Japanese Journal of Clinical Oncology Advance Access originally published online on August 12, 2006
Japanese Journal of Clinical Oncology 2006 36(9):537-546; doi:10.1093/jjco/hyl081
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© 2006 Foundation for Promotion of Cancer Research
Analysis of Prognostic Variables among Patients with Locally Advanced Head and Neck Cancer Treated with Late Chemo-Intensification Protocol: Impact of Nodal Density and Total Tumor Volume
1 Department of Oncology, Batra Hospital and Medical Research Centre, New Delhi and 2 Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India
For reprints and all correspondence: Kundan Singh Chufal, Senior Resident, Department of Oncology, Batra Hospital and Medical Research Centre, 1, Tughlakabad Institutional Area, New Delhi 110062, India. E-mail: kundan_25{at}rediffmail.com
Received April 17, 2006; accepted June 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The aim of the present study was to define the prognostic impact of nodal density (ND) and total tumor volume along with many other tumor, treatment and patient related variables using the late chemo-intensification treatment regimen with conventionally fractionated radiotherapy (70 Gy/7 weeks).
Methods: A total of 74 patients with Stage III and IV biopsy proven squamous cell carcinoma of oropharynx, hypopharynx and larynx were treated with this regimen. ND and total tumor volume was measured on high resolution CT scans for all the patients. Chemotherapy consisted of continuous infusion of 5 FU at 350 mg/m2/day and cisplatin as 1 h infusion at 10 mg/m2/day on days 1–5 of week 6 and 7 of radiotherapy.
Results: Grade III mucositis was present in 48 (64.9%) patients. Overall complete response rate was 77%. At 28 months, locoregional relapse-free survival (LRFS), overall survival (OS) and distant metastases-free survival (DMFS) was 70.8%, 66.9% and 81.9%, respectively. In the final multivariate Cox-regression model tumor stage, ND, primary site and nodal stage were independent variables predicting for LRFS. Similarly AJCC group staging, ND and total treatment volume were found to have significant impact, independently over LRFS.
Conclusions: There is tremendous variation in terms of ND and total tumor volume within AJCC nodal staging and tumor staging, respectively. ND had significant impact over LRFS and OS. Future phase III trial may need stratification on the basis of these variables.
Key Words: head and neck cancer • nodal density • concurrent • total tumor volume • chemoboost
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INTRODUCTION |
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Increasing tumor volume adversely affects the local control rate (LCR) (1). It was Fletcher who first validated this concept and showed that clonogen number directly relates to tumor volume (2). High resolution contrast enhanced computed tomography (HRCECT) had supplemented clinical examination as a major method for diagnosing the involvement of neck in head and neck tumors (3,4). For more than 1 cm lymph nodes, HRCECT can also detect metastases if the nodes have central area of hypodensity (5). This finding implicates that these nodes had central necrosis with hypoxia. A relationship between response to chemotherapy or radiotherapy and the density of the lymph node in HRCECT was demonstrated in some trials (6,7). Complete responses (CR) after chemotherapy or radiotherapy were achieved less often if more than one-third of the metastatic lymph node area was occupied by a hypodense zone (8). This phenomenon was attributed to hypoxia, which can be regarded as a major cause of treatment failure (9,10). AJCC staging system is widely used to predict prognosis and categorize the patients with head and neck cancer. Within the same T stage, however, there can be a range of tumor volumes having varied impact on LCR. Similarly the same N stages may have lymph nodes with various extent of central necrotic area. There are inherent variations related to characteristics of tumor in patients with head and neck cancer. Can we categorize the patients into different subgroups independent of AJCC staging on the basis of total tumor volume and nodal density (ND)? Do these variables have any impact on survival and LCR? Seeking answers to these questions, we tried to analyze the impact of tumor volume and ND along with other prognostic factors on treatment outcome using concurrent chemoradiotherapy regimen with late chemo-intensification (LCI) protocol as outlined in Fig. 1. We have already published our clinical results using this concurrent chemoradiotherapy regimen (11).
