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Two countries – Two treatment strategies for rectal cancer
Radiotherapy and Oncology, Volume 121, Issue 3, December 2016, Pages 357 - 363
Background and purpose
Trials in rectal cancer have shown that radiotherapy (RT) decreases local recurrence rates, whereas the effects on survival are uncertain. Swedish and Norwegian oncologists have had different treatment recommendations. The aim was to evaluate local recurrence rates and survival in the two countries.
Patients and methods
Between 1995 and 2012 rectal cancer patients registered in Sweden and Norway were analyzed, presenting population-based “real world” data.
Totally 29,029 Swedish and 15,456 Norwegian patients were analyzed. Resection for cure was performed in two-thirds of the patients. RT was given to 49% of Swedish patients, mainly short-course RT and to 26% of Norwegian patients, predominantly chemoradiotherapy (CRT). In Sweden, the proportion irradiated was stable whereas in Norway, an increase from 10% to 40% was seen. Local 5-year recurrence rates were initially higher in Norway (12%) than in Sweden (8%), whereas they were equally low (4%) during the latter time. No survival differences were seen, however, survival improved with time in both countries.
Two entirely different approaches to preoperative therapy resulted in similar survival with initially higher local recurrence rates in Norway, but similarly low rates in later years. This raises questions about optimal RT rates and regimens.
Keywords: Local recurrence, Population data, Radiotherapy, Rectal cancer, Survival.
Treatment for rectal cancer has changed dramatically over the past decades, in particular with new surgical principles and increased use of radiotherapy (RT). Several randomized studies have reported diminished local recurrence rates by 50–60% after preoperative RT , , , and . Many countries adopted this combined treatment strategy, but there were also indications that surgery following the embryological planes, performing a total mesorectal excision (TME) without RT, could result in low local recurrence rates .
In Sweden, RT had been introduced before the “TME era”. Large trials showed that when indication for RT was present, it should be given preoperatively, and short-term morbidity was acceptable provided optimal radiation techniques available at the time were used , , , and . Moreover, a survival benefit was found in the Swedish Rectal Cancer trial . In Norway, RT was given postoperatively to selected patients , and preoperative therapy was rarely used. During the early 1990s, national training programs in the TME-technique were held in both countries  and . In Sweden, RT continued to be used preoperatively, predominantly as a short-course regimen (5 gray (Gy) ×5 during one week). Preoperative therapy was implemented also in Norway, but long-course chemoradiotherapy (CRT) was used (50 Gy in 5 weeks with concomitant 5-fluorouracil or capecitabine and delayed surgery), at first only to the most advanced cases (fixed T4 tumors), later also to patients with threatened circumferential resection margins. Thus, the two neighboring countries chose different treatment strategies.
A quality registration for rectal cancer started in the mid-1990s in both countries. Subsequently, two national population-based registries exist, one where preoperative RT was given to many patients (Sweden)  and one where few patients were irradiated initially, followed by an increase in the use of preoperative CRT (Norway)  and . The aim was to compare the results of the two treatment strategies for rectal cancer on a national basis to explore the potential impact of preoperative RT/CRT on local recurrence and survival.
Materials and methods
The Norwegian Rectal Cancer Registry was established in 1993, and the Swedish Rectal Cancer Registry in 1995. Between 1995 and 2012 totally 29,029 patients in Sweden and 15,456 patients in Norway were registered (Table 1). These numbers correspond to an annual incidence of 18.8 per 100,000 inhabitants in Sweden and 19.5 in Norway. The corresponding age-standardized rates (World 1960) are 8.8 and 10.6, respectively.
Characteristics of patients included in the Swedish and Norwegian quality registries.
