ELSEVIER

l Clinical Investigation

Int. J. Radiation Oncology Bicrl. Phyr.. Vol. 4). No. 2. pr 41.7.-440. IYW Copyright 0 IYYX Elmter Science IIIC. Printed in the USA. Ail rights reserved

Ii3h0-10lhi’~X F!Y,IKI -i IHI

PI1 SO360-3016(97)00711-6

IN SEARCH OF A DOSERESPONSE RELATIONSHIP WITH RADIOTHERAPY IN THE MANAGEMENT OF RECURRENT RECTAL

CARCINOMA IN THE PELVIS: A SYSTEMATIC REVIEW

REBECCA WONG, M.B., CH.B., F.R.C.P.C.,” GILLIAN THOMAS, M.D., F.R.C.P.C..+ BERNARD CUMMINGS, M.B., CH.B., F.R.C.P.C., F.R.C.R., F.R.P.C.R.,”

PETER FROUD, M.B., CH.B., F.R.C.R., F.R.C.P.C.,’ WENDY SHELLEY, M.D., M.Sc., F.R.C.P.C..$ RODNEY WITHERS, M.B., B.S., PH.D., D.Sc., M.R.A.C.R., F.R.A.C.R.,’ AND JACK WILLIAMS, PH.D.*

‘“Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, North York, Ontario, M4N 3M.5. Canada: ‘Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, M5G2M9, Canada; ‘Department of Radiation

Oncology. Vancouver Island Cancer Center, Victoria, BC, V8R 158. Canada; $Department of Radiation Oncology. Kingston Regional Cancer Centre. Kingston, Ontario, K7L 5P9, Canada; and ‘Department of Radiation Oncology.

UCLA Medical Plaza #B265, Los Angeles, CA 90024-695 I

Purpose: A systematic review of the literature was undertaken to address the question: “What ls the most m dose fractionation schedule for the relief of symptoms in patients with pelvic recurrence from rectal or colorectaI carcinoma?” Methods and Materials: Cancerlit/Medline-computerized databases were searched between the years 1966-1996. Studles that explored the response to radiotherapy in patients with pelvic recurrence from rectal/r@o&gmeid carcinoma were included. Factors that may contribute to differences in results were postulated in advance and the variations encountered between articles were presented. Art&s with data appllcahle to recurrent d&ease only were included in the prlmary analysis. The effect of including articles that reported outcomes of recurrences with unres&.able primaries and residual disease was presented as a sensitivity analysis. Results: only retrospective series (level V evidence) were available. The many sources of potential hiss inkerent inretrospective analyses make the data suitable for hypothesis gaeration only. Comparison of respanse was made between “lower” vs. “higher” doses, using 4550 Gy as the dividiag dose, base on the p&nary y&s. There were no sign&ant differences observable in terms of initial response and the proportlon m&n&l&@ a response at 6 months, wlthm the range of doses employed. When data from articles that reported outcemes of recurrent disease with primary untreated cancers and postoperative resldual dlsease were inch&d, there was a suggestion for a more favorable response with higher doses. Thii requires cautious interpretation within the methodological limitations of the data. Con&&n: The optlmal dose fractionation schedule for the palliation of pelvic recurrent e from rectal carchmma -defined. Well-designed randomized studies, with study arms that are suffw&ntIy diverse blologlcally to allow the detection of a dose-response relationship if one existed, equipped with suitable symptom control end points, are necessary to provide a clinically relevant answer. 0 1998 Elsevier Science Inc.

Rectal cancer, Radiotherapy, Pelvic recurrence, Systematic review.

INTRODUCTION

Pelvic recurrence following curative resection remains a persistent problem in the management of rectal carcinoma, despite recent advances with the introduction of adjuvant therapies. Radiotherapy remains the treatment of choice for the palliation of symptomatic pelvic recurrences for patients with no previous exposure to pelvic irradiation. Despite its widespread use over many decades, the optimal dose frac- tionation continues to be debated by radiation oncologists. Several authors ( 15, 37) have attempted to answer the more general question of whether a dose-response relationship

exists in the control of primary, residual, and or recurrent disease from colorectal carcinoma. The strength of infer- ence from these data is limited by the inherent heterogeneity in combining patients from different stages of the natural history of their illness. diverse goals of therapy, and differ- ent end points of interest, makes it difficult to draw an evidenced-based conclusion to guide therapy for patients with recurrent colorectal carcinoma. Other authors (3. 4, 8, 13, 14, 27, 28) have reviewed the topic, although a system- atic review approach has not been performed. The authors performed a systematic review of the literature to address the question “What is the most effective dose fractionation

-_- .-...I_ I_ Reprint requests to: Dr. K. S. R. Wong, Toronto Sunnybrook tario, Canada M4N 3M5.