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PATIENTS AND METHODS |
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STUDY DESIGN
Between April 2001 and May 2004, 74 patients with previously untreated, advanced SCC of head and neck cancer entered in a protocol based at Department of Radiotherapy, King George's Medical University. Before enrollment of the patients, our institutional review board and clinical research committee approved the trial. Written informed consent was obtained from each patient before his or her participation in the study. Eligibility was limited to patients with primary tumors of oropharynx, larynx and hypopharynx with stage III and IV (M0) disease according to AJCC Cancer Staging Manual, Fifth Edition. Patients were required to have pathologically confirmed Squamous cell carcinoma of head and neck (SCCHN), a Karnofsky performance status of 70–100, an adequate enteral diet, adequate bone marrow reserve (leukocyte count >4 x109/L and platelet count >10 x 109/L), a normal aspartate aminotransferase (AST) and bilirubin levels and a creatinine level <1.2 mg/dL. Patients with multiple primary carcinomas were excluded from this study, as were patients whose tumor represented a second primary carcinoma. According to the treatment plan (as explained in Fig. 1), all patients were treated with continuous intravenous infusion of 5 FU [350 mg/m2 for Day 1–5 (120 h infusion) Week 6 and 7] and cisplatin 10 mg/m2 intravenously Day 1–5, Week 6 and 7) during the last 2 week of radiotherapy. All patients received a conventionally fractionated irradiation i.e. 2 Gy per fraction five times in a week to a total dose of 70 Gy in 7 weeks in two phases. All toxicities were scored according to Radiation Therapy Oncology Group (RTOG) criteria (12).
TUMOR VOLUME AND NODAL DENSITY MEASUREMENT
HRCECT scans of the entire neck region including the primary site were performed on GE Medical system, machine model CT/e. Iodine-based contrast material (150 ml) was injected intravenously starting with a bolus of 50 ml (3 ml/s) followed by slow (1 ml/s) infusion of the remaining dose. Total tumor volume of the primary and involved neck nodes was calculated as a cuboid volume using maximum dimension in each plane. ND was graded according to the criteria of the institute Gustave Roussy, France (6). The density of node was compared with that of nuchal muscle at the same level. A node was classified as Isodense if one-third or less than one-third of its cross-section consisted of hypodense zone and as hypodense if more than one-third of the node's cross-section was found to be hypodense. The largest visible node of at least 1 cm was chosen for grading purpose.
RESPONSE ASSESSMENT, ENDPOINTS AND STATISTICS
Patients were followed weekly during the treatment. Response and treatment related toxicities were quantified by clinical and radiographic examinations. Response was evaluated according to the WHO criteria (13). For residual nodes or primary disease at any time during follow up, consultation was sought from surgical oncologists. Primary endpoints of the study were to quantify the effects of ND and tumor volume on locoregional relapse-free survival (LRFS) and overall survival (OS). The data were analyzed using the SPSS version 10 statistical software. The relationship between variables was assessed using the Spearman rank correlation coefficient (r). To test the equality of means independent sample t-test was used. Times for endpoints were calculated from the date of registration. Time dependent variables were analyzed using Kaplan–Meier methods. The differences in endpoints within the subgroups identified in the study were tested using the pairwise Log-rank test where only two variables had to be compared. Final multivariate analysis was done utilizing Cox's proportional hazard model using forward stepwise method. Variable with maximum significance was first entered into the model. Events for LRFS included first recurrence of disease at local or regional site or persistant disease. Persistant disease was regarded as a failure on last date of radiotherapy. For distant metastases free survival (DMFS), first recurrence at distant site was taken as event. Events for OS included all deaths. Seventeen patients (23%) were lost to follow up and were counted as events.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The patients and treatment characteristics are shown in Table 1. All patients were treated under the same hospital conditions and received the same treatment and supportive care. Patients were divided into two subgroups according to ND and total tumor volume (TTT). Subgroups according to these two factors were tested for equality of means for different treatment and patient related variables (Table 2). Toxicities were manageable. Confluent oral mucositis was present in 48 patients (64.9%) while pharyngitis of Grade III nature was present in 51 (68.9%) patients.
