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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

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
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  A Pilot Study of High-Dose Intraarterial CisplatinChemotherapy with Concomitant AcceleratedRadiotherapy for Patients with Previously UntreatedT4 and Selected Patients with T3N0–N3M0 SquamousCell Carcinoma of the Upper Aerodigestive Tract Robert L. Foote,  M.D. 1 Jan L. Kasperbauer,  M.D. 2 Scott H. Okuno,  M.D. 3 Douglas A. Nichols,  M.D. 4 Kerry D. Olsen,  M.D. 2 Paul D. Brown,  M.D. 1 Yolanda I. Garces,  M.D. 1 Daniel J. Sargent,  Ph.D. 5 Scott E. Strome,  M.D. 2 1 Division of Radiation Oncology, Mayo Clinic andMayo Foundation, Rochester, Minnesota. 2 Department of Otorhinolaryngology, Mayo Clinicand Mayo Foundation, Rochester, Minnesota. 3 Division of Medical Oncology, Mayo Clinic andMayo Foundation, Rochester, Minnesota. 4 Department of Radiology, Mayo Clinic and MayoFoundation, Rochester, Minnesota. 5 Division of Biostatistics, Mayo Clinic and MayoFoundation, Rochester, Minnesota.See related editorial on pages 447–50, this issue.Supported by the National Cancer Institute grantCA-15083. Address for reprints: Robert L. Foote, M.D., Divi-sion of Radiation Oncology, Mayo Clinic, 200 FirstStreet SW, Rochester, MN 55905; Fax: (507) 284-0079; E-mail: foote.robert@mayo.eduReceived April 27, 2004; revision received August5, 2004; accepted August 23, 2004. BACKGROUND.  This Phase I clinical trial was developed to assess the feasibility of combining high-dose intraarterial cisplatin chemotherapy with concurrent, con-comitant boost accelerated radiation therapy for patients with previously un-treated T4 and select patients with T3N0–N3M0 squamous cell carcinoma of theupper aerodigestive tract. METHODS.  Between July 1999, and February 2002, 19 patients were treated with 3or 4 weekly cycles of intraarterial Cisplatin chemotherapy (150 mg/m 2 ) with con-current, concomitant boost accelerated radiation therapy (72 grays in 42 fractionsover 6 weeks). RESULTS.  Two patient deaths occurred among the first 15 patients enrolled. Bothpatients presented with febrile neutropenia, and both died of complications re-lated to infection. The number of cycles of intraarterial cisplatin was reduced fromfour cycles to three cycles, and an additional four patients were treated. The fourthpatient treated on the modified protocol developed febrile neutropenia, sepsis, anda thromboembolic event, which resulted in lower extremity amputations. Themaximum acute toxicity experienced was Grade 2 in 6 patients, Grade 3 in 5patients, Grade 4 in 6 patients, and Grade 5 in 2 patients. With a median follow-upof 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 werefree from disease progression (95%CI, 80.3–100%). CONCLUSIONS.  The results of this study suggest that concurrent intraarterial cis-platin chemotherapy at a dose of 150 mg/m 2  with concomitant boost acceleratedradiation therapy is not feasible.  Cancer   2005;103:559–68. © 2004 American Cancer Society. KEYWORDS: intraarterial chemotherapy, head and neck carcinoma, acceleratedradiation therapy, acute toxicity. S ince the early 1970s, attempts have been made to enhance sur-vival of patients with head and neck carcinoma. Multiple random-ized studies of induction or neoadjuvant chemotherapy followed by radiation therapy or surgery have not demonstrated a survival advan-tage. 1,2 Despite the failure of induction or neoadjuvant intravenouschemotherapy to improve survival, its use in combination with radi-ation therapy can alleviate the need for ablative surgery in selectpatient populations. 3 Several recent preliminary studies have suggested that combining  559 © 2004 American Cancer SocietyDOI 10.1002/cncr.20803Published online 13 December 2004 in Wiley InterScience (www.interscience.wiley.com).  chemotherapy with concurrent radiation therapy notonly improves local tumor control but also improvesoverall survival. 4–7 Concomitant chemotherapy andradiation therapy offers the potential for both organpreservation and improved survival. Several strategieshave been developed to increase the efficacy of thistechnique while decreasing treatment associated tox-icity. One particularly promising approach is the useof intraarterial chemotherapy. The rationale behindthe intraarterial versus intravenous administration of chemotherapeutic agents is based on two fundamen-tal principles: 1) a dose relation with a clinically effec-tive chemotherapeutic agent and 2) the dynamics of drug distribution during the first pass through an or-gan system. Intraarterial administration of chemo-therapeutic agents permits relatively selective tumordelivery, facilitating a higher relative drug concentra-tion at the tumor site. 8 In addition, modifications of the approach can be employed to prolong the dura-tion of tumor exposure to drug. Finally, because thedrug is administered intraarterially, systemic strate-gies can be employed to limit toxicity. 