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© 1999 American Society for Clinical Oncology Liposomal Doxorubicin and Conventionally Fractionated Radiotherapy in the Treatment of Locally Advanced Non–Small-Cell Lung Cancer and Head and Neck CancerFrom the Departments of Radiotherapy and Oncology, Nuclear Medicine, and Otolaryngology—Head and Neck Surgery, University Hospital of Iraklion; the Department of Radiotherapy and Oncology, Saint Savvas Hospital, Athens; the Tumor and Angiogenesis Research Group, Crete; and National Center for Scientific Research, Demokritos, Athens, Greece. Address reprint requests to Michael I. Koukourakis, MD Tumor and Angiogenesis Research Group, 18 Dimokratias Ave, Iraklon 71306, Crete, Greece; email targ{at}her.forthnet.gr
PURPOSE: Stealth (ALZA Corporation, Palo Alto, CA) liposomal drug formulation allows a higher intratumoral accumulation and a prolonged plasma half-life of the encapsulated drugs. In the study presented here, we evaluated the feasibility of Stealth liposomal doxorubicin (Caelyx; ALZA Corporation) administered concurrently with conventionally fractionated radiotherapy in the treatment of non–small-cell lung cancer (NSCLC) and head and neck cancer (HNC). PATIENTS AND METHODS: Fifteen patients with NSCLC and 15 with squamous-cell HNC were recruited in two phase I dose-escalation trials. The starting dose of Caelyx was 10 mg/m2 every 2 weeks (for three cycles during radiotherapy) and was increased by 5 mg/m2 dose increments for every three patients. RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m2 for HNC and 25 mg/m2 in NSCLC patients. Oral/pharyngeal mucositis was the dose-limiting toxicity for HNC patients. "In field" radiation skin toxicity was slightly increased. Hematologic toxicity was minimal. Single photon emission computed tomographic evaluation of Caelyx distribution, using technetium-99m–diethylenetriamine pentaacetic acid labeling, revealed a high intratumoral accumulation of the drug. The tumor to thoracic vessel area count ratio in the NSCLC cases ranged from 0.6 to 1.6 (mean ± SD, 1.01 ± 0.29), whereas this ratio was higher (0.8 to 1.85; mean ± SD, 1.35 ± 0.39) in HNC cases (P = .049). The complete response rate was 21% in the NSCLC cases and 75% in the HNC cases. NSCLC cases with higher Caelyx tumor accumulation responded better to the regimen. The tumor microvessel density assessed with the anti-CD31 monoclonal antibody directly correlated with the degree of the Caelyx accumulation (P = .007; r = .92). CONCLUSION: We conclude that combination of radiotherapy with Stealth liposomal doxorubicin is feasible. The potential role of such a regimen in the treatment of highly angiogenic tumors requires further investigation.
DESPITE THE RECENT progress in radiation oncology, effective eradication of locally advanced cancer still remains a difficult problem. Five-year survival rates for locally advanced head and neck cancer (HNC) ranges from 20% to 40%.1,2 For locally advanced non–small-cell lung cancer (NSCLC), the results from radiotherapy are far worse.2-4 Accelerated and/or hyperfractionation techniques may increase the local control rate by 10% to 20%.2 Although some randomized studies provided evidence of improved survival after induction chemotherapy in NSCLC,5,6 others did not.7-9 Concurrent chemoradiotherapy showed encouraging results in recent randomized studies.10,11 The use of chemotherapy as induction therapy before radiotherapy is no longer believed to confer significant advantage in the treatment of HNC, whereas concurrent chemoradiotherapy is still under intense investigation.12 Recently, several novel anticancer drugs with different mechanisms of action have begun to be studied in clinical practice. Novel antimetabolites (ie, gemcitabine, capecitabine), taxanes (paclitaxel and docetaxel), and topoisomerase I inhibitors (topotecan and irinotecan) have shown important radiosensitizing properties in vitro.13-15 Although treatment with radiotherapy combined with novel drugs is still in the early phase of clinical experimentation, encouraging results have been reported.16,17 Pegylated liposome technology (Stealth; ALZA Corporation, Palo Alto, CA) represents a unique drug-carrier system. Stealth liposomal drugs have a prolonged circulation half-life, their size and structure being a major obstacle for their extravasation.18 Because of these features, the carried drug is selectively accumulated in tissues with increased vascular permeability.19 Indeed, scintigraphic studies confirmed a significantly higher intratumoral accumulation of liposomes, compared with the accumulation in normal adjacent tissues.20 High selective drug localization to tumors