2003 Highlights From: XII European Cancer Conference Copenhagen, Denmark September 21-25, 2003

meeting highlight s

2003

Highlights From: XII European Cancer Conference Photographer: Morten Bjarnhof. Photo courtesy of Wonderful Copenhagen® at www.woco.dk

Activity of Erlotinib (OSI-774, Tarceva™) in Bronchoalveolar Carcinoma Overexpression of epidermal growth factor (EGF) has been detected by immunohistochemistry (IHC) in 47% of adenocarcinomas of the lung,1 and is associated in most cases with advanced-stage disease and poor prognosis. In phase II clinical trials, EGF receptor (EGFR)–targeted therapy using the small-molecule EGFR tyrosine kinase inhibitors erlotinib (OSI-774, Tarceva™) or gefitinib resulted in objective response rates (ORR) of 9%-20% in patients with non–small-cell lung cancer (NSCLC) in whom prior chemotherapy had failed, with control of disease-related symptoms reported in 35%-54% of patients.2-4 In the phase II trials of gefitinib, patients with adenocarcinomas had better response rates compared with patients with other lung cancer histologies.5 This trend was also observed in the recently reported Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 2 trial that compared standard chemotherapy with paclitaxel/carboplatin versus gefitinib plus paclitaxel/carboplatin.6 Although adding the EGFR inhibitor to standard chemotherapy did not improve survival in the entire cohort of previously untreated patients with NSCLC, in the subgroup of patients with adenocarcinomas, survival was significantly longer with paclitaxel/carboplatin/gefitinib (17.1 months) compared with paclitaxel/carboplatin/placebo (13.6 months; log-rank test, P = 0.05). Approximately 24% of adenocarcinomas Prepared by: Angelia D. Gibson, PhD, David Lee, PhD, Kavita Maung, PhD, Preeta Tyagi, PhD Reviewed by: Chandra P. Belani, MD, Vinay K. Jain, MD, Sakkaraiappan Ramalingam, MD, Rafael Rosell, MD

Copenhagen, Denmark September 21-25, 2003

are bronchoalveolar carcinomas (BACs), a clinically distinct histologic subtype that is largely regarded as chemotherapy-resistant by most clinicians.7 Anecdotal reports suggest that EGFR inhibition is especially effective therapy for BAC, inducing longterm clinical responses and disease palliation in patients with chemotherapy-resistant disease.8-11 Moreover, a retrospective analysis of patients treated with gefitinib for NSCLC found that presence of any BAC features (P = 0.005) and being a lifetime nonsmoker (P = 0.007) were the only independent predictors of response to EGFR inhibition with gefitinib.12 Observations that EGFR inhibition appears most beneficial to patients with adenocarcinomas, particularly those with BAC features, prompted several groups to conduct trials on the EGFR inhibitors and to exclusively enroll patients with adenocarcinomas or BACs. At the XII European Cancer Conference, held September 25-30, 2003, in Copenhagen, Denmark, Patel and colleagues updated the results of a phase II study of erlotinib, which enrolled patients with BAC or adenocarcinomas with BAC clinical features.13 Eligible patients had unresectable, measurable, and pure BAC according to World Health Organization classification, BAC with invasion or adenocarcinoma with BAC, and had previously been treated with ≤ 1 previous treatment regimen. Patients were required to have a Karnofsky performance status (PS) of ≥ 60%. Treatment consisted of erlotinib 150 mg daily. The primary objective of this study was to determine the ORR in patients with BAC treated with erlotinib. The secondary objectives were to characterize the toxicities of this agent, along with analysis of EGFR signaling pathway components in patients with sensitive and resistant disease. Of 111 patients screened, 79 were eligible for the study. A majority of patients

Table 1: Phase II Trial of Erlotinib (OSI-774, Tarceva™) in BAC: Patient Characteristics Number of Patients Median Age, Years (Range)

52 66 (33-85)

Karnofsky Performance Status 70%

6%

80%

61%

90%-100%

33%

Smoking Former or current

75%

Never (<100 cigarettes/lifetime)