9–15 Recent stud-ies have utilized the intraarterial approach to provideescalating doses of chemotherapy in an attempt toimprove local control and to offer a survival advan-tage. 16,17 Study designs also have attempted to useconcomitant intraarterial chemotherapy and radio-therapy to capitalize on the recognized radiosensitiz-ing effects of specific chemotherapeutic agents. 18–20 Initial studies suggest that high-dose intraarterial cis-platin chemotherapy with concurrent radiation ther-apy is a potential method for treating advanced squa-mous cell carcinoma of the upper aerodigestive tract.Because these data are so recent, it remains unclear whether this approach is feasible for widespread ap-plication and whether there is any potential survivaladvantage compared with standard treatment withsurgery followed by radiation therapy. 17 Fractionation is one of the most important factorsin the outcome of radiotherapy. Conventional radio-therapy using a fractionation schedule of 1.8–2.0 grays(Gy) per fraction in 5 daily fractions per week up to atotal dose of 65–75 Gy may not be the optimal treat-ment for some squamous cell carcinomas of the upperrespiratory and digestive tracts. The Radiation Ther-apy Oncology Group recently completed a large, four-arm, randomized trial designed to determine the op-timal radiation fractionation schedule for advancedsquamous cell carcinoma of the head and neck region. Accelerated radiation therapy using a concomitantboost and hyperfractionated radiation therapy pro-vided improved local tumor control and disease-spe-cific survival compared with conventionally fraction-ated radiation therapy and accelerated split-courseradiation therapy. 21 In light of the evidence cited above that intraar-terial cisplatin chemotherapy given concomitantly  with conventionally fractionated radiation therapy and accelerated concomitant boost radiation therapy may improve local tumor control and overall survivalin patients with advanced squamous cell carcinomasof the upper aerodigestive tract, we developed a PhaseI clinical trial to assess the feasibility of combining high-dose intraarterial cisplatin chemotherapy withconcurrent, concomitant boost accelerated radiationtherapy for patients with previously untreated T4 andselect patients with T3N0–N3M0 squamous cell carci-noma of the upper aerodigestive tract. MATERIALS AND METHODS Eligibility for this clinical trial required a diagnosis of clinical Stage T4 or selected T3N0–N3M0 squamouscell carcinoma of the oral cavity, oropharynx, hypo-pharynx, and larynx. Selected patients with T3 tumorsincluded some for whom resection may have resultedin significant dysfunction and morbidity. Patients withprimary sites in the nasopharynx, paranasal sinus, andsalivary glands were excluded, as were patients withmetastatic disease involving cervical lymph nodesfrom an unknown primary site. Patients were requiredto be age    18 years, and the primary tumor andlymph node disease were required to be surgically resectable. Tumor and lymph node classifications were assigned according to the 1997 staging system of the American Joint Committee on Cancer. 22 Cross-sectional imaging studies were included in clinicalstaging. When positron emission tomography scans were obtained, they were not used in clinical staging.Patients with hematogenous metastases (M1) were ex-cluded. All patients were previously untreated and hadan Eastern Cooperative Oncology Group performancestatus of 0, 1, or 2. All patients had a life expectancy   6months. Ineligible patients included pregnant women,nursing women, and women of childbearing potential who were unwilling to employ adequate contraception.In addition, patients were ineligible if they had priorchemotherapy, immunotherapy, or radiotherapy; hadknown human immunodeficiency infection (HIV), hadother malignant disease requiring therapy; or were re-ceiving concurrent coumadin therapy.Pretreatment evaluation in all patients included amedical history and physical examination, including height, weight, complete blood cell count, serumchemistry tests (which included sodium, potassium,magnesium, alkaline phosphatase, aspartate amino-transferase, total bilirubin, creatinine, and lactate de-hydrogenase), thyroid cascade, chest X-ray, magnetic 560 CANCER February 1, 2005 / Volume 103 / Number 3  resonance images (MRI) and computed tomography (CT) scans of the head and neck, serum