| Japanese Journal of Clinical Oncology | Pages |
Local-Regional Control by Conventional Radiotherapy According to Tumor Volume in Patients with Squamous Cell Carcinoma of the Pharyngolarynx
Introduction
Materials And Methods
Patient Selection
Treatment
Study End-point
Measurement and Expression of Tumor Volume
Statistical Methods
Results
Local Control
Regional Control
Survival Outcome
Prognostic Indicators for Survival Outcomes
Discussion
References
Local-Regional Control by Conventional Radiotherapy According to Tumor Volume in Patients with Squamous Cell Carcinoma of the Pharyngolarynx
Methods: Definitive RT for 48 patients with squamous cell carcinoma of the lateral wall of the oropharynx, pyriform sinus and supraglottic larynx was reviewed. Tumor volume was estimated from computed tomography and it was expressed as the diameter of a sphere the volume of which is equal to the primary tumor (Td) and sum of the volumes of metastatic adenopathies (Nd). All patients received [ge]60 Gy (median 66 Gy) to the gross tumor by conventional fractionation with or without chemotherapy.
Results: A median period of follow-up for survivors was 32.7 months (range, 12.4-68.6). The 2 year local control rate for T1/2 (n = 30) and T3/4 (n = 18) patients was 72 and 65%, respectively (P = 0.966), however, the rates for Td < 4 cm tumors (n = 37) and Td [ge] 4 cm tumors (n = 11) were significantly different (80% vs 27%, P < 0.001). The 2 year regional control rates for Nd < 3 cm lesions (n = 29) and Nd [ge] 3 cm (n = 19) lesions were 85 and 42%, respectively (P < 0.001). The 2 year ultimate regional control rates for N2/3 disease with Nd < 4 cm (n = 11) and Nd [ge] 4 cm (n = 11) were 100 and 42%, respectively (P = 0.004).
Conclusions: Conventional radiotherapy may allow organ preservation and ultimate local control in patients with Td < 4 cm and Nd < 4 cm disease, but larger volume tumors should be considered candidates for the most intensive chemoradiotherapy.
INTRODUCTION
Definitive radiotherapy (RT) is the principal treatment for head and neck cancer, not only for unresectable disease, but also for early stage disease when the patient hopes for a good cosmetic and functional outcome. Small tumors, such as early glottic cancer, can be controlled well with conventional RT alone; however, in advanced disease, RT is frequently followed by local-regional failure. Accordingly, RT with hyperfractionation is now used for cancer of the pharyngolarynx (1-3). A number of phase III trials have been performed in the last decade, and promising results regarding the benefit of altered fractionation with or without chemotherapy for advanced head and neck cancer have accumulated (4-9). However, acute adverse reactions in the experimental arms were invariably more pronounced than in the control arms (i.e. conventional RT). The risk-benefit of altered fractionation with or without chemotherapy should be carefully considered based on precise predictive assay before it becomes widely practised. Many clinicopathological and biological factors, such as age, gender, performance status, TNM classification, clonogen number (10), hypoxic fraction (11), surviving fraction at 2 Gy (SF2) (12), potential doubling time (Tpot) (13) and p53 expression (14), have been postulated to be correlated with radiocurability.
The TNM stage classification is mainly based on the anatomical distribution of the tumor, which reflects its resectability, but tumor volume seems to be a more relevant factor determining the outcome of treatment by RT (10,15,16). Our purpose was to determine the effect of tumor volume measured on CT scans obtained during treatment planning on local-regional control in definitive RT by conventional fractionation (2.0 Gy per fraction, five fractions per week) for squamous cell carcinoma of the lateral wall of the oropharynx, pyriform sinus and supraglottic larynx.
