Tumor progression in waiting time for radiotherapy in head and neck cancer

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1 Radiotherapy and Oncology 84 (27) Waiting time Tumor progression in waiting time for radiotherapy in head and neck cancer Anni Ravnsbæk Jensen a,b, *, Hanne Marie Nellemann c, Jens Overgaard a a Department of Experimental Clinical Oncology, b Department of Oncology, and c Department of Radiology, Aarhus University Hospital, Denmark Abstract Introduction: Waiting-time prior to radiotherapy is a well-known problem. This study aims to determine the impact of time on tumor growth in a patient population with squamous-cell carcinoma of the head and neck (SCCHN). Material and methods: In a consecutive cohort, all patients with both a diagnostic scan and a treatment-planning scan were identified. In total 648 patients were seen, and 414 treated with primary radiotherapy. Ninety-five had two scans and 61 sets were eligible for comparison. Endpoints were change in tumor volume, tumor volume doubling time (TVD) and disease progression measured by TNM-classification and RECIST criteria. Results: Median interval between eligible scans was 28 (5 95) days. Thirty-eight (62%) had measurable increase in tumor volume, median 46% (6 495%). For all patients TVD was median 99 days, but for the half of patients with fastest growing tumors TVD was 3 days (15 41). Tumor volume increase was significantly correlated to time and histological differentiation. Twelve (2%) developed new lymph-node metastasis and 1 (16%) progressed in TNM-classification. Evaluated by RECIST criteria 18 (3%) patients had progressive disease. Interpretation: This study shows a negative impact of waiting time in patients with SCCHN. Within an average time of 4 weeks the majority of the patients developed significant signs of tumor progression. It was not possible to define a threshold for acceptable time intervals in order to avoid volume changes, or to define a subgroup that has no negative impact of delay. c 27 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 84 (27) 5 1. Keywords: Head and neck cancer; Delay; Waiting time; Radiotherapy; Tumor volume doubling time Waiting time prior to radiotherapy is a major problem in many radiotherapy centers with reported delays of 7 days or even more [1,2]. Though frequently reported, it is still not an acceptable situation having the biology of cancer diseases in mind [3]. Studies analyzing the impact of waiting time on local control probability and survival for patients with squamous cell carcinoma of the head and neck (SCCHN) have shown various results [4 8]. This might partly be explained by a potential risk of selection bias such as giving priority to patients with advanced tumor burden. To reduce bias, we analyzed the impact of time on objective tumor parameters which are known to affect prognosis. Thus a clear correlation between tumor size and treatment response is known for patients with head and neck cancers [9 11]. It is also well documented that the local control probability is related to nodal status and to the volume of metastatic nodes [12 14]. This study aims to determine the impact of time between a diagnostic and a treatment planning scan on tumor growth and on the development of new lymph node metastasis in a population based cohort of patients with SCCHN. Materials and methods All patients with squamous cell carcinoma in pharynx, larynx or oral cavity seen at the Department of Oncology, Aarhus University Hospital from January 2 up to May 25 were identified. Altogether 648 patients were seen and 414 received primary radiotherapy with curative intent (Fig. 1). Ninety-five patients were identified, with both a diagnostic scan (MR or CT) and a treatment planning CT scan (Fig. 1). The final study group consisted of 61 patients with two sets of comparable scans, on which it was also possible to make valid tumor measurements. For the remaining 34 patients, tumors were either not measurable or patients were not lying in comparable positions on both scans. For each case the diagnostic and the planning scan were evaluated successively in order to make measurements at the same level and discriminate developing lymph nodes. Tumor size and number and size of metastatic lymph nodes were measured by the same radiologist. Lymph nodes were considered positive only if the largest diameter was more than 1 cm. Endpoints were changes in tumor volume, tumor volume doubling time, changes in TNM stage, and progressive /$ - see front matter c 27 Elsevier Ireland Ltd. All rights reserved. doi:1.116/j.radonc