pregnancy test(only for women of childbearing potential), staging endoscopy (direct laryngoscopy, flexible bronchos-copy, and flexible esophagoscopy) with biopsy, pul-monary function, audiogram, quality-of-life assess-ment, and functional studies (including voicerecording, flow volume loop, fiberoptic endoscopicevaluation of swallowing, and video swallow). The pa-tients were seen in consultation by a medical oncolo-gist, a radiation oncologist, and a head and neck can-cer surgeon. Adequate hematologic, renal, and hepaticfunctions were required for patients to enter the study. All patients were deemed surgically resectable,and it was recommended strongly that the primary tumor extent be outlined using mucosal tattoos during the time of endoscopy in case salvage surgery becamenecessary in the future. Patients who had macroscopicbone involvement that were considered potentially resectable were not eligible for this study; instead,they underwent definitive surgical resection.The study was approved and reviewed annually by the Mayo Clinic Institutional Review Board. Writteninformed consent was obtained from all patients be-fore the initiation of treatment. A multidisciplinary management team that included head and neck sur-geons, medical oncologists, neuroradiologists, and ra-diation oncologists provided patient care. All patientsunderwent a pretreatment dental evaluation with ap-propriate care.The treatment scheme is outlined in Figure 1. Allpatients were treated with a full course of acceleratedconcomitant boost radiation therapy. The primary tu-mor and regional lymph nodes received 1.8 Gy perfraction once daily 5 days per week to deliver 54 Gy in30 fractions over 6 weeks. After 32.4 Gy in 18 fractionsover 3.5 weeks, a concomitant boost was started using 1.5 Gy per fraction per day to a smaller boost field atleast 6 hours after the initial large-field treatment. Theconcomitant boost was delivered daily during the last12 treatment days. The reduced boost volume encom-passed the primary tumor and clinically positivelymph nodes. The total tumor dose was 72 Gy given in42 fractions over 6 weeks. The primary treatmentfields were reduced off the spinal cord to limit thespinal cord dose to a total of 45 Gy. A single clinically N1 lymph node would receive a dose of 72 Gy. Electivelymph node areas received a dose of 54 Gy. For pa-tients with N2 or N3 neck disease, the total dose was54 Gy, and they underwent planned neck dissection 6 weeks after the completion of radiation therapy.Megavoltage radiotherapy was generated by a 6-MV linear accelerator. Multiple fields were used to developa three-dimensional conformal treatment plan. Elec-tron beams were used to treat selected lymph noderegions, as indicated. There were no planned or tox-icity-mandated breaks scheduled during the adminis-tration of the radiation therapy.Concurrently, 4 courses of chemotherapy with in-traarterial bolus infusions of cisplatin (150 mg/m 2 perday) were given on Days 1, 8, 15, and 22 of radiationtherapy. The intraarterial cisplatin was administeredstrictly following the protocol as described in the ra-diation therapy and intraarterial cisplatin (RADPLAT)Radiation Therapy Oncology Group (RTOG) study 96-15. 23 The patients were hospitalized for hydration andantiemetic therapy. The intraarterial chemotherapy  was administered in the neuroangiography suite by aneuroradiologist. The patient was dismissed from thehospital approximately 24 hours after the administra-tion of intraarterial chemotherapy. If the absoluteneutrophil count was    1500    10 6 /L, the plateletcount was    75,000    10 9 /L, creatinine was    1.5mg/dL, or creatinine clearance was  50 mL/minute,or the patient developed    Grade 2 neurotoxicity orother Grade 3 or 4 nonhematologic toxicity (excluding mucositis), the chemotherapy was held until the val-ues improved beyond these defined limits, and thepatient was retreated without dose adjustment. If thechemotherapy was held for    2 weeks, then chemo-therapy was discontinued. Sodium thiosulfate at 9g/m 2  was administered intravenously over 15–20 min-utes concurrent with but beginning 2–3 minutes priorto intraarterial cisplatin, which was administered over3–5 minutes. Intravenous sodium thiosulfate also wasadministered at 12 g/m 2 postchemotherapy over 6hours.Patients were monitored at least once every fiveradiation therapy treatments in an effort to managetreatment-induced side effects, particularly mucositis,myelosuppression, dehydration, and weight loss. Neu-tropenia with fever resulted in mandatory hospitaliza-tion and appropriate antibiotic therapy. Hospitaliza-tion also was required when mucosal injury precludedan adequate oral intake. Percutaneous endoscopicgastrostomy (PEG) feeding tubes were placed asneeded. Tracheostomies were performed in patients with significantly compromised airways, either at pre-sentation or during the course of their treatment. Acute radiation therapy and chemotherapy toxicity  FIGURE 1.  