Table 1.
| Median age 65 years Range 32-87 years Male/female 42/6 |
|||||
| TNM stage (1992, UICC): | |||||
| T1 | 8 | N0 | 20 | ||
| T2 | 22 | N1 | 6 | ||
| T3 | 13 | N2 | 12 | ||
| T4 | 5 | N3 | 10 | ||
| Supraglottic larynx: | |||||
| T1 | T2 | T3 | T4 | Total | |
| N0 | 2 | 6 | 1 | 0 | 9 |
| N1 | 0 | 1 | 0 | 0 | 1 |
| N2 | 2 | 1 | 0 | 0 | 3 |
| N3 | 0 | 2 | 0 | 0 | 2 |
| Total | 4 | 10 | 1 | 0 | 15 |
| Td* | Median 1.0 cm (range 1.0-2.6) | ||||
| Nd[dagger] | 0.0 cm (0.0-3.5) | ||||
| Lateral wall of oropharynx: | |||||
| T1 | T2 | T3 | T4 | Total | |
| N0 | 0 | 2 | 1 | 1 | 4 |
| N1 | 0 | 1 | 0 | 0 | 1 |
| N2 | 0 | 2 | 4 | 0 | 6 |
| N3 | 1 | 0 | 1 | 1 | 3 |
| Total | 1 | 5 | 6 | 2 | 14 |
| Td | Median 2.8 cm (range 0.0[Dagger]-7.0) | ||||
| Nd | 1.7 cm (0.0-7.5) | ||||
| Pyriform sinus: | |||||
| T1 | T2 | T3 | T4 | Total | |
| N0 | 2 | 4 | 1 | 0 | 7 |
| N1 | 0 | 1 | 2 | 1 | 4 |
| N2 | 0 | 2 | 1 | 0 | 3 |
| N3 | 1 | 0 | 2 | 2 | 5 |
| Total | 3 | 7 | 6 | 3 | 19 |
| Td | Median 3.6 cm (range 2.0-6.4) | ||||
| Nd | 3.1 cm (0.0-7.9) | ||||
MATERIALS AND METHODS
Patient Selection
Between 1992 and 1997, 74 patients with cancer of the lateral wall of the oropharynx, pyriform sinus or supraglottic larynx were treated by definitive RT at the National Cancer Center Hospital East. The 48 cases among them that matched the following criteria were selected: (1) previously untreated, biopsy proven squamous cell carcinoma; (2) no co-existing or prior malignancy; (3) no prior chemotherapy, RT or surgery to the head and neck region; (4) those administered a total dose of 60 Gy or more with conventional fractionation; (5) no evidence of distant metastasis; and (6) local-regional control followed up for more than 2 years.
Twenty-six patients were excluded for the following reasons: (1) death due to intercurrent disease or lost to follow-up within 2 years of the commencement of RT without evidence of local-regional recurrence (n = 11); (2) administration of 60 Gy not completed (n = 9); (3) co-existing malignancy (n = 5, four head and neck cancers and one lung cancer); (4) treated by accelerated hyperfractionation with 1.5 Gy twice daily (n = 1). The reasons for failure to complete administration of 60 Gy were as follows: (1) death due to sepsis as a result of concurrent chemotherapy during RT (n = 1); (2) patient refusal because of severe mucositis (n = 3); (3) abscess formation within the treatment volume (n = 1); (4) sudden death during RT (n = 1); (5) death due to myocardial infarction during RT (n = 1); (6) worsening of alcohol abuse (n = 1); (7) airway stenosis due to local edema, requiring tracheostomy (n = 1).
There were 42 males and six females and their median age was 65 years (32-87 years). Nineteen cancers originated in the pyriform sinus, 14 in lateral wall of the oropharynx and 15 in the supraglottic larynx. All patients had an ECOG Performance Status of 0-2. The distribution of the TNM classifications (according to the 1992 UICC) was as listed in Table 1.