could be of great importance when chemotherapy is to be combined with radiation. Radiosensitization of the normal tissues encompassed within the radiation fields could thus be substantially reduced because the drug remains tumor-localized during radiotherapy. Anthracyclines are potent radiosensitizers21; use of them concurrently with radiotherapy often results in unacceptable augmentation of normal tissue radiation toxicity.22,23 Their activity in NSCLC has been well established,24,25 and some activity has been also documented in HNC.26,27 Stealth liposomal doxorubicin (Caelyx; ALZA Corporation, Palo Alto, CA) is a new doxorubicin formulation now available for clinical use. Encouraging results regarding single-agent Caelyx treatment for AIDS-related Kaposi's sarcoma and ovarian and metastatic breast cancers have been reported in the literature.28-30 Stealth liposomal doxorubicin has been shown to enhance the effect of single-fraction and fractionated radiotherapy in squamous cell xenografts.31 In the study presented here, we evaluated the safety and feasibility of Stealth liposomal doxorubicin as a radiosensitizer during standard radiotherapy for locally advanced NSCLC and HNC. Moreover, we used scintigraphy to study the differential accumulation of the radiolabeled drug in tumors and normal tissues.
Recruitment Criteria Fifteen patients with histologically confirmed inoperable (stage IIIb/IV) NSCLC and 15 with locally advanced squamous cell HNC were entered onto this phase I/II study. Five of 15 NSCLC patients had limited metastatic disease and were referred for radiotherapy because of large thoracic masses and life-threatening symptomatology (hemoptysis, superior vena cava syndrome). Patients with WBC counts less than 2,500/µL and platelet counts less than 120,000/ µL were excluded. Patients with hemoglobin values less than 10 g/dL underwent transfusions until their hemoglobin levels exceeded more than 12 g/dL. Pregnant women or patients with major heart, lung, liver, renal, or psychiatric disease, and those with hematologic malignancies were excluded. Patients with a history of severe allergic response to any drug or substance were also excluded. Written informed consent was obtained from all patients.
Pretreatment and Treatment Evaluation Response to treatment was assessed with a CT scan on day 25 (to allow eventual modification of the radiotherapy fields) and 45 to 60 days after treatment completion. The duration of response was measured from the time the criteria for the objective response were first met. CT scans were performed every 2 months for the first 6 months and every 3 to 4 months (or sooner if necessary) thereafter. Complete response (CR) was defined as the disappearance of a measurable lesion within 2 months after treatment completion and lasting for at least 2 months after response documentation. Remnant scars visible on CT scans and that measured less than 5% of the initial tumor volume and showed no signs of progression within 2 months after response documentation were considered to indicate CRs. Similarly, partial responses and minimal responses were defined as 50% to 95% and 25% to 49% reductions in tumor size, respectively. Smaller reductions in tumor size (0% to 24%) that lasted at least 2 months after response documentation were considered to indicate stable disease. All other cases were considered to have progressive disease, regardless of the initial response. Fourteen of 15 NSCLC cases had assessable disease apparent on CT scan, and the remaining case involved known residual disease after incomplete surgery that was not measurable on subsequent CT scans. Of the 15 HNC, three (20%) had had incomplete surgical resections performed before recruitment onto the study; therefore, measurable disease by CT scan before radiotherapy was available for only 12 of the 15 cases.
Radiotherapy Schedule Radiotherapy treatment planning for HNC cases was performed on the basis of recent CT scans of the skull base, splanchnic cranium, and neck area in each patient. Lateral opposed portals encompassing the primary tumor as well as the upper (and/or middle) neck area were used to deliver a daily dose of 2 Gy (five fractions per week) until a total dose of 44 Gy was reached. A direct field was used to irradiate lower neck and supraclavicular nodes up to a total dose of 46 Gy (2 Gy/d). One or two lateral or oblique fields (2 Gy per fraction) limited to the bulky tumoral area were used to increase the total dose to 70 Gy. Total doses for palpable nodes were boosted to 64 to 68 Gy. The planned overall treatment time was 6.5 to 7 weeks. The median follow-up duration of our patients was 8 months (range, 6 to 12 months).
