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Split-course Accelerated Hyperfractionation Radiotherapy for Advanced Head and Neck Cancer: Influence of Split Time and Overall Treatment Time on Local Control

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Tetsuo Akimoto
Tetsuo Akimoto
Tetsuo Akimoto
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Norio Mitsuhashi at Tokyo Women's Medical University
Norio Mitsuhashi
Kazushige Hayakawa at Kitasato University
Kazushige Hayakawa
Hideyuki Sakurai at University of Tsukuba
Hideyuki Sakurai
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We analyzed 52 patients with stage III and IV head and neck cancer who were given split-course accelerated hyperfractionated radiotherapy with curative intent, focusing particularly on the influence of split-time on local control. An initial complete response was achieved in 16 patients (31%), and the rate of persistent local control at 3 years was 23%. The cause specific survival rate at 3 years was 29%. Univariate analysis of local control according to the split-time duration and overall treatment time showed that shorter duration (≤ 14 days or ≤ 45 days, respectively) had a significantly positive impact on local control (P < 0.05). Multivariate analysis using local control as an endpoint also demonstrated that gender (women showing a better outcome than men) and split-time (≤ 14 days was better than >14 days) were statistically significant factors for local control. These results suggest that shortening the split-time during radiotherapy might improve local control in accelerated hyperfractionation.
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Jpn J Clin Oncol 1997;27(4)240–243
Split-course Accelerated Hyperfractionation Radiotherapy for
Advanced Head and Neck Cancer: Influence of Split Time and
Overall Treatment Time on Local Control
 ,  ,  ,  ,  ,  ,
 ,  ,      
Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Japan
We analyzed 52 patients with stage III and IV head and neck cancer who were given
split-course accelerated hyperfractionated radiotherapy with curative intent, focusing
particularly on the influence of split-time on local control. An initial complete response was
achieved in 16 patients (31%), and the rate of persistent local control at 3 years was 23%.
The cause specific survival rate at 3 years was 29%. Univariate analysis of local control
according to the split-time duration and overall treatment time showed that shorter
duration (14 days or 45 days, respectively) had a significantly positive impact on local
control (
P
< 0.05). Multivariate analysis using local control as an endpoint also
demonstrated that gender (women showing a better outcome than men) and split-time
(14 days was better than >14 days) were statistically significant factors for local control.
These results suggest that shortening the split-time during radiotherapy might improve
local control in accelerated hyperfractionation.
Key words: accelerated hyperfractionation – head and neck cancer – split-time – overall treatment time –
radiotherapy
INTRODUCTION
Patients with advanced head and neck cancer given conventional
fractionation radiotherapy have shown a poor 2-year survival rate
of <20% (1). Therefore, over the last decade, hyperfractionated
radiotherapy has been attempted to improve the results (2,3).
Accelerated hyperfractionation, which uses a larger dose per
fraction and requires a shorter overall treatment time than
hyperfractionation, has been shown to be particularly useful for
advanced head and neck cancer, and we have also reported
significantly improved results in patients with hypopharyngeal
cancer treated in this way, in comparison with conventional
fractionation (4). The biological basis of this approrch is that
shortening of the overall treatment time might reduce the
accelerated tumor cell repopulation that occurs during the course
of radiotherapy (5). In fact, this has been confirmed by several
trials aimed at shortening the overall treatment time by modifying
the fractionation parameters, i.e. increasing the number of
fractionations per day or the dose per fraction, and having a
shorter split-time or none at all (6–8). Continuous hyperfractionated
Received November 12, 1996; accepted February 28, 1997
For reprints and all correspondence: Tetsuo Akimoto, Department of Radiology
and Radiation Oncology, Gunma University School of Medicine, 3–39–22
Showa-machi, Maebashi, Gunma 371, Japan
accelerated radiation therapy (CHART) (9) or very accelerated
hyperfractionation (10) has yielded an excellent local control rate,
but leads to severe acute and late complications.