Treatment
RT was delivered with 6 MV X-rays to all patients. Our treatment policy for head and neck cancer during this period was as follows: (1) for resectable, early stage disease in which the patient refused surgery requiring total laryngectomy, RT alone at a total dose of 60-70 Gy; (2) for unresectable, locally advanced disease, FP-RT, i.e. two courses of 30 Gy RT concurrent with cisplatin (bolus injection of 40 mg/m2 on days 1 and 8) and 5-FU (continuous infusion of 200 mg/m2 on days 1-4 and 8-11) with a 2 week rest. The dose in the second course could be raised as high as 42 Gy according to the tumor response. Two patients (T3N0 and T3N1 pyriform sinus cancer) treated in the early period received two courses of induction chemotherapy (cisplatin 80 mg/m2 on day 1 plus 5-FU 800 mg/m2 on days 1-4 continuous infusion) followed by 60 Gy of RT. Both patients became free of macroscopic tumor after induction chemotherapy. Parallel opposed with or without anterior portals covering the gross tumor and whole neck region were used initially and the doses to the spinal cord were restricted to 40-44 Gy. Cone down field covered the primary tumor and metastatic lymph nodes (minimum diameter >10 mm).
Study End-point
Local (primary tumor), regional (metastatic adenopathies in the neck) control status and survival time after the commencement of RT were reviewed according to the medical records and radiographic examinations.
Measurement and Expression of Tumor Volume
Tumor volume was estimated from computed tomography (CT) scans with contrast enhancement during RT planning. The primary tumor and metastatic lymph nodes were outlined separately with a mouse device and the area was measured with a built-in image analysis system. In cases in which artifacts derived from the dentures precluded delineation of the tumor, the physical examination and diagnostic magnetic resonance images were referred and outlined using images with a larger window width. Whenever there was aggregation of the primary tumor and adjacent metastatic lymph nodes, the aggregated mass was considered the primary tumor. Tumor and nodal volumes were calculated by multiplying each cross-sectional area by slice thickness and adding the slices together. The sum of the volume of each node in N2 or N3 disease was estimated and analyzed.
Dubben et al. stated that the precision requirements of volume measurements for predictive assay are low (±50% standard deviation) and that tumor volume can reasonably be estimated from one or two diameters measured on radiographs (10). In this study, we acquired volume data by a more accurate but time-consuming method. Accordingly, the volume was expressed as the diameter of a sphere (Td and Nd) whose volume was equal to the primary tumor (Td) and the sum of nodal volumes (Nd) as a simple means of estimating tumor size in ordinary clinics.
Statistical Methods
Local-regional control and survival outcomes were estimated by the Kaplan-Meier method (17). Univariate and multivariate analyses were performed by the log-rank test and Cox's proportional hazard model (18).
RESULTS
The median dose administered to the primary tumor and metastatic adenopathies was 66.0 Gy (range, 60.0-72.0 Gy) with median elapsed treatment days of 54 days (range, 43-81 days).
The relationships between T-stage and Td and between N-stage and Nd are shown in Fig. 1. Nine patients underwent FP-RT and all of them had Td [ge] 4 cm or Nd [ge] 3 cm. Four of the 37 patients (11%) with Td < 4 cm tumors underwent FP-RT and each of them had bulky lymph node metastasis that was judged to be unresectable by head and neck surgeons.
