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

Abstract

BACKGROUND

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.

METHODS

Between July 1999, and February 2002, 19 patients were treated with 3 or 4 weekly cycles of intraarterial Cisplatin chemotherapy (150 mg/m²) with concurrent, concomitant boost accelerated radiation therapy (72 grays in 42 fractions over 6 weeks).

RESULTS

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%).

CONCLUSIONS

The results of this study suggest that concurrent intraarterial cisplatin chemotherapy at a dose of 150 mg/m² with concomitant boost accelerated radiation therapy is not feasible. Cancer 2005. © 2004 American Cancer Society.

Since the early 1970s, attempts have been made to enhance survival of patients with head and neck carcinoma. Multiple randomized studies of induction or neoadjuvant chemotherapy followed by radiation therapy or surgery have not demonstrated a survival advantage.1, 2 Despite the failure of induction or neoadjuvant intravenous chemotherapy to improve survival, its use in combination with radiation therapy can alleviate the need for ablative surgery in select patient populations.3

Several recent preliminary studies have suggested that combining chemotherapy with concurrent radiation therapy not only improves local tumor control but also improves overall survival.4–7 Concomitant chemotherapy and radiation therapy offers the potential for both organ preservation and improved survival. Several strategies have been developed to increase the efficacy of this technique while decreasing treatment associated toxicity. One particularly promising approach is the use of intraarterial chemotherapy. The rationale behind the intraarterial versus intravenous administration of chemotherapeutic agents is based on two fundamental principles: 1) a dose relation with a clinically effective chemotherapeutic agent and 2) the dynamics of drug distribution during the first pass through an organ system. Intraarterial administration of chemotherapeutic agents permits relatively selective tumor delivery, facilitating a higher relative drug concentration at the tumor site.8 In addition, modifications of the approach can be employed to prolong the duration of tumor exposure to drug. Finally, because the drug is administered intraarterially, systemic strategies can be employed to limit toxicity.9–15 Recent studies have utilized the intraarterial approach to provide escalating doses of chemotherapy in an attempt to improve local control and to offer a survival advantage.16, 17 Study designs also have attempted to use concomitant intraarterial chemotherapy and radiotherapy to capitalize on the recognized radiosensitizing effects of specific chemotherapeutic agents.18–20 Initial studies suggest that high-dose intraarterial cisplatin chemotherapy with concurrent radiation therapy is a potential method for treating advanced squamous cell carcinoma of the upper aerodigestive tract. Because these data are so recent, it remains unclear whether this approach is feasible for widespread application and whether there is any potential survival advantage compared with standard treatment with surgery followed by radiation therapy.17

Fractionation is one of the most important factors in the outcome of radiotherapy. Conventional radiotherapy using a fractionation schedule of 1.8–2.0 grays (Gy) per fraction in 5 daily fractions per week up to a total dose of 65–75 Gy may not be the optimal treatment for some squamous cell carcinomas of the upper respiratory and digestive tracts. The Radiation Therapy Oncology Group recently completed a large, four-arm, randomized trial designed to determine the optimal radiation fractionation schedule for advanced squamous cell carcinoma of the head and neck region. Accelerated radiation therapy using a concomitant boost and hyperfractionated radiation therapy provided improved local tumor control and disease-specific survival compared with conventionally fractionated radiation therapy and accelerated split-course radiation therapy.21

In light of the evidence cited above that intraarterial cisplatin chemotherapy given concomitantly with conventionally fractionated radiation therapy and accelerated concomitant boost radiation therapy may improve local tumor control and overall survival in patients with advanced squamous cell carcinomas of the upper aerodigestive tract, we developed a Phase I clinical trial 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.

