.

Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: Which anatomic structures are affected and can they be spared by IMRT?

To identify the anatomic structures whose damage or malfunction cause late dysphagia and aspiration after intensive chemotherapy and radiotherapy (RT) for head-and-neck cancer, and to explore whether they can be spared by intensity-modulated RT (IMRT) without compromising target RT. A total of 26 patients receiving RT concurrent with gemcitabine, a regimen associated with a high rate of late dysphagia and aspiration, underwent prospective evaluation of swallowing with videofluoroscopy (VF), direct endoscopy, and CT. To assess whether the VF abnormalities were regimen specific, they were compared with the VF findings of 6 patients presenting with dysphagia after RT concurrent with high-dose intra-arterial cisplatin. The anatomic structures whose malfunction was likely to cause each of the VF abnormalities common to both regimens were determined by literature review. Pre- and posttherapy CT scans were reviewed for evidence of posttherapy damage to each of these structures, and those demonstrating posttherapy changes were deemed dysphagia/aspiration-related structures (DARS). Standard three-dimensional (3D) RT, standard IMRT (stIMRT), and dysphagia-optimized IMRT (doIMRT) plans in which sparing of the DARS was included in the optimization cost function, were produced for each of 20 consecutive patients with advanced head-and-neck cancer. The posttherapy VF abnormalities common to both regimens included weakness of the posterior motion of the base of tongue, prolonged pharyngeal transit time, lack of coordination between the swallowing phases, reduced elevation of the larynx, and reduced laryngeal closure and epiglottic inversion, contributing to a high rate of aspiration. The anatomic structures whose malfunction was the likely cause of each of these abnormalities, and that also demonstrated anatomic changes after RT concurrent with gemcitabine doses associated with dysphagia and aspiration, were the pharyngeal constrictor muscles (median thickness near midline 2.5 mm before therapy vs. 7 mm after therapy; p = 0.001), the supraglottic larynx (median thickness, 2 mm before therapy vs. 4 mm after therapy; p < 0.001), and, similarly, the glottic larynx. The constrictors and the glottic and supraglottic larynx were, therefore, deemed the DARS. The lowest maximal dose delivered to a stricture volume was 50 Gy. Reducing the volumes of the DARS receiving > or =50 Gy (V(50)) was, therefore, a planning and evaluation goal. Compared with the 3D plans, stIMRT reduced the V(50) of the pharyngeal constrictors by 10% on average (range, 0-36%, p < 0.001), and doIMRT reduced these volumes further, by an additional 10% on average (range, 0-38%; p <0.001). The V(50) of the larynx (glottic + supraglottic) was reduced marginally by stIMRT compared with 3D (by 7% on average, range, 0-56%; p = 0.054), and doIMRT reduced these volumes by an additional 11%, on average (range, 0-41%; p = 0.002). doIMRT reduced laryngeal V(50) compared with 3D, by 18% on average (range 0-61%; p = 0.001). Certain target delineation rules facilitated sparing of the DARS by IMRT. The maximal DARS doses were not reduced by IMRT because of their partial overlap with the targets. stIMRT and doIMRT did not differ in target doses, parotid gland mean dose, spinal cord, or nonspecified tissue maximal dose. The structures whose damage may cause dysphagia and aspiration after intensive chemotherapy and RT are the pharyngeal constrictors and the glottic and supraglottic larynx. Compared with 3D-RT, moderate sparing of these structures was achieved by stIMRT, and an additional benefit, whose extent varied among the patients, was gained by doIMRT, without compromising target doses. Clinical validation is required to determine whether the dosimetric gains are translated into clinical ones.

Selective High-Dose Intra-Arterial Cisplatin as Palliative Treatment for Incurable Head and Neck Cancer

Objective: The purpose of the present study was to evaluatethe palliative effect of selective intra-arterialchemotherapy in progressive unresectable head andneck cancer previously treated with radiochemotherapy.Patients and Methods: 8 patients with advanced residualor recurrent squamous cell carcinoma of the head andneck were evaluated. These patients were included in thepresent study particularly because of progredient painand recurrent bleedings due to tumor progression. In addition6/8 patients suffered from unpleasant tumor-relatedsmell. All patients received simultaneous infusions ofcisplatin (150 mg/m2) intra-arterially to the tumor andsodium thiosulfate intravenously (9 g/m2) for systemicneutralization of cisplatin. The patients were treated by atmost 4 cycles of selective intra-arterial chemotherapy viafemoral approach. Results: Tumor-associated pain, occurrenceof tumor bleeding and tumor-related smellwere reduced after at least 2 cycles of intra-arterialchemotherapy in all patients. Clinical and radiological assessmentof the primary tumor site revealed a partial responsein 4 patients while 4 patients were classified asnonresponders. Intra-arterial cisplatin treatment was welltolerated. Conclusion: Selective intra-arterial cisplatintherapy can be delivered safely for palliation of tumor-relatedsymptoms of incurable head and neck cancer.