25%

Previous Chemotherapy None

75%

1 Regimen

25%

Abbreviation: BAC = bronchoaveolar adenocarcinoma

(72%) had adenocarcinoma with BAC features and 25% had pure BAC. The 52 evaluable patients had a median age of 66 years (range, 33-85) and a Karnofsky PS ≥ 70% (Table 1). Among these, 75% of patients were smokers or former smokers and 75% Table 2: Erlotinib (OSI-774, Tarceva™) in BAC: Results Patients (N = 52) Activity Confirmed PR

25%

Ongoing PR

13%

Progression after PR for 3-13 months

12%

Grade 3 Toxicity Rash

8%

Arthralgias

2%

Diarrhea

2%

Abbreviation: BAC = bronchoaveolar adenocarcinoma

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were chemotherapy-naive. At a median follow-up of 9 months, partial response was achieved in 25% of patients (Table 2). The response was ongoing in half of these patients, whereas the other half had progression after 3-13 months of response. There was a trend for improved response rate with erlotinib in patients who had never smoked (46% in nonsmokers vs. 21% in smokers; P = 0.09). This is consistent with data from a retrospective analysis that indicated nonsmokers had higher probability of responding to the EGFR inhibitor gefitinib.12 Other variables, like sex (31% response in women vs. 12% in men; P = 0.18), pathology (17% response in patients with pure BAC vs. 24% in other BACs; P = 0.71), and previous chemotherapy (23% response in chemotherapy-naive patients vs. 25% in patients with 1 prior regimen; P = 1), were not correlated with response. Grade 3 skin rash was noted in 4 patients. Other grade 3 toxicities were arthralgias and diarrhea (n = 1 each). One patient withdrew from the study because of toxicity. There were 4 deaths, 2 from disease progression and 1 from pulmonary embolism. In one patient, the cause of death was unknown.

Clinical Relevance Erlotinib, a small-molecule EGFR inhibitor, has activity in BAC. The Southwest Oncology Group has reported a response rate of 14% with gefitinib in BAC. These 2 studies suggest that the EGFR pathway may be an important disease target for patients with BAC.14 The observation from this trial that erlotinib was twice as active in nonsmokers as in smokers warrants further investigation of differences in disease biology between smokers and nonsmokers. The encouraging response data from this trial have led the investigators to launch a phase III trial exploring the use of erlotinib alone versus a standard cisplatin-based doublet for BAC.

Addition of the Anti-EGFR Antibody Cetuximab to Chemotherapy Improves Response in NSCLC Cetuximab is a chimeric monoclonal antibody that acts against the EGFR. It has been evaluated in clinical trials as a single agent and in combination with other cytotoxic agents and radiation therapy. Furthermore, cetuximab has been found to reverse irinotecan resistance in patients with metastatic colon carcinoma.15 Although cetuximab and other smallmolecule inhibitors target the EGFR, there

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Table 3: Efficacy of Cisplatin/Vinorelbine Alone and in Combination with Cetuximab in Advanced Chemotherapy-Naive NSCLC Toxicity

Response Rate Disease Control Rate (CR + PR + SD) Response Rate in Patients with Acneiform Rash (n = 15) Disease Control Rate in Patients with Acneiform Rash (n = 15)

Cetuximab/ Cisplatin/ Vinorelbine (n = 39) 56% 97%

5 (33%)

15 (100%)

Cisplatin/ Vinorelbine (n = 37) 30% 73%

Table 4: Selected Grade 3/4 Toxicities Cetuximab/ Cisplatin/ Vinorelbine (n = 42)

Cisplatin/ Vinorelbine (n = 43)

Neutropenia

18 (43%)

13 (30%)

Nausea/Vomiting

6 (14%)

4 (9%)

Infection

4 (9.5%)

2 (5%)

Fever/Chills/Sweating

3 (7%)

1 (2%)

Acneiform Rash

2 (5%)