At our institution, split-course accelerated hyperfractionation
was introduced as a treatment for advanced head and neck cancer
in 1987. The purpose of this study was to analyze the results
obtained retrospectively, focusing especially on the influence of
split-time duration, which affects the overall treatment duration,
on treatment outcome, and to determine whether or not these
factors have an impact on local control.
MATERIALS AND METHODS
We analyzed 52 patients with previously untreated stage III and IV
head and neck cancer who underwent accelerated hyperfractiona-
tion therapy with curative intent at Gunma University Hospital
between 1987 and 1994. Patients who were irradiated with
palliative intent or those with stage I and II disease or distant
metastases were excluded from this analysis. The characteristics
of the patients and tumors are listed in Table 1. All the patients had
histologically proven squamous cell carcinoma and were staged
according to the 1987 UICC staging system (11).
Radiation therapy with high-energy 6 or 10 MV X-rays was
applied. All the patients were treated with two lateral opposing or
anterior-lateral fields encompassing the primary tumor and
cervical lymph nodes, and booster doses were given for the
primary lesion with localized fields after 40–50 Gy. The treatment
241
Nucleic Acids Research, 1994, Vol. 22, No. 1
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Jpn J Clin Oncol 1997;27(4)
plan was to deliver a fractionated dose of 1.5 or 1.6 Gy twice a day
with a minimum inter-fraction interval of 5 h, and to use a 2-week
split-time after 36 Gy or 38.4 Gy to allow recovery from the acute
mucosal reaction. Patients who had a mild acute mucosal reaction
were treated using a split-time of <2 weeks. The standard total
dose in this regimen was 66 Gy in fractions of 1.5 Gy or 64 Gy
in fractions of 1.6 Gy. The numbers of patients receiving each
dose fraction were 10 with 1.5 Gy and 42 with 1.6 Gy, and the
mean and median total doses were 67 Gy and 66 Gy with a range
of 60.8–75 Gy, respectively.
Salvage surgery was performed in 10 patients (two for local
recurrence and eight for residual disease), while the others (26
patients) who had residual tumors following irradiation were
ineligible for salvage surgery because the tumors were unresectable
or the patients’ clinical condition was poor.
The local response was determined on the basis of clinical and
endoscopic findings or biopsy at the primary site. We defined a
complete response as a lack of visible evidence on endoscopy or
radiology, or in the biopsy specimen taken from the original
tumor site 3 months after radiotherapy.
All patients were followed up until death or for a minimum of
2 years, and the median follow-up period was 59 months with a
range of 25–114 months. The survival rate was calculated by the
Kaplan–Meier method (12). The χ
2
test was used to assess
differences among proportions (13), and the Cox–Mantel test was
employed to evaluate the significance of differences in survival
among subgroups (14). Variables that were thought to influence
local control were analyzed by multivariate analysis with Cox’s
proportional hazard model (15).
Table 1. Patient and tumor characteristics
Patient characteristics
Sex (male/ female) 36/16
Age (years): mean (range) 60 (32–90)
Tumor characteristics
Stage III/IV 18/34
T-factor (1/2/3/4) 3/5/31/13
N-factor (0/1/2/3) 19/5/18/10
Site
Hypopharynx 19
Larynx 6
Oral cavity 17
Oropharynx 5
Paranasal 5
Histological grade
Well differentiated 18
Moderately differentiated 15
Poorly differentiated 5
Unclassified
14
Table 2. Influence of split-time on local control (χ
2
test )
Split-time Total number Complete Incomplete P-values
(days) of patients response response
14 17 9 8
<0.05
>14 35 7 28
Figure 1. Recurrence-free survival curve of 16 patients with a complete
response
RESULTS
TUMOR RESPONSE AND SURVIVAL
A complete response was achieved in 16 (31%) of the 52 patients,
and the other 36 had residual local or nodal disease. According to the
T and N classification, cervical lymph node metastasis had a
significant negative impact on local control (P < 0.05). Within a
median follow-up period of 59 months, five locoregional recur-
rences and/or distant metastases were observed at 3, 4, 7, 12 and 32
months after treatment. Among these, only one patient was
surgically salvaged, and the others died of progressive disease with
or without distant metastasis. The actuarial locoregional control rate
at 3 years was 23%, and the recurrence-free survival rate for the
patients with a complete response at 3 years was 64% (Fig. 1). Of
the initial non-responders, three survived following salvage surgery.