|Sweden N (%)||Norway N (%)|
|Males||16,903 (58.2)||8899 (57.6)|
|Females||12,126 (41.8)||6557 (42.4)|
|Median age (years)||72||71|
|Radiotherapy (RT)||14,212 (49.0)||3984 (25.8)|
|Synchronous metastases (M1)||5521 (19.0)||3211 (20.8)|
|Metastases-free (M0) clinical stage I–III||23,508 (81.0)||12,245 (79.2)|
|RT (% of M0)||12,398 (52.7)||3222 (26.3)|
|Local excision||1333 (4.6)||460 (3.0)|
|Not resected||2851 (9.8)||1182 (7.6)|
|RT (% of not resected)||544 (19.1)||273 (23.1)|
|Resected (AR, HA, APE)||19,324 (66.6)||10,603 (68.6)|
|R2 resection (% of resected)||783 (4.1)||182 (1.7)|
|Radically resected (stage I–III)||18,541 (63.9)||10,421 (67.4)|
|Males||10,848 (58.5)||6062 (58.2)|
|Females||7693 (41.5)||4359 (41.8)|
|Anterior resection||10,480 (56.5)||6124 (58.8)|
|Hartmann||2106 (11.4)||792 (7.6)|
|Abdomino-perineal excision||5936 (32.0)||2850 (27.3)|
|Other or unknown||19 (0.1)||657 (6.3)|
|RT (% of radically resected)||11,345 (61.2)||2853 (27.4)|
|Preoperative RT||11,342 (61.2)||2508 (24.1)|
|Postoperative RT||7 (0.0)||345 (3.3)|
Surgery, staging and adjuvant chemotherapy
The majority of surgeons had adopted the TME-technique in both countries prior to 1995, with rather abrupt improvement of outcomes , , and . The loco-regional staging was initially done by digital rectal palpation and rigid rectoscopy, but since 2004 by magnetic resonance imaging (MRI) of the pelvis , , and . Staging for metastases was also similar between the countries, initially with pulmonary X-ray and ultrasonography of the liver, later with computed tomography of the chest and abdomen. Adjuvant chemotherapy has not been recommended, but has been used at some hospitals in Sweden , less in Norway.
In Sweden, preoperative short-course RT followed by surgery within a week has been recommended for resectable tumors at risk of local failure, initially based upon clinical evaluation but since 2004 upon MRI characteristics. These tumors are presently designated intermediate risk tumors. Locally advanced, non-resectable tumors, about 10–15% of the population, were treated with long-course RT (2 Gy fractions to 50 Gy), initially alone, within a Nordic randomized trial concomitant with 5-fluorouracil , or after 2007 with CRT. Some patients (n = 840) participated in the Stockholm III trial randomizing between short-course RT with immediate or delayed surgery and long-course RT  and .
In Norway, initially selected patients with involved margins (<1 mm) or perforation had postoperative CRT , but gradually, preoperative CRT was preferred , initially as part of the Nordic randomized trial , subsequently according to guidelines. Norwegian guidelines initially recommended preoperative CRT only for T4 or fixed tumors, but later also for tumors near (⩽3 mm) the mesorectal fascia on MRI. Short-course radiotherapy with delayed surgery has been recommended in later years to elderly or comorbid patients .
The present guidelines in the two countries are given in Supplementary Table 1.
The registries have high validity of data , , and . Most variables were comparable, however, metastatic disease was registered as synchronous if present at diagnosis or surgery in Sweden, and within four months of diagnosis in Norway. The registration of radical surgery also differed; in Sweden, surgery was initially considered radical if reported by both the surgeon and pathologist, whereas after 2003 in Sweden and during the entire time period in Norway, the surgeon reported non-radical surgery (R2) and the pathologist reported free (R0) or involved (R1) resection margins.
For simplicity, (C)RT has been analyzed with ‘yes or no’ since these variables were registered throughout the whole time period, with more detailed information in later years. In addition, randomized trials have not shown any difference in local recurrence rates or survival when comparing preoperative 5 × 5 Gy with CRT in patients with intermediate rectal cancer , , , and .
Pathological T and N stages are impossible to compare directly. In patients who were operated immediately after RT, the pathologic stage would be designated pT and pN. However, in patients who underwent short-course RT or CRT with delayed surgery, tumor down-staging can occur and the designation would be ypT and ypN.
Recurrence or metastases are reported by the clinician, and all pathology reports for biopsies and surgical specimens are registered. In addition, all hospitals receive queries for occurrence of local recurrence or metastatic disease; in Sweden after 1, 3 and 5 years, in Norway yearly until 5 years .
According to Swedish laws, quality registries are accepted provided that information about the registration is given at places where the patients can read it (out-patient units or hospital wards), and that they can decline such registration. This is, however, exceptional. This study has been approved by the research ethics committee, Uppsala, Sweden. In Norway, registration in the national cancer registry and the quality registries is mandatory. No separate ethical approval was needed since this study was based on de-identified registry data.