0

Hypersensitivity

0

0

Toxicity

NA

NA

Abbreviations: NA = not applicable; NSCLC = non–small-cell lung cancer

are differences in the mechanism of action that may have important clinical consequences. In contrast to small-molecule tyrosine kinase inhibitors, antibodies such as cetuximab inhibit receptor phosphorylation and also stimulate receptor internalization, thus removing this signaling moiety from the cell surface, which might be required in order for this class of agents to increase the efficacy of combination chemotherapy.16 The Lung Cancer Cetuximab Study group conducted a randomized phase II study to evaluate the benefit of adding an EGFR-targeted antibody, cetuximab, to chemotherapy (cisplatin/vinorelbine) for patients with advanced NSCLC. The primary endpoint of the study was ORR. Secondary endpoints were time to progression (TTP), overall survival (OS), and toxicity. The results of this randomized phase II trial by Rosell et al were recently reported the XII European Cancer Conference17 The trial enrolled patients with EGFRpositive (≥ 1+ by IHC), histologically confirmed advanced NSCLC. Patients with stage IV disease or stage IIIB NSCLC with documented pleural effusion who had not received prior chemotherapy were eligible. Patients could not have had prior exposure to monoclonal antibodies or EGFR-targeted therapies. Patients were randomized to receive cisplatin 80 mg/m2 on day 1 plus vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks with or without cetuximab 250 mg/m2 every week (with a 400-mg/m2 loading dose). Response to therapy was monitored by computed tomography (CT) every 2 cycles. A total of 85 patients were randomized, with 42 patients receiving cetuximab/vinorelbine/ cisplatin and 43 patients treated with vinorelbine/cisplatin without cetuximab. The study arms were well balanced for patient characteristics. The median ages were 59 years (range, 37-75 years) and 58

years (range, 34-73 years) in the cetuximabcontaining and chemotherapy-only arms, respectively. Approximately 90% of patients in each group had stage IV NSCLC. Seventy-six patients were evaluable for response (Table 3). The ORR was higher in the cetuximab-containing arm at 56%, compared with 30% for patients treated with chemotherapy alone. Forty-one percent and 43% of patients in the 2 arms exhibited stable disease, respectively. Disease control (response rate plus disease stabilization rate) occurred in 97% and 73% of patients, respectively. Five of 15 patients (33%) who experienced an acneiform rash (all grades) experienced a response, and all 15 patients exhibited disease control. Grade 3/4 toxicities were similar between the 2 treatment arms (Table 4). Neutropenia occurred in 18 patients (43%) in the cetuximab-containing arm and in 13 patients (30%) in the chemotherapy-only arm. Nausea/vomiting occurred in 6 patients (14%) and 4 patients (9%), respectively. Four patients in the cetuximab group (9.5%) and 2 patients receiving chemotherapy alone (5%) had grade 3/4 infection. As expected, acnelike rash was observed in the cetuximab group, but only 2 patients (5%) experienced grade 3/4 severity. No hypersensitivity reaction to cetuximab was noted.

Clinical Relevance The addition of cetuximab to vinorelbine/cisplatin resulted in higher response rates compared with administration of chemotherapy alone (56% vs. 30%). Furthermore, combining cetuximab with the cisplatin/vinorelbine regimen did not result in increased toxicity and was well tolerated. The impact of the increased response efficacy seen with cetuximab in combination with chemotherapy on survival was not reported; however, the results of this randomized phase II study are encouraging in comparison with the complete lack of benefit seen with administration of small-molecule inhibitors of EGFR in combination with chemotherapy.16,18

