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Timing and dosage of postoperative radiotherapy for squamous cell carcinoma of the upper aerodigestive tract
J Oral Maxillofac Surg 51 :119 4-1197,1993
Timing and Dosage of Postoperative Radiotherapy for Squamous Cell Carcinoma of the Upper Aerodigestive Tract FEDERICO L. AMPIL, MD,· KENNAN J. BUECHTER, MD,t LEE E. BAIRNSFATHER, PHD,:f: AND WILLIAM W. SHOCKLEY, MD§ Seventy patients who received postoperative irradiation (PI)after curative surgery for stage III or IV squamous cell carcinoma of the upper aerodigestive tract were studied retrospectively to compare the rate of local and regional recurrence (LRR) and the effect of total dose on LRR rate in patients irradiated timely (n = 40) with those who were not (n = 30). Overall, the LRR rate was higher when PI was delayed than when timely (37% vs 20%). No advantage resulted from increasing total dose when PI was delayed; the LRR rate in the primary site and upper neck was 18% with less than 60 Gy and was 26% with 60 Gy or more; the LRR rate in the lower neck was 13% with 50 Gy or less and was 14% with more than 50 Gy. These data seem to corroborate the findings of other investigators regarding the importance of initiating timely PI, but not the observation that a pronounced delay is not detrimental provided higher tumoricidal doses are used.
The influence of an arbitrary delay of more than 6 weeks prior to elective postoperative irradiation (PI) on the rate of local and regional recurrence (LRR) of squamous cell carcinoma of the upp er aerodigestive tract remains an unsettled issue. Several studies! " have found it detrimental to delay PI, while another study" has shown no difference between timely and delayed PI. A recent report" suggested that a protracted delay of PI does not have a negative impact on locoregional disease control as long as 60 Gy or higher tumoricidal doses are used. Recommendations concerning total dose of PI have varied from 50 to 70 Gy.3.6-1O However,
the optimum total dose for subclinical disease remains to be determined. The objective of this retrospective study was to compare the rate of LRR and the effect of total dose on LRR rate in patients who received timely PI with those who did not.
Materials and Methods One hundred twenty-nine patients were irradiated using cobalt 60 or a 6-m V linear accelerator following curative resection of head and neck cancer at the university-affiliated institutions during a 24-year period, 1975-1989. This study was limited.to 70 patients who were similar in most respects except for the timing of their PI. The following clinical features made them eligible for inclusion in the study: I) squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; 2) stage III or IV disease according to the system developed by the American Joint Committee on Cancer;" 3) PI administered via parallel opposed lateral portals, which encompassed the primary tumor site and upper neck (primary treatment field), and an anterior lower neck "yoke" portal; 4) no 10coregional disease or distant metastasis present at the time of initiation of PI; and 5) ~valuable for LRR at
Received from Louisiana Stat e Univers ity School of Medicine in Shreveport . Shre veport, LA. • Department of Radiology. t Form erly, Department of Surgery; curr ently, Department of Surgery, Louisiana State University School of Medicine in New Orleans. New Orleans, LA. Department of Biometry . § Formerl y, Department of'Otolaryngolcgy-i-Head Neck Surgery; currentl y, Department of Otolaryngology-s-Head Neck Surgery, University of North Carolina School of Medicine, Chapel Hill. NC. Address correspondence and reprint requests to Dr Ampil: Department of Radiology, Louisiana State University Medical Cent er. 1501 Kings Highway, PO Box 33932, Shreveport. LA 71130-3932.