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SURVIVAL AND LOCAL TUMOR CONTROL
Overall complete response rate was 77%. Sixteen (24.4%) of the 41 patients with complete remission experienced a local and/or regional failure. The time interval was between 3 month and 42.3 month after completion of treatment. Distant metastases were noted in 11 (14.9%) patients between 12.7 and 33.7 month of follow up. Median follow up time was 28.8 ± 9.6 months (95% CI 25.6, 30.1). OS, LRFS and DMFS were 70.8%, 66.9% and 81.9% at 28 months. Median OS time was 35.1 months (95% CI 30.1, 40.1) while median survival time was not reached for LRFS and DMFS. Mean LRFS time was 33.2 months (95% CI 30.0, 36.3) and mean DMFS time was 37.9 months (95% CI 35.5, 40.2).
CORRELATION
Among the variables representing the tumor burden a good correlation was observed between the nodal stage and TTV (r = 0.282, P = 0.015), between ND and AWHL (r = –0.564, P = 0.000), between the Nodal stage and ND (r = 0.4777, P = 0.000) and between TTV and ND (r = 0.254, P = 0.029). The proportion of hypodense nodes within each nodal category was 4/23 (N1), 15/24 (N2) and 21/27 (N3). Response to the treatment (OS) showed good correlation with ND (r = 0.433, P = 0.000) and with TTT (r = –0.13, P = 0.006).
PROGNOSTIC FACTORS
Prognostic factors with an impact on OS and LRFS are given in Tables 3 and 4, respectively. In univariate analysis patients with hypodense lymph nodes had OS of 54.8% at 28 month while it was 81.7% in patients with Isodense nodes. Median OS was 28.6 months (95% CI 24.7, 32.4) and 41.4 month (95% CI 30.6, 52.2) in patients with hypodense and Isodense nodes, respectively (P = 0.0046). TTV more than 25 cm3 was associated with OS of 59.2% at 28 months compared with patients with smaller tumor volumes showing OS of 77.4% (Fig. 2). Median OS time among patients with TTV of more than 25 cm3 and TTV less than or equal to 25 cm3 was 29.0 months (95% CI 23.6, 34.5) and 36.1 months (95% CI 32.6, 39.5), respectively (P = 0.0038). There was lot of variation in total tumor volume among T3 tumor stage (Fig. 3) and when the patients were split into subgroups, OS at 28 months among 32 patients with TTV of less than or equal to 25 cm3 was 77.4% with mean survival time (Median survival time not reached) of 36.1 months (95% CI 32.5, 39.5) and for 31 patients with TTV of more than 25 cm3 was 61.5% with median survival time of 29.4 months (95% CI 21.9, 36.7). This difference was statistically significant (P = 0.0173). For LRFS the difference between the two groups was not significant (Fig. 2). In addition survival was significantly influenced by TTT. When it was less than or equal to 51 days, OS at 28 months was 76.5% with median OS time of 41.4 month (95% CI 30.6, 52.2) and when it was more than 51 days, OS was 54.3% with median OS time of 28.6 month (95% CI 21.3, 35.9).