Intra-arterial Cisplatin and Concomitant Radiation Therapy Followed by Surgery for Advanced Paranasal Sinus Cancer

To report the long-term efficacy of a combined regimen of intra-arterial high-dose cisplatin chemotherapy and concomitant radiation therapy followed by organ-sparing surgery when possible in the treatment of advanced paranasal sinus cancer. Review of prospectively collected data. Academic referral center. Patients Nineteen patients with advanced paranasal sinus malignancies with a minimum follow-up of 2 years. Malignancies included 14 squamous cell carcinomas (74%), 2 adenocarcinomas (10%), 2 adenoid cystic carcinomas (10%), and 1 undifferentiated carcinoma (5%). Sixteen patients (84%) had T4 disease. Intervention Treatment consisted of preoperative radiation therapy (2.0 Gy/fraction per day; total dose, 50 Gy in 5 weeks) given concomitantly with 3 to 4 weekly infusions of intra-arterial cisplatin (150 mg/m(2) per week) and systemic sodium thiosulfate neutralization. The regimen included planned surgery performed approximately 8 weeks after completion of radiation therapy. Ten patients underwent a transcranial anterior craniofacial resection; 1, a medial maxillectomy; and 1, an endoscopic restaging only. After a median follow-up of 53 months, actuarial overall survival at 2 and 5 years was 68% and 53%, respectively. One patient died of myocardial infarction during treatment. No other treatment-limiting toxic effect was noted. Although 3 patients had persistence of disease, delayed local failure occurred only in 2 and distant metastasis in 3. Except for cataract in 2 patients, no visual loss developed. Despite the advanced stage and unfavorable nature of cancer in this cohort, our results indicate that this regimen holds promise and merits further study.

Complications Associated with Selective High-dose Intraarterial Cisplatin and Concomitant Radiation Therapy for Advanced Head and Neck Cancer

To describe the incidence and severity of complications associated with intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer. One hundred five patients treated between June 1993 and March 1998 were studied. Forty-seven (44%) had T4 lesions and 40 (37%) had bulky (N2/3) nodal disease. Three hundred eighty-five procedures were performed. All patients were treated with selective intraarterial tumor-directed cisplatin (150 mg/m(2) weekly x 4), simultaneous intravenous thiosulfate (9 g/m(2)) for systemic neutralization of cisplatin, and conventional external-beam radiation to the primary tumor and nodal disease (total dose of 66-74 Gy). One hundred five patients were evaluated for complications. Twenty-two (5.7%) groin hematomas occurred, none of which needed therapy. Two asymptomatic common carotid artery dissections were reported. Two patients experienced acute occlusion of the external iliac artery requiring a femorofemoral bypass. Overall, there were 41 grade III/IV chemotoxic events related to treatment. Chemotoxic events included 29 mucosal events, nine hematologic events, two otologic events, and one gastrointestinal event. No renal events occurred. There were three permanent and three transient neurologic events. Selective high-dose intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer can be performed safely with a relatively low complication rate compared to standard intravenous chemotherapy treatment protocols.

Cisplatin tumor concentrations after intra‐arterial cisplatin infusion or embolization in patients with oral cancer