*
© 1993 American Association of Oral and Maxillofacial Surgeons 0278-2391/93/5111-0004$3.00/0
1194
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AMPIL ET AL
the time of death or after a minimum follow-up of 2 years. Surgical procedures were described as supraglottic or total laryngectomy with or without pharyngectomy or radical neck dissection, composite resection, pharyngectomy, or wide tumor resection with or without neck node dissection. In the first group (n = 40), PI was given within 6 weeks after surgery. In the second group (n = 30), because of some delay in wound healing, PI was given later than 6 weeks. In both groups, radiation therapy was administered for 5 consecutive days each week until the prescribed dosage was achieved. Radiation dose was calculated at midplane for the opposed lateral portals and at a depth of 1.5 to 3 em for the lower neck portal. The prescribed total tumor dose is shown in Table 1. A shrinking field technique for the lateral portals was used after administration of40 to 50 Gy. Midline spinal cord shielding in the lower neck portal was performed when the prescribed dosage was more than 50 Gy, The spinal cord dosage did not exceed 45 Gy. The daily dose was 1.8 to 2.0 Gy. Dental evaluation and management was ordinarily handled prior to irradiation. Follow-up information was available for all 70 patients for periods that varied from 6 to 125 months, the average being 30 months. Results were compared for statistically significant differences by x2 analysis mid Fisher's exact analysis using algorithms described by Mehta and colleagues'? and implemented by Statxact software (Cytel Software Corp, Cambridge, MA).13
Table 1.
Mean age (yr) Range Primary tumor site Oral cavity Oropharynx Larynx Hypopharynx Larynx-hypopharynx Stage 111 IV Median total dose (Gy) Primary tumor site and upper neck Range Lower neck Range Total
No Prolonged Delay (n)
Prolonged Delay (n)
59 46-76
57 41-69
5 7 20 5 3
3 II
12 2 2
23
8 22
60 54-66 50 45-60
60 50-68 50 46-60
40
30
17
No. Recurrence/ No. Patients (%)
Risk Factor Age (yr) <65 ~65
Disease stage" 111 IV Primary tumor extent* T2 T3 T4 Retional tumor extent* NO-I N2-3 Disease site Oral cavity Oropharynx Larynx-hypopharynx Timing of postoperative irradiation No prolonged delay Prolonged delay Total dose (Gy) Primary site and upper neck <60 ~60
Lower neck ;$;50 >50
P
15/56 (27) 4/14 (29)
NS
6/25 (24) 13/45 (29)
NS
1/10 (10) 3/36 (8) 3/24 (13)
NS
4/42 (10) 8/28 (29)
<.05
1/8 (13) 7/18 (39) 11/44 (25)
NS
8/40 (20) 11/30 (37)
NS
5/25 (20) 9/45 (20)
NS
4/49 (8) 1/21 (5)
NS
* According to the system developed by the American Joint Committee on Cancer.
Where values of less than .05 were found, the differences were considered significant. The diagnosis of LRR was based on obvious clinical findings (n = 4) or on histologic evidence (n = 15).
Patient Characteristics
Variable
Table 2. Risk Factors for Local and Regional Recurrence
Cancer staged according to the system developed by the American Joint Committee on Cancer.
Results The characteristics of the compared groups of patients are shown in Table 1. A significant difference in the listed features was not apparent. The overall LRR rate was 27% (19 of 70). A univariate analysis of risk factors for LRR is shown in Table 2. The only factor ofsignificance was the clinical extent of regional disease at presentation. A meaningful assessment of the prognostic importance of the presence of tumor at the resection margins was not possible due to the infrequent (n = 3) occurrence of this situation in this series. These three patients were free of disease at the time of death or follow-up. Because pathologic nodal status was not mentioned in six patients, there were only 64 patients who were evaluable with respect to pathologic status of removed nodes and the rate of regional recurrence. Regional recurrence rate was 0% (none of 18) when neck nodes were free
POSTOPERATIVE RADIOTHERAPY: TIMING AND DOSAGE