Phase I Study of EMD 72000/ Paclitaxel in Lung Cancer Overexpression of the EGFR in NSCLC tumors appears to be correlated with poor prognosis.19 The EGFR signaling pathway plays an important role in cellular growth, differentiation, and survival, and therefore is a target for NSCLC therapy. Epidermal growth factor receptor can be inhibited by blocking signal transduction either at the level of intracellular tyrosine kinase domain or at the extracellular ligand-binding domain. Data from phase II trials indicate that small-molecule inhibitors of tyrosine kinase such as gefinitib and erlotinib are effective as salvage therapy for NSCLC.2-4 However, the combination of a small-molecule EGFR inhibitor with chemotherapy does not improve the outcome compared with chemotherapy alone in the first-line treatment of advanced NSCLC.20 Monoclonal antibodies directed against the external domain of the EGFR represent another therapeutic strategy to inhibit EGFR signaling.17 The chimeric anti-EGFR monoclonal antibody cetuximab has shown clinical activity in combination with chemotherapy in patients with EGFR-positive NSCLC. EMD 72000, a humanized monoclonal antibody that binds to EGFR with high specificity, is designed to block receptor– ligand binding and consequently inhibit tumor growth. EMD 72000 has shown preclinical antitumor activity alone and in combination with gemcitabine in human tumor xenografts.21 In a phase I dose-escalation study, the maximum tolerated dose (MTD) of single-agent EMD 72000 was established at 1600 mg per week. At this dose, EMD 72000 resulted in an ORR of 23% in 22 patients with EGFR-positive solid malignancies (gastric, colorectal, and head and neck). The main side effects noted in this study were skin rash of mild to moderate severity, fever, and headaches. Preliminary pharmacokinetic data also suggest that lessfrequent dosing schedules of EMD 72000 are feasible.22 As a single agent, paclitaxel, although active in advanced NSCLC, has an ORR of approximately 25%.23 Kollmannsberger and colleagues conducted a phase I dose-escalation study to determine the MTD of the Table 5: Dose-Escalation Design with EMD 72000 Dose Level

Weekly EMD 72000 (I.V. Over 1 Hour)*

Level 1 (n = 3)

100 mg

Level 2 (n = 3)

200 mg

Level 3 (n = 4)

400 mg

Level 4 (n = 7)

800 mg

*Paclitaxel 175 mg/m2 I.V. was given with EMD 72000 over 3 hours on day 1 of a 21-day cycle.

Table 6: Efficacy and Toxicity of EMD 72000/ Paclitaxel in Advanced NSCLC Response Overall Response Rate

Evaluable Patients (N = 16) 5 (31%)

Complete response

1 (6%)

Partial response

4 (25%)

Stable Disease

7 (44%)

Clinical Relevance

Grade 3/4 Toxicities Allergic reaction to paclitaxel Dyspnea

Toxicity was mild and mostly consisted of cutaneous acneiform rash. One patient experienced EMD 72000–related grade 1 flushing and grade 2 bronchospasm that were prevented with appropriate premedication with subsequent doses. Grade 3/4 dyspnea, thought to be an allergic reaction to paclitaxel, was noted in 2 patients.

1 (6%) 4 (25%)†

†Two cases were caused by allergic reaction to paclitaxel.

Abbreviation: NSCLC = non–small-cell lung cancer

combination of EMD 72000 and paclitaxel 175 mg/m2 in patients with EGFR-positive (> 1+ by IHC) advanced NSCLC.24 The updated results of this study were presented at the XII European Cancer Conference.25 Patients with histologically confirmed stage IIIB/IV NSCLC, whether chemotherapy-naive or previously treated with chemotherapy, were included in this study. Patients were required to have EGFR-positive tumors accessed by IHC and adequate hepatic, renal, and bone marrow function. Eligible patients received weekly doses of EMD 72000 at 1 of 4 dose levels (100, 200, 400, or 800 mg per week) in combination with paclitaxel, which was administered at a dose of 175 mg/m2 every 21 days without premedication. The dose-escalation design is shown in Table 5 and the standard 3+3 study design was used. Seventeen patients with a median age of 63 years (range, 29-71 years) were entered in this study. Seventy-one percent of patients were male and 94% had stage IV disease. Adenocarcinoma was the most common histology in 82% of patients. Approximately half of the patients had received prior chemotherapy. Of the 17 patients treated in the study, 3 patients each were treated at dose levels 1 and 2, 4 were treated at dose level 3, and 7 were treated at dose level 4. No dose-limiting toxicity was seen in any patient cohort at any of the dose levels evaluated in the study. The MTD had not been reached as of the presentation. All 34 tumors evaluated were EGFR-positive. Among 16 evaluable patients who had received ≥ 2 treatment cycles (range, 2-16 cycles), 1 patient (6%) exhibited a complete response and 4 patients (25%; 2 chemotherapy-naive and 2 pretreated) exhibited a PR, for an ORR of 31%. Seven patients (44%) showed stable disease (Table 6). Initial pharmacokinetic data assessed by measuring serum concentrations versus time profiles showed the half-life of EMD 72000 to be approximately 4-6 days. There were no pharmacokinetic interactions between EMD 72000 and paclitaxel.