2 6 Tumor progression in waiting time 648 patients initially seen at the department of radiotherapy 234 patients referred to Surgery/ palliation 414 patients had primary radiotherapy 124 patients without treatment planning scans 29 patients given primary radiotherapy with planning scans 195 patients without diagnostic scans 95 patients with a diagnostic and a treatment planning scan 61 patients eligible for the study 34 patients with scans not comparable or tumors not assessable 9 Larynx 35 Pharynx 17 Oral cavity Fig. 1. Patient selection scheme. disease measured by RECIST criteria [15]. TNM staging was done according to the UICC classification [16]. SPSS 13. statistical software for PC was used. Chisquare was used for testing differences in distribution of factors in n-by-n tables. The relationship between tumor volume and waiting time was analyzed using Spearman s q. The impact of tumor differentiation, site and size were analyzed using partial correlation. All tests were twotailed and a p-value of.5 or less was considered to be statistically significant. Tumor volume was estimated by calculating the volume of an ellipse; whenever the third diameter was not available, the mean of the two others was used. The third diameter was only used when measurable on both scans. Volume increases below 5% were regarded as within measurement errors. Tumor volume doubling time (TVD) was calculated by the formula: TVD = (ln2/ln (V 2 /V )). Results Ninety-five patients had two scans performed and compared to all the patients treated with curatively intended radiotherapy these patients had more advanced disease, primarily because the group contained relatively less patients with small larynx tumors. Of the 95 sets of scans, it was possible to find comparable scans for 61 patients, and there were no differences between all the 95 patients and the 61 patients with comparable scans. Eligible for the study were 47 men and 14 women with a median time between the scans of 28 days (5 95). The composition of this group in relation to the whole patient cohort is shown in Table 1. For 45 patients the measured volume was primary tumor and lymph node metastases and for 16 patients where tumor bed was not measurable, the measured volumes were from lymph node metastasis only. There was no difference in growth rate between the two groups. Overall, 38 patients (62%) showed a measurable increase in total tumor volume (primary tumor and regional lymph nodes) with a median volume increase of 46% (6 495), Fig. 2. The growth could be rather dramatic (Fig. 3), but the outcome was heterogeneous and ranged from very fast growing tumors to tumors with no measurable growth. The volume increase was dependent on the scanning interval (Table 2, Fig. 2). Thus, among patients with an interval of 2 weeks or less 4 of 12 patients showed significant progression (33%), for the interval of 2 4 weeks 13 of 19 patients showed measurable progression (68%) and a similar frequency of 7% (21/3) was found for patients with more than 4 weeks interval between scans. In order to compensate for the difference in scanning intervals the tumor volume doubling time was estimated using data for the total volume of malignant lesions. For all 61 tumors a median tumor volume doubling time of 99 days (15 to >234) was observed. The TVD was independent of the initial tumor size (p =.81) and of the site of the primary tumor (p =.58), but was found to be most pronounced in tumors with moderate to poorly differentiated squamous cell carcinomas (p =.3). The wide range indicated that about 38% had no measurable TVD whereas on the other hand the quartile of patients with the highest growth rates had a median TVD of 27 days (15 35), and for the half of patients with fastest growing tumors the median TVD was 3 days (15 99). In general, our patients had quite advanced tumors with 23% being classified as T4, 58% were N2 or N3, and 62% in stage IV at the time of the first scan. For patients with tumors less than T4 2/47 (5%) progressed to a larger T-classification and 8/55 (15%) patients with less than N3 disease additionally progressed to a larger N-classification resulting in 4 of 23 (17%) patients with less than stage IV tumors showing progression to a higher stage. Since this due to the initial advanced stage may underestimate the true progression, this was also measured by use of the RESIST criteria which are independent of actual stage. Using this parameter 18 patients (3%) showed progressive disease (>2% increase in largest tumor diameter and/or appearance of new lesions). Thus overall did 21 (34%) patients show increase in T or N-classification and/or RECIST progression (Table 2). Both the progression in T, N, stage and the positive RE- SIST criteria were correlated with increasing time interval between the scans. Discussion Several studies have analyzed the impact of patient and/ or professional delay on local control probability and overall