Regional Cancer Center. 2075 Bayview Ave., North York, On- Accepted for publication I8 August 1997.

137

438 I. J. Radiation Oncology 0 Biology l Physics Volume 40, Number 2, 1998

Table 1. Search strategy

1. colorectal neoplasms/radiotherapy 2. rectal neoplasms/radiotherapy 3. lor2 4. preoperative care, postoperative care, textwords including

preop:, post op:, neutron was excluded from 3 5. limit 4 to English language

schedule for the relief of symptoms in patients with pelvic recurrence from rectal carcinoma?”

METHODS AND MATERIALS

Search strategy A systematic review of the relevant English language

literature was undertaken. A computerized literature search was performed using cancerlit/medline databases, for the time period of 1966 to Dee 1996 inclusive, using the strat- egy as outlined in Table 1. In addition, references as well as personal files were searched for relevant articles. Articles identified from before 1966 were included where relevant, although a hand search of the published articles before this period was not undertaken.

Computerized search for medline was available dating back to 1966 only. There are no reliable MeSH headings that can identify the group of patients with pelvic recurrence from colorectal/rectal neoplasms. “Radiotherapy” was a useful subject heading to delimit the number of articles retrieved when the MeSH headings “colorectal/rectal neo- plasms’ ’ were searched. As we were not interested in pa- tients treated in an adjuvant or neoadjuvant setting, the strategies outlined in Table 1 were used to exclude these. The role of neutron therapy for colorectal carcinoma repre- sent a significant number of articles retrieved. As this re- mains an experimental therapy for this disease entity, and neutron doses are not readily converted to conventional radiation dose equivalents, these were also excluded.

Due to the limitations of the indexing system employed by most medical databases (6), only approximately 60% of appropriate articles are likely to be retrieved through such a search strategy (26). In general, depending on the design of the search strategy, specificity will be lost in exchange for sensitivity and vice versa. The remaining relevant articles were identified through content experts, and references fi-om appropriate articles.

Inclusion criteria Articles identified through this search strategy were

screened by the author R.W. using predetermined inclusion criteria as outlined in Table 2. Articles satisfying all inclu- sion criteria are included in this review.

Treatment modality. The treatment modality of interest in this review is radiotherapy, and more specifically, dose response. Reference of patient outcome to radiotherapy delivered are required, although no minimum requirements were set. Articles reporting on concomitant radiotherapy

and chemotherapy for all patients were not included in the current review. Small subgroups of patients receiving con- comitant chemotherapy alone was not used as an exclusion criterion.

Outcome and radiotherapy dose delivered available. There were no restriction on the type of outcome and the amount of detail required on the radiotherapy delivered, although some reference to these two parameters are re- quired for its inclusion.

Recurrent series vs. combination series. The current re- view aims to explore the role of radiotherapy in patients with pelvic recurrence from rectal or colorectal carcinoma. Reports in the literature often combine patients with pri- mary, residual, and recurrent disease. Whether the studies set out to include only patients with recurrent disease or not, has major implications on the natural history to be expected from the study sample. Differences in life expectancies and symptomatology between these subgroups have been sug- gested by many authors. Inclusion of these rather heteroge- neous disease states may result in conclusions based on small subgroups being extrapolated upon the original pop- ulation. To explore the impact of including patients other than recurrences post radical surgery, the authors made a careful distinction between “recurrent series” and “com- bination series.” “Recurrent series’ ’ included articles where the original authors inchided patients with recurrent disease only, or where outcome data for the subset of patients with recurrent disease only was available within the original article to allow extraction. “Combination series” refers to articles where outcome of patients with recurrent disease, unresected primary, and or postoperative residual are reported together. Articles reporting on radiotherapy in the management of primary and residual diseases only were excluded from the current report.

Methodological assessment A systematic examination of the methodological aspects

of these articles was undertaken in an attempt to determine the comparability of the included articles. Seven major factors that may contribute to potential sources of hetero- geneity in the reported results were postulated prior to the analysis of the extracted data (Table 3). Not all elements within each category that could potentially influence out- come can be examined and selected parameters as discussed below are compared across studies in an attempt to explore comparability across studies.

Type of article. Sackett (19) described five levels of evidence in relation to the study design, this criteria was used to classify articles identified.