1196 of metastatic disease, 0% (none of 16) when only one node was involved with disease, and 40 % (12 of 30) when several nodes contained metastasis (P < .001). A lower overall LRR rate was observed in patients who were irradiated timely than in those who were not (Table 2). The location of recurrent disease is shown in Table 3. Median survival from the time ofLRR was 5 months. When LRR rates were analyzed as a function oftiming and total dose of PI (Table 4), a lower recurrence rate was not seen in the primary treatment field or lower neck with an increase in total dose for patients with a prolonged delay in the initiation of PI. In contrast, in patients whose initiation of PI was not excessively delayed, lower LRR rates were associated with those patients who received higher radiation doses than with those treated with lower doses . However, the observed differences were not statistically meaningful. As shown in Table 4, the possible harmful effect of a prolonged delay of PI is evident in all subgroups of patients except in those who received less than 60 Gy to the primary treatment field. Again, these differences in LRR rates were not statistically significant. When LRR rates in the primary treatment field were determined as a function of total dose at a particular anatomic primary tumor site, the rate was 33% (one of three) with less than 60 Gy and was 0% (9one of five) with 60 Gy or higher for lesions of the oral cavity. The LRR rate was 38% (three of eight) with less than 60 Gy and was 40% (four of 10) with 60 Gy or higher for oropharyngeal neoplasms (P = .70) and the LRR rate was 7% (one of 14) with less than 60 Gy and 17% (five of 30) with 60 Gy or higher for laryngeal and hypopharyngeal tumors (P > .05). Fifteen of the 19 recurrences (79%) were detected within 2 years following the diagnosis of cancer. Seven patients received additional therapy (ie, local tumor excision, palliative radiotherapy, or multidrug chemotherapy) while the other 12 did not; the median survival was 8 months and 4 months, respectively. Radiation myelitis or osteoradionecrosis was not seen in any patient. Some patients experienced varying degrees of taste loss, transient mucositis, and xerostomia.
Table 3.
Location of Recurrent Disease
Location
No Prolonged Delay n (%)
Prolonged Delay n (%)
P
Primary tumor site Upper neck Lower neck
3 (8) 4 (10) I (3)
4 (13) 3 (10) 4 (13)
NS NS NS
40
30
Total
Table 4. Local and Regional Recurrence With Timing and Total Dose of Postoperative Irradiation Dosage to Potential Site of Disease and LRR Rate n (%) Primary Tumor Site
and Upper Neck
Timing No prolonged delay Prolonged delay
Lower Neck
<6OGy
>o6OGy
~ S OG y
3/14(21)
4/26 (15)
1/26 (4)
0/14 (0)
2/11 (18)
5/19(26)
3/23 (13)
1/7 (14)
>SOGy
Discussion The overall LRR rate of 27% in this PI study compares well with the 20% to 25% reported by other investigators.4.9.'4.15 In our statistical analysis, we tried to determine factors that could predict LRR; the clinical and pathologic status of regional nodes were thesignificant factors. Other investigators l,14,16,)7 have similarly observed that LRR rates were higher in patients with clinically ad vanced stages of regional disease (NzN3) than in those with No-N) disease and in patients with histologically proven metastatic disease in multiple lymph nodes than in those with isolated nodal involvement. Several groups of investigators'P? have suggested that PI should begin within as short a period of time as possible after surgery. When examining the results of those series that have included an analysis of the effect of the interval between surgery and PI, two conflicting observations have been made: that a prolonged delay in the initiation of PI has an adverse impact on locoregional control'v' and, alternatively, that such a delay does not increase the LRR rate" as long as higher tumoricidal doses are used." Vikram and associates I found that the LRR rate was 31% in the 51 patients with more than a 6-week delay in initiation of PI and was 6% in the 54 patients whose PI was not delayed; the neck was irradiated in all patients (as well as the primary site in 90 patients); total dose to the primary treatment field was between 45 to 60 Gy and to the lower neck was between 45 to 55 Gy. The University of Illinois group? had a similar experience in patients with tumor-free margins of resection; LRR rate was 16% (four of 25) in patients whose PI was not delayed and was 100% (four of four) in those whose PI was delayed; these patients apparently received 55 to 65 Gy in 6 to 7.5 weeks. On the other hand, Amdur and colleagues" noted that, "the interval between surgery and irradiation (~ 6 weeks vs 6 to 10 weeks) did 110t affect the control
