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Positron emission tomography in the detection of residual laryngeal carcinoma
Positron emission tomography in the detection of residual laryngeal carcinoma JOHN R. AUSTIN, MD, FRANKLIN C. WONG, MD, PhO, and E. EDMUND KIM, MD, Houston, Texas
Positron emission tomography measures the metabolic activity of tissue. Because metabolism rates are higher in tumors than in normal tissue, positron emission tomography can be used to identity abnormal tissue. Positron emission tomography has proved useful in detecting residual or recurrent tumor in the brain and gastrointestinal tract after definitive treatment. We selectively used positron emission tomography in a preliminary trial to examine patients with laryngeal cancer who had previously been treated with organ-preservation therapy with radiation therapy alone or in combination with induction chemotherapy. These patients are often difficult to examine both clinically and radiographicaily because of posttreatment edema and fibrosis. From 1991 to 1993 patients at our institution who were treated with either radiation therapy or a combination of induction chemotherapy and radiotherapy for laryngeal carcinoma were evaluated after treatment. If clinical examination was suspicious for residual tumor or recurrence, a computed tomography or magnetic resonance imaging scan was obtained. In 10 patients neither clinical examination nor conventional imaging could absolutely rule out residual/recurrent carcinoma. In these patients positron emission tomography with 2-fluoro-2-deoxy-o-glucose was used to detect disease. The results from positron emission tomography were compared with the results from subsequent biopsy [five patients] or clinical follow-up. Positron emission tomography had a sensitivity of 67% and a specificity of 57%. The positive predictive value of positron emission tomography was 67%. The negative predictive value of positron emission tomography was 80%. Positron emission tomography may offer the clinician a useful diagnostic tool for cancer surveillance in organ-sparing treatment protocols for patients with laryngeal cancer. [OTOLARYNGOLHEAD NECK SURG 1995; 113:404-7.]
~rgan-preservation therapy is increasingly being used as the initial therapy for locally advanced carcinoma of the larynx. This trend is a result of the favorable clinical outcomes of the Veterans Affairs Laryngeal Cancer Study ~and a subsequent study of organ-preservation therapy for patients with this disease. 2 Evaluation of the local treatment response in patients with advanced laryngeal cancer is more important after treatment with radiotherapy plus chemotherapy or radiotherapy alone than it is when
From the Department of Head and Neck Surgery (Dr. Austin) and the Department of Nuclear Medicine (Drs. Wong and Kim), The University of Texas M. D. Anderson Cancer Center. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, San Diego, Calif., Sept. 18-21, 1994. Received for publication Nov. 28, 1994; accepted April 14, 1995. Reprint requests: John R. Austin, MD, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 069, Houston, TX 77030. Copyright © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$5.00 + 0 23/1/65703 404
surgery is used as the primary treatment modality. Although a consensus has not been reached about the optimal treatment for early-stage (T1 and T2) laryngeal cancer, it is generally agreed that radiotherapy is an acceptable form of primary therapy. Posttreatment examination of patients treated with radiotherapy alone or radiotherapy and chemotherapy can be difficult. Clinical examination of the larynx after therapy is difficult because of edema, mucositis, tenacious secretions, and the inability to palpate the endolarynx. Posttreatment imaging by computed tomography (CT) or magnetic residence imaging (MRI), which rely on anatomic correlation, is not always able to detect recurrent or residual disease. The inability of conventional imaging to differentiate posttreatment changes is because of edema, loss of tissue planes, scarring, residual masses, or other abnormalities2 Biopsies of the larynx can miss disease and possibly cause chondritis and airway compromise. Positron emission tomography (PET) with 18labeled 2-ftuoro-2-deoxy-i>glucose (FDG) measures the rate of glucose metabolism in tissue. In
OtolaryngologyHead and Neck Surgery Volume 113 Number 4