Table 2. Article inclusion criteria

1. Article concerns patients with rectal/colorectal carcinoma with recurrent pelvic disease

2. Treatment modality is radiotherapy to the pelvis 3. Outcome data available 4. Radiotherapy data available

Systematic review: RT and pelvic recurrence 0 R. WONG et rd. 139

Table 3. Potential sources of heterogeneity of results

I. Type of article (randomized vs. retrospective case series) 2. Patient inclusion criteria 3. Definition of pelvic recurrence 1. Dose range employed 5. Reason for dose selection 6. End point evaluation: objective vs. subjective 7. Cointervention

Patient inclusion criteria. The potential impact of recur- rent disease only vs. recurrent and or residual, unresectable, disease, was already discussed. The proportion of patients with metastatic disease and the proportion of patients who are symptomatic at the time of therapy may reflect variation in the indications for therapy, life expectancies, and re- sponse to therapy.

Definition of recurrent disease. Variations in the criteria used to identify the cohort of patients to be included in these studies, such as clinical symptomatology vs. radiological parameters or pathological diagnosis, could result in pa- tients with varying extend of disease being included, and indeed, may even allow the inclusion of patients who may not truly have recurrent disease.

End point definition. Due to the incurable nature of the illness, treatment end points should appropriately be in relation to symptom relief and the ability to defer symptom and disease progression. Initial symptom response rate, du- ration of symptom relief. and duration of disease control (local control) are frequently end points chosen by research- ers to reflect on the effectiveness of therapy. The definition of the time frame in which this is reported represent a potential variable that requires consideration to determine whether data is comparable. The more challenging problem, however, relates to the subjective nature of these end points and their vulnerability to observer bias. This can occur at the level of the patient reporting the symptom, the physician recording the symptom, the researcher interpreting the doc- umenting, the radiologists, and/or physician interpreting and performing the necessary studies to document response and or recurrence. The use of local control may indeed convey a false sense of objectivity in the absence of a predeter- mined follow-up protocol and “blinded” observers. The results, therefore. require interpretation within this context.

Indications ,for different radiotherapy doses. A correla- tion between outcome and intervention if one existed, can potentially be attributed to the intervention if one is reason- ably satisfied that the patients are relatively homogeneous and there are no coexisting factors that could predict for the variation in outcome. which is the basis for randomized controlled clinical trials. In studies of less stringent design, the strength of inference continue to hinge upon whether there are systematic differences between patients and the presence of confounders in the assignment of therapy.

L)ose ,fmctionation effect and dose range being tested. The issue of dose fractionation is fundamental to the inter- pretation of its biological effect. Although there are several models in use for estimating biologically equivalent values,

the optimal method of comparing different fractionation regimens has not been determined. As it is not possible based on the published data to correlate response to a common parameter reflective of the dose fractionation em- ployed, the results will be reported base on the total dose delivered. The data in the lower dose range% should be interpreted cautiously because the lower doses may have been given in larger fraction sizes. The numbers of patients within each dose range are uneven, reflecting in part the selective nature of the pattern of dose prescription. In some dose ranges. conclusions may be drawn based on very small numbers of patients.

Cointervention. Chemotherapy, typically S-fluorouracil, is known to have a radiosensitising effect that is docu- mented in vitro. Its cytotoxic effect makes it useful for the palliative treatment of recurrent colorectal carcinoma. The concomitant use of both agents will likely have an impact on the response rate attributable to radiotherapy, and the toxicities reported. As well, the impact of subsequent che- motherapy, and indeed manifestations of distant metastasis that required other interventions, will influence the report- ing of symptoms and the detection and documentation of clinical evidence of disease progression.

Other factors such as analgesics may have a significant impact on the end points of interest. although it is only feasible to acknowledge its potential influence on the data.

Data extraction Data extraction was performed by the author R.W. using

a standardized format, designed to extract equivalent data from all series. These include study design. basic demo- graphic data of the patient groups, method of determining frequency of follow-up, criteria for the designation of re- current disease. outcomes of interest, and dose fractionation delivered and toxicities of therapy where available.

End point selection jk- review Initial response rate, symptom control at around 6

months, and local control at 12 months are the parameters reported most uniformly as a measure of effectiveness of therapy. These are selected prior to the analysis of the data collected.