At the time of this analysis, 41 patients had died, including four
concurrent deaths. The 3- and 5-year cause-specific survival rates for
all patients were 29% and 19%, respectively. The 5-year survival
rate (53%) for patients with a complete response was significantly
better than that (7%) of non-responders (Fig. 2).
I
NFLUENCE OF SPLIT-TIME AND OVERALL TREATMENT TIME
The mean and median time of split and the overall treatment
duration in all patients were 17 and 18 days with a range of 0–48
days and 48 and 46.5 days with a range of 30–77 days,
respectively. Among all the patients, 17 could be treated within
the planned split-time of 14 days or less. The reasons for
prolongation of the split-time were: acute mucosal reaction in 33
patients, and calendar holidays in three, respectively. Univariate
analysis for local control according to the duration of the
split-time (Table 2) showed that the complete response rate was
significantly higher (P < 0.05) in patients with a split-time of 14
days (53%) than in those with a split-time of >14 days (20%). The
same trend was also recognized upon analysis of the overall
treatment time (Table 3). Multivariate analysis using local control
as an endpoint showed that gender (women having a better
outcome than men) and split-time duration (14 versus >14 days)
were statistically significant factors for local control (Table 4),
whereas overall treatment time did not reach a significant level.
242
Accelerated hyperfractionation
Figure 2. Survival curves according to local response. The survival of patients
with a complete response was significantly better than that of patients with
incomplete responses (P < 0.05).
Table 3. Influence of overall treatment time on local control (χ
2
test)
Overall treatment
Total number Complete Incomplete P-values
time (days) of patients response response
45 25 11 14
<0.05
>45 27 5 22
Table 4. Multivariate analysis of possible factors affecting local control
(Cox’s proportional hazard model)
Variable
95% C.I. P-value
Sex 0.007–0.421 0.006
Age 0.811–1.067 0.301
T 0.263–7.569 0.688
N 0.481–7.021 0.373
Total dose 0.933–2.175 0.101
Split-time 1.025–40.712 0.047
(14 versus >14 days)
Overall treatment time
0.0l9–l.48l 0.108
C.I., confidence interval
DISCUSSION
The results of this study support the assumption that shortening
the overall irradiation treatment time has a positive impact on
local control (16). This improvement is thought to be due to a
reduction in accelerated tumor-cell repopulation during treatment
when a large dose is delivered within a shortened treatment period
(17). Shortening of the split-time or rest period during treatment
is therefore also closely related to improvement of local control,
because accelerated tumor cell repopulation will probably occur
in the rest period. In the present study, however, the main reason
for prolonging the split-time was acute mucosal reaction, and the
duration of the split-time depended on the severity of such
reactions. Thus, shortening the rest period may increase the
severity of the acute mucosal reaction and lead to a reduction in
therapeutic tolerance.
Previous studies using different fractionation schemes have
demonstrated that the main factors influencing the occurrence of
acute and/or late complications are dose per fraction, daily
inter-fraction interval and total dose. Accelerated fractionation
programs using 1.75 Gy (10) or 1.8 Gy (18), or a shorter
inter-fraction interval of <4.5 h (19,20) have resulted in increased
severe acute and/or late complications requiring intensive nutritional
support for completion of treatment in some patients. Wang et al. (3)
considered that accelerated fractionation using a dose fraction of
1.6 Gy twice a day with a rest period of 2 weeks was acceptable
in terms of acute and late effects. Alteration of the split-time
duration alone within the limit of tolerance of normal tissue,
without modifying other fractionation parameters, may therefore
be reasonable for improving local control, although intensive
supportive care in relation to nutrition and acute mucosal
reactions would be necessary for completion of the treatment. In
a recent study of T3 carcinoma of the head and neck, Wang et al.
(3) also suggested that the midcourse treatment ‘gap’ should be
kept as short as possible (21).