tumor tissue, anaerobic glycolysis is prevalent, and the rate of metabolism of glucose is higher than that in normal tissue. 4 Unlike conventional imaging modalities, which depend on anatomic correlation and can thus be rendered ineffective by the anatomic changes caused by radiotherapy plus chemotherapy or radiotherapy alone, PET evaluates metabolic changes. Images from PET with FDG have been used to detect both previously untreated carcinoma of the head and neck and residual carcinoma of the head and neck remaining after radiotherapyY In addition, studies have shown that normal tissue within the radiation field does not show changes in metabolic activity, whereas tumor that is responding to radiotherapy does show a decrease in metabolic activity/ Because PET has ,proved successful in detecting recurrent and residual cancer of the head and neck in patients treated with prior radiotherapy, we elected to use PET to examine patients with laryngeal cancer treated at The University of Texas M. D. Anderson Cancer Center by conservative modalit i e s - e i t h e r radiotherapy alone or combined radiotherapy and chemotherapy. METHODS A N D MATERIAL
In a preliminary clinical trial from 1991 to 1993, patients with laryngeal cancer treated at M. D. Anderson Cancer Center with radiotherapy alone or radiotherapy and induction chemotherapy were evaluated for the presence of disease after treatment. In 10 patients neither clinical examination nor conventional imaging techniques (CT or MRI) could conclusively rule out the presence of residual or recurrent disease. These 10 patients were the subjects of the study reported here. This study received institutional review board approval. Three of the patients had been treated with chemotherapy and radiotherapy. They received cisplatin and 5-fluorouracil followed by twice-a-day hyperfractionated radiation. The average total dose to the primary site was 76.6 Gy. Seven of the patients had been treated with radiotherapy alone. The average dose to the primary was 70.3 Gy. PET was performed with a Posicam 6.5 scanner (Positron Corp., Houston, Tex.). For each patient, 10 _+ 1 mCi of FDG was injected intravenously, and 21 transaxial images were obtained between 41 and 60 minutes after the injection. The axial and reconstructive coronal PET images were evaluated by a panel of two nuclear physicians from M. D. Anderson. Areas of abnormal F D G uptake were identified visually, and the uptake was classified as mildly,
AUSTIN et al.
405
moderately, or markedly increased. Those areas were correlated by location, extent, and functional activity with abnormal areas on CT or MRI images. Standard uptake values (SUVs) for FDG were obtained from the peak activity, and color-coded SUV images of the lesion were generated by the computer. A SUV greater than 3.5 is considered positive for disease. The CT and PET images of a patient treated with 60 Gy for a T2 glottic cancer are shown in Figs. 1 and 2, respectively. During this study, at the discretion of the primary surgeon, a biopsy was performed after PET. Biopsy specimens were obtained from five (50%) patients four with positive findings on PET and one with a negative finding. Of the five patients who did not undergo a biopsy, all had been followed up from 7 to 24 months at the time of this writing. RESULTS
The patient profile and the correlation between the results of PET and the results of subsequent biopsy and/or clinical follow-up are presented in Table 1. Of the PET results, two were true-positive, four were true-negative, three were false-positive, and one was false-negative. The sensitivity of PET (the proportion of patients with residual/recurrent carcinoma who were so identified by PET) was 67%. The specificity of PET (the proportion of patients free of residual/recurrent carcinoma who were so identified by PET) was 57%. The positive predictive value of PET was 67%. The negative predictive value of PET was 80%. Because the sample size in this study was small, a confidence interval with a significant power cannot be determined. DISCUSSION
Recurrent or residual squamous cell carcinoma of the larynx in patients treated with radiation or combined chemotherapy and radiotherapy is difficult to detect with CT or MRI. PET was previously used to detect untreated disease and to follow treatment response. In one study the authors reported that PET detected disease that MRI had not identified. 5 Subsequent work with PET showed that PET could detect unknown primary tumors that clinical examination and radiologic imaging had failed to identify,s Although PET may be able to detect unknown primaries and can also be used to follow clinical response, this may not be the most cost-effective use of PET. PET is an expensive test and requires resources that are not available at all medical facilities. In our study we used PET only in patients for
406
Otolaryngology Head and Neck Surgery October 1995
AUSTIN et al.
Fig. t. CT of larynx in patient 8 treated with 60 Gy of radiation for T2 cancer, Scan reveals fullness a n d edema of true vocal cord but no conclusive evidence of residual c a r c i n o m a .