Methods qf’ analysis The odds ratio was selected as the summary statistic to

compare results across the studies. There is insufficient information within the data presented in the literature to allow handling of the dose-response data as a continuous variable. In addition, different studies employ different dose intervals in their reporting. The choice of a dichot- omous outcome was used to allow for comparison be- tween studies. To obtain this, the authors divided patients within each article into two categories, “lower” vs. “higher” dose. The threshold employed to make this division, represents the dose that was identified in the original article as the “threshold” beyond which a sig- nificant difference in outcome was observed. Where the

440 I. J. Radiation Oncology 0 Biology l Physics Volume 40, Number 2, 1998

Table 4. Initial response, dose grouping and odds ratio by author

Author Dose

grouping Dose range

(GY) Response/No. of patients

in each group Response rate

(%I Odds ratio (95%

confidence interval)

Recurrent series Dobrowsky

Allum

Pacini

Thomas

Urdaneta Laffe

Soleimani

Combination series Rao (no. of symptoms)

Wang

lower

higher

lower higher lower

higher lower higher lower

higher lower

higher

lower

higher lower

higher

15-34 11/13 34-44 414 44-54 515 Y-70 14116 <20 8112 30-40 618 35-40 38153 40-50 38/44 m-65 39146 30-40 25128 40-60 517 <20 l/l 20-30 313 30-45 22126 45-60 12113 <20 l/9 20-30 12119 30-40 28134 40-46 lOI11 46-60 616

<20 6148 20-40 19139 40-45 34158 45-60 20-23 <20 5/l 1 20-30 25140 30-40 28144 40-50 12116

88 1.26 (0.16-9.85)

90

67 75 78

85 90 71 87

92 70

100

41

87 60

75

1.46 (0.22-9.77)

1.5 (0.62-3.62)

0.24 (0.02-2.5)

1.71 (0.23-12.71)

4.4 (0.69-27.83)

6.34 (2.63-15.26)

1.88 (0.63-5.58)

Odds ratio are calculated comparing “higher” vs. “lower” doses using 45-50 Gy as the division, except where the original authors have identified a significant dose cut off, then this dose was used to calculate the odds ratio.

In Rao’s series, the response relates to the number of symptoms rather than the number of patients. Series not represented in this table where data is not available, reasons include: initial response not reported as end point (7, 15, 35), dose

range too narrow to inspect dose response relationship (5, 11, 29), initial response reported for the whole group without data by dose (9, 22), and no dose response relationship detected in univariant analysis, no raw data (12).

original article commented on the absence of any differ- ence in outcome across the dose range employed, and had presented the corresponding number of patients within each category, we have used 45-50 Gy as the division between “lower” vs. “higher” dose categories. A range was used as different dose groupings were used in dif- ferent studies. This specific range was selected as it represent the dose level identified as the threshold in two (7, 15) of the three (7, 15, 37) positive studies.

The odds ratio results are presented in Tables 4-6, for initial response, symptom control at 6 months, and local control at 12 months. These are divided into “recurrent” and “combination” series where data are available. This is presented also in graph form for initial response in Fig. 1. The first author’s name and year of publication is presented on the left, the point estimate for odds ratio and its 95% confidence intervals at either side, is plotted upon a log scale on the right. A point estimate that is greater than 1 (to the right) would suggest higher dose provides superior outcome when compared to lower dose, and vice versa. Where the confidence intervals include unity, the

difference between the two categories is not statistically significant. In view of the heterogeneity encountered between the articles included, no attempt was made to provide a typical odds ratio that would statistically com- bine the odds ratios across the studies. Data from “re- current series” were presented in the figures and tables in parallel with data from “combination series” to facilitate comparison. However, the data from the “recurrent” series only are most relevant and form the basis upon which the primary conclusion will be drawn. Data from the “combination series” will be taken into consider- ation only as part of the subsequent sensitivity analysis.

Sensitivity analysis Sensitivity analysis in qualitative terms was planned in-

corporating data from “combination series.” A sensitivity analysis represent an exploration of the

impact of the inclusion and exclusion of data that are borderline in terms of their suitability in addressing the question at hand. The interpretation of the sensitivity anal- ysis hinges on whether these studies are felt to be adding

Systematic review: RT and pelvic recurrence l R. WONG er trl. 441

Table 5. Symptom relief at 6 months, dose grouping, and odds ratio by author

Author Dose grouping Dose range (Gy)

No. with symptom relief/

No. in group

% Symptom relief at 6 months or

median duration

Odds ratio (95% confidence

Interval) -__ ____~.

Recurrent series Allurn PacmiKiatto

James Thomas Smedal William

Combination series Overgaard

Wang

lower

higher - - -

lower

higher lower

higher

-

35-40 40-50 50-65

-

- -

535 36-45 46-55 256 <20 21-30 31-40

4 l-50 or over

- 1303 1 II44 17146

-

- -

9119 17/28 19/31 ll/ll O/l1 3/40 9144 7116

median 3 months 31%’ I .3 I iO.h2--2 76)

.i 7 5% median 3 months range: 3-8 months SO%, (>(I months) 23% ( >h months) -.-

h3Q 6.01 i I 64-22.03)

100% 23% X.79 ~3.17-35.64)

58% _____--

Odds ratio are calculated comparing “higher” vs. “lower” doses using 45-50 Gy (20) as the division, except where the original authors ( 15, 37) have identified a significant dose cut off, then this dose was used to calculate the odds ratio.