MATERIALS AND METHODS

Eligibility for this clinical trial required a diagnosis of clinical Stage T4 or selected T3N0–N3M0 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. Selected patients with T3 tumors included some for whom resection may have resulted in significant dysfunction and morbidity. Patients with primary sites in the nasopharynx, paranasal sinus, and salivary glands were excluded, as were patients with metastatic disease involving cervical lymph nodes from an unknown primary site. Patients were required to be age ≥ 18 years, and the primary tumor and lymph 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 clinical staging. When positron emission tomography scans were obtained, they were not used in clinical staging. Patients with hematogenous metastases (M1) were excluded. All patients were previously untreated and had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. All patients had a life expectancy ≥ 6 months. 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 prior chemotherapy, immunotherapy, or radiotherapy; had known human immunodeficiency infection (HIV), had other malignant disease requiring therapy; or were receiving concurrent coumadin therapy.

Pretreatment evaluation in all patients included a medical history and physical examination, including height, weight, complete blood cell count, serum chemistry tests (which included sodium, potassium, magnesium, alkaline phosphatase, aspartate aminotransferase, total bilirubin, creatinine, and lactate dehydrogenase), thyroid cascade, chest X-ray, magnetic 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 bronchoscopy, and flexible esophagoscopy) with biopsy, pulmonary function, audiogram, quality-of-life assessment, and functional studies (including voice recording, flow volume loop, fiberoptic endoscopic evaluation of swallowing, and video swallow). The patients were seen in consultation by a medical oncologist, a radiation oncologist, and a head and neck cancer surgeon. Adequate hematologic, renal, and hepatic functions 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 became necessary in the future. Patients who had macroscopic bone 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. Written informed consent was obtained from all patients before the initiation of treatment. A multidisciplinary management team that included head and neck surgeons, medical oncologists, neuroradiologists, and radiation oncologists provided patient care. All patients underwent a pretreatment dental evaluation with appropriate care.

The treatment scheme is outlined in Figure 1. All patients were treated with a full course of accelerated concomitant boost radiation therapy. The primary tumor and regional lymph nodes received 1.8 Gy per fraction once daily 5 days per week to deliver 54 Gy in 30 fractions over 6 weeks. After 32.4 Gy in 18 fractions over 3.5 weeks, a concomitant boost was started using 1.5 Gy per fraction per day to a smaller boost field at least 6 hours after the initial large-field treatment. The concomitant boost was delivered daily during the last 12 treatment days. The reduced boost volume encompassed the primary tumor and clinically positive lymph nodes. The total tumor dose was 72 Gy given in 42 fractions over 6 weeks. The primary treatment fields were reduced off the spinal cord to limit the spinal cord dose to a total of 45 Gy. A single clinically N1 lymph node would receive a dose of 72 Gy. Elective lymph node areas received a dose of 54 Gy. For patients with N2 or N3 neck disease, the total dose was 54 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 develop a three-dimensional conformal treatment plan. Electron beams were used to treat selected lymph node regions, as indicated. There were no planned or toxicity-mandated breaks scheduled during the administration of the radiation therapy.

Figure 1. Intraarterial cisplatin (C) and accelerated, concomitant boost radiation therapy (I) treatment schedule.

Concurrently, 4 courses of chemotherapy with intraarterial bolus infusions of cisplatin (150 mg/m² per day) were given on Days 1, 8, 15, and 22 of radiation therapy. The intraarterial cisplatin was administered strictly following the protocol as described in the radiation therapy and intraarterial cisplatin (RADPLAT) Radiation Therapy Oncology Group (RTOG) study 96-15.23 The patients were hospitalized for hydration and antiemetic therapy. The intraarterial chemotherapy was administered in the neuroangiography suite by a neuroradiologist. The patient was dismissed from the hospital approximately 24 hours after the administration of intraarterial chemotherapy. If the absolute neutrophil count was < 1500 × 10⁶/L, the platelet count was < 75,000 × 10⁹/L, creatinine was > 1.5 mg/dL, or creatinine clearance was < 50 mL/minute, or the patient developed ≥ Grade 2 neurotoxicity or other Grade 3 or 4 nonhematologic toxicity (excluding mucositis), the chemotherapy was held until the values improved beyond these defined limits, and the patient was retreated without dose adjustment. If the chemotherapy was held for > 2 weeks, then chemotherapy was discontinued. Sodium thiosulfate at 9 g/m² was administered intravenously over 15–20 minutes concurrent with but beginning 2–3 minutes prior to intraarterial cisplatin, which was administered over 3–5 minutes. Intravenous sodium thiosulfate also was administered at 12 g/m² postchemotherapy over 6 hours.