Figure 1. Distribution of tumor volume (expressed as Td and Nd) within each T- and N-stage. Open circles represent tumors treated by radiotherapy alone and circles with dots represent those treated by radiotherapy plus concurrent combination chemotherapy using cisplatin and 5-FU. Two patients (with T3N0 and T3N1 disease) in whom induction chemotherapy was followed by complete resolution of the tumor were estimated to have a Td and Nd of 0 cm. Thirty-one patients were alive and remained free of recurrence after RT at the last follow-up and the median follow-up period has been 29.6 months (range, 3.2-68.6 months). Six patients have been followed for less than 2 years and four of them have experienced recurrence of neck node metastasis, one has had a distant relapse and one secondary malignancy without evidence of tumor at the original site. The last patient with T1N0 cancer of the suprahyoid epiglottis experienced recurrence in the arytenoid and underwent total laryngectomy 15.1 months after the RT. Pathological examination revealed no evidence of residual tumor within the original site and the case was therefore handled as a censored case as to local control 15.1 months after the RT. The 5 year local control rate was 54.8% (range, 34.9-74.0%). There were no differences in local control rates according to the three anatomical sites of the tumors (data not shown). The 2 year local control rates for T1-4 tumors were 86, 68, 90 and 20%, respectively. Seventeen patients experienced local recurrence (two patients in T1, nine in T2, two in T3 and four in T4) and seven of the 17 patients were successfully salvaged by surgery. The 2 year ultimate local control rates after salvage surgery were 100, 86, 90 and 20%, respectively. There were no statistical differences in local control rates between T1, T2 and T3 tumors (P > 0.500). Two cases of T2, four of T3 and five of T4 tumors were estimated as Td [ge] 4 cm. Two patients with T3 tumors obtained complete tumor resolution after induction chemotherapy and therefore pretreatment Td was estimated as 0 cm. The Kaplan-Meier estimates of local control rate for each stratum of Td are shown in Fig. 2, which indicates that Td < 4 cm tumors had local control rates of >60%, but that larger tumors tended to relapse early. There was a significant difference between the 2 year local control rates of Td < 4cm (81%; 95% confidence interval 67-94%) and [ge] 4 cm tumors (30%; 0 - 64%; P < 0.001), as shown in Fig. 3. The difference between the 2 year ultimate local control rates after salvage surgery of Td < 4 cm tumors and Td [ge] 4 cm tumors was more pronounced (91%; 81-100% vs 30%; 0-64%, P < 0.0001). The 5 year local and ultimate local control rates for those with Td < 4 cm tumors were 65% (43-88%) and 91% (81-100%), respectively. Figure 2. Kaplan-Meier estimation of local control rates for each stratum of Td. Thick solid line, Td < 2 cm (n = 17); thick dotted line, Td [ge] 2 cm and < 3 cm (n = 15); thin solid line, Td > 3 cm and < 4 cm (n = 5); and thin dotted line, Td > 4 cm (n = 11). Figure 3. Kaplan-Meier estimation of local control rates for Td < 4 cm (n = 37) and Td [ge] 4 cm tumors (n = 11). The difference is statistically significant (P < 0.001). All regional failures for node-positive patients occurred within the treatment volumes that received [ge]60 Gy. Twenty-nine patients did not experience regional recurrence and the median follow-up period for patients without recurrence was 29.6 months (range, 2.7-68.6 months). Four patients were followed for less than 2 years. Three of them experienced local failure (two were successfully salvaged) and one died of lung metastasis. The 2 year regional control rates according to N-stage were N0, 84%; N1, 83%; N2, 70%; and N3, 30% (Fig. 4). Nineteen patients with N2/3 disease (9/12 with N2 disease and 10/10 with N3 disease) were estimated to have an Nd [ge] 3 cm. The 2 year regional control rates after RT for those with Nd < 3 cm lesions (n = 29) and Nd [ge] 3 cm lesions were 85% (72-99%) and 42% (21-68%), respectively (P < 0.001; Fig. 5). Three of the seven patients with N0/1 disease and regional failure had prior local recurrence. All patients with N2/3 disease experienced their first recurrence in the neck. Seven of the 18 patients with regional recurrences were successfully salvaged (N0, 2/5; N1, 0/2; N2, 2/4; N3, 