Overgaard’s data applies to 89 evaluable patients with symptoms, who maintained a response for 26 months or until death. Series not represented in this table where data is not available (5, 7, 9-11, 23. 29, 30, 34).

systematic or random error to the measurement of interest. A sensitivity analysis lends itself to testing the robustness of any conclusions drawn from the primary analysis. For the purposes of this review, the impact of the inclusion of “combination series” will be explored.

RESULTS

Literature search and article inclusion Four hundred ninety articles were identified using the

strategy as outlined in Table 1, through the computerized search within the period 1966-1996 inclusive. A total of 19 articles were identified by applying the inclusion criteria in Table 2. Two patient groups were reported twice (20, 29, 33, 36). A total of 17 series was therefore available. Except for two series (22, 37). all are reported since 1966. The

computerized literature search captured 67% of the relevant articles that were identified.

Methodological assessment Type of articte. No randomized studies were identified

addressing the issue of interest. Only retrospective case series were available, providing level V evidence as defined by Sackett (19). Sample size within individual studies ranged from 12 to 143 in the “recurrent series,” taking into account only patients with recurrent pelvic disease, and 35-111 in the combination series.

Znclusion criteria. Twelve articles are included in the “recurrent series” (1, 7, 10-12, 20, 22-24, 29, 30, X5), six articles reported on recurrent disease only (1, 7, 10, 12. 22, 35). In the remaining six. while data on patients with recur- rent, residual, or primary disease were reported. data perti-

Table 6. Local control at 12 months, dose grouping, and odds ratio. by author

Author Dose grouping Dose range Local control/No. in group Odds ratio (95% confidence interval)

Recurrent series Lybeert raw data not available 250 Gy vs. <50 Gy was identified as

significant in a multivariant analysis statistically significant

Combination series Overgaard lower <35 o/12 5.i( I .2x-2 1.79)

3-5 2/18 46-55 7/39

higher 256 6/16

Lybeert identified radiation doses (250 Gy vs. lower) as significant for recurrent free survival Odds ratio for Overgaard’s data was calculated using 56 Gy as the threshold, which was reported as being significant by the author.

Series not included where data is not available (1. 5, 9-12, 20, 22-24, 29. 30. 34. 35, 37).

442 I. J. Radiation Oncology 0 Biology 0 Physics Volume 40, Number 2, 1998

Odds Ratio with 95% confidence interval for initial response comparing higher versus lower dose

I

________--_--_--_------ ------- Log Odds Ratios ---------------_-__------------ .Ol .1 .5 1 2 10 100 ___________________----------------------------

“recurrent I’ series

Dobrowsky 85 Al lum 87 Pacini 86 Thomas 80 Urdaneta 72 Soleimani 72

I ---------+: ----------

- - - - - - -+- :--------- --+- :----

_-__-__-____ ,------+----- -------+-- :--------me

-+------:----------

1VcomJ3ination" series

Rao Wang

78 f ----: ----- 62 --f-- : _^____

I

Fig. 1. The first author’s name and year of publication is presented on the left, a horizontal line, with the point estimate for odds ratio at its center and its 95% confidence intervals at either side, is plotted upon a log scale on the right. A point estimate that is greater than 1 (to the right) would suggest higher dose provides superior outcome when compared to lower dose, and vice versa. Where the confidence interval include unity, the differences between the two categories is not statistically significant. Series are grouped together by “recurrent” and “combination” series. Only series with data available is presented.

nent only to recurrent disease were identifiable for inclusion in this review. Five series were included in the “combina- tion series” (5, 9, 15, 34, 37).

The extent to which metastatic disease was searched was not uniform. In the “recurrent”: group, the proportion of patients free of distant metastasis ranged from 69% (20) to 100% (12) in six series (7, 10, 12, 20, 24, 30). In the remaining six series (1, 11, 22, 23, 29, 35), no data was provided.

The proportion of patients symptomatic at presentation was variable. In the “recurrent series,” this was 66% (lo), 85% (24), and 100% (12, 20) where it is available. This is not available in 8 of the 12 articles (7, 11, 22, 23, 29, 30, 35). In the “combination series,” this information is avail- able for all five articles included. Proportion of symptomatic patients was 63% (34), 74% (5), 82% (15), 83% (37), and 100% (9), respectively.