Patients were monitored at least once every five radiation therapy treatments in an effort to manage treatment-induced side effects, particularly mucositis, myelosuppression, dehydration, and weight loss. Neutropenia with fever resulted in mandatory hospitalization and appropriate antibiotic therapy. Hospitalization also was required when mucosal injury precluded an adequate oral intake. Percutaneous endoscopic gastrostomy (PEG) feeding tubes were placed as needed. Tracheostomies were performed in patients with significantly compromised airways, either at presentation or during the course of their treatment. Acute radiation therapy and chemotherapy toxicity was scored utilizing the Common Toxicity Criteria version 2.0.

Prior to each subsequent treatment with intraarterial cisplatin, the patient underwent a history, including performance status, physical examination (including height and weight), complete blood cell count, and serum chemistry tests. On Day 14, the patient underwent repeat endoscopy to evaluate response to treatment.

Six weeks after the completion of treatment, patients underwent a history, including performance status, physical examination (including weight), CT and MRI studies of the head and neck, quality-of-life assessment, and repeat functional studies. The patient also underwent endoscopy with biopsies. If there was no pathologic evidence of primary tumor, then patients with N2 or N3 lymph node disease underwent a planned, modified neck dissection. If there was pathologic evidence of residual disease, then the patient also underwent resection of the primary tumor. The patients were then evaluated every 3 months for the first year, every 4 months for the second year, and every 6 months for Years 3–5. These evaluations included a history, including performance status, examination (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), audiogram (annually), quality-of-life evaluation (annually), and repeat functional studies (annually). The complete blood count, serum chemistry tests, thyroid cascade, and chest X-ray were obtained every other visit during Years 1 and 2. The medical oncologist, radiation oncologist, and head and neck cancer surgeon evaluated the patient's status during each visit. Salvage surgery was recommended for all patients if it was appropriate for local or regional disease recurrence.

The primary endpoint for the trial was the percentage of patients who completed therapy successfully without excessive toxicity. A patient must have met all of the following criteria to be considered a success: 1) full dose of radiotherapy with ≤ 5 days of treatment interruption, 2) at least 3 or 4 of the planned doses of cisplatin at the dosage specified by the protocol, and 3) no unexpected Grade 4 toxicity. Mucosal and hematologic toxicities were considered expected. The sample size for the trial was 30 patients. If ≥ 24 patients completed therapy successfully, as defined above, the pilot study was considered feasible. The probability 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 the true success rate was 85%. With an expected success rate of 75%, 30 patients would provide an estimate of the success rate to ± 15%. Survival and the time to specific events were calculated from the date of registration, 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 events of interest, including overall survival, disease-specific survival, local tumor control without surgery, and local tumor control with surgery.24 Except for the overall survival calculations, a patient was considered censored at death if the event in question had not occurred. 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 squamous cell carcinoma of the upper aerodigestive tract were enrolled onto this clinical trial. All patients were eligible, and all patients were assessable for toxicity, patterns of recurrence or progression, and survival. The clinical characteristics of these 19 patients and their tumors are detailed in Table 1. Tumor and lymph node distribution patterns are presented in Table 2.