EMD 72000, a humanized monoclonal EGFR antibody, can be administered safely in combination with paclitaxel in patients with advanced NSCLC. The maximum tolerated dose of the combination has not been reached in this phase I clinical trial and no dose-limiting toxicity was observed at the highest dose level of EMD 72000. The encouraging antitumor activity (response rate, 31%) noted in this phase I study warrants further evaluation in phase II clinical trials. Furthermore, initial pharmacokinetic data also suggests that EMD 72000 can be administered at higher doses less frequently (eg, once every 2 or 3 weeks) with paclitaxel. A trial is being conducted to evaluate the safety and efficacy of administering EMD 72000 once every 3 weeks with paclitaxel in patients with NSCLC. Randomized studies are also being planned to determine if EMD 72000 improves outcomes when combined with docetaxel as second-line therapy for NSCLC.

Multicenter Phase II Study of Gemcitabine/Oxaliplatin in Advanced NSCLC The combination of gemcitabine/cisplatin is active in patients with advanced NSCLC. In a randomized trial in patients with advanced NSCLC (N = 522), gemcitabine/cisplatin was superior to cisplatin alone, with an ORRs 30% and 11%, respectively (P < 0.0001), an increase in median survival of 1.5 months (P = 0.004), and an increase in TTP of nearly 2 months (P = 0.0013).26 However, gemcitabine/cisplatin was also associated with significantly more grade 4 thrombocytopenia than cisplatin alone (25% vs. < 1%), and nonhematologic toxicity profiles were comparable. Oxaliplatin is a potent cytotoxic agent with no renal toxicity and lower hematologic and gastrointestinal toxicity rates than cisplatin.27 Additionally, preclinical studies have shown synergism between gemcitabine and oxaliplatin, a combination demonstrating superior cytotoxicity on a human colon

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Figure 1: Treatment Schema of Gemcitabine/Oxaliplatin Gemcitabine 1000 mg/m2 I.V. Oxaliplatin 130 mg/m2 I.V. Cycle Repeats Day 1

8

15

22

cancer cell line (HCT 116) and at least equal cytotoxicity on another colon cancer cell line (Colo 320 DM) and a leukemia cell line (CEM) compared with gemcitabine/cisplatin.28 Taken together, these observations suggest that oxaliplatin is worthy of evaluation in combination with gemcitabine for the treatment of advanced NSCLC. A phase I/II study of gemcitabine/oxaliplatin in NSCLC and patients with ovarian carcinoma established the feasibility of this combination at a recommended dose of gemcitabine 1500 mg/m2 followed by oxaliplatin 85 mg/m2, given every 2 weeks.29 The investigators reported an ORR of 34% in 35 patients with NSCLC, with manageable hematologic toxicity occurring in < 10% of the treatment cycles at the recommended dose. Two phase I studies have used different schedules of gemcitabine/oxaliplatin. Mavroudis and colleagues showed that gemcitabine 1000-1600 mg/m2 given on days 1 and 8 every 21 days could be safely combined with oxaliplatin 60-120 mg/m2 given on day 8.30 A California Consortium trial studied a fixed dose of oxaliplatin 130 mg/m2 given on day 1 every 21 days followed by escalating doses of gemcitabine Table 7: Gemcitabine/Oxaliplatin in NSCLC: Toxicity Response

Patients (N = 54)

Overall Response Rate

12 (22%)

Complete response

11 (20%)

Stable Disease

19 (35%)

Disease Control Rate Toxicity

Clinical Relevance

1 (2%)

Partial response

57% Grade 3

Grade 4

Neutropenia

4 (7%)

1 (2%)

Thrombocytopenia

3 (6%)

1 (2%)

Leukopenia

1 (2%)

0

Anemia

1 (2%)

0

Hematologic

Nonhematologic Gastrointestinal

5 (9%)

0

Cardiovascular

0

2 (4%)

Hepatic

2 (4%)

0

Neurologic

1 (2%)