Definition for recurrence. The criteria for recurrent dis- ease were defined in some fashion in only two studies (1,7). Lybeert et al. (7) used clinical identification of a pelvic mass, radiographic evidence of pelvic bone destruction, and/or sciatic/perineal pain, suggesting retroperitoneal pel- vic involvement, occurring after a pain free interval as the criteria. Allum et al. (1) used clinical and radiologic criteria, with additional histological confirmation for those develop- ing perineal pain after previous primary tumor removal. In the “recurrent series,” two studies (12,20) used symptoms attributable to recurrent disease as an inclusion criteria. In the remaining articles a statement that patients had recurrent disease within the pelvis, without further elaboration on the

criteria used, was the only description for the patients in- cluded.

End point definition. All articles reported some kind of symptom relief response data. Ten (1, 5, 9, 10, 12, 15, 23, 29, 34, 35) of the 17 series described some definition of the end point assessment for degree of symptom relief. Various descriptors such as fair, good, excellent etc. are used in the majority of cases, within a three (1,9, 10, 12, 15,23) to four (5, 29, 34, 35)-point scale. In additioa, Whiteley et al. (29) report incorporates performance status and clinical assess- ment of tumor regression as part of the end point assess- ment. Rao et ~2. (34) use the number of symptoms relieved as the criterion. Only Soleimani et al. (23) address the issue of reproducibility of observations by using two independent observers.

Local control data was reported in two articles only (7, 15). Lybeert et al. (7) used “time to evidence of tumor after radiotherapy” as the definition, and Overgaard et al. (15) described using WHO recommendations (17).

Indications for difSerent radiotherapy doses, Variation in dose fractionation is perhaps the greatest source of het- erogeneity in results. In one study (36), no reason was given. In six (5, 7, 10, 15, 22, 34) studies, it was stated that where palliation only was the goal of therapy, lower doses were given. If the goal of therapy was to increase local control (7, 34), or for cure (5, 22, 34) patients were given “radical” higher doses. The parameters used to define patients suitable for palliation only included age (5, 7), size of tumor (7, 9, 12, 22), metastatic disease status (5, 15), and general condition (1, 5, 9, 12). The

Systematic review: RT and pelvic recurrence l R. WONG ef al. 443

Table 7. Sample size, range of (total) dose delivered, initial response rate by author, and year of publication --~

No. of patients with recurrent disease Range of total dose Initial response rate

Author/( year of publication) (total No. in study) (median) i%N) -_. ----

Recurrent series Lybeert (92) Dobrowsky (85) Allum (87) Pacini (86)Kiatto (82) Hodson (83) James (93) Thomas (80) Urdaneta-Lafee (72) Soleimani (72) Whiteley (70) Smedal(67 ) William (56)

Combination series Griffith (88) De Renzis (86) Overgaard (84) Rao (78) Wang(62)

95 (95) 58(58) 18 (18)

143 (206) 12 (42)

143 (143) 41(107) 42(102) 79 (110)

103(165) 50(50) 82(82)

40 (55) 16(35) 77(113)

121 (144) 86 (111)

6-66 Gy (44 Gy) 15-70 Gy 5-4.5 Gy 35-65 Gy 30 Gy in 3 fr at 4 weekly intervals NSD 1414 (Approx 40 Gy) 30-60Gy lo-60 Gy 400 rets-1750 rets (approx 10-60 Gy) 20-25 Gy 20-60Gy 30-60Gy

13-45 Gy(35 Gy) 40-45 Gy with boost 15-20 Gy if curative intent 23-72 Gy <lOOO rets-1700 rets <2@-over 50 Gy .-

Majority of treatment regimens employ approximately 2 Gy per fraction with five fractions per week. NA: initial response rate was not reported.

VA XY 70 no 88 70 X6 88 73 9s NA 87

7x 71 NA 47 62

above selection criteria potentially selects out patients that are biologically quite different, to receive lower vs. higher doses.

Dose fractionation efhect and dose range being tested. The dose ranges, and/or median dose where available, are outlined in Tables 4-6.

The median dose delivered was in the order of 45 Gy. The dose ranges tested range between lo-30 Gy at the “low” end. to 50-70 Gy at the “high” end of the spectrum. Where details are provided, the majority of these doses were de- livered in 2-2.5 Gy per fraction, employing five daily frac- tions per week. While higher doses are generally delivered in approximately 2 Gy fractions, lower doses are frequently delivered with larger doses per fraction. Allurn (1) used large single fractions in the low dose patients, and Hodson (1 1 ), employed one fraction every 4 weeks. Three authors (12. 23, 34) reported results using nominal standard dose (NSD). For comparison, this is converted to Gy using the conversion equation described by Orton et al. (18) using the assumption of 2 Gy per fraction.