3/7). The 2 year ultimate regional control rates for Nd < 3 cm lesions and Nd [ge] 3 cm lesions were 89 and 70.6%, respectively (P = 0.047). Three N2 patients and eight N3 patients were estimated to have Nd [ge] 4 cm lesions. Eight of these 11 patients experienced regional recurrence and two were successfully salvaged by neck dissection. The 2 year ultimate regional control rates for N2/3 disease with Nd < 4 cm (n = 11) and Nd [ge] 4 cm (n = 11) were 100 and 42% (10-73%), respectively (P = 0.004; Fig. 6). Figure 4. Regional control rates according to N-stage. Thick solid line, N0 (n = 21); thick dotted line, N1 (n = 6); thin solid line, N2 (n = 11); and thin dotted line, N3 (n = 10). Figure 5. Regional control rates according to nodal volume (expressed by Nd). Thick solid line, Nd < 3 cm (n = 29); and thick dotted line, Nd [ge] 3 cm (n = 19). The difference is statistically significant (Two year regional control rates, 85% and 42%, P < 0.001). Figure 6. Kaplan-Meier estimation of ultimate regional control rates after radiotherapy and salvage neck dissection for regional failure in N2/3 disease according to nodal volume expressed by Nd. Solid lines, Nd < 4 cm (n = 11); and dotted lines, Nd [ge] 4 cm (n = 11). Thin lines represent regional control rates after RT. The P values for the difference between regional and ultimate regional control rates were 0.054 and 0.004, respectively. Although the local-regional control status of all patients was followed for more than 2 years, two patients were followed for less than 2 years with regard to survival. One had T2N0 cancer of the anterior pillar of the tonsil and the tumor had not completely resolved after RT. This patient underwent salvage surgery 3 weeks after the end of RT and survived without recurrence for 12.4 months at the time of last follow-up. The other patient had T3N3 pyriform sinus cancer and the neck disease remained at the end of FP-RT. Salvage was performed by radical neck dissection and the patient survived without disease for 21.8 months at the time of last follow-up. The median period of follow-up for survivors was 32.7 months (range, 12.4-68.6 months). The 3 year cause-specific and progression-free survival rates for all patients were 78 and 52%, respectively. Cause-specific survival rates for stage I (n = 4), II (n = 12), III (n = 8) and IV (n = 24) patients were 100, 81, 100 and 65%, respectively. The 2 year cause-specific survival rates for patients with Td < 4 cm and Td [ge] 4 cm primary tumors were 92% (83-100%) and 23% (0-46%), respectively (P < 0.0001). Patients with Nd < 3 cm and Nd [ge] 3 cm neck adenopathies were 82% (68-96%) and 63% (41-85%), respectively (P = 0.148). Table 2. Univariate analysis revealed that Td (<4 cm vs [ge]4 cm; P < 0.0001) and N-stage (N0-2 vs N3; P = 0.022) significantly influenced cause-specific survival. T-stage (T1/2 vs T3/4; P = 0.060), total dose (<66 Gy vs [ge]66 Gy; P = 0.056), duration of treatment interruption (<2 weeks vs [ge]2 weeks; P = 0.058) and clinical stage (stage I-III vs stage IV; P = 0.074) correlated with less significance. Nd (<3 cm vs [ge]3 cm; P = 0.221) and patient age (<70 years vs [ge]70 years; P = 0.637) did not significantly influence cause-specific survival (Table 2). On multivariate analysis, Td was the only independent factor predicting cause-specific survival (P = 0.0002) and the other factors were insignificant, as shown in Table 2. The patients were divided in two groups: a low-risk group, Td < 4 cm and Nd < 3 cm (n = 25); and a high-risk group, Td [ge] 4 cm or Nd [ge] 3 cm (n = 23). The 3 year progression-free survival rates for low- and high-risk patients were 71% (95% confidence interval, 52-91%) and 37% (14-59%), respectively (P = 0.040); nevertheless, all nine patients treated by FP-RT were at high risk (Fig. 7). Figure 7. Progression-free survival after the commencement of radiotherapy in patients with low-risk (i.e. Td < 4 cm and Nd < 3 cm, n = 25) and high-risk (i.e. Td [ge] 4 cm or Nd [ge] 3 cm, n = 23). The difference was statistically significant (P = 0.040). As Dubben et al. stated (10), empirically, volume is regarded as the most reliable predictor of tumor control after RT. The importance of tumor volume for local control after RT has also been reported for various head and neck cancers (11,16) and in site-specific fashion for supraglottic cancer (19), T4 laryngeal cancer (20) and nasopharyngeal cancer (21). Theoretically, the predictive assay of RT response may be a polynomial function that includes clonogen number, hypoxic fraction, labeling index, SF2, Tpot and so on. The number of tumor clonogens requiring sterilization is considered to increase with tumor volume and some authors postulate that there is a linear correlation between clonogen number and tumor volume (10,15,16). Although Bentzen and Thames state that patient-to-patient variability in radiocurability and the other factors also make the volume effect be less pronounced than would be expected from a simple proportionality between them (22), the significance of other factors predictive of tumor radiosensitivity is still controversial (10) and they cannot quantitate radiocurability as yet, as compared with tumor volume. Johnson et al. reported an interrelationship between tumor volume, estimated by direct measurement using computed tomography data, and local control rates for various head and neck cancers. The largest component, 27% of the subjects, were cancers of the base of the tongue, whose radiocurability is relatively poor compared with other sites in the pharyngolarynx (16). They showed that tumors with a volume under 40 cm3 (Td < 4.3 cm) had significantly better local control rates after an accelerated superfractionated protocol (concomitant boost technique) than larger tumors. Our review also revealed a striking difference in 2 year local control rates between Td < 4 cm and Td [ge] 4 cm tumors (2 year local control rates of 81% vs 30%; P < 0.001). In this study there were no significant site-specific differences in radiocurability between the three sites, i.e. the supraglottic larynx, lateral wall of the oropharynx and pyriform sinus. Mendenhall et al. reported that tumors less than 6 cm3 in volume (Td < 2.3 cm) had significantly better local control rates than [ge]6 cm3 tumors in a review of 59 patients irradiated twice daily for supraglottic cancers (19). They commented that tumor volume had a strong impact, especially in T3 tumors. In our study, it was impossible to demonstrate such a relationship in small tumors, Td [ge] 2 cm, because the number of patients was limited. Chua et al. reported among 290 nasopharyngeal cancers treated at Queen Mary Hospital in Hong Kong, tumors more than 60 cm3 in volume (Td = 4.9 cm) were associated with significantly worse 5 year local control (56%) and disease-free survival (53%). They noted that there were no differences in local control rate between T-stages for tumors less than 20 cm3. They also reported that there was no clear relationship between tumor volume and T-stage and showed that tumor volume was an independent prognostic indicator of local control in multivariate analysis (21). Evidence is being accumulated that accelerated and/or hyperfractionated RT with or without concomitant chemotherapy improves tumor control, the larynx preservation rate and disease-free survival (4-9), especially in advanced or unresectable head and neck cancer. Wendt et al. (8) reported that the 3 year local control rate was 35% in patients with stage III/IV cancers in various head and neck regions treated with 1.8 Gy twice daily RT concurrent with multi-drug chemotherapy. Among these 140 patients, 87 (62%) had T4 disease and 18 (13%) had N3 disease. Britzel et al. also reported a local-regional benefit of concurrent chemoradiotherapy compared with radiotherapy alone for head and neck cancers through randomized trials (7). Primary tumors of >4 cm in one-dimensional measurements were eligible and 56% of the 56 patients in the chemoradiotherapy arm had T2 or T3 tumors. Radiotherapy was delivered by hyperfractionation and the 3 year local control rate was 70%. These intensive approaches cause more severe mucositis and impair patients' nutritional status and thus intensive supportive care by expert physicians is invariably needed. Clinical staging, especially for T-stage, is mainly based on resectability of the tumor and it does not reflect tumor volume. Nevertheless, reports of clinical outcome of RT for head and neck cancers have usually been described by using the TNM staging system. Is such a description adequate to clarify the relationship between clonogen number within the disease and the local-regional control rate? Recently, the