1197
Al\1PIL ET AL
rate, even with stratification by status of surgical margin, tumor dose, and number of indications for irradiation." The doses administered to most of their patients were 60 Gy or higher. Schiff and associates' from the Memorial SloanKettering Cancer Center recently reported the results of their analysis of the impact on locoregional tumor control of both the radiation dosage and the time interval between surgery and PI. They found that the harmful effect of prolonged delay in PI was only apparent in those patients who received less than 60 Gy. Of the 74 patients who received less than 60 Gy, LRR rate was 27% in the 33 patients whose PI was delayed compared with 7% in those 41 patients whose PI was not delayed (P = .05). On the other hand, the LRR rate in those 37 patients treated with doses of 60 Gy or higher was 15% in the 20 patients whose PI was not delayed and 12% in the group of 17 patients whose radiation therapy was delayed (P = .85). In our series, albeit the observed differences were not statistically significant, the LRR rate was higher in patients with a prolonged interval between surgery and PI than in those without a prolonged delay. We were not able to confirm the finding ofSchiff and colleagues" that a prolonged delay in onset of PI was harmful only in those patients who received less than 60 Gy. Although they, in addition, stated that, "there may be a . time interval between surgery and initiation of postoperative radiation for which even doses of 60 Gy or higher do not overcome the effect of time delay." In the present series, the adverse effect on locoregional tumor control of delay in PI was noted even with the use of total doses of60 Gy or higher. We also observed a high percentage of LRR of resected tumors of the oropharynx, larynx, and hypopharynx despite the use of 60 Gy or higher. Total doses between 65 to 70 Gy have been recommended by several investigators'v" who have observed decreasing recurrence rates with the use of increasing total doses of radiation following an analysis offailures above the clavicle in their patients treated with PI. This review ofcases was undertaken because ofconflicting reports concerning the deleterious effect of a prolonged delay in the initiation of PI in patients with squamous cell carcinoma of the upper aerodigestive tract. Our retrospective analysis indicates that I) PI should be administered as soon as the operative wound is fully healed, and 2) escalated total doses of PI may have to be considered when a prolonged interval between ,definitive surgery and the initiation of PI is unavoidable. A prospective randomized trial to address these questions would be valuable. This study, as most retrospective analyses, has a
number oflimitations (ie, there was no randomization of patients into treatment groups; the choice of dose option for a particular patient is complex and cannot be determined retrospectively, etc) and therefore, our observations should be interpreted with caution.
References I. Vikram B, Strong EW, Shah J, et al: Elective postoperative radiation therapy in stages III and IV epidermoid carcinoma of the head and neck. Am J Surg 140:580, 1980 2. Vikram B, Strong EW, Shah JP, et al: Failure in the neck following multi modality treatment for advanced head and neck cancer. Head Neck Surg 6:724, 1984 3. Mantravadi RVP, Haas RE, Liebner EJ, et al: Postoperative radiotherapy for persistent tumor at the surgical margin in head and neck cancers. Laryngoscope 93:1337, 1983 4. Amdur RJ, Parsons JT, Mendenhall WM, et al: Postoperative irradiation for squamous cell carcinoma of the head and neck: An analysis of treatment results and complications. Int J Radiat OncolBiol Phys 16:25, 1989 5. Schiff PB, Harrison LB, Strong EW, et al: Impact of the time interval betvveen surgery and postoperative radiation therapy on locoregiona1 control in advanced head and neck cancer. J Surg Oncol 43:203, .1990 