Intraarterial cisplatin (C) and accelerated, concomitant boostradiation therapy (I) treatment schedule. Intraarterial Cisplatin/Foote et al. 561   was scored utilizing the Common Toxicity Criteriaversion 2.0.Prior to each subsequent treatment with intraar-terial cisplatin, the patient underwent a history, in-cluding performance status, physical examination (in-cluding height and weight), complete blood cell count,and serum chemistry tests. On Day 14, the patientunderwent repeat endoscopy to evaluate response totreatment.Six weeks after the completion of treatment, pa-tients underwent a history, including performancestatus, physical examination (including weight), CTand MRI studies of the head and neck, quality-of-lifeassessment, and repeat functional studies. The patientalso underwent endoscopy with biopsies. If there wasno pathologic evidence of primary tumor, then pa-tients with N2 or N3 lymph node disease underwent aplanned, modified neck dissection. If there was patho-logic evidence of residual disease, then the patientalso underwent resection of the primary tumor. Thepatients were then evaluated every 3 months for thefirst year, every 4 months for the second year, andevery 6 months for Years 3–5. These evaluations in-cluded a history, including performance status, exam-ination (including weight), complete blood cell count,serum chemistry tests, thyroid cascade, chest X-ray,CT and MRI studies of the head and neck (as clinically indicated), pulmonary function tests (annually), au-diogram (annually), quality-of-life evaluation (annu-ally), and repeat functional studies (annually). Thecomplete blood count, serum chemistry tests, thyroidcascade, and chest X-ray were obtained every othervisit during Years 1 and 2. The medical oncologist,radiation oncologist, and head and neck cancer sur-geon evaluated the patient’s status during each visit.Salvage surgery was recommended for all patients if it was appropriate for local or regional disease recur-rence.The primary endpoint for the trial was the per-centage of patients who completed therapy success-fully without excessive toxicity. A patient must havemet all of the following criteria to be considered asuccess: 1) full dose of radiotherapy with    5 days of treatment interruption, 2) at least 3 or 4 of the planneddoses of cisplatin at the dosage specified by the pro-tocol, and 3) no unexpected Grade 4 toxicity. Mucosaland hematologic toxicities were considered expected.The sample size for the trial was 30 patients. If     24patients completed therapy successfully, as definedabove, the pilot study was considered feasible. Theprobability of declaring the approach feasible was 6%if the true success rate was 65%, and there was an 85%probability of declaring the approach feasible if thetrue success rate was 85%. With an expected successrate of 75%, 30 patients would provide an estimate of the success rate to    15%. Survival and the time tospecific events were calculated from the date of regis-tration, and the results were analyzed as of August,2002. No patient was lost to follow-up. The Kaplan–Meier method was used to estimate the time to eventsof interest, including overall survival, disease-specificsurvival, local tumor control without surgery, and lo-cal tumor control with surgery. 24 Except for the overallsurvival calculations, a patient was considered cen-sored at death if the event in question had not oc-curred. All  P   values reported are 2-sided, and  P   values  0.05 were considered statistically significance. RESULTS Between July, 1999, and February, 2002, 19 patients with T4 and selected patients with T3N0–N3M0 squa-mous cell carcinoma of the upper aerodigestive tract were enrolled onto this clinical trial. All patients wereeligible, and all patients were assessable for toxicity,patterns of recurrence or progression, and survival.The clinical characteristics of these 19 patients andtheir tumors are detailed in Table 1. Tumor and lymphnode distribution patterns are presented in Table 2.Two patient deaths occurred among the first 15patients enrolled onto this study. Both patients pre-sented with febrile neutropenia at the time of death,both patients died of complications related to infec-tion, including sepsis, and one patient also suffered amyocardial infarction. Given these occurrences, thetrial was suspended temporarily pending further re-view of toxicity and clinical outcome data. Fifty-twoincidents of toxicity   Grade 3 had been reported. In TABLE 1Patient Characteristics ( n   19 patients) Characteristic No. of patients  Age (yrs)Median 63Range 28–77GenderMale 12Female 7ECOG performance status0 61 112 2Primary tumor siteOral cavity —Oropharynx 11Larynx 7Hypopharynx 1 ECOG: Eastern Cooperative Oncology Group. 