Fig. 2. PET image showing an SUV of 7.5 predominant in the right side of the endolarynx. Biopsy showed invasive squamous cell carcinoma of the right true v o c a l cord.
whom clinical examination and conventional imaging techniques (CT o r MRI) were equivocal. In these patients, inconclusive clinical and radiologic examinations would usually lead the primary surgeon to recommend a biopsy. In this study four of five patients with positive PET results underwent biopsy. Three of the PET results were shown to be false-positive. One of the five patients with a negative PET result underwent biopsy. The PET result
was shown to be false-negative. In the false-negative case, the surgeon's clinical suspicion outweighed both the CT and PET results. The positive biopsy was followed by a laryngectomy. CONCLUSION
This study suggests a further use for PET in the evaluation of squamous cell carcinoma of the head and neck. For patients treated by therapy designed
Otolaryngology Head and Neck Surgery
Volume 143 Number 4
AUSTIN et al.
407
Table 1. Patient profile Patient no.
PET SUV
PET finding
1
3.0
Neg
Pos
CT CT CT CT CT CT MRI CT
7 3 2 7 2 10 4 6
7.5 6.0 3.5 3.0 3.0 3.0 3.0 7.5
Pos Pos Pos Neg Neg Neg Neg Pos
Neg None Neg None None None None Pos
CT
2
10.0
Pos
Pos
Stage/location
Prior therapy
Imaging technique
1
T3N2A/Trans
Chem + RT
CT
2 3 4 5 6 7 8 9
T3N1/Supra T3N1/Supra T3N0/Supra T2N0/Supra T3N0/Supra T3N1/Supra T2N0/Supra T2N0/glottic
Chem + RT Chem 4- RT RT RT RT RT RT RT1-
10
T3N0/Supra
RT1-
Interval [mo]*
Biopsy finding
Therapy/follow-up
Result
Laryngectomy/ DOD None/18 mo NED None/16 mo NED None/7 mo NED None/23 mo NED None/24 mo NED None/27 mo NED None/7 mo NED Laryngectomy/ 9 mo NED Chem/DOD
False-neg Fatse-pos False-pos False-pos True-neg True-neg True-neg True-neg True-pos True-pos
Cham, Chemotherapy; DOD, died of disease; NED, no evidence of disease; Nag, negative; Pos, positive; RT, radiotherapy; Supra, supraglottic; Trans, transgtettic. *Interval betweencompletion of treatmentand PET; 1-Radiotherapyat outside facility.
to avoid surgery and preserve all or part of the larynx, P E T may be a useful test to detect residual/recurrent disease when clinical examination or radiologic tests are inconclusive. Extension of this work in a larger population of patients treated by conservation techniques is warranted. REFERENCES
1. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685-90. 2. Shirinian MH, Weber RS, Lippman SM, et al. Laryngeal preservation by induction chemotherapy plus radiotherapy in locally advanced head and neck cancer: the M. D. Anderson Cancer Center Experience. Head Neck 1994;16:39-44. 3. Gussack GS, Hudgins PA. Imaging modalities in recurrent head and neck tumors. Laryngoscope 1991;101:119-24.
4. Glaspy JA, Hawkins R, Hoh CK, Phelps ME. Use of positron emission tomography in oncology. Oncology 1993;7:41-55. 5. Bailet JW, Abemayor E, Jabour BA, et al. Positron emission tomography: a new, precise imaging modality for detection of primary head and neck tumors and assessment of cervical adenopathy. Laryngoscope 1992;102:281-8. 6. Minn H, Paul R, Ahonen A. Evaluation of treatment response to radiotherapy in head and neck cancer with fluorine-18 fluorodeoxyglucose. J Nucl Med 1988;29:1521-5. 7. Rege SD, Chaiken L, Hoh CK, et al. Change induced by radiation therapy in FDG uptake in normal and malignant structures of the head and neck: quantitation with PET. Radiology 1993;189:807-12. 8. Rege SD, Maass A, Chaiken L, et al. Use of positron emission tomography with fluorodeoxyglucose in patients with extracranial head and neck cancers. Cancer 1994;73:3047-58.