Multivariate analysis showed that the overall treatment time in
this series was not a significant factor for local control. This might
have been due to the fact that, firstly, this study included two
different fraction doses (1.5 and 1.6 Gy) and that, secondly, there
was a wide range of total doses, although the treatment period and
irradiation dose before the split-time did not differ markedly
among the patients. Both factors thus affect the duration of the
overall treatment time.
In conclusion, the present study has confirmed that a shorter
split-time or overall treatment time may improve local tumor
control when accelerated hyperfractionation is used. In order to
determine the optimal treatment schedule for maintaining the best
balance between local control and complications, further study
and longer follow-up, including careful analysis of late complica-
tions, are needed.
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Nasopharyngeal Carcinoma (NPC) is a major health problem in southern and eastern Asia. In Indonesia NPC is the most frequent cancer in the head and neck area. NPC is very sensitive to radiotherapy resulting in 3-year disease-free and overall survival of approximately 70% and 80%, respectively. Here we present routine treatment results in a prospective study on NPC in a top referral; university hospital in Indonesia. All NPC patients presenting from September 2008 till January 2011 at the ear, nose and throat (ENT) department of the Dr. Sardjito General Hospital, Universitas Gadjah Mada, Yogyakarta, Indonesia, were possible candidates. Patients were included if the biopsy was a histological proven NPC without distant metastasis and were assessed during counselling sessions prior to treatment, as being able to complete the entire treatment. In total 78 patients were included for treatment analysis. The median time between diagnosis and start of radiotherapy is 120 days. Forty-eight (62%) patients eventually finished all fractions of radiotherapy. The median duration of the radiotherapy is 62 days for 66 Gy. Median overall survival is 21 months (95% CI 18-35) from day of diagnosis. The results presented here reveal that currently the treatment of NPC at an Indonesian hospital is not sufficient and cannot be compared to the treatment results in literature. Main reasons for these poor treatment results are (1) a long waiting time prior to the start of radiotherapy, (2) the extended overall duration of radiotherapy and (3) the advanced stage of disease at presentation.
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... ig zu größeren Bestrahlungsfeldern. Eine präoperative Strahlentherapie kann durchgeführt werden, wenn a priori eine komplette Exzision des Tumors nicht möglich ist. Durch die Bestrahlung wird die Tumormasse verkleinert und peripher gelegene Zellen werden vernichtet, so dass das zu entfernende Gewebsvolumen verkleinert wird (KASER-HOTZ et al. 2001).AKIMOTO et al. 1997, DÖRR et al. 1996, FU et al. 2000, HORIOT et al. 1997) Zunehmend werden unkonventionelle Fraktionierungsprotokolle in der klinischen Anwendung eingesetzt, um die lokale Tumorkontrolle zu verbessern und / oder die Strahlentoleranz von Normalgeweben zu erhöhen (BAUMANN 2001, DÖRR et al. 1996). ...