Table 1. Patient Characteristics (n = 19 patients)

Characteristic	No. of patients
ECOG: Eastern Cooperative Oncology Group.
Age (yrs)
Median	63
Range	28–77
Gender
Male	12
Female	7
ECOG performance status
0	6
1	11
2	2
Primary tumor site
Oral cavity	—
Oropharynx	11
Larynx	7
Hypopharynx	1

Table 2. Tumor (T) and Lymph Node (N) Distribution (n = 19 patients)

Tumor status	Lymph node status				Total
	N0	N1	N2	N3
a T3 base of tongue carcinoma with an extensive in situ component.
T3	3	—	7a	—	10
T4	3	—	5	1	9
Total	6	0	12	1	19

Two patient deaths occurred among the first 15 patients enrolled onto this study. Both patients presented with febrile neutropenia at the time of death, both patients died of complications related to infection, including sepsis, and one patient also suffered a myocardial infarction. Given these occurrences, the trial was suspended temporarily pending further review of toxicity and clinical outcome data. Fifty-two incidents of toxicity ≥ Grade 3 had been reported. In addition to the 2 incidents of Grade 5 febrile neutropenia, there were 17 incidents of Grade 4 acute toxicity including leukopenia (5 incidents), neutropenia (2 incidents), dysphagia (1 incident), mucositis (3 incident), thrombocytopenia (1 incident), anorexia (1 incidents), dehydration (1 incident), fatigue (1 incident), neuromotor (1 incident), and pulmonary (1 incident). All remaining 13 of the initial 15 patients completed therapy. Ten patients were able to receive all 4 planned doses of intraarterial cisplatin, 4 patients received 3 doses, and 1 patient was able to receive 2 doses.

Based on the 2 incidents of Grade 5 toxicity, the investigators reviewed data from other high-dose intraarterial cisplatin protocols with their principle investigators. The protocol was modified to eliminate the third dose of chemotherapy in all patients, and the patients were prehydrated with at least 2 L of fluid rather than 1 L, which was included initially in the trial. The trial was then opened for patient accrual with the modifications described above. An additional four patients were treated. Three patients were able to receive all three doses of intraarterial cisplatin, and one patient received two doses. The fourth patient treated on the modified protocol developed febrile neutropenia, sepsis, acute renal failure, disseminated intravascular coagulation (DIC), and a thromboembolic event, which resulted in an amputation below the knee on the left leg and a partial amputation of the right foot. This series of toxicity events began the day after completion of all treatment. The protocol was then permanently closed.

Seventeen of 19 patients received the planned full course of radiation therapy (72 Gy). The 2 patients who died as a result of complications related to neutropenic fever had received 27 Gy (once-a-day treatments) 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 maximum toxicity experienced was Grade 2 in 6 patients (32%), Grade 3 in 5 patients (26%), Grade 4 in 6 patients (32%), and Grade 5 in 2 patients (11%). The median 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 tube placed prior to treatment. One patient had a tracheostomy tube placed 9 days into treatment. Four patients required placement of a tracheostomy tube after treatment, including one patient who underwent a total laryngectomy for salvage surgery. At last follow-up, 6 of 17 patients who completed treatment still had a tracheostomy tube. Three of 17 patients who completed treatment had a PEG tube placed prior to treatment. Ten patients had a PEG tube placed during treatment. Two patients had a PEG tube placed after treatment was completed. At the last follow-up, 7 of 17 patients who completed treatment still had a PEG tube, including 1 patient with complete pharyngeal stenosis. Nine patients had a tracheostomy tube, PEG tube, 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/larynx), tumor classification (T3 vs. T4), lymph node status (N0 vs. N2 and N3), and neck dissection (yes vs. no). Age was associated significantly with having a tracheostomy tube at last follow-up (2 sample t test; P = 0.0122). Higher tumor classification showed a nonsignificant trend toward an increased rate of having a PEG tube at last follow-up (Fisher 2-tailed exact test; P = 0.070).

Table 3. Chemoradiotherapy Acute Toxicity ≥ Grade 3 (n = 19)

Toxicity	No. of patients	%
AST: aspartate aminotransferase; ANC: absolute neutrophil count. a Both Grade 5
AST	1	5
Anemia	2	11
Neuromotor	1	5
Fistula-tracheocutaneous	1	5
Hyperglycemia	2	11
Neurologic	1	5
Thrombocytopenia (platelet transfusion)	1	5
Prothrombin time	1	5
Febrile neutropenia	2a	11
Infection, low ANC	1	5
Renal failure	1	5
Pulmonary	1	5
Anorexia	2	11
Dyspnea	1	5
Fatigue	2	11
Dysphagia	8	42
Proteinuria	1	5
Mucositis	5	26
Dehydration	2	11
Hypotension	2	11
Gastrointestinal	1	5
Voice change	1	5