Positron emission tomography measures the metabolic activity of tissue. Because metabolism rates are higher in tumors than in normal tissue, positron emission tomography can be used to identity abnormal tissue. Positron emission tomography has proved useful in detecting residual or recurrent tumor in the brain and gastrointestinal tract after definitive treatment. We selectively used positron emission tomography in a preliminary trial to examine patients with laryngeal cancer who had previously been treated with organ-preservation therapy with radiation therapy alone or in combination with induction chemotherapy. These patients are often difficult to examine both clinically and radiographicaily because of posttreatment edema and fibrosis. From 1991 to 1993 patients at our institution who were treated with either radiation therapy or a combination of induction chemotherapy and radiotherapy for laryngeal carcinoma were evaluated after treatment. If clinical examination was suspicious for residual tumor or recurrence, a computed tomography or magnetic resonance imaging scan was obtained. In 10 patients neither clinical examination nor conventional imaging could absolutely rule out residual/recurrent carcinoma. In these patients positron emission tomography with 2-fluoro-2-deoxy-o-glucose was used to detect disease. The results from positron emission tomography were compared with the results from subsequent biopsy [five patients] or clinical follow-up. Positron emission tomography had a sensitivity of 67% and a specificity of 57%. The positive predictive value of positron emission tomography was 67%. The negative predictive value of positron emission tomography was 80%. Positron emission tomography may offer the clinician a useful diagnostic tool for cancer surveillance in organ-sparing treatment protocols for patients with laryngeal cancer. [OTOLARYNGOLHEAD NECK SURG 1995; 113:404-7.]
~rgan-preservation therapy is increasingly being used as the initial therapy for locally advanced carcinoma of the larynx. This trend is a result of the favorable clinical outcomes of the Veterans Affairs Laryngeal Cancer Study ~and a subsequent study of organ-preservation therapy for patients with this disease. 2 Evaluation of the local treatment response in patients with advanced laryngeal cancer is more important after treatment with radiotherapy plus chemotherapy or radiotherapy alone than it is when
From the Department of Head and Neck Surgery (Dr. Austin) and the Department of Nuclear Medicine (Drs. Wong and Kim), The University of Texas M. D. Anderson Cancer Center. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, San Diego, Calif., Sept. 18-21, 1994. Received for publication Nov. 28, 1994; accepted April 14, 1995. Reprint requests: John R. Austin, MD, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 069, Houston, TX 77030. Copyright © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$5.00 + 0 23/1/65703 404
surgery is used as the primary treatment modality. Although a consensus has not been reached about the optimal treatment for early-stage (T1 and T2) laryngeal cancer, it is generally agreed that radiotherapy is an acceptable form of primary therapy. Posttreatment examination of patients treated with radiotherapy alone or radiotherapy and chemotherapy can be difficult. Clinical examination of the larynx after therapy is difficult because of edema, mucositis, tenacious secretions, and the inability to palpate the endolarynx. Posttreatment imaging by computed tomography (CT) or magnetic residence imaging (MRI), which rely on anatomic correlation, is not always able to detect recurrent or residual disease. The inability of conventional imaging to differentiate posttreatment changes is because of edema, loss of tissue planes, scarring, residual masses, or other abnormalities2 Biopsies of the larynx can miss disease and possibly cause chondritis and airway compromise. Positron emission tomography (PET) with 18labeled 2-ftuoro-2-deoxy-i>glucose (FDG) measures the rate of glucose metabolism in tissue. In
OtolaryngologyHead and Neck Surgery Volume 113 Number 4