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Multifactorial Index of Radiocurability of Oral Cancers
Thesis
Full-text available
  • Feb 1999
This study attempts the identification of various tumour, host and treatment factors that may influence and can predict the probability of control of primary tumour in oral cancer patients treated by radical radiotherapy. 1. High fraction size schedule, such as the AF in this study, of 3 weeks duration is probably the most suitable for advanced oral cancers. The better results are probably due to the high fraction sizes which means lesser effect of missed doses 2. Effectiveness of large fraction sizes is related to less recovery (especially of the kinetic apparatus) during the inter-fraction interval. 3. The overall treatment time per se does not appear to be important; affecting fast and slow proliferating tumours in opposite ways. 4. Missing treatments in the first two weeks is very critical. This is probably because for most of the tumours the Tk falls in this period. 5. 'Cumulative inter-fraction interval' (CIFI) concept is introduced. Analysis in terms of CIFI is the best way to identify the importance of treatment misses at any time during a course of radiotherapy. 6. Rapid proliferation and short Tk go hand in hand. Shown by findings in relation to CIFI, T duration, etc. 7. Hb is not a surrogate for oxygen carrying capacity of blood. It represents effect of ane interaction between the host and tumour related to iron metabolism and erythropoiesis affecting tumour growth. This interaction is better represented by MCH and MCHC. 8. A positive association between cytologically determined cell division index (CDI), which evaluates both amitotic and mitotic index, and tumour size suggest its potential usefulness as a cytoproliferative score to identify growth characteristics of tumours. The findings suggest that large tumours are more resistant not only because they contain larger absolute number of clonogenic cells but also, may be more probably, because they have a higher dividing/growth fraction and potential ability to repopulate during radiotherapy. 9. Serial cytological assay of acute nuclear changes ('SCANC'ing) is a useful predictive and research tool. 10. The finding that multinucleation had maximum relation with radiosensitivity suggest that death due to acytokinesis resulting from interference with the functioning of the kinetic apparatus, most probably the cell membrane, is an important cause of tumour cell kill in radiotherapy. 11. Histology does not influence tumour radiosensitivity. 12. The classical empirical factors such as Tsize, invasiveness and lymph node involvement do not have significant influence on radiosensitivity. Whatever apparent relation present is due to the indirect influence of proliferative characteristics and intrinsic radiosensitivity. 13. Time to recurrence analysis is potentially useful method to identify presence of radiation induced alterations in growth characteristics. It can complement findings of the other types of analysis. 14. Based on the findings of the study, mainly that acytokinesis is the most common mode of death in sensitive tumours and that treatment interruptions during the first two weeks are critical for most tumours since their ‘kick-off time to accelerated repopulation (Tk) during fractionated radiotherapy occurs within this period, a new type of cell kill called the k kill (k for kinesis) is introduced. The k kill is due to radiation induced damage to the kinetic apparatus of the cell which if present during cell division causes imbalance between karyokinesis and cytokinesis leading to multinucleation death commonly. This damage is proposed to be fraction size dependent and recovery can occur during interfraction intervals. This can explain many of the paradoxes in radiotherapy as well as the inter-relation between radiosensitivity and proliferation. The presence of the k kill is what led Bergonie and Tribondeau to promulgate their famous law.
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Chemoradiation for organ preservation in the treatment of muscle-invasive bladder cancer
Article
  • Apr 2016
Introduction: Standard therapy for muscle invasive bladder cancer includes neoadjuvant chemotherapy followed by radical cystectomy with urinary diversion. Three decades of interest in primary radiation and chemotherapy for bladder preservation have yielded mature that deserve closer examination. Methods: We reviewed the literature with an emphasis on outcomes from major clinical trials and prospective studies, while highlighting important aspects of effective treatment delivery and unanswered questions surrounding this approach. Results: There are no randomized trials comparing radical cystectomy to primary chemotherapy and radiation for bladder preservation, and future phase III comparisons are unlikely to be planned. Mature results from single institution protocols and phase II cooperative group trials demonstrate favorable disease-specific survival and bladder preservation rates. Here we review the results of relevant clinical trials, including cancer-related and patient functional outcomes. We outline multi-modal treatment specifics with respect to radiation delivery, incorporation of transurethral resection and chemotherapy selection, and future directions for optimizing results of non-operative strategies. Conclusions: Combination chemotherapy and radiation can be used as an alternative to conserve the native bladder in appropriately selected patients, mirroring successful non-operative treatment paradigms used for organ-preservation for other cancer sites.