6. Arnpil F, Datta R, Shockley W: Adjuvant postoperative external beam radiotherapy in head and neck cancer. J Oral Maxillofac Surg 46:569, 1988 7. Brady LW, Davis LW: Treatment of head and neck cancer by radiation therapy. Semin Oncol 15:29, 1988 8. Kumar PP, Good RR, Epstein BE: Relationship of dose to local control in advanced stage III and IV head and neck cancer treated by surgery and postoperative radiotherapy. Am J Clin Oncol 10:240, 1987 9. Marcus RB Jr, Million RR, Cassisi NJ: Postoperative irradiation for squamous cell carcinomas of the head and neck: Analysis of time-dose factors related to control above the clavicles. Int J Radiat Oncol BioI Phys 5:1943, 1979 10. Wang CC: Head and neck neoplasms, ill Mansfield CM (ed): Therapeutic Radiology, New Directions in Therapy (ed I). New York, NY, Medical Exam, 1983, pp 147-148 1I. Beahrs OH, Henson DE, Hutter RVP, et al: American Joint Committee on Cancer. Manual for Staging of Cancer (ed 3). Philadelphia, PA, Lippincott, 1988 12. Mehta CR, Patel NR, Wei U: Computing exact permutation distributions with restricted randomization designs. Biometrika 75:295, 1988 13. Mehta CR: Statxact Version 1.00. Cambridge, MA, Cytel Software Corporation, 1989 14. Mantravadi RVP, Skolnik EM, Haas RE, et al: Patterns of cancer recurrence in the postoperatively irradiated neck. Arch Otolaryngol 109:753, 1983 15. Ravasz LA, Slootweig PJ, Hordijk GJ, et al: The status of the resection margin as a prognostic factor in the treatment of head and neck carcinoma. J Cranio-Max-Fac Surg 19:314, 1991 16. Leemans CR, Tiwari R, Van Dcr Waall, et al: The efficacy of comprehensive neck dissection with or without postoperative radiotherapy in nodal metastases ofsquamous cell carcinoma of the upper respiratory and digestive tracts. Laryngoscope 100:1194, 1990 17. Maulard C, Housset M, BruneI P, et al: Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 102:884, 1992 18. Feldman M, fletcher GH: Analysis of the parameters relating to failures above the clavicles in patients treated by postoperative irradiation for squamous cell carcinomas of the oral cavity or oropharynx. Int J Radiat Oncol BioI Phys 8:27, 1982
Timing and Dosage of Postoperative Radiotherapy for Squamous Cell Carcinoma of the Upper Aerodigestive Tract FEDERICO L. AMPIL, MD,· KENNAN J. BUECHTER, MD,t LEE E. BAIRNSFATHER, PHD,:f: AND WILLIAM W. SHOCKLEY, MD§ Seventy patients who received postoperative irradiation (PI)after curative surgery for stage III or IV squamous cell carcinoma of the upper aerodigestive tract were studied retrospectively to compare the rate of local and regional recurrence (LRR) and the effect of total dose on LRR rate in patients irradiated timely (n = 40) with those who were not (n = 30). Overall, the LRR rate was higher when PI was delayed than when timely (37% vs 20%). No advantage resulted from increasing total dose when PI was delayed; the LRR rate in the primary site and upper neck was 18% with less than 60 Gy and was 26% with 60 Gy or more; the LRR rate in the lower neck was 13% with 50 Gy or less and was 14% with more than 50 Gy. These data seem to corroborate the findings of other investigators regarding the importance of initiating timely PI, but not the observation that a pronounced delay is not detrimental provided higher tumoricidal doses are used.
The influence of an arbitrary delay of more than 6 weeks prior to elective postoperative irradiation (PI) on the rate of local and regional recurrence (LRR) of squamous cell carcinoma of the upp er aerodigestive tract remains an unsettled issue. Several studies! " have found it detrimental to delay PI, while another study" has shown no difference between timely and delayed PI. A recent report" suggested that a protracted delay of PI does not have a negative impact on locoregional disease control as long as 60 Gy or higher tumoricidal doses are used. Recommendations concerning total dose of PI have varied from 50 to 70 Gy.3.6-1O However,
the optimum total dose for subclinical disease remains to be determined. The objective of this retrospective study was to compare the rate of LRR and the effect of total dose on LRR rate in patients who received timely PI with those who did not.