3 A. Ravnsbæk Jensen et al. / Radiotherapy and Oncology 84 (27) Table 1 Patient characteristics 414 patients given radiotherapy with curative intent 29 patients with treatment planning scan 61 patients with comparable scans Age (median) 6 (32 92) 58 (32 9) p <.1 a 56 (32 81) p <.1 b Gender p =.54 p =.58 Male 324 (79%) 23 (79%) 47 (77%) Female 89 (21%) 6 (21%) 14 (23%) T-stage (%) p <.1 p <.1 T (28%) 65 (22%) 1 (16%) T (35%) 19 (38%) 19 (31%) T 3 17 (26%) 77 (27%) 15 (25%) T 4 45 (11%) 36 (12%) 14 (23%) T x 4 (1%) 4 (2%) 3 a (5%) N-stage p <.1 p <.1 N 23 (56%) 135 (46%) 13 (21%) N 1 57 (13%) 45 (15%) 13 (21%) N 2 14 (25%) 93 (32%) 29 (48%) N 3 21 (5%) 19 (7%) 6 (1%) N x 2 (1%) 1 (%) Stage p <.1 p <.1 I 88 (21%) 41 (14%) 1 (1%) II 83 (2%) 58 (2%) 5 (9%) III 11 (27%) 77 (27%) 17 (28%) IV 131 (32%) 114 (39%) 38 (62%) Site p <.1 p <.1 Oral cavity 18 (26%) 92 (32%) 17 (28%) Larynx 198 (48%) 98 (34%) 9 (15%) Pharynx 18 (26%) 1 (34%) 35 (57%) Type of diagnostic scan MR 34 (56%) CT 27 (44%) Days between scans (median) 28 (5 95) The patient cohort compared with all having a treatment planning scan and patients eligible for the final study group. a All 414 patients vs. 29 with treatment planning scans. b All patients vs. 61 patients with two scans. survival with conflicting results. These studies are all retrospective and the interpretation is difficult due to random variations and confounding factors. A Danish study found a significant longer waiting time for patients with small tumors than for patients with large tumors [17], and it might be that patients with a history of fast growth or advanced state might bypass the waiting list and receive more prompt treatment in centers struggling with capacity problems. It has been suggested that the aggressiveness of the disease itself influences delay, a phenomenon called the waiting time paradox [18]. In the current study we analyzed the impact of time on well-established prognostic factors in a complete singlecenter patient cohort in order to avoid selection bias. Compared with the entire patient cohort, the eligible patients included a higher proportion with locally advanced disease, mainly because none of the patients with small glottic cancers had two scans. It might introduce a bias, but we did not find any correlation between tumor size and growth and other studies suggest the same impact of delay in glottic cancer as in other sites in head and neck [7,8]. Sixteen percent progressed in T or N classification even though our patients had rather advanced stage at presentation. For patients with locally advanced disease, the TNM classification is not sufficient to evaluate tumor progression, as patients in stage IV cannot progress to a higher stage. Analyzing tumor growth according to the TNM classification may thereby tend to underestimate disease progression. The mean increase in volume of the primary target lesion (tumor bed or the lymph node with the largest diameter at diagnosis) was 38% in 28 days and is in accordance with the results found by Waaijer et al., who found a mean increase on 7% in 56 days [19]. Corresponding to these findings we also found TVD within the same range being mean 87 (61 112) days in our study and mean 96 (26 256) days in the study by Waaijer (Fig. 4). The consequences of delay in start of radiotherapy are related to TVD and for a patient with a fast-growing tumor an interval of less than one month can have a significant adverse effect on the outcome [2]. Mackillop et al. have estimated an 8% loss in local tumor control probability by a 4 weeks delay for tumors with a TVD on 9 days [21]. Our study confirms that it seems to be a valid estimate of TVD. However the growth rates do not follow a Gaussian distribution and we found a large heterogeneity in growth rates with TVD ranging from 15 days to tumors with no measur-

4 8 Tumor progression in waiting time a Increase in total volume % b Tumour volume doubling time c Progression according to RECIST Time (days) Total volume at diagnosis (cm3) Time (days) Fig. 2. Volume increase while waiting. (a) Increase in malignant tumor volume. 62% had measurable increase in volume with median of 46%. (s) Highly differentiated tumors, (d) Poorly/moderately differentiated tumors p <.1 for time vs. growth, p <.1 for correlation to histological differentiation. (b) Tumor volume doubling time as a function of malignant tumor volume at diagnosis, p >.5. (c) Progression according to RECIST. (d) Change in largest tumor diameter%, (h) Appearance of new lesions. Patients above the dotted line have progression according to RECIST criteria. able growth. Assuming an initial tumor control rate of 5% and using the data from Mackillop et al. [21] we did estimate quite marked reductions in tumor control probability. For the quartile of patients with the highest growth rates (TVD < 35 days), a more than 2% loss in local tumor control probability could be expected within 4 weeks time (from 5% to approx. 