TNM classifications of head and neck cancer was revised (23) and, for hypopharyngeal cancer, the T categories were partly defined by the greatest dimension of the tumor. This concept of the new TNM classification is somewhat more appropriate for the prediction of radiocurability of the disease, although its measurement seems to have some difficulty in certain cases and such a T-category cannot reflect the tumor volume especially in the case of superficially spreading tumors. Perez et al. reviewed 154 squamous cell cancers of the tonsillar fossa treated by RT alone and found a significant relationship between unique T-stage (stratified as T1/2 vs T3/4), using one-dimensional measurement of the tumor and local control rate. However, the 10 year disease-free survival rates for N0 disease were similar: T1, 69%; T2, 48%; T3, 50%; and T4, 57%, respectively (24). The local-regional benefit of different treatment regimens should be compared among tumors of comparable volume, rather than the TNM stage at present. In this study, treatment was heterogeneous because of the nature of the retrospective review and the 5 year local control rate for those with Td < 4 cm tumors (< 33 cm3 in tumor volume) were 65% (95% confidence interval 43-88%). Two patients underwent induction chemotherapy for Td [ge] 4 cm tumors and the result was complete tumor resolution. They received 60 Gy per 6 weeks of RT after that and survived without recurrence at about 5 years (57.3 and 68.6 months). This suggests that, as stated by Brenner (15), tumor volume at the commencement of RT is more suitable than that prior to induction chemotherapy for the prediction of radiocurability. Multivariate analysis revealed Td to be the only independent prognostic factor of cause-specific survival. This suggests that local control is mandatory for the success of radiotherapy for head and neck cancer. It is noteworthy that, in this study, seven of the nine patients with Td < 4 cm tumors who experienced local recurrence were successfully salvaged and the 5 year ultimate local control rate was 91%. Therefore, further intensification of organ-conserving treatment aimed at improving the local control rate should be done with careful consideration of the safety of salvage surgery, especially for patients with small tumors. Cooperation with the surgeon is indispensable when changes in fractionation schedule or use of combination chemotherapy are planned for these tumors. Local control by conventional RT alone was uncommon for Td [ge] 4 cm tumors and salvage surgery was hardly ever possible for these patients. Hence the most intensive chemoradiotherapy regimen should be considered for this category of tumors. The concept discussed above is equally applicable to the relationship between the volume of metastatic adenopathy and regional control. Further investigation is needed to clarify the prognostic significance of nodal volume on survival. Sufficient 2 year ultimate regional control rate could be obtained by RT and salvage neck dissection for N2 and N3 disease with Nd < 4 cm lesions. Nd and N-stage were correlated well and the same was true when Nd < 4 cm and Nd [ge] 4 cm were replaced by N0-2 and N3. It is also noteworthy that, as shown in Fig. 2, there were no statistical difference of local control rate for Td < 2 cm, 2 cm [le] Td < 3 cm and 3 cm [le] Td < 4 cm tumors. This suggests that assessment of the significance of other factors such as Tpot, SF2, hypoxic fractions, labeling index and so on may also be needed for further individualization of treatment. Unless this significance can be clarified, tumor volume should be recognized as the most reliable measure of the outlook for (ultimate) local-regional control in patients with squamous cell carcinoma of the pharyngolarynx.
Local Control
Regional Control
.
Survival Outcome
Covariates
Univariates (log-rank)
Multivariates (Cox's proportional hazards analysis)
T-stage (T1/2 vs T3/4)
0.060
0.363
N-stage (N0/1 vs N2/3)
0.022
0.200
Clinical stage (I-III vs IV)
0.074
0.624
Td (<4 cm vs [ge]4 cm)
<0.001
<0.001
Nd (<3 cm vs [ge]3 cm)
0.221
0.532
Total dose (<66 Gy vs [ge]66 Gy)
0.056
0.119
Delay of treatment (<2 weeks vs [ge]2 weeks)
0.058
0.956
Age (<70 years vs [ge]70 years)
0.637
Prognostic Indicators for Survival Outcomes
DISCUSSION
References
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