Materials and Methods One hundred twenty-nine patients were irradiated using cobalt 60 or a 6-m V linear accelerator following curative resection of head and neck cancer at the university-affiliated institutions during a 24-year period, 1975-1989. This study was limited.to 70 patients who were similar in most respects except for the timing of their PI. The following clinical features made them eligible for inclusion in the study: I) squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; 2) stage III or IV disease according to the system developed by the American Joint Committee on Cancer;" 3) PI administered via parallel opposed lateral portals, which encompassed the primary tumor site and upper neck (primary treatment field), and an anterior lower neck "yoke" portal; 4) no 10coregional disease or distant metastasis present at the time of initiation of PI; and 5) ~valuable for LRR at
Received from Louisiana Stat e Univers ity School of Medicine in Shreveport . Shre veport, LA. • Department of Radiology. t Form erly, Department of Surgery; curr ently, Department of Surgery, Louisiana State University School of Medicine in New Orleans. New Orleans, LA. Department of Biometry . § Formerl y, Department of'Otolaryngolcgy-i-Head Neck Surgery; currentl y, Department of Otolaryngology-s-Head Neck Surgery, University of North Carolina School of Medicine, Chapel Hill. NC. Address correspondence and reprint requests to Dr Ampil: Department of Radiology, Louisiana State University Medical Cent er. 1501 Kings Highway, PO Box 33932, Shreveport. LA 71130-3932.
*
© 1993 American Association of Oral and Maxillofacial Surgeons 0278-2391/93/5111-0004$3.00/0
1194
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AMPIL ET AL
the time of death or after a minimum follow-up of 2 years. Surgical procedures were described as supraglottic or total laryngectomy with or without pharyngectomy or radical neck dissection, composite resection, pharyngectomy, or wide tumor resection with or without neck node dissection. In the first group (n = 40), PI was given within 6 weeks after surgery. In the second group (n = 30), because of some delay in wound healing, PI was given later than 6 weeks. In both groups, radiation therapy was administered for 5 consecutive days each week until the prescribed dosage was achieved. Radiation dose was calculated at midplane for the opposed lateral portals and at a depth of 1.5 to 3 em for the lower neck portal. The prescribed total tumor dose is shown in Table 1. A shrinking field technique for the lateral portals was used after administration of40 to 50 Gy. Midline spinal cord shielding in the lower neck portal was performed when the prescribed dosage was more than 50 Gy, The spinal cord dosage did not exceed 45 Gy. The daily dose was 1.8 to 2.0 Gy. Dental evaluation and management was ordinarily handled prior to irradiation. Follow-up information was available for all 70 patients for periods that varied from 6 to 125 months, the average being 30 months. Results were compared for statistically significant differences by x2 analysis mid Fisher's exact analysis using algorithms described by Mehta and colleagues'? and implemented by Statxact software (Cytel Software Corp, Cambridge, MA).13
Table 1.
Mean age (yr) Range Primary tumor site Oral cavity Oropharynx Larynx Hypopharynx Larynx-hypopharynx Stage 111 IV Median total dose (Gy) Primary tumor site and upper neck Range Lower neck Range Total
No Prolonged Delay (n)
Prolonged Delay (n)
59 46-76
57 41-69
5 7 20 5 3
3 II
12 2 2
23
8 22
60 54-66 50 45-60
60 50-68 50 46-60
40
30
17
No. Recurrence/ No. Patients (%)
Risk Factor Age (yr) <65 ~65
Disease stage" 111 IV Primary tumor extent* T2 T3 T4 Retional tumor extent* NO-I N2-3 Disease site Oral cavity Oropharynx Larynx-hypopharynx Timing of postoperative irradiation No prolonged delay Prolonged delay Total dose (Gy) Primary site and upper neck <60 ~60
Lower neck ;$;50 >50
P
15/56 (27) 4/14 (29)
NS
6/25 (24) 13/45 (29)
NS
1/10 (10) 3/36 (8) 3/24 (13)
NS
4/42 (10) 8/28 (29)
<.05
1/8 (13) 7/18 (39) 11/44 (25)
NS
8/40 (20) 11/30 (37)
NS
5/25 (20) 9/45 (20)
NS
4/49 (8) 1/21 (5)
NS
* According to the system developed by the American Joint Committee on Cancer.