One neoadjuvant course of intra-arterial high-dose cisplatin (cis-diamminedichloroplatinum [CDDP]) tumor perfusion combined with intravenous sodium thiosulfate (STS) (cisplatin neutralizer) infusion is part of a multimodality concept for treatment of oral cancer. Recently, crystalline cisplatin embolization has been described as a novel treatment variant with increased tumor response rates. We have compared tumor and plasma concentrations of cisplatin and STS by means of microdialysis in 10 patients with oral cancer treated with intra-arterial cisplatin perfusion (150 mg/m(2) in 500 mL of 0.9% sodium chloride) and 6 patients with oral cancer treated with crystalline cisplatin embolization (150 mg/m(2) in 45-60 mL of 0.9% sodium chloride), respectively. The microdialysis catheter was placed into the tumor, and the intra-arterial catheter into the tumor-feeding artery. Cisplatin was rapidly administered through the intra-arterial catheter and STS (9 g/m(2)) was infused intravenously to reduce the systemic toxicity of cisplatin. STS infusion was started 10 seconds after the cisplatin infusion was started. After embolization, cisplatin tumor maximum concentration (C(max)) and tumor area under the concentration-time curves (AUCs) were about 5 times higher than those achieved after intra-arterial perfusion (C(max), 180.3 +/- 62.3 micromol/L versus 37.6 +/- 8.9 micromol/L), whereas the opposite was true for plasma concentrations (C(max), 0.9 +/- 0.2 micromol/L versus 4.7 +/- 0.6 micromol/L). STS plasma levels were about 3 times higher than its tumor concentrations (C(max) tumor, 1685 +/- 151 micromol/L; C(max) plasma, 5051 +/- 381 micromol/L). After the standard intra-arterial perfusion, the average STS/CDDP AUC ratios for tumor and plasma were 211 +/- 75 and 984 +/- 139, respectively. After cisplatin embolization, the respective ratios were 48.5 +/- 29.5 and 42966 +/- 26728. Molar STS/CDDP ratios of greater than 500 are required outside the tumor to neutralize cisplatin, whereas tumor ratios should be lower than 100 to avoid a loss of tumor cell killing. The first goal is achieved with both treatment modalities and the second only with cisplatin embolization, suggesting that crystalline cisplatin embolization is superior to intra-arterial cisplatin perfusion in terms of tumor cisplatin concentrations. Whether this translates into higher tumor response rates needs to be investigated further.

High-dose intra-arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m(2) received at the start of and during RT boost treatment). Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months. In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.

Tumor hypoxia and anemia: Impact on the efficacy of radiation therapy

The adverse effects of tumor hypoxia and anemia on the efficacy of radiation therapy have been increasingly recognized. In vitro data indicate that radiation therapy under hypoxic conditions is approximately one third as effective as that under normoxic conditions. There is accumulating clinical evidence of significantly reduced local-regional tumor control and overall survival in anemic patients receiving radiotherapy for head and neck, respiratory tract, pelvic, or genitourinary cancers. In our own study using intraarterial high-dose cisplatin and radiation therapy, we observed that pretreatment hemoglobin level was significantly predictive of complete response (CR) at primary and nodal sites, local-regional failure-free survival, and overall survival by multivariate analyses. With the general lack of success in overcoming the effects of tumor hypoxia through such measures as hyperbaric oxygen and radiosensitizing agents, the focus of clinical research has shifted to directly correcting anemia. A planned randomized trial by the Radiation Therapy Oncology Group will assess the effects of correction of anemia with epoetin alfa on local-regional tumor control and survival in anemic head and neck cancer patients receiving radiation therapy.

Ototoxic effects of supradose cisplatin with sodium thiosulfate neutralization in patients with head and neck cancer.

To assess the incidence and magnitude of ototoxicity in patients undergoing an experimental targeted chemoradiation protocol incorporating extremely high-dose intra-arterial cisplatin therapy with systemic sodium thiosulfate neutralization for the treatment of advanced carcinomas of the head and neck. Inception cohort study. University-based, tertiary care referral center for advanced head and neck malignant disease. The first 70 patients with advanced carcinomas of the head and neck consecutively entered in the protocol. Patients received up to 4 weekly courses of intra-arterial cisplatin (150 mg/m2 per infusion), together with systemic sodium thiosulfate and external beam radiation (68-70 Gy). Audiometric analysis was performed before the initiation of therapy, and subsequent to the second and fourth cisplatin infusions. Audiometric thresholds. Ototoxicity was defined as an increase in pure-tone threshold of 15 dB at 1 frequency or 10 dB at 3 frequencies, between 250 and 4000 Hz. The incidence of ototoxicity was 25% at 150 mg/m2, 50% at 300 mg/m2, 64% at 450 mg/m2, and 60% at 600 mg/m2. Hearing at frequencies of 2000 Hz or less was minimally or not affected. Previous hearing loss did not appear to affect the incidence of ototoxicity. A plateau of hearing loss at 60-dB hearing level, as noted by other authors, was not observed. There were no cases of debilitating tinnitus or of vestibular loss. Ototoxicity did occur but was largely confirmed to the higher frequencies. Hearing losses resulting from this chemoradiation protocol were not sufficiently severe to alter its application.