Four patients experienced complications related to the intraarterial catheterization procedure. One patient developed an asymptomatic right external carotid artery dissection during the catheterization procedure for the initial intraarterial chemotherapy administration; in this patient, there was 60–70% recanalization with infusion of Reopro, and the patient also developed bilateral groin abscesses, 1 of which required incision and drainage. The second patient developed transient left hemiplegia 5–10 minutes after removal of the femoral catheter during the initial intraarterial chemotherapy administration. Angiography confirmed an acute right middle cerebral artery angular-branch thrombus. Heparin was administered, and the hemiplegia completely resolved within 30 minutes. It also was noted that this patient had occlusion of the left internal maxillary artery demonstrated on angiography that was presumed secondary to a dissection, which occurred during the first-stage procedure of the third intraarterial chemotherapy administration. The third patient developed bilateral common femoral artery pseudoaneurysms that required surgical repair 8 weeks and 13 weeks after completion of the fourth cycle of intraarterial chemotherapy. The fourth patient developed bilateral femoral artery pseudoaneurysms after the second cycle of intraarterial chemotherapy, both of which required surgical repair, and one side required repair twice. One additional patient had a 99% stenosis of the distal common iliac artery discovered during initial angiography for intraarterial chemotherapy administration; the patient required stent placement through the stenosis to pass a catheter.

The median follow-up for patients at risk was 21 months (range, 6.2–34.6 months) (Table 4). The Kaplan–Meier overall survival rate at 1 year was 89.5% (95% confidence interval [95%CI], 76.7–100%) (Fig. 2). At 1 year, 92.9% of patients were free from disease progression (95%CI, 80.3–100%) (Fig. 3).

Table 4. Patient Status at Last Follow-Up

Patient no.	Follow-up status	Follow-up (mos)	PEG	Tracheostomy
PEG: percutaneous endoscopic gastrostomy tube; ANED: alive, no evidence of disease; DNED: dead, no evidence of disease; AWD: alive with disease; DWD: dead with disease. a This patient underwent a total laryngectomy as part of salvage surgery.
1	ANED	34.1	No	Yes
2	DNED	22.0	Yes	No
3	ANED	28.3	No	No
4	ANED	32.1	Yes	No
5	ANED	31.6	No	Yesa
6	AWD	27.5	Yes	Yes
7	DWD	14.7	Yes	Yes
8	ANED	21.1	Yes	Yes
9	DNED	1.1	No	No
10	ANED	21.4	No	No
11	ANED	17.4	No	No
12	ANED	20.4	No	No
13	AWD	20.7	No	No
14	DNED	1.0	Yes	No
15	ANED	16.1	No	No
16	ANED	12.2	No	No
17	ANED	7.9	Yes	Yes
18	ANED	9.1	No	No
19	ANED	6.1	Yes	No

Figure 2. Overall survival. The dotted lines represent the 95% confidence intervals.

Figure 3. Freedom from disease progression. The dotted lines represent the 95% confidence intervals.

Among the 17 patients who were assessable for pattern of disease recurrence or progression, 16 patients experienced a complete pathologic response at the primary site after chemoradiotherapy. One patient had residual disease in the thyroid gland and underwent a supracricoid laryngectomy. At the time of this report, four patients had developed a delayed local recurrence. In one patient, successful surgical salvage was possible. In another patient, the recurrence was deemed resectable, but the patient did not elect to undergo surgical resection. In the remaining two patients, surgical salvage was not possible. Thus, local control was achieved without surgical resection in 12 patients and with surgical resection in 14 patients. Figure 4 presents the Kaplan–Meier projection of local control without the need for surgery. No patient has experienced recurrence or delayed metastasis in the neck (2 of 12 patients had residual lymph node disease at the time of planned neck dissection after 54 Gy, and 1 patient with an N2c neck died during treatment prior to the planned neck dissection). No patient has developed distant metastasis.