Where values of less than .05 were found, the differences were considered significant. The diagnosis of LRR was based on obvious clinical findings (n = 4) or on histologic evidence (n = 15).
Patient Characteristics
Variable
Table 2. Risk Factors for Local and Regional Recurrence
Cancer staged according to the system developed by the American Joint Committee on Cancer.
Results The characteristics of the compared groups of patients are shown in Table 1. A significant difference in the listed features was not apparent. The overall LRR rate was 27% (19 of 70). A univariate analysis of risk factors for LRR is shown in Table 2. The only factor ofsignificance was the clinical extent of regional disease at presentation. A meaningful assessment of the prognostic importance of the presence of tumor at the resection margins was not possible due to the infrequent (n = 3) occurrence of this situation in this series. These three patients were free of disease at the time of death or follow-up. Because pathologic nodal status was not mentioned in six patients, there were only 64 patients who were evaluable with respect to pathologic status of removed nodes and the rate of regional recurrence. Regional recurrence rate was 0% (none of 18) when neck nodes were free
POSTOPERATIVE RADIOTHERAPY: TIMING AND DOSAGE
1196 of metastatic disease, 0% (none of 16) when only one node was involved with disease, and 40 % (12 of 30) when several nodes contained metastasis (P < .001). A lower overall LRR rate was observed in patients who were irradiated timely than in those who were not (Table 2). The location of recurrent disease is shown in Table 3. Median survival from the time ofLRR was 5 months. When LRR rates were analyzed as a function oftiming and total dose of PI (Table 4), a lower recurrence rate was not seen in the primary treatment field or lower neck with an increase in total dose for patients with a prolonged delay in the initiation of PI. In contrast, in patients whose initiation of PI was not excessively delayed, lower LRR rates were associated with those patients who received higher radiation doses than with those treated with lower doses . However, the observed differences were not statistically meaningful. As shown in Table 4, the possible harmful effect of a prolonged delay of PI is evident in all subgroups of patients except in those who received less than 60 Gy to the primary treatment field. Again, these differences in LRR rates were not statistically significant. When LRR rates in the primary treatment field were determined as a function of total dose at a particular anatomic primary tumor site, the rate was 33% (one of three) with less than 60 Gy and was 0% (9one of five) with 60 Gy or higher for lesions of the oral cavity. The LRR rate was 38% (three of eight) with less than 60 Gy and was 40% (four of 10) with 60 Gy or higher for oropharyngeal neoplasms (P = .70) and the LRR rate was 7% (one of 14) with less than 60 Gy and 17% (five of 30) with 60 Gy or higher for laryngeal and hypopharyngeal tumors (P > .05). Fifteen of the 19 recurrences (79%) were detected within 2 years following the diagnosis of cancer. Seven patients received additional therapy (ie, local tumor excision, palliative radiotherapy, or multidrug chemotherapy) while the other 12 did not; the median survival was 8 months and 4 months, respectively. Radiation myelitis or osteoradionecrosis was not seen in any patient. Some patients experienced varying degrees of taste loss, transient mucositis, and xerostomia.
Table 3.
