Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This systematic review aims to provide a comprehensive and reliable summary of the effect of hyperthermia on rectal cancer when applied concomitantly with radiotherapy.
The specific aim is to review prospective randomized phase II en III trials evaluating the effect of combined hyperthermia and radiation therapy on tumor control and normal tissue side effects in patients treated for locally advanced (T3/4, N+) rectal cancer.
Background
For many years surgery has been the treatment of choice for patients with rectal cancer. The most important prognostic factors are T stage, N stage, the actual number of nodes (Gunderson 1974) involved, and the distance from the anal verge (Rich 1983). During the last decade local and regional recurrences have dropped from 25‐50% (Pilipshen 1984; Rich 1983) to 5‐12%, mainly due to improved operating techniques, nowadays by performing a total mesorectal excision (Cawthorn 1990; Heald 1986; Kapiteijn 2001), thus taking into account the lateral spread of the tumor and lymph nodes. It has been realized, that the circumferential resection margin seems to play an important predictive role in the occurrence of a local recurrence (Adam 1994; deHaas 1996; Marijnen 2003; Quirke 1986). In addition to better operating techniques, further improvements in local control and survival have been made possible by the additional use of adjuvant radiotherapy. Randomized controlled trials have recently been able to show the superiority of preoperative chemo‐ radiation therapy (Anonymous 1990; Dahl 1990; Pahlman 1990; Sauer 2004) compared to postoperative chemo‐radiation therapy (Anonymous 1985; Fisher 1988; Krook 1991). This has led to the recently revised recommendations, now suggesting preoperative chemo‐radiation therapy followed by a total mesorectal excision as the standard treatment of choice for the majority of all patients diagnosed with advanced rectal cancer.
Preoperative staging was not routinely used in the past and earlier staging techniques have also been unable to specifically differentiate between small and locally advanced rectal cancers (deLange 1994; Hulsmans 1994; Schnall 1994). During the last few years however, significant progress has been made in the use of modern MRI and CT techniques to better predict the tumor stage and the circumferential resection margin. This has enabled an upfront selection of locally advanced tumors (T3/ T4 and /or N2) with high relapse rates, thus facilitating a more tailored preoperative strategy. This has produced an increasing interest directed towards a more aggressive preoperative treatment in order to downsize or even eradicate the tumor. The use of preoperative radiotherapy with concomitant chemotherapy can significantly improve the likelihood of microscopically free resection margins and even result in pathologic complete remissions, which might potentially allow to omit surgery (Habr 2004; Sauer 2004).
In line with these preoperative treatment developments, the use of hyperthermia (HT) in combination with radiotherapy (RT) has come to the forefront, because hyperthermia combined with radiotherapy may reach equivalent results than concurrent chemo‐radiation. This is because hyperthermia is known to especially improve the efficacy of radiotherapy in hypoxic tumors. With increasing tumor volumes the oxygenation status worsens, and as a result the percentage of tumor necrosis increases . This oxygenation status of a tumor, the tumor hypoxia grade, is known to represent an independent prognostic factor (Brizel 1999; Hockel 1996; Wouters 2002) for local control. The potential benefit of combining HT and RT has been pointed out several times, mostly in cervical cancer, but its role in rectal cancer has not been defined yet.
Therefore, we will conduct a systematic review and perform meta‐analyses whenever possible to investigate the possible role of hyperthermia in combination with radiotherapy in patients with rectal cancer.
Objectives
This systematic review aims to provide a comprehensive and reliable summary of the effect of hyperthermia on rectal cancer when applied concomitantly with radiotherapy.
The specific aim is to review prospective randomized phase II en III trials evaluating the effect of combined hyperthermia and radiation therapy on tumor control and normal tissue side effects in patients treated for locally advanced (T3/4, N+) rectal cancer.
Methods
Criteria for considering studies for this review
Types of studies
Prospective phase II or III trials, fully published in journals and those identified from other sources (abstracts and proceedings of relevant scientific meetings, and contacts with investigators) for which full details are available from investigators.
Types of participants
Patients of any age with histological proven advanced rectal cancer, and with performance status 0‐2 according to the WHO criteria.
In this review we will use the following definition of "advanced rectal cancer": UICC stage T3‐4 and/or N+ M0.
Studies in which it is not possible to separate data on patients receiving concomitant hyperthermia plus radiotherapy versus radiotherapy alone, even after contacting the authors, will be excluded. Furthermore, exclusion of studies that do not distinguish between primary tumors and/or recurrent and anal cancer.