3%), and for the half of patients with the fastest growing tumors (TVD < 99 days) the estimated loss in local control probability would be more than 8% within 4 weeks (from 5% to 42%) [21]. The impact on survival of such decrease in local control probability may be substantial. Thus previous overviews have indicated that about 7 out of 1 loco-regional failures after radiotherapy for SCCHN may eventually die due to lack of tumor control [22,23]. It should not be forgotten that the present numbers are model calculations and estimates. However, they are founded in well-described clinical studies and there are no obvious arguments against their clinical validity. As described did we observe a large range between fastand slow-growing tumors, also among tumors from the same site and of the same size. It was not possible to distinguish the very fast-growing tumors from the remaining except by histological differentiation and it is therefore even less acceptable with long time intervals for patients with poorly or moderately differentiated tumors. However, even among the well-differentiated tumors did 4 of 13 (31%) show a measurable increase in tumor volume. In this study we are only dealing with a smaller part of the total time between diagnosis and start of treatment. In 22 the median time interval for patients with cancer in head and neck in Denmark was 7 days for this patient group, a 3 weeks increase from the time observed in 1992 [1]. According to the model by Mackillop [21] and demonstrated above, it corresponds to a substantial loss in local control probability even assuming the most conservative estimates of TVD. The treatment outcome after radiotherapy for SCCHN is constantly improving. In Denmark we have developed our treatment strategy based on a series of large national randomized clinical trials [24,25]. As an example we have achieved an approximately 1% gain in tumor control by using moderate accelerating fractionation schemes with six fractions peer week [25,26]. The large trial by which this treatment principle was derived [24] to place in the 199s, and it is a bitter irony that while we were developing the rationale for a biological based treatment improvement, this gain or even more may have been lost in the same time period due to the above-described increase in time between diagnosis and start of therapy [1]. Other factors may additional aggravate the situation. We compared initial MR scans to later CT scans and it might be one of the reasons that so many scans were not comparable. However, when comparing the two modalities in this order, we might have underestimated tumor growth, as there is a tendency to overestimate tumor size on MR compared to CT [27]. Also the observed increase in tumor volume, and the appearance of new lymph node metastasis within the same T and N stage do not only affect prognosis but also increase radiotherapy field sizes and thereby the frequency and severity of early and late morbidity caused by the volume effect [28,29].

5 A. Ravnsbæk Jensen et al. / Radiotherapy and Oncology 84 (27) Fig. 3. Examples of tumor progression. (a) N-stage. A patient with 47 days in between scans. Note growth of the lymph node metastasis and appearance of a contra-lateral metastasis. Scans are within the same level but with differences in positioning of the chin. (b) T-stage. A patient with 19 days between scans. Note the progressive bone destruction. Table 2 Changes in volume and RECIST criteria according to time interval between scans Time interval (days) Number of patients Increase in volume Change in T or N classification a Progression according to RECIST Change in RECIST and/or T or N classification Any sign of progression (33%) 4 (33%) (68%) 4 (21%) 6 (32%) 7 (37%) 13 (68%) > (7%) 6 (2%) 12 (4%) 14 (47%) 21 (7%) All (62%) 1 (16%) 18 (2%) 21 (34%) 38 (62%) a Note that several patients had initially tumors classified as T4 and/or N3. Conclusion This study shows a negative impact of waiting time in a substantial part of patients with SCCHN. With a median of 4 weeks interval between two scans did the majority of patients develop significant increase in measurable parameters for tumor volume or progression. It was not possible to define a threshold for acceptable time intervals in order to avoid volume changes, or to define a subgroup that has no negative impact of delay. * Corresponding author. Anni Ravnsbæk Jensen, Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Building 5, DK-8 Aarhus C, Denmark. address: anni@oncology.dk

6 1 Tumor progression in waiting time Volume increase % Time (days) Fig. 4. Volume increase while waiting including other known data on tumor growth. (h) Data from Waaijer et al. [19] with a mean increase in tumor volume of 7% in 56 days. (d) Data from current study with mean increase in tumor volume of 38% in 28 days. Received 4 January 27; received in revised form 1 April 27; accepted 4 April 27; Available online 9 May 27 References [1] Primdahl H, Nielsen AL, Larsen S, Andersen E, Ipsen M, Lajer C, et al. Changes from 1992 to 22 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: a Danish nationwide survey from DAHANCA. Acta Oncol 26;45: [2] Robinson D, Massey T, Davies E, Jack RH, Sehgal A, Moller H. Waiting times for radiotherapy: variation over time and between cancer networks in southeast England. Br J Cancer 25;92: [3] Rutqvist LE. Waiting times for cancer patients a slippery slope in oncology. 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