0

Abbreviation: NSCLC = non–small-cell lung cancer

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700-1750 mg/m2 given on days 1 and 8.31 Dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 confusion, and the investigators recommended a dose of 1000 mg/m2 along with oxaliplatin 130 mg/m2 for future studies. Based on these studies, Cappuzzo and colleagues conducted a multicenter, phase II trial of gemcitabine/oxaliplatin in chemotherapy-naive patients with NSCLC. The results of this trial were presented at the XII European Cancer Conference.32 Patients with locally advanced or metastatic NSCLC were eligible for the study. No previous chemotherapy was permitted. Eligible patients received gemcitabine 1000 mg/m2 as a 30-minute intravenous (I.V.) infusion on days 1 and 8 every 3 weeks followed by oxaliplatin 130 mg/m2 as a 2-hour I.V. infusion on day 1. Treatment was planned for 2-8 cycles (Figure 1). The primary endpoints of this study were response rate and toxicity. The secondary endpoints were progression-free survival and OS. A total of 54 patients were enrolled in the study, with a median age of 61 years (range, 36-73 years), and all patients had a Karnofsky PS of ≥ 70%. Eighty-one percent of the patients had stage IV disease. Adenocarcinoma was the histology observed in 50% of the patients, with an additional 31% of patients having squamous cell carcinoma. The ORR was 22%, with 2% of the patients exhibiting a complete response. An additional 35% of the patients had disease stabilization, for a disease control rate of 57% (Table 7). The regimen was well tolerated, with a low incidence of grade 4 toxicities (Table 7). Grade 4 neutropenia and thrombocytopenia were observed in 1 patient each. Two patients experienced grade 4 cardiac toxicity. Grade 3 nonhematologic toxicities included gastrointestinal toxicity in 9% of the patients and hepatic toxicity in 4%. Grade 3 neurotoxicity was observed in only 1 patient. The combination of gemcitabine/oxaliplatin administered on a 21-day schedule is safe and is associated with a low incidence of grade 4 toxicities. The combination is also effective for the treatment of NSCLC, as evident by the response rate of 22% and disease control rate of 57%. The response rate noted with this combination appears similar to the response rate associated with gemcitabine/cisplatin in advanced NSCLC. In addition to its favorable toxicity profile, oxaliplatin may be more suited for outpatient therapy and may eventually replace cisplatin in various combination regimens, as the administration of oxaliplatin does not require I.V. hydration.

Impact of Positron Emission Tomography Imaging on Radiation Therapy Planning for NSCLC Precise target definition can improve cure rates for radiation therapy by reducing the number of geographic misses with the radiation beam and facilitating radiation dose escalation within a precisely defined target volume. Moreover, accurate target definition can reduce the risk of radiation-induced toxicity by limiting irradiation of adjacent nonmalignant tissues. Consequently, high-resolution structural data provided by CT technologies are indispensable for radiation therapy planning. Positron emission tomography (PET) scanning using [18F]fluorodeoxyglucose (FDG) provides physiologic information that is complementary to the structural data obtained with CT. Important applications for FDG-PET have been found for the diagnosis and staging of lung cancer, as well as for assessing response to therapy and detecting recurrent disease.33 At the XII European Cancer Conference, De Jaeger and Comans reviewed the impact and limitations of functional imaging with FDG-PET on planning radiation therapy for NSCLC (Table 8).34 De Jaeger and Comans presented scans to demonstrate that, compared with standard CT imaging, data obtained from combined CT/PET scanners can improve definition of the nodal target volume as well as the primary lung tumor for radiation therapy. They also reviewed evidence from published literature of improved target definition with PET scanning. A metaanalysis of studies conducted in the 1990s found that PET was superior to CT for mediastinal staging of NSCLC, providing higher sensitivity (79% vs. 60%) and specificity (91% vs. 77%).35 Data from a few small prospective comparative studies have suggested that incorporation of PET scanning data into radiation therapy planning can reduce the geographic miss rate and improve the accuracy of target definition.36,37 In these clinical trials, information obtained from PET scans led to changes in planned target volume (PTV) in 34%100% of cases (Table 9).36,38-41 In most of these studies, FDG-PET scans detected involved nodes that were missed with conventional CT imaging, and the PTV for radiation was consequently increased, in one study by as much as 76%.36,40,41 At the XII European Cancer Conference, van der Wel et al reported that the geographical miss rate with PET/CT–based PTV was 14% compared with the miss rate with PTV based on CT scans alone.37 Positron emission tomography scanning may be especially useful for patients with