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Squamous cell carcinoma of the oropharynx: Ki-67 and p53 can identify patients at high risk for local recurrence after surgery and postoperative radiotherapy
Article
  • Dec 2000
  • INT J RADIAT ONCOL
Purpose: To assess the prognostic value of biologic (p53, Ki-67) and clinical factors in squamous cell carcinoma of the oropharynx after radical surgery and postoperative radiotherapy (RT). Methods and materials: Between 1985 and 1995, a total of 102 patients with 104 tumor sites were entered onto the study. Fifty-five primary tumors (53%) involved the tonsils, 26 (25%) the soft palate, and 23 (22%) the base of the tongue. Median age was 53 years (range 36-80 years). The clinical T- and N-categories (UICC 1997) were: T1 (30), T2 (47), T3 (22), T4 (5), N0 (33), N1 (28), N2 (42), and N3 (1). Histologically-clear margins were achieved in all patients by initial surgery. Postoperative RT to the primary and regional lymphatics was given, to a total of 60 Gy in 6 weeks, and single daily fractions of 2 Gy. The expression of the nuclear p53- and Ki-67-labeling index (LI) was investigated by immunostaining using the monoclonal antibodies DO-7 and MIB 1. The nuclear p53-intensity (p53-I) was graded into 4 categories (0/+/++/) by densitometry. Median follow-up was 43 months (range 14-132 months). Results: Cancer-specific survival, disease-free survival, and locoregional tumor control rates were 74%, 69%, and 75%, respectively, at 5 years. Significant prognostic factors for disease-free survival were: T-category (T1/2: 77% vs. T3/4: 53%, p = 0.02), tumor site (tonsils: 79% vs. soft palate: 70% vs. base of tongue: 45%, p = 0.05), duration of RT (< or = 46 days: 80% vs. > 46 days: 60%, p = 0.04), Ki-67 LI (< or = 20%: 84% vs. > 20%: 49%, p = 0.006) and p53-I (0/+: 56% vs. ++/ : 79%, p = 0.008). A significant prognostic impact on locoregional control was noted for the duration of RT (< or = 46 days: 86% vs. > 46 days: 68%, p = 0.01), tumor site (tonsils: 88% vs. soft palate: 67% vs. base of tongue: 51%, p = 0.02), Ki-67 LI (< or = 20% LI: 87% vs. > 20% LI: 56%, p = 0.018), and the p53-I (0/+: 58% vs. ++/ : 88%, p = 0.0006). On multivariate analysis, the p53 nuclear intensity (p = 0.002) and the Ki-67 index (p = 0.01) remained the only significant factors for locoregional control. Conclusion: Ki-67 labeling index above 20% and a weak p53 nuclear intensity (0/+) are both able to identify patients with squamous cell carcinoma of the oropharynx being at high risk for local recurrence after surgery and postoperative RT. Consequently, in this subgroup an intensification of treatment may be contemplated in prospective trials.
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Prognostic Significance of Dysadherin and E-cadherin Expression in Patients with Head and Neck Cancer Treated by Radiation Therapy
Article
Full-text available
  • Nov 2008
The aim of this study was to evaluate the impact of dysadherin and E-cadherin expression on the clinical outcomes, including the treatment outcomes and recurrence pattern, in patients with head and neck cancer. Tumor specimens were obtained from 48 head and neck cancer patients who were treated by radiation therapy and the specimens were immunohistochemically stained for dysadherin and E-cadherin. The expressions were graded according to the percentage area occupied by cancer cells showing positive staining for E-cadherin and dysadherin as follows: grade 0, less than 10%; grade 1, 10-50%; grade 2, more than 50%. The correlations between the expression of E-cadherin and dysadherin and the clinical outcomes, including the treatment outcomes and recurrence pattern, were analyzed. The complete response (CR) rate in the patients with a dysadherin expression grade of 0 or 1 was 70% and that in the patients with dysadherin expression grade of 2 was 38%; the difference was significant (p < 0.05). Regarding the pattern of recurrence, the expression grade of dysadherin or E-cadherin alone was not correlated with the recurrence pattern; however, patients with a difference in the expression grade between dysadherin and E-cadherin (Dys-Ecad value) of 1 or 2 showed a significantly higher rate of lymph node and/or distant metastasis (55%) as compared with those with a Dys-Ecad value of < 1 (22%) (p < 0.05). Dysadherin and E-cadherin expression might serve as useful prognostic factors in patients with head and neck cancer treated by definitive radiation therapy.