Cointerventions. The selection criteria for this review specifically excluded articles employing combination ra- diotherapy and chemotherapy as the primary treatment approach. Chemotherapy was included in two reports. This was deiivered to 16 of 95 patients in Lybeert’s series, and 10 of 113 patients in Overgaard’s series. The indications for this treatment were not elaborated upon. The use of subsequent chemotherapy was not mentioned in any series. Due to the small number of patients who received chemotherapy within these two series, they were not excluded.

ANALYSIS OF STUDY RESULTS

Initial response, duration of response for symptom relief vs. total dose

Information on initial symptom relief was not available in 3 of the 12 “recurrent” series (7, 15, 35). In two (I 1, 29), the range of dosage employed was too narrow and was considered not applicable. Hodson (11) employed 30 Gy in three fractions at four weekly intervals, and Whiteley (29) reported experiences with total doses ranging between 20-25 Gy. Of the remaining seven series, no dose-response relationship was identified. Raw data is available for all except James (12), who presented the results of a univariate analysis, which found dose was not a significant prognostic factor for predicting initial response. The range of initial response rate reported is 70-95% (Table 7). The odds ratio comparing “high” (>45-50 Gy) vs. “low” (<45-50 Gy) are presented in Table 4. Based on the recurrent series, no dose-response relationship (comparing less than vs. greater than 45-50 Gy) was identified pertaining to initial symptom relief.

Data on durability of symptom relief was not available in 6 of 12 series (7, 10, 11, 23, 29, 30). This is expressed as a range by Thomas et al., being 3 to 18 months. A median duration of response in two series (1, 12), being 3 months in both cases. As proportion maintaining a response at or equal to 6 months in three series (20,22, 35). This was 23% (22), 33% (20), and 50% (35), respectively.

Local control was reported in 1 out of the 12 of the recurrent series. Lybeert reported a significant dose re- sponse relationship at 12 months identify@ 50 Gy as the threshold, when comparing doses ranging from 6-66 Gy.

444 I. J. Radiation Oncology l Biology l Physics Volume 40, Number 2, 1998

Only patients with no evidence of distant metastasis at the time of presentation, and was alive 2 months after the start if radiotherapy, were included for this analysis (Table 6).

SENSITIVITY ANALYSIS

Combination series data were examined within the con- text of a sensitivity analysis. Initial response data were available in only 2 of 5 series (34, 37). Rao reported a significant dose-response relationship across the dose range tested (<lo00 rets, to 1700 rets), using number of symp- toms relieved as the denominator. Wang et al. presented the number of responses by dose range delivered. The numbers do not support any dose-response relationship. The authors commented on the subsequent duration of response. Patients receiving >41 Gy appears to have more durable responses. No statistical analysis was conducted by the original au- thors, however (Table 4).

Durability of response was available in 2 of 5 series (15, 37). Overgaard er al. (15) reported a statistically significant dose-response relationship using 56 Gy as the cut off re- sulting in symptom control at 6 months or until death in (45 of 78) 58% at the lower vs. (11 of 11) 100% at the higher doses for evaluable patients (p < 0.01). The dose employed ranged from 23-72 Gy. The definition of evaluable patients was not further described. Wang et al. (37) commented that there appears to be a significant dose response using 40 Gy as the threshold comparing doses ranging from <20 to over 50 Gy, providing a symptom control rate at 6 months of (12 of 52) 23% vs. (7 of 12) 58% (Table 5).

Local control data were available in 1 of 5 series (15). Overgaard et al. (15) again provided figures in support of a dose-response relationship for local control using the dose cut off of 56 Gy. Local control rate at 6 months reported for evaluable patients only, was 10 of 69 (14%) vs. 6 of 15 (40%) (p > 0.05) below and above the 56 Gy (Table 5).

DISCUSSION

This systematic review has revealed the limitations in the data available in the literature when an attempt is made to determine whether a radiotherapy dose-response relation- ship exists in terms of symptom relief and the local control of pelvic recurrence from rectal carcinoma. Relevant inter- pretable data proved surprisingly sparse. The only parame- ter consistently reported was the initial response rate. Be- yond this, perhaps heavily limited by the quality of follow-up data available, duration of symptom relief, and local control rate are described only by some authors. Base on the primary analysis, the authors conclude that the opti- mal dose fractionation schedule for palliation of pelvic recurrence from rectal carcinoma remains undefined.