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LRFS was significantly influenced by the ND and T stage. At 28 months LRFS was 80.8% and 61.6% among patients with Isodense and hypodense nodes. Median survival was not reached for patients with Isodense nodes while it was 33.0 month (95% CI 25.4, 34.4) for patients with hypodense nodes (P = 0.0179). Patients with T3 stage had LRFS of 77.8% at 28 months and median survival time was not reached while patients with T4 stage tumor had LRFS of 35.6% with median survival time of 27.2 months (95% CI 25.6, 48.9). The difference was statistically significant (P = 0.0140). ND was having significant impact over both LRFS and OS. Within the same N stage survival rates were significantly different among the subgroup according to ND for both OS and LRFS (Figs 4 and 5). Test statistics for equality of survival distribution for ND adjusted for N stage was P = 0.0029 for OS and P = 0.005 for LRFS (Table 5). Proportion of patients with hypodense node was increasing as the nodal stage was increasing. In N1 stage 17.4%, N2 stage 62.5% and N3 stage 77.7% of patients were having hypodense nodes. In the final multivariate Cox-regression model T stage, ND, primary site and nodal stage were independent variables predicting for LRFS (Table 6). Similarly AJCC group staging, ND and TTV were found to have significant impact, independently over LRFS.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Both tumor volume and ND had impact on OS in the final multivariate Cox-regression analysis for patients treated with the LCI protocol. Other factor which had independent prognostic significance was AJCC group staging. For LRFS ND, T stage, primary site and nodal stage had independent prognostic significance in decreasing order (Table 6). Nodal stage and TTV had good correlation and was expected as we had majority of patients with N3 disease (36.5%) and TTV was combined volume of primary tumor and nodal volume. Also when the nodal stage was increasing more nodes were hypodense (Table 5). AWHL in patients with hypodense node was 10.2 gm/dl while it was 11.4 gm/dl in isodense node (Table 2). This correlation substantiates the hypothesis that hypodense nodes represent hypoxia. With increasing volume, tumor will have central area where oxygenation is not sufficient and thus hypoxia develops. The same was true in our series where ND was correlated significantly with TTV. All the variables mentioned above have already been reported as prognostic factors consistently (2,6–8), except for ND. Regarding ND, conflicting results were presented by Wang et al. (14). They used chemotherapy and correlated response rate with ND. Probably their endpoints were not suitable to assess the impact of ND. In chemotherapy, better endpoints would be locoregional relapse-free rate and OS.
NODAL DENSITY
Eric Lartigau et al. (15) found that very low PO2 values, corresponding to radiobiologic hypoxia, were present in most of the head and neck tumors. In their study PO2 values decreased with increasing nodal size. For the patients with CT defined track of the oxygen measuring probe, the mean and median PO2 in the area of the tumor considered to be hypodense were lower than those in Isodense area. Correlation of hypoxia to the clinical response to treatment was shown by Nordsmark et al. (9). In their interesting study, they showed that pretreatment tumor oxygenation status was predictive of radiation response, when using the fraction of PO2 values <2.5 mm Hg as endpoint. The relative risk of failure was 3.56 times higher in the most hypoxic subgroup. Grabenbauer et al. (8) studied the impact of nodal CT density on the treatment outcome among patients treated with concurrent chemoradiotherapy and radiotherapy alone. In their study patients with hypodense node had tumor control of 30% at the end of 3 years while patients with Isodense node had that of 21%. Among patients who received concurrent chemotherapy with cisplatin-based regimen the tumor control at 3 years was 0% and 91% for hypodense and Isodense nodes, respectively. In our study LRFS at 28 months was 61.6% and 80.8% for hypodense and Isodense nodes, respectively. Although we had large bulk of patients with N3 disease (36.5%) and hypodense nodes (54.1%), our LRFS rate were still better than the concurrent chemotherapy arm of Grabenbauer et al. (8) for hypodense nodes. The better outcome may be because of the cumulative intense chemotherapy during the last two weeks of treatment. This LCI protocol, also known as chemoboost, has been reported earlier (11,16–18). However, probably ours is the first study reporting ND as prognostic factor for this concurrent chemoradiotherapy protocol. On the basis of these studies mentioned above, it could be speculated that the same biological phenomenon is represented both as hypodense area greater than one-third nodes as measured by HRCECT scanning and as very low PO2 values.