tumor tissue, anaerobic glycolysis is prevalent, and the rate of metabolism of glucose is higher than that in normal tissue. 4 Unlike conventional imaging modalities, which depend on anatomic correlation and can thus be rendered ineffective by the anatomic changes caused by radiotherapy plus chemotherapy or radiotherapy alone, PET evaluates metabolic changes. Images from PET with FDG have been used to detect both previously untreated carcinoma of the head and neck and residual carcinoma of the head and neck remaining after radiotherapyY In addition, studies have shown that normal tissue within the radiation field does not show changes in metabolic activity, whereas tumor that is responding to radiotherapy does show a decrease in metabolic activity/ Because PET has ,proved successful in detecting recurrent and residual cancer of the head and neck in patients treated with prior radiotherapy, we elected to use PET to examine patients with laryngeal cancer treated at The University of Texas M. D. Anderson Cancer Center by conservative modalit i e s - e i t h e r radiotherapy alone or combined radiotherapy and chemotherapy. METHODS A N D MATERIAL
In a preliminary clinical trial from 1991 to 1993, patients with laryngeal cancer treated at M. D. Anderson Cancer Center with radiotherapy alone or radiotherapy and induction chemotherapy were evaluated for the presence of disease after treatment. In 10 patients neither clinical examination nor conventional imaging techniques (CT or MRI) could conclusively rule out the presence of residual or recurrent disease. These 10 patients were the subjects of the study reported here. This study received institutional review board approval. Three of the patients had been treated with chemotherapy and radiotherapy. They received cisplatin and 5-fluorouracil followed by twice-a-day hyperfractionated radiation. The average total dose to the primary site was 76.6 Gy. Seven of the patients had been treated with radiotherapy alone. The average dose to the primary was 70.3 Gy. PET was performed with a Posicam 6.5 scanner (Positron Corp., Houston, Tex.). For each patient, 10 _+ 1 mCi of FDG was injected intravenously, and 21 transaxial images were obtained between 41 and 60 minutes after the injection. The axial and reconstructive coronal PET images were evaluated by a panel of two nuclear physicians from M. D. Anderson. Areas of abnormal F D G uptake were identified visually, and the uptake was classified as mildly,
AUSTIN et al.
405
moderately, or markedly increased. Those areas were correlated by location, extent, and functional activity with abnormal areas on CT or MRI images. Standard uptake values (SUVs) for FDG were obtained from the peak activity, and color-coded SUV images of the lesion were generated by the computer. A SUV greater than 3.5 is considered positive for disease. The CT and PET images of a patient treated with 60 Gy for a T2 glottic cancer are shown in Figs. 1 and 2, respectively. During this study, at the discretion of the primary surgeon, a biopsy was performed after PET. Biopsy specimens were obtained from five (50%) patients four with positive findings on PET and one with a negative finding. Of the five patients who did not undergo a biopsy, all had been followed up from 7 to 24 months at the time of this writing. RESULTS
The patient profile and the correlation between the results of PET and the results of subsequent biopsy and/or clinical follow-up are presented in Table 1. Of the PET results, two were true-positive, four were true-negative, three were false-positive, and one was false-negative. The sensitivity of PET (the proportion of patients with residual/recurrent carcinoma who were so identified by PET) was 67%. The specificity of PET (the proportion of patients free of residual/recurrent carcinoma who were so identified by PET) was 57%. The positive predictive value of PET was 67%. The negative predictive value of PET was 80%. Because the sample size in this study was small, a confidence interval with a significant power cannot be determined. DISCUSSION
Recurrent or residual squamous cell carcinoma of the larynx in patients treated with radiation or combined chemotherapy and radiotherapy is difficult to detect with CT or MRI. PET was previously used to detect untreated disease and to follow treatment response. In one study the authors reported that PET detected disease that MRI had not identified. 5 Subsequent work with PET showed that PET could detect unknown primary tumors that clinical examination and radiologic imaging had failed to identify,s Although PET may be able to detect unknown primaries and can also be used to follow clinical response, this may not be the most cost-effective use of PET. PET is an expensive test and requires resources that are not available at all medical facilities. In our study we used PET only in patients for
406
Otolaryngology Head and Neck Surgery October 1995
AUSTIN et al.
Fig. t. CT of larynx in patient 8 treated with 60 Gy of radiation for T2 cancer, Scan reveals fullness a n d edema of true vocal cord but no conclusive evidence of residual c a r c i n o m a .