Physicians who do subscribe to the presence of a dose- response relationship when dealing with patients with re- current pelvic disease from rectal carcinoma, tend to pre- scribe doses similar to those required for the curative therapy of epithelial tumors, perhaps limited only by con-

cerns for smal1 bowel tolerance, with the reasoning for maximizing the probability of local control. It is interesting to note that the majority of the evidence that perhaps sup- port the presence of a dose-response relationship when dealing with the management of patients with recurrent pelvic disease from rectal carcinoma is not based on data from articles specifically reporting on patients with recur- rent disease, but on data that included significant proportion [16% (34), 23% (37) and 32% (15)] of patients with unre- sected primaries and residual postsurgery. In fact, the only evidence for the presence of a dose-response relationship in the “recurrent” series setting, is reported by Lybeert ef al.

(7), who described significant improvement in local control when comparing doses greater, or less than 50 Gy, delivered to patients with pelvic recurrence, in the absence of distant metastasis. This has to be viewed within the context of the other data that is available as presented. Furthermore, the possibility of publication bias, the reporting, and selective publication of positive results, may also be important in the interpretation of the literature on this topic.

In addition to the factors already considered, the ade- quacy of the planning target volume definition, more spe- cifically, the accuracy of the tools available to define which, represents the single most important additional aspect of radiotherapy that could influence effectiveness. This factor could potentially be a major confounder given the unique problems in imaging disease in the postoperative pelvis. This is perhaps most critical when higher dose fractionation ranges are being evaluated, where the clinical target vol- umes, at least for part of the treatment, would tend to be designed with less generous margins around the demonstra- ble gross tumor volumes.

Thoeni et al. (32) reviewed the role of CT in the imaging of colon and rectal cancer. Several authors (16, 21, 25, 31) have addressed the role of CT in determining in presence or absence of any recurrent pelvic disease. Depending in part on the selection criteria for the inception cohort, sensitivity in the range of 66-lOO%, and specificity in the range of 50-97%, has been reported. Mendez ef al. (16) further note that the sensitivity of CT in patients where the primary surgery was anterior resection, was significantly inferior to patients who had abdominal perineal resections (38 vs. 92%, respectively). Magnetic resonance imaging holds promise in providing greater accuracy. Perma et al. (21) compared the role of MRI and CT in the evaluation of a cohort of 18 patients clinically suspected as having recur- rence, using medical records and follow-up data as the “gold standard.” Sensitivity and specificity rates for MRI was 91 and lOO%, respectively, which was superior to CT scan, with sensitivity and specificity rates of 82 and 50%, respectively. Blomqvist et al. (2) also supported the supe- riority of MRI over CT, with data available for a subset of 11 patients where the extend of involvement could be cor- related with subsequent operative and histological findings. MR correctly identified the presence of adjacent StrUCtUre involvement in six out of nine proven cases and CT three out of nine. Of note, however, was that the error rate

remains high for both modalities, with 11 instances by MR and 2 1 instances by CT where the suggested relationship of presence or absence of involvement did not correlate with subsequent surgical findings.

The ability to deliver higher dose ranges to an adequate volume could potentially be enhanced by more accurate imaging techniques. However, the availability of these tech- niques, such as MRI, in routine clinical practice, in turn hinges around the existence of any clinically relevant ben- efits by incorporating it into the treatment decision-making process.

In an attempt to provide quality data that would lead to the eventual definition of the optimal radiotherapy dose fractionation for the treatment of patients with pelvic recurrences from rectal carcinoma, it is perhaps most practical initialiy to compare, in a prospective random- ized setting, two representative dose fractionations, rep- resenting “lower” vs. “higher” doses. The selection of dose fractionation has to incorporate factors such as patient, and physician acceptance in terms of duration of

time on treatment, and similarity to “standard” clinical practice, regimens that are sufficiently different biologi- cally that they would likely allow the detection of any difference in effectiveness should this exist, The inclu- sion of detailed information on the design of the planning target volumes and the imaging techniques to be used would compliment the study design. The use of appro- priate relevant primary end point(s), such as pain relief, and quality of life improvement, the incorporation of appropriate secondary end points such as toxicities. are all essential components that will go towards a successful study design. The use of well-validated instruments with consensus among research groups on the methodology of handling data of this type, are necessary to generate results that could have the potential for influencing future clinical practice. Ciinical trial designs with these ap- proaches would also pave the way to improving the methodology, and hence. the quality of evidence clini- cians could depend on, for the evaluation of palliative interventions and strategies for cancer patients.

Systematic review: RT and pelvic recurrence l R. WONG rt cd. 435

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