Caelyx Administration and Dose Escalation
Toxicities, Treatment Modification, and Supportive Care For all types of severe nonhematologic "in field" chemoradiotherapy-related toxicities, such as grade 3 mucosal (esophageal or oral/pharyngeal) toxicity, extensive in-field moist skin desquamation with ulceration, severe pain, and exertional dyspnea (lung cancer cases), radiotherapy and chemotherapy were interrupted until the patient recovered (ie, until a regression of symptomatology to grade 1). Patients with mucositis were treated with nonsteroidal anti-inflammatory drug regimens (primarily nimesulide) and prophylactic oral antifungal therapy. Acute radiation pneumonitis was treated with antibiotics and corticosteroids if necessary. Any infection was treated with appropriate antibiotic therapy. Moderate paresthesia related to the irradiation was managed by shielding the spinal cord during future sessions. For Caelyx-related severe nonhematologic toxicities (pulmonitis, severe erythrodysesthesia, severe allergic reactions, or other less frequently expected toxicities), chemotherapy was interrupted and treatment was continued using radiotherapy alone. In cases of moderate erythrodysesthesia, the Caelyx dose was reduced by 50%. For severe asthenia, both radiotherapy and chemotherapy were interrupted until the patient recovered.
Definition of Maximum Tolerated Dose
Caelyx Radiolabeling and Scintigraphic Imaging Procedure
Eleven patients with NSCLC treated at the 15 to 25 mg/m2 dose level and seven with HNC treated at the 20 to 25 mg/m2 dose level underwent Caelyx-labeled scintigraphic evaluation. Written informed consent was obtained before the scintigraphic test was performed. All patients had measurable disease apparent on CT scans. The informed consent and the presence of measurable disease were the criteria for the selection of patients for the scintigraphy. Scintigraphy was performed during the first day of radiotherapy before the radiotherapy was performed, when the first cycle of Caelyx was to be given. Five mg of undiluted Caelyx was incubated with 20 mCi of 99mTc-DTPA for 20 minutes. The 5-mg dose of the radiolabeled Caelyx was taken from the total therapeutic dose that was to be given. The radiolabeled drug was diluted in 50 mL of a dextrose-water solution and injected intravenously within 5 minutes. Two hours later, the patient underwent planar and single photon emission computed tomographic (SPECT) scintigraphy using a single-head SPECT camera. It was suggested that scintigrams performed 2 hours after injection of liposomal drugs are representative of the early phase of the drugs' distribution. Pharmacologic data suggest that one third of an injected dose of Caelyx is distributed into the tissues within 3 to 4 hours and that a slow phase of clearance with a median half-life of 45 to 55 hours then follows.18 Standard regions of interest (ROIs) were drawn on the tumor, normal lung, and on the thoracic large vessel and liver area. The tumor to normal tissue count ratio was then calculated. In two NSCLC and two HNC cases, the scintigraphy was repeated during the third cycle of Caelyx infusion (after a 40-Gy radiotherapy dose). Delayed scintigrams, performed 10 hours after injection of the Caelyx infusion, were also obtained in five patients.
Immunohistochemistry
Phenotypic Analysis of Peripheral Blood Lymphocytes
Statistical Analysis
Table 1 lists all patients' characteristics.
Immediate Side-Effects Related to Drug Administration
In-Field Toxicity in NSCLC Patients
Acute pulmonary toxicity during radiotherapy was not observed in any of the 15 lung cancer patients. However, one (6%) of the 15 patients expressed severe dyspnea 4 months after the end of radiotherapy and died. A chest x-ray performed before the patient died showed characteristic findings of radiation pneumonitis. Moreover, one (6%) of the 15 patients developed atypical pneumonia 2 months after the end of chemoradiotherapy. Less severe, localized lung fibrosis accompanied by mild exertional dyspnea was observed in another two (12%) of 15 patients 6 months after treatment was completed. Grade 2 in-field radiotherapy skin toxicity (moist patchy desquamation) was observed in two of 15 patients. These patients were treated as part of the 20 to 25 mg/m2 dose level cohorts. All the remaining cases developed grade 1 skin toxicity. One NSCLC patient developed a herpes zoster infection in the irradiated area and was treated with oral acyclovir.