Fig. 2. PET image showing an SUV of 7.5 predominant in the right side of the endolarynx. Biopsy showed invasive squamous cell carcinoma of the right true v o c a l cord.
whom clinical examination and conventional imaging techniques (CT o r MRI) were equivocal. In these patients, inconclusive clinical and radiologic examinations would usually lead the primary surgeon to recommend a biopsy. In this study four of five patients with positive PET results underwent biopsy. Three of the PET results were shown to be false-positive. One of the five patients with a negative PET result underwent biopsy. The PET result
was shown to be false-negative. In the false-negative case, the surgeon's clinical suspicion outweighed both the CT and PET results. The positive biopsy was followed by a laryngectomy. CONCLUSION
This study suggests a further use for PET in the evaluation of squamous cell carcinoma of the head and neck. For patients treated by therapy designed
Otolaryngology Head and Neck Surgery
Volume 143 Number 4
AUSTIN et al.
407
Table 1. Patient profile Patient no.
PET SUV
PET finding
1
3.0
Neg
Pos
CT CT CT CT CT CT MRI CT
7 3 2 7 2 10 4 6
7.5 6.0 3.5 3.0 3.0 3.0 3.0 7.5
Pos Pos Pos Neg Neg Neg Neg Pos
Neg None Neg None None None None Pos
CT
2
10.0
Pos
Pos
Stage/location
Prior therapy
Imaging technique
1
T3N2A/Trans
Chem + RT
CT
2 3 4 5 6 7 8 9
T3N1/Supra T3N1/Supra T3N0/Supra T2N0/Supra T3N0/Supra T3N1/Supra T2N0/Supra T2N0/glottic
Chem + RT Chem 4- RT RT RT RT RT RT RT1-
10
T3N0/Supra
RT1-
Interval [mo]*
Biopsy finding
Therapy/follow-up
Result
Laryngectomy/ DOD None/18 mo NED None/16 mo NED None/7 mo NED None/23 mo NED None/24 mo NED None/27 mo NED None/7 mo NED Laryngectomy/ 9 mo NED Chem/DOD
False-neg Fatse-pos False-pos False-pos True-neg True-neg True-neg True-neg True-pos True-pos
Cham, Chemotherapy; DOD, died of disease; NED, no evidence of disease; Nag, negative; Pos, positive; RT, radiotherapy; Supra, supraglottic; Trans, transgtettic. *Interval betweencompletion of treatmentand PET; 1-Radiotherapyat outside facility.
to avoid surgery and preserve all or part of the larynx, P E T may be a useful test to detect residual/recurrent disease when clinical examination or radiologic tests are inconclusive. Extension of this work in a larger population of patients treated by conservation techniques is warranted. REFERENCES
1. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685-90. 2. Shirinian MH, Weber RS, Lippman SM, et al. Laryngeal preservation by induction chemotherapy plus radiotherapy in locally advanced head and neck cancer: the M. D. Anderson Cancer Center Experience. Head Neck 1994;16:39-44. 3. Gussack GS, Hudgins PA. Imaging modalities in recurrent head and neck tumors. Laryngoscope 1991;101:119-24.
4. Glaspy JA, Hawkins R, Hoh CK, Phelps ME. Use of positron emission tomography in oncology. Oncology 1993;7:41-55. 5. Bailet JW, Abemayor E, Jabour BA, et al. Positron emission tomography: a new, precise imaging modality for detection of primary head and neck tumors and assessment of cervical adenopathy. Laryngoscope 1992;102:281-8. 6. Minn H, Paul R, Ahonen A. Evaluation of treatment response to radiotherapy in head and neck cancer with fluorine-18 fluorodeoxyglucose. J Nucl Med 1988;29:1521-5. 7. Rege SD, Chaiken L, Hoh CK, et al. Change induced by radiation therapy in FDG uptake in normal and malignant structures of the head and neck: quantitation with PET. Radiology 1993;189:807-12. 8. Rege SD, Maass A, Chaiken L, et al. Use of positron emission tomography with fluorodeoxyglucose in patients with extracranial head and neck cancers. Cancer 1994;73:3047-58.