Figure 4. Local tumor control. The dotted lines represent the 95% confidence intervals.

Four of 19 patients from the current study have died. Two patients died of chemotherapy-related complications (neutropenic fever with infection) early in the treatment course. One patient died of pneumonia at 22 months without evidence of disease, and 1 patient died of disease at 14.7 months (locally recurrent carcinoma was suspected clinically and radiographically in this patient, but biopsies were negative).

DISCUSSION

The purpose of this Phase I clinical trial was to determine whether it would be feasible to deliver 4 weekly cycles of intraarterial cisplatin chemotherapy at a dose of 150 mg/m² concurrent with accelerated, concomitant boost radiation therapy. We found that it was not feasible. We were able to deliver all 4 weekly cycles in 10 of 15 patients (67%). We modified the protocol to eliminate the third cycle of chemotherapy (cisplatin was delivered in Weeks 1, 2, and 4). This was discontinued when the fourth patient treated developed Grade 4 toxicity. The RTOG recently completed a multiinstitutional clinical trial evaluating the feasibility of concomitant, intraarterial, high-dose cisplatin with conventionally fractionated radiation therapy. Peer reviewed results are not yet available.

We found intraarterial cisplatin chemotherapy at a dose of 150 mg/m² was too toxic. There were two deaths due to complications secondary to febrile neutropenia and one severe toxicity resulting in amputation of a leg and a foot due to complications related to febrile neutropenia, sepsis, and DIC. We do not believe that this toxicity was due to a “learning curve,” because the treatment-related deaths occurred in the ninth and fourteenth patients treated. The Grade 4 toxicity that required amputation occurred in the fourth patient who was treated with the reduced number of cycles of cisplatin (nineteenth patient overall).

Table 5 summarizes the published experience using intraarterial cisplatin chemotherapy given at a dose of 150 mg/m² weekly for 4 weeks either alone or concomitantly with radiation therapy.25–32 It was not feasible to give all four cycles in these series. Between 69% and 94% of patients were able to receive all 4 cycles. The incidence of treatment-related death varied from 0% to 10%. Two deaths were due to neutropenic sepsis; four deaths were related to aspiration pneumonia, which resulted in sepsis; five deaths were related to acute cardiac events; three deaths were due to pulmonary emboli; two deaths were due to generalized debility with electrolyte abnormalities; and one death was due to tetraplegia. The incidence of Grade 3 or 4 hematologic toxicity varied from 0% to 38%.

Table 5. Recent Published Experience using High-Dose Intraarterial Cisplatin

Study	No. of patients	No. receiving all 4 cycles of IAC (%)	Treatment-related deaths (%)	Grade 3–4 hematologic toxicity (%)
IAC: intraarterial cisplatin; NR: not reported.
Robbins et al., 199425	9	7 (78.0)	0 (0.0)	0.0
Robbins et al., 199426	29	27 (93.0)	0 (0.0)	8.0
Robbins et al., 199627	42	38 (90.0)	1 (2.0)	5.0
Robbins et al., 199728	60	55 (92.0)	1 (2.0)	10.0
Samant et al., 199929	25	23 (92.0)	1 (4.0)	16.0
Ahmed et al., 200030	31	26 (84.0)	3 (10.0)	NR
Robbins et al., 200023	213	170 (80.0)	6 (3.0)	8.0
Samant et al., 200131	45	31 (69.0)	3 (7.0)	9.0
Balm et al., 200432	79	74 (94.0)	2 (2.5)	38.0
Current series	19	10/15 (67.0)	2 (11.0)	11.0

In the current study, there was a very high completion rate for accelerated, concomitant boost radiation therapy (17 of 19 patients; 89%). The only patients who did not complete the radiation therapy were the two patients who died early in the course of radiation therapy secondary to febrile neutropenia.