Table 8: Benefits and Limitations of PET Imaging for Radiation Therapy Planning Benefits

Limitations

Can identify involved nodal areas that may be missed with CT

Limited structural resolution of clinical PET scanners (~ 7 mm)

Can exclude uninvolved atelectatic lung tissue that would be considered metastatic on conventional CT analysis

Variability in FDG uptake

May permit dose escalation within precisely defined tumor volume

Respiration/motion artifacts

Preliminary data suggest PET/CT imaging improves tumor control probability over CT imaging alone in setting of radiation therapy planning

Lack of correlation between PET data and true surgical extensions of tumors

Abbreviations: CT = computed tomography; FDG = [18F]fluorodeoxyglucose; PET = positron emission tomography

Table 9: Clinical Impact of PET on Planned Target Volume in NSCLC Study

Number of Patients Radiation Therapy Altered*

Planned Target Volume Decreased

Increased

Erdi et al36

11

100%

18%

19%

Munley et al38

35

34%

NR

NR

29% (Average)

–

Vanuytsel et al39

73

62%

Kalff et al40

34

65%

Mah et al41

30

NR

21% 15% (Treatment volume) (Treatment volume) 24%-70%

30%-76%

*Planned radiation therapy was altered based on PET information. Abbreviations: NR = not reported; NSCLC = non–small-cell lung cancer; PET = positron emission tomography

tumor-associated atelectasis, in which it is difficult to distinguish tumor tissue from atelactatic tissue. In some studies, information from FDG-PET led to reductions in the PTV caused by exclusion of atelectatic but uninvolved lung tissue, which cannot be discriminated from malignant tissue with conventional CT.36,42 Investigators have reported that routine incorporation of metabolic imaging data significantly reduced interobserver variability in tumor target volume delineation (P < 0.01).43 The mean ratio of largest to smallest gross tumor volume was 2.31 with CT alone, compared with 1.56 with PET/CT. Noting that there is a clear relationship between tumor response and radiation dose, De Jaeger and Comans discussed how information from PET might permit escalation of the radiation dose within a precisely defined target volume or alterations in tumor-control probability curves such that optimal local control may be achieved at lower radiation doses.34 Preliminary data from the study by van der Wel et al provides proof of concept for this hypothesis.37 The investigators found that tumor control probability was higher in the lung (P = 0.005), esophagus (P = 0.005), and central nervous system (P = 0.041) when radiation therapy planning was based on information from PET/CT scans rather than CT alone.37

Nevertheless, De Jaeger and Comans cautioned that there are still some caveats to routine incorporation of PET data for radiation therapy planning. Limited resolution of current PET scanners could lead to registration errors, as the radiation therapy treatment position cannot always be reproduced on the PET scanner. Additionally, there is interpatient variability in the FDG uptake intensity, which warrants determination of individual threshold values. There is currently a lack of data on correlation between PET scan findings and precise definition of extent of tumors, which needs to be addressed in future studies. Finally, the problem of respiration and motion artifacts introduces error for both PET and CT scans, although several groups are studying the feasibility of respiration-gating techniques that could reduce motion artifacts with PET.44-46

Clinical Relevance FDG-PET scanning provides metabolic information that is complementary to the high-resolution anatomic/structural data obtained with conventional or helical CT and also improves the ability to precisely define nodal target volume for radiation therapy. It is hoped that this improvements in target volume definition will ultimately translate to improved long-term locoregional control rates for

radiation therapy of NSCLC. Recent availability of combined CT/PET scanners as well as ongoing research in determining individual threshold FDG uptake values, improving structural resolution of the PET scanner, and correcting for motion/respiration errors will add to the value PET imaging provides for radiation planning for NSCLC as well as other solid tumors.

References

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