Location of Recurrent Disease
Location
No Prolonged Delay n (%)
Prolonged Delay n (%)
P
Primary tumor site Upper neck Lower neck
3 (8) 4 (10) I (3)
4 (13) 3 (10) 4 (13)
NS NS NS
40
30
Total
Table 4. Local and Regional Recurrence With Timing and Total Dose of Postoperative Irradiation Dosage to Potential Site of Disease and LRR Rate n (%) Primary Tumor Site
and Upper Neck
Timing No prolonged delay Prolonged delay
Lower Neck
<6OGy
>o6OGy
~ S OG y
3/14(21)
4/26 (15)
1/26 (4)
0/14 (0)
2/11 (18)
5/19(26)
3/23 (13)
1/7 (14)
>SOGy
Discussion The overall LRR rate of 27% in this PI study compares well with the 20% to 25% reported by other investigators.4.9.'4.15 In our statistical analysis, we tried to determine factors that could predict LRR; the clinical and pathologic status of regional nodes were thesignificant factors. Other investigators l,14,16,)7 have similarly observed that LRR rates were higher in patients with clinically ad vanced stages of regional disease (NzN3) than in those with No-N) disease and in patients with histologically proven metastatic disease in multiple lymph nodes than in those with isolated nodal involvement. Several groups of investigators'P? have suggested that PI should begin within as short a period of time as possible after surgery. When examining the results of those series that have included an analysis of the effect of the interval between surgery and PI, two conflicting observations have been made: that a prolonged delay in the initiation of PI has an adverse impact on locoregional control'v' and, alternatively, that such a delay does not increase the LRR rate" as long as higher tumoricidal doses are used." Vikram and associates I found that the LRR rate was 31% in the 51 patients with more than a 6-week delay in initiation of PI and was 6% in the 54 patients whose PI was not delayed; the neck was irradiated in all patients (as well as the primary site in 90 patients); total dose to the primary treatment field was between 45 to 60 Gy and to the lower neck was between 45 to 55 Gy. The University of Illinois group? had a similar experience in patients with tumor-free margins of resection; LRR rate was 16% (four of 25) in patients whose PI was not delayed and was 100% (four of four) in those whose PI was delayed; these patients apparently received 55 to 65 Gy in 6 to 7.5 weeks. On the other hand, Amdur and colleagues" noted that, "the interval between surgery and irradiation (~ 6 weeks vs 6 to 10 weeks) did 110t affect the control
1197
Al\1PIL ET AL
rate, even with stratification by status of surgical margin, tumor dose, and number of indications for irradiation." The doses administered to most of their patients were 60 Gy or higher. Schiff and associates' from the Memorial SloanKettering Cancer Center recently reported the results of their analysis of the impact on locoregional tumor control of both the radiation dosage and the time interval between surgery and PI. They found that the harmful effect of prolonged delay in PI was only apparent in those patients who received less than 60 Gy. Of the 74 patients who received less than 60 Gy, LRR rate was 27% in the 33 patients whose PI was delayed compared with 7% in those 41 patients whose PI was not delayed (P = .05). On the other hand, the LRR rate in those 37 patients treated with doses of 60 Gy or higher was 15% in the 20 patients whose PI was not delayed and 12% in the group of 17 patients whose radiation therapy was delayed (P = .85). In our series, albeit the observed differences were not statistically significant, the LRR rate was higher in patients with a prolonged interval between surgery and PI than in those without a prolonged delay. We were not able to confirm the finding ofSchiff and colleagues" that a prolonged delay in onset of PI was harmful only in those patients who received less than 60 Gy. Although they, in addition, stated that, "there may be a . time interval between surgery and initiation of postoperative radiation for which even doses of 60 Gy or higher do not overcome the effect of time delay." In the present series, the adverse effect on locoregional tumor control of delay in PI was noted even with the use of total doses of60 Gy or higher. We also observed a high percentage of LRR of resected tumors of the oropharynx, larynx, and hypopharynx despite the use of 60 Gy or higher. Total doses between 65 to 70 Gy have been recommended by several investigators'v" who have observed decreasing recurrence rates with the use of increasing total doses of radiation following an analysis offailures above the clavicle in their patients treated with PI. This review ofcases was undertaken because ofconflicting reports concerning the deleterious effect of a prolonged delay in the initiation of PI in patients with squamous cell carcinoma of the upper aerodigestive tract. Our retrospective analysis indicates that I) PI should be administered as soon as the operative wound is fully healed, and 2) escalated total doses of PI may have to be considered when a prolonged interval between ,definitive surgery and the initiation of PI is unavoidable. A prospective randomized trial to address these questions would be valuable. This study, as most retrospective analyses, has a
number oflimitations (ie, there was no randomization of patients into treatment groups; the choice of dose option for a particular patient is complex and cannot be determined retrospectively, etc) and therefore, our observations should be interpreted with caution.
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