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The hazard of accelerated tumor clonogen repopulation during radiotherapy
Article
  • Jan 1988
When analysis of results of radiotherapy for nearly 500 patients with oropharyngeal cancer showed evidence for rapid tumor regrowth during extensions of treatment from about 5 weeks to about 8 weeks, we searched the literature on radiotherapy for head and neck cancer to determine whether it revealed similar evidence of accelerated tumor regrowth. Estimates of doses to achieve local control in 50% of cases (TCD50) were made from published local control rates, and the dependence of these doses on overall treatment duration was evaluated. In parallel, published scattergrams were analyzed to estimate the rate of tumor regrowth over the period of 4-10 weeks from initiation of therapy. Both analyses suggested that, on average, clonogen repopulation in squamous cell carcinomas of the head and neck accelerates only after a lag period of the order of 4 +/- 1 weeks after initiation of radiotherapy and that a dose increment of about 0.6 Gy per day is required to compensate for this repopulation. Such a dose increment is consistent with a 4-day clonogen doubling rate, compared with a median of about 60 days in published reports of unperturbed tumor growth rates. The values presented here are average values for a large number of patients: it is necessary, not only to verify the results of these retrospective analyses in prospective studies, but also to develop methods to predict the time of onset and rate of accelerated tumor clonogen repopulation in the individual patient.
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Chi-square tests with one degree of freedom; extensions of the MANTEL-HAENSZEL procedure
Article
  • Sep 1963
A published method for analyzing multiple 2×2 contingency tables arising in retrospective studies of disease is extended in application and form. Extensions of application include comparisons of age-adjusted death rates, life-table analyses, comparisons of two sets of quantal dosage-response data, and miscellaneous laboratory applications as appropriate. Extensions in form involve considering multiple contingency tables with arbitrarily many rows and/or columns, where rows and columns are orderable, and may even be on a continuous scale. The assignment of some score for each row or column is essential to use of the method. With scores assigned, a deviation of the sum of cross products from expectation, and its variance conditioned on all marginal totals, are computed for each table and a chi square is determined corresponding to the grand total of the deviations. For various specific instances and for various scoring procedures, the procedure extends or is equivalent to the asymptotic form of many known non-parametric techniques.
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Regression Models and Life-Tables (With Discussion)
Article
  • Nov 1971
The analysis of censored failure times is considered. It is assumed that on each individual are available values of one or more explanatory variables. The hazard function (age‐specific failure rate) is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time. A conditional likelihood is obtained, leading to inferences about the unknown regression coefficients. Some generalizations are outlined.
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Accelerated fractionation radiotherapy and concomitant chemotherapy in patients with stage IV inoperable head and neck cancer
Article
  • Nov 1995
  • CANCER-AM CANCER SOC
Background. Stage IV inoperable head and neck cancer has a 2-year mortality rate of greater than 70% when treated with conventional radiotherapy. A Phase II study was undertaken to evaluate the effects of concomitant chemotherapy and accelerated, interrupted, twice-a-day radiotherapy on tumor response, locoregional control, survival, and morbidity. Methods. Thirty-four patients with Stage IV inoperable squamous cell carcinoma of the head and neck and a minimum follow-up of 36 months were evaluated. Concomitant chemoradiotherapy was administered during weeks 1, 3, and 5 (with planned breaks during weeks 2 and 4), consisting of cisplatin 60 mg/m2 on Day 1, continuous 5-day infusion of 5-fluorouracil, 750 mg/m2 per day, and radiotherapy, 2 Gy twice a day, more than 6 hours apart, followed by 3 days of radiation therapy alone (final “boost”) in week 6, for a total dose of 70 Gy and treatment duration of 5½ weeks (38 days). Results. Twenty-seven patients achieved a clinical complete response (82%). Actuarial locoregional control at 3 years was 73% and the actuarial 3-year survival probability, including all deaths, was 38%. All locoregional recurrences were manifested within 12 months. Of the 20 deaths, 12 were tumor related (locoregional and/or metastatic), 3 were treatment related, and 5 were due to other causes. Acute toxicity consisted of grade 3 mucositis and dysphagia and grade 2–3 leukopenia, not requiring treatment interruption or cessation. Conclusion. Concomitant accelerated radiation therapy and chemotherapy is a feasible treatment approach in this prognostically poor patient population, yielding dramatic tumor responses and impressive locoregional control at the cost of somewhat increased acute toxicity. Although serious late complications have not been observed, caution should be exercised in view of the relatively short follow up. Cancer 1995; 76:1655–61.