In-Field Toxicity in HNC Patients
Nonhematologic Systemic Toxicity
Hematologic Toxicity
Response and Outcome
After 6 to 12 months of follow-up, five of 15 NSCLC patients with (three of whom responded completely to therapy) were alive with no evidence of local progression. One patient with CR died of distant metastasis after 7 months and one died of radiation pneumonitis with no evidence of local relapse after 4 months. All nine HNC patients who responded completely to treatment and three patients with nonmeasurable disease recruited onto the protocol were also alive with no evidence of local or distant recurrence. The Kaplan-Meier local relapse and overall survival curves for NSCLC are shown in Fig 2.
The assessment of the "out-of-field" response rate of metastatic lesions was feasible in three NSCLC patients. All three patients had stable disease after treatment was completed.
Tumor and Normal Tissue Distribution of Caelyx Caelyx was invariably highly accumulated in the tumor area. We chose to compare the tumor accumulation with the TVA accumulation, because this would give an estimate of the rate at which the drug passes from the blood pool into the tumoral tissue. The tumor to TVA count ratio (t/v) obtained by scintigraphic SPECT image analysis in NSCLC cases ranged from 0.6 to 1.6 (mean ± SD, 1.01 ± 0.29). Figure 3 shows a CT scan from a lung adenocarcinoma (Fig 3A) and the 99mTc-DTPA–Caelyx SPECT scintigraphy of the same chest area (Fig 3B). In HNC cases, the t/v ratio ranged between 0.8 and 1.85 (mean ± SD, 1.35±0.39), which is significantly higher than that of the NSCLC cases (unpaired two-tailed t test; P = .049). In a subset of five patients, delayed scintigrams were obtained 10 hours after the Caelyx injection. The tissue/TVA ratio was increasing for liver, lung, and tumoral tissue, but the tumor/TVA ratio showed the highest rate of increase (data not shown).
Scintigrams obtained during the third Caelyx cycle, after the completion of 40 Gy of radiotherapy, confirmed a significant Caelyx accumulation in the shrunken tumor areas. Figure 4 shows a planar radiolabeled Caelyx scintigraphic image of a large nasopharyngeal tumor before (Fig 4A) and after (Fig 4B) the delivery of 40 Gy of radiation. A high Caelyx accumulation in the residual tumor was observed.
T/V Ratio and Response
T/V Ratio and Microvessel Score
Stealth liposomal drug formulation is a promising, novel way of delivering chemotherapeutic agents. Pegylated liposomes bear a tightly packed semisolid phospholipid layer and are coated with short polyethylene glycol chains. This Stealth formulation effectively escapes macrophage-mediated phagocytosis,37 which was the major problem with the first generation of liposomal drugs that were directed to the reticuloendothelial system rather than the tumor.38 Stealth liposomal doxorubicin (Caelyx) is the first drug representative of this novel technology to be introduced in clinical oncology practice. One third of an injected dose of Caelyx is cleared from plasma within 3 to 4 hours.39 The remainder is slowly cleared, with a median half-life of 45 to 55 hours. Stealth liposomes, being larger than erythrocytes, tend to accumulate in tissues with immature leaky vascularization, which is often observed in tumors.40 Prolonged circulation of the drug would therefore result in continuous selective accumulation in tumors, compared with normal tissues. This was confirmed in a study by Stewart and Harrington,39 who showed that 48 to 72 days after an indium-111–radiolabeled Caelyx injection, there was an increasingly higher intratumoral drug accumulation, compared with accumulation in the blood pool. The vast majority of Stealth liposomes enter the tumor interstitium through gaps (fenestrae) in the endothelial cell walls of newly formed vessels that feed the tumors,41,42 whereas a smaller proportion of liposomes may actually pass directly through the thin walls of the defective endothelial cells lining the neovessel via a process called transcytosis.43 After their extravasation in the interstitial fluid surrounding the tumor, physicochemical destabilization and subsequent breakdown of the liposomal envelope are effected as a consequence of a constellation of conditions present there, such as the low pH,33 the presence of lipases released from dying neoplastic cells,44 and the release of various enzymes or oxidizing molecules and radicals by inflammatory or phagocytic