562 CANCER February 1, 2005 / Volume 103 / Number 3  addition to the 2 incidents of Grade 5 febrile neutro-penia, there were 17 incidents of Grade 4 acute toxicity including leukopenia (5 incidents), neutropenia (2 in-cidents), dysphagia (1 incident), mucositis (3 inci-dent), thrombocytopenia (1 incident), anorexia (1 in-cidents), dehydration (1 incident), fatigue (1 incident),neuromotor (1 incident), and pulmonary (1 incident). All remaining 13 of the initial 15 patients completedtherapy. Ten patients were able to receive all 4planned doses of intraarterial cisplatin, 4 patients re-ceived 3 doses, and 1 patient was able to receive 2doses.Based on the 2 incidents of Grade 5 toxicity, theinvestigators reviewed data from other high-dose in-traarterial cisplatin protocols with their principle in-vestigators. The protocol was modified to eliminatethe third dose of chemotherapy in all patients, and thepatients were prehydrated with at least 2 L of fluidrather than 1 L, which was included initially in thetrial. The trial was then opened for patient accrual with the modifications described above. An additionalfour patients were treated. Three patients were able toreceive all three doses of intraarterial cisplatin, andone patient received two doses. The fourth patienttreated on the modified protocol developed febrileneutropenia, sepsis, acute renal failure, disseminatedintravascular coagulation (DIC), and a thromboem-bolic event, which resulted in an amputation below the knee on the left leg and a partial amputation of theright foot. This series of toxicity events began the day after completion of all treatment. The protocol wasthen permanently closed.Seventeen of 19 patients received the planned fullcourse of radiation therapy (72 Gy). The 2 patients who died as a result of complications related to neu-tropenic fever had received 27 Gy (once-a-day treat-ments) and 39 Gy (2 days into the concomitant boost,twice-a-day treatment).The total severe (Grade 3, 4, and 5), acute toxicity from this treatment is detailed in Table 3. The maxi-mum toxicity experienced was Grade 2 in 6 patients(32%), Grade 3 in 5 patients (26%), Grade 4 in 6 pa-tients (32%), and Grade 5 in 2 patients (11%). Themedian weight loss during treatment was 1.4 kg (range, from    0.7 kg to 6.2 kg). Seven of 17 patients who completed treatment had a tracheostomy tubeplaced prior to treatment. One patient had a trache-ostomy tube placed 9 days into treatment. Four pa-tients required placement of a tracheostomy tube aftertreatment, including one patient who underwent atotal laryngectomy for salvage surgery. At last follow-up, 6 of 17 patients who completed treatment still hada tracheostomy tube. Three of 17 patients who com-pleted treatment had a PEG tube placed prior to treat-ment. Ten patients had a PEG tube placed during treatment. Two patients had a PEG tube placed aftertreatment was completed. At the last follow-up, 7 of 17patients who completed treatment still had a PEGtube, including 1 patient with complete pharyngealstenosis. Nine patients had a tracheostomy tube, PEGtube, or both at the last follow-up. The probability of having a tracheostomy or PEG tube at last follow-up was analyzed by performance status (0, 1, or 2), age,primary tumor site (oropharynx vs. hypopharynx/lar- ynx), tumor classification (T3 vs. T4), lymph nodestatus (N0 vs. N2 and N3), and neck dissection (yes vs.no). Age was associated significantly with having atracheostomy tube at last follow-up (2 sample  t   test;  P   0.0122). Higher tumor classification showed a non- TABLE 2Tumor (T) and Lymph Node (N) Distribution ( n   19 patients) Tumor statusLymph node statusTotalN0 N1 N2 N3 T3 3 — 7 a — 10T4 3 — 5 1 9Total 6 0 12 1 19 a T3 base of tongue carcinoma with an extensive in situ component. TABLE 3Chemoradiotherapy Acute Toxicity  > Grade 3 ( n   19) Toxicity No. of patients %  AST 1 5 Anemia 2 11Neuromotor 1 5Fistula-tracheocutaneous 1 5Hyperglycemia 2 11Neurologic 1 5Thrombocytopenia (platelet transfusion) 1 5Prothrombin time 1 5Febrile neutropenia 2 a 11Infection, low ANC 1 5Renal failure 1 5Pulmonary 1 5 Anorexia 2 11Dyspnea 1 5Fatigue 2 11Dysphagia 8 42Proteinuria 1 5Mucositis 5 26Dehydration 2 11Hypotension 2 11Gastrointestinal 1 5 Voice change 1 5  AST: aspartate aminotransferase; ANC: absolute neutrophil count. a Both Grade 5 Intraarterial Cisplatin/Foote et al. 563
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