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Nonparametric Estimation From Incomplete Observations
Article
  • Jun 1958
In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has \(0 \leqslant t_1^\prime \leqslant t_2^\prime \leqslant \cdots \leqslant t_N^\prime .\) Then \(\hat P\left( t \right) = \Pi r\left[ {\left( {N - r} \right)/\left( {N - r + 1} \right)} \right]\), where r assumes those values for which \(t_r^\prime \leqslant t\) and for which \(t_r^\prime\) measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations. Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
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Accelerated superfractionated irradiation for advanced carcinoma of the head and neck: Concomitant boost technique
Article
  • Sep 1991
  • INT J RADIAT ONCOL
Between 1980 and 1988, 94 patients with AJCC Stage III and IV squamous cell carcinoma of all sites of the upper aero-digestive tract were treated with radiotherapy. We report here on 62 patients who are followed for a minimum of 2 years. Of these, 30 patients were treated with conventional once-a-day radiotherapy and 32 patients were irradiated using an accelerated superfractionation regimen during part of the treatment course. The altered fractionation schedule employed a concomitant boost technique with clinically demonstrable disease being irradiated twice-a-day during the first or second half of the treatment course. Daily radiation fractions were 1.8 Gy and the boost field was treated with 1.6 Gy after a 4- to 6-hr interval. No significant differences in acute treatment toxicity were observed in the two treatment groups. Patients treated with conventional and accelerated fractionation regimens experienced 36 months actuarial local tumor control rates of 40% and 67% (p = 0.03), respectively, which translated into an actuarial disease-free survival of 40% and 64% (p = 0.04). The increased locoregional control rates in patients treated with accelerated fractionation were associated with an adjusted and overall survival advantage at the p = 0.05 level. We conclude that our regimen of accelerated superfractionated irradiation with shortening of the treatment course resulted in improved control and survival rates at conventional doses of 68.4 to 73.8 Gy.
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Accelerated repopulation: Friend or foe? Exploiting changes in tumor growth characteristics to improve the “Efficiency” of radiotherapy
Article
  • Nov 1991
  • INT J RADIAT ONCOL
Accelerated repopulation (rapid multiplication of surviving clonogens) during a course of radiation therapy may contribute to local failure. This possibility has prompted accelerated treatment programs in an attempt to reduce overall treatment time, thereby minimizing the impact of repopulation. However, accelerated dose delivery at the start of treatment may not be advantageous since many of the tumor cells are likely to be hypoxic (non-cycling cells) and therefore relatively radioresistant. Conversely, accelerated treatment is likely to be most helpful later in treatment when the tumor has shrunk and accelerated repopulation of clonogens is a dominant factor. A series of calculations are presented that stimulate changes in tumor size, clonogen number, clonogen repopulation, and growth fraction during a course of fractionated radiation treatments for an idealized 2 cm diameter spherical tumor. The efficiency of each fraction of radiation is calculated for different radiation fractionation schemes. Efficiency is defined as the change in Log clonogen number (reflecting cell death due to radiation minus repopulation that has occurred during the interval between fractions) per Gy. These calculations suggest that relatively low total daily doses (approximately 2 Gy) are most efficient early in treatment. Higher daily doses are less efficient since the growth fraction is relatively low at the start of treatment. Later in treatment, as the tumor shrinks and the growth fraction approaches 1, accelerated repopulation becomes a major problem and higher total daily doses are more efficient. At this point, accelerated hyperfractionation should be used to increase the daily dose without exposing normal tissues to high fraction sizes. Thus, changes in tumor growth characteristics are exploited and dose delivery can be optimized by escalating daily irradiation doses during a course of fractionated irradiation. Strict interpretation of these conclusions must be tempered by the various assumptions and uncertainties included in this model. The concept of efficiency is useful since it reflects the competing effects of clonogen repopulation and radiation induced clonogen sterilization.
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