Now we have established that patients with hypodense node within the same nodal stage (Figs 4 and 5) had inferior LRFS and OS as compared with Isodense nodes. Do we need to change our approach for the patients according to their ND, for example by changing the chemotherapy drug or protocol? We have earlier reported our concurrent chemotherapy protocol for locally advanced head and neck cancer using Mitomycin C (19). Now we are trying to do the secondary analysis, which will reveal the differences between the outcome in patients with hypodense nodes and isodense nodes. And if there is no significant difference, probably this will justify the use of Mitomycin specifically for hypoxic nodes determined by non-invasive procedure such as CECT scans.
TUMOR VOLUME
The estimation of tumor volume solely on clinical grounds (20) did not demonstrate an independent prognostic value for the endpoint of survival in an EORTC study. Tumor volumes as determined by CT are good reflection of tumor bulk as they measure it in all directions. The method by which the volume is determined, however, seems to be a crucial point. According to Collins et al. (21) and Grabenbauer et al. (8), the cuboid tumor volume, which is determined by measuring the maximum dimension in each plane using CT or MR data, can be regarded as a good reflection of the true tumor volume. Therefore we decided to follow these criteria. A further consideration is the number of clonogens that have to be sterilized for tumor care; in general, a smaller tumor is more easily controlled with certain radiation dose than a larger tumor. There is in fact substantial evidence in clinical literature for a decisive impact of tumor volume on the treatment outcome and the evidence continue to accrue. The correlation between local recurrence and tumor size was significant (P < 0.001) in 308 stage I–IV laryngeal carcinoma patients (22,23). Grabenbauer et al. (8) showed in their study that patients with low tumor volume had 69% survival and 67% tumor control at 3 years among patients receiving concurrent chemoradiotherapy while it was 22% and 23% with large tumor volume. In our study the OS was also better for patients with low tumor burden (Table 3) and it showed improved trend for LRFS in patients with low tumor burden but it was statistically not significant (Fig. 2). This LCI regimen was equally effective among the patients with varied TTV in terms of LRFS among patients subgrouped according to TTV. In two prospective studies (24,25) it was shown that patients in T3 stage grouping could be divided into two groups with significantly different outcome. Same was evident in our study when we split our patients with T3 stage into two subgroups primarily based on TTV (Fig. 3). OS was better in patients with TTV of less than or equal to 25 cm3 (77.4% at 28 months) when compared with TTV of more than 25 cm3 (61.5% at 28 months). The difference was statistically significant. There was trend toward improvement in LRFS with low tumor volume in T3 stage but the difference was statistically not significant. Within same T stage we can have tumors with different tumor volumes having varied response to treatment. This fact raises a question: is the same treatment protocol for patients with different tumor volumes justifiable? Should we categorize the patients with different prognosis because of varying total tumor volumes into one group as per the AJCC staging (for example T3 stage in this series)?
OTHER FACTORS
The importance of treatment protraction is an established factor even for early stage tumors which influences the survival and local control (26,27). In univariate analysis using Log-rank test, only TTT had an impact on OS (Table 3). Nodal stage, primary site and AJCC group staging are well-established prognostic factors (8,6,22,23). These were also significant in our multivariate Cox-regression analysis for OS and LRFS (Table 6). We conclude that for advanced SCCHN treated using concurrent chemoradiotherapy, nodal CT density and TTV both have independent prognostic significance over treatment outcome. This leads to a question as to whether one treatment protocol can be imposed for all patients. As the numbers of patients in the study were limited, one can answer this question only in the light of randomized phase III trial allocating different treatments to the patients with different nodal CT density and TTV. In our institution we are trying to develop a protocol where patients with N3 tumors and/or hypodense nodes will receive mitomycin-based regimen (19), while other group (less than N3 tumor and/or Isodense nodes) will receive the LCI regimen (11).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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