Types of interventions
Any regimen of pelvic radiotherapy given concurrently or not with any hyperthermia regimen. Analyses will be stratified according to radiotherapy dose, overall treatment time of radiotherapy and hyperthermia quality parameters.
Only studies which used a minimum temperature of 41 degrees Celsius for hyperthermia will be included.
Studies with less than 20 patients and with a mean or median follow‐up of less that 12 months will be discussed in consensus for inclusion.
Types of outcome measures
Clinically relevant outcomes will be studied:
‐ Local tumour recurrence: at 2 and 5 years
‐ Acute and late severe normal toxicity
‐ Clinical complete response at 2 months
‐ Survival: 2 and 5‐years overall survival
Search methods for identification of studies
A search for identification of studies on the review topic is undertaken of the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL, 2005 Issue 4), EMBASE (Webspirs) (1980 to present), Embase (1980 to present). Further, the Cochrane Colorectal Cancer Groups specialised register.
Searches will be performed without restricting the language of studies retrieved.
The Cochrane Central Register of Controlled Trials (CENTRAL) (20.12.05) ( 21 hits)
#1 (neoplasm* or cancer or tumor or tumour or malignan or oncolog* or carcinom* or neoplas* or growth or adenom* or cyst*) 55432
#2 (rect* or colorect*) 8104
#3 (radiotherapy or (computer next assisted next radiotherapy) or (intensity next modulated next radiation next therapy) or (radioation next dosage) or (radiotherapy next high next energy)or (radiation next oncology) or irradiation) 10499
#4 ((hyperthermic next therapy) or hyperthermia) 607
#5 (#1 AND #2 AND #3 AND #4) 21
EMBASE (Webspirs) 20.12.05: (78 hits)
#17 and #18 and #19 and #20 and #21 78
#21 (hyperthermic therapy) or (hyperthermia) 18628
#20 (radiotherapy) or (computer assisted radiotherapy) or (intensity modulated radiation therapy) or ( radioation dosage) or (radiotherapy high energy) or (radiation oncology) or (irradiation) 196029
#19 rect* or colorect* 118925
#18 neoplasm* or cancer or tumor or tumour or malignan or oncolog* or carcinom* or neoplas* or growth or adenom* or cyst* 1796461
Searches and results below from saved search history RCT/CCT SS Embase nov 2005
#17 #12 not #16 1386021
#16 #14 not #15 2475774
#15 #13 and #14 396189
#14 (ANIMAL or NONHUMAN) in DER 2871963
#13 HUMAN in DER 5151934
#12 #9 or #10 or #11 2249468
#11 (SINGL* or DOUBL* or TREBL* or TRIPL*) near ((BLIND* or MASK*) in TI,AB) 78196
#10 (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER*) in TI,AB 407159
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 2056492
#8 "SINGLE‐BLIND‐PROCEDURE"/ all subheadings 5520
#7 "DOUBLE‐BLIND‐PROCEDURE"/ all subheadings 57259
#6 "PHASE‐4‐CLINICAL‐TRIAL"/ all subheadings 517
#5 "PHASE‐3‐CLINICAL‐TRIAL"/ all subheadings 6599
#4 "MULTICENTER‐STUDY"/ all subheadings 33298
#3 "CONTROLLED‐STUDY"/ all subheadings 2030870
#2 "RANDOMIZATION"/ all subheadings 16125
#1 "RANDOMIZED‐CONTROLLED‐TRIAL"/ all subheadings 99033
MEDLINE (Webspirs) 01.11.05: (119 hits)
#41 #36 and #37 and #38 and #39 and #40 119
#40 (hyperthermic therapy) or (hyperthermia) 18613
#39 (radiotherapy) or (computer assisted radiotherapy) or (intensity modulated radiation therapy) or ( radioation dosage) or (radiotherapy high energy) or (radiation oncology) or (irradiation) 246214
#38 rect* or colorect* 149960
#37 neoplasm* or cancer or tumor or tumour or malignan or oncolog* or carcinom* or neoplas* or growth or adenom* or cyst* 2749453
Searches and results below from saved search history Phase 3 RCT/CCT Medline nov 2005
#36 #9 or #25 or #35 2508870
#35 #34 not (#9 or #25) 1816814
#34 #32 not #33 2289401
#33 (TG=ANIMALS) not ((TG=HUMAN) and (TG=ANIMALS)) 3769204
#32 #26 or #27 or #28 or #29 or #31 3216348
#31 (#30 in TI) or (#30 in AB) 1666256
#30 control* or prospectiv* or volunteer* 2349412
#29 PROSPECTIVE‐STUDIES 193506
#28 FOLLOW‐UP‐STUDIES 305935