Regine et al. at the University of Kentucky successfully reduced the toxicity secondary to high-dose intraarterial cisplatin chemotherapy by giving only 1 or 2 cycles during the last week or 2 of radiation therapy.33 Those authors reported only 1 episode of Grade 3 hematologic toxicity in 42 patients treated. They reported an 88% complete response rate at the primary tumor site and an 85% complete response rate for patients with lymph node disease. Their 2-year local regional tumor control, disease-specific survival, and overall survival rates were 73%, 63%, and 57%, respectively, with a median follow-up of 30 months. Alternatively, Wilson et al. at George Washington University were able to administer 4 cycles of intraarterial cisplatin chemotherapy to 57 of 58 patients prior to beginning radiation therapy.34 This resulted in 65% of their previously untreated patients (28 of 43 patients) remaining alive without evidence of disease at a median follow-up of 30 months. Four of 15 (27%) previously treated patients in that study were alive without evidence of disease at a median follow-up of 17.5 months. Those authors reported no Grade 3 or 4 toxicity.

Administering intraarterial cisplatin concomitantly with radiation therapy appears to be more effective than neoadjuvant/sequential treatment, which was administered at George Washington University.34 If concomitant, high-dose intraarterial cisplatin and accelerated, concomitant boost radiation therapy are going to be evaluated further, then we recommend reducing the number of cycles from 4 cycles to 1 or 2 cycles administered either during the first or second weeks or during the last 2 weeks of radiation therapy, as reported by Regine et al. at the University of Kentucky.33

Data concerning organ function and quality of life after intraarterial chemoradiation for organ preservation are sparse. Murry et al. studied swallowing function and quality of life in 60 consecutive patients who underwent RADPLAT for advanced-stage head and neck carcinoma. Evaluation instruments in their study included a head and neck radiotherapy questionnaire and a swallowing questionnaire. Twenty-seven patients completed the questionnaires prior to treatment, at Week 7, at the completion of treatment, and 6 months after treatment. Those authors reported that quality of life and swallowing function decreased acutely during chemoradiation therapy. At 6 months after chemoradiation therapy, the mean quality-of-life scores exceeded pretreatment levels. Patients who had oropharyneal carcinoma had a poorer outcome compared with patients who had laryngeal and hypopharyngeal carcinoma. Swallowing improved beyond pretreatment levels for patients with hypopharyngeal carcinoma, but swallowing was slightly below the pretreatment level for patients with carcinomas of the oropharynx and larynx.35

Ackerstaff et al. also evaluated quality of life after RADPLAT. Twenty-six of 50 treated patients in their study were available for quality-of-life assessment 1 year after treatment. Assessment included the Functional Assessment of Cancer Therapy-Head and Neck questionnaire (FACT-H&N) and the University of Washington questionnaire. Those investigators found that the functional well being and head and neck scales showed a statistically significant improvement over time. Twenty-one of 26 patients in their study were able to return to an oral diet; 23 patients had voice quality and strength that, more or less, were normal; and 10 of 18 patients who were employed prior to treatment were able to return to their work within 12 months.36

We reported the early swallowing function and quality of life in the first 11 patients treated with intraarterial cisplatin and concurrent, accelerated, concomitant boost radiation therapy.37 Up to 5 months after the completion of treatment, we noted a significant decline in swallowing functional measures, including videofluoroscopic swallow studies. The performance status scale demonstrated worse scores for both eating in public and normalcy of diet. The quality of life, as measured by the FACT-H&N, did not change significantly from pretreatment to posttreatment. Whether the swallowing function and quality of life will continue to decline or eventually plateau and perhaps improve will be determined by longer follow-up.

The fundamental objectives of chemoradiotherapeutic strategies for the treatment of patients with advanced head and neck carcinoma are improved survival, organ and function preservation, and improved quality of life. Our early results are too premature to evaluate these endpoints when using intraarterial cisplatin chemotherapy concurrently with accelerated, concomitant boost radiation therapy. The significant attendant acute toxicity and deaths that resulted in the appropriate cessation of this pilot study were of major concern.