cells residing within the tumors.45,46 The cytotoxic effect of radiotherapy may therefore further contribute to the establishment of intratumoral conditions that rapidly breakdown the extravasated liposomes. Liposomes may also be ingested by tumor-infiltrating macrophages, which then causes the intracellular digestion of the liposomes' lipid membranes and the in situ release of very high concentrations of doxorubicin (as well as its active metabolites).47 In the study presented here, we evaluated the accumulation of radiolabeled 99mTc-DTPA-Caelyxin in nine NSCLC patients and seven HNC patients who were undergoing concurrent Caelyx chemoradiotherapy. A high accumulation of the drug into the patients' tumors was documented 2 hours after injection. In lung carcinomas, the mean accumulation of Caelyx was equal to the that observed in the major TVA. The concentration of the drug in this area should be the highest in the body because more than 70% of the drug remains into the blood 2 hours after injection.40 Indeed, this was confirmed by our scintigrams. However, tumoral tissue showed drug concentrations comparable to those in the TVA, confirming the strong preferential uptake of the drug by the tumoral tissue. This preferential uptake seemed to be increasing with time in a small cohort of patients who underwent delayed evaluation 10 hours after the injection of Caelyx. This is in accordance with previous studies with indium-111–labeled liposomes in which the best visualization of tumors was noted 3 to 4 days after injection.40 In our study, Caelyx accumulation in normal lung tissue was two to four times lower than that in cancerous lung tissue. An even higher accumulation of radiolabeled Caelyx was observed in head and neck carcinomas, in which the mean radioactivity was 1.3 times higher than that recorded in the TVA. In our previous studies on lung and head and neck cancer vascularization, we observed that head and neck carcinomas are more frequently highly vascularized, compared with non–small-cell lung carcinomas.35,41 Moreover, we showed that 20% of squamous cell carcinomas have a very high density of dilated vascularization, which is never seen in non–small-cell lung carcinomas. This difference of vessel density may well explain the higher distribution of Caelyx in head and neck carcinomas. Indeed, in a small group of NSCLC patients, we confirmed a direct correlation of tumor microvessel score with the Caelyx intratumoral accumulation. A substantial enhancement by Stealth liposomal doxorubicin of the fractionated radiotherapy efficacy on HNC xenografts has been reported.31 The study presented here, however, is the first study to report the feasibility of concurrent Caelyx administration with conventionally fractionated radiotherapy in NSCLC and HNC. A dose of Caelyx up to 25 mg/m2 every 2 weeks (for three cycles) could be safely given in patients undergoing chest radiotherapy. The maximum tolerated dose in HNC patients was 20 mg/m2. The DLT was grade 3 mucositis, which forced unacceptable treatment delays. Hematologic toxicity was minimal, whereas in-field skin toxicity was slightly increased. The CR rate obtained for lung carcinomas was 21% and that for head and neck carcinomas was 75%. In lung cancer cases, at least, the response rate seemed to be directly associated with the ability of the drug to be captured by the tumor. It seems that highly angiogenic tumors better accumulate liposomal drugs. In a recent study, we showed that very highly vascularized head and neck carcinomas are not chemo- or radiocurable because they rapidly relapse after an initial incomplete response.48 Therefore, it may be that treatment with Stealth liposomal drugs (eg, Caelyx) in combination with radiotherapy is important in the eradication of highly vascularized tumors. The study presented here provides the basis for subsequent evaluation of novel chemoradiotherapy regimens based on treatment with Stealth liposomal doxorubicin. It also provides the methodology for a simple scintigraphic procedure for the assessment of Caelyx affinity to tumors and suggests that studies on tumor vascularization may prove of importance in identifying groups of patients who would better respond to radiosensitization with liposomal drug formulations such as Caelyx.
Supported by the Tumor and Angiogenesis Research Group and Schering Plough S.A.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