#27 explode EVALUATION‐STUDIES/ all subheadings 531959
#26 TG=COMPARATIVE‐STUDY 1215526
#25 #24 not #9 372114
#24 #22 not #23 682054
#23 (TG=ANIMALS) not ((TG=HUMAN) and (TG=ANIMALS)) 3769204
#22 #10 or #11 or #12 or #13 or #15 or #16 or #17 or #18 or #19 or #20 or #21 770288
#21 RESEARCH‐DESIGN 35244
#20 random* in AB 331801
#19 random* in TI 49610
#18 placebo* in AB 91766
#17 placebo* in TI 14691
#16 PLACEBOS 25694
#15 (#14 in TI) or (#14 in AB) 84407
#14 (singl* or doubl* or trebl* or tripl*) near (blind* or mask*) 115054
#13 (clin* near trial*) in AB 93475
#12 (clin* near trial*) in TI 26129
#11 explode CLINICAL‐TRIALS/ all subheadings 169332
#10 CLINICAL‐TRIAL in PT 417339
#9 #7 not #8 319942
#8 (TG=ANIMALS) not ((TG=HUMAN) and (TG=ANIMALS)) 3769204
#7 #1 or #2 or #3 or #4 or #5 or #6 347788
#6 SINGLE‐BLIND‐METHOD 9333
#5 DOUBLE‐BLIND‐METHOD 83062
#4 RANDOM‐ALLOCATION 53856
#3 RANDOMIZED‐CONTROLLED‐TRIALS 34179
#2 CONTROLLED‐CLINICAL‐TRIAL in PT 69546
#1 RANDOMIZED‐CONTROLLED‐TRIAL in PT 206973
Reference lists from identified studies will be scrutinised for any other additional studies. The electronic searches for clinical trials will be complemented with manual searches of the following oncology journals: International Journal of Radiation, Oncology, Biology and Physics; Radiotherapy and Oncology; Journal of Clinical Oncology; Clinical Oncology; International Journal of Hyperthermia. Abstracts from the principal oncology conferences with a minimum follow up of 3 years will also be hand searched. Colleagues, collaborators and other experts in the field will be asked to identify missing and unreported trials.
Data collection and analysis
Phase II and III studies identified by the search will be assessed to determine if they meet the inclusion criteria. They will be assessed by three independent reviewers (DDH, LL, PL) both for the quality of the methods against pre‐determined criteria (see below) and for the results of key outcomes, which will be identified and tabulated.
Two reviewers (DDH, GL) will extract the data independently to ensure validity and discrepancies will be resolved by a third referee (DDR). All data extracted from the include studies will be included in this analyses. The following data will be collected from the manuscript: identifiers, gender, age, performance status at the time of randomisation, initial disease stage, definition of chemotherapy regimen, induction treatment that led to a complete response, start date of induction treatment, randomisation date, treatment allocated, overall treatment time of irradiation according to the protocol and updated information on survival, metastasis, and loco‐regional recurrence
Methodological quality will be assessed according to the following criteria:
Was the randomisation process adequate?
Was there adequate allocation concealment?
Were the analyses performed according to intention to treat?
Were the groups similar at baseline for the most important prognostic indicators?
Were eligibility criteria specified?
Were losses to follow up fully accounted for and was the withdrawal/drop‐out rate unlikely to cause bias?
Were co‐interventions which may have influenced the results controlled for?
Statistical Analysis
A weighted estimate of the typical treatment effect across studies will be computed for 2‐year survival data as well as 5‐year survival data, local control and toxicities. The risk ratio (RR) was used as the effect measure. Chi‐square heterogeneity tests were used to test for statistical heterogeneity among trials. As we anticipated that the trial results would be heterogeneous, all analyses will be performed using a random‐effects model.
Sources of heterogeneity in the assessment of the primary outcome measure wil be explored by random‐effects meta‐regression. These analyses will assess the effect of different treatment regimens on the primary outcomes.
This procedure gives an indication of the robustness of the results.