Statistical methods and analytical strategy
Since all data are population-based, and the total patient numbers differ between countries, percentages are shown. Categorical variables were compared using the chi-square test. Overall survival was estimated using the Kaplan–Meier method. Local recurrence and distant metastases rates were estimated using the Aalen-Johansen estimator, taking into account competing risk of death. Relative survival was estimated using the Ederer II estimator as the ratio of observed survival in the study groups compared to expected survival in the general population, matched for age, sex, and time. An estimation of the number of cancer-deaths and non-cancer deaths in radically resected patients was done . Follow-up started at the date of surgery; if not resected, from the date of diagnosis. Ideally, follow-up should have started when treatment decision was made (today usually in a multidisciplinary team (MDT) conference), but this date was not registered.
Of greatest interest when exploring the impact of different preoperative strategies would be to analyze patients where radical surgery was intended, whether the tumor was upfront considered resectable or non-resectable, i.e. patients planned for major radical surgery without distant metastases. This group may be easy to define in clinical practice, e.g. at an MDT conference, but this was not possible using registered data. Thus, in addition to all patients with a primary rectal cancer without distant metastases (M0, i.e. clinical stage I–III), patients who underwent major resection, either anterior resection (AR), Hartmanns’ procedure (HA) or abdomino-perineal excision (APE), and those who obtained radical surgery (R0/R1 resection) were analyzed. The number of patients in the different groups and the outcomes analyzed are shown in Fig. 1.
Flowchart of patients included in the two quality registries and outcome analyses for the patient groups. Figures are numbers (percentages). Outcomes presented are shown to the right. *Prior to 2004, also R1-resections were included in Sweden. M0: no metastases. M1: metastases. R2: macroscopic non- radical resection. OS: overall survival. RS: relative survival. LR: local recurrence.
Characteristics of patients with rectal cancer in Sweden and Norway
There were no differences in gender or age distribution between the countries (Table 1). Approximately 20% of the patients had synchronous metastases with a slightly higher proportion in Norway than Sweden, probably due to different registration routines. This proportion did not change with time (data not shown). A major resection (AR, HA, APE or rarely procto-colectomy) was performed in 66–69% of the patients and a local excision in 3–5% with no differences between countries. Patients who did not undergo tumor resection (about 30% in both countries) were generally much older (median 80 years) than those who underwent resection (median 70 years). A non-radical resection was seen more frequently in Sweden than in Norway (4.1% vs 1.7%, p < 0.001), which likely is explained by different registration routines.
Overall, significantly more patients in Sweden (49.0%) had RT than in Norway (25.8%, p < 0.001) (Table 1). This difference persisted in M0 patients (52.7% vs 26.3%) and in patients with radical resection. RT was mostly given preoperatively. In Sweden, the majority had short-course RT, in Norway CRT. Significantly more patients in Norway (n = 345, 3.3%) had postoperative (C)RT than in Sweden (n = 7, 0.0%), p < 0.001).
Over the 18-year period the proportion of patients receiving pre- or postoperative RT or CRT has varied considerably, particularly in Norway (Fig. 2). In the time period 1996–2004, 10.3% of all patients had RT in Norway and 44.8% in Sweden. In 2008–2012, the difference was smaller, 38.8% in Norway and 52.8% in Sweden. The differences between the countries were similar in M0 patients and radically resected patients (Supplementary Fig. 1). Since Sweden used mostly short-course RT, whereas Norway used long-course (C)RT, the number of radiation fractions given was rather similar during the first half of the period, whereas during the latter time period, more fractions were given in Norway (about 1025 fractions per 100 patients compared to about 475 in Sweden).
Radiotherapy (RT) for all patients diagnosed with rectal cancer in Sweden and Norway from 1996 to 2012.
Treatment results in all patients
No differences were seen in 2- and 5-year overall (OS) (Fig. 3) or relative (RS) survival (data not shown) for all patients in the two countries. Both OS and RS improved over time. There were no differences in OS or RS between countries when analyzed separately in patients with M0 (data not shown) or M1 disease (Supplementary Fig. 2).
Overall survival at 2 and 5 years for all patients diagnosed with rectal cancer in Sweden and Norway.
Treatment results in patients with major radical resection (stage I–III, AR, HA or APE)
There were no differences in gender or age distribution between the two countries. The postoperative 30 days mortality has gradually decreased to less than 2% in both countries since about 2005, while anastomotic leakage around 8–10% in patients following AR has been almost unchanged over the years in both countries (data not shown).
The 2- and 5-year risk of local recurrence after a major radical resection has been reduced during the time period in both countries (Fig. 4). The 5-year rates were reduced from about 8% before 2000 to 4% after 2005 in Sweden and from 10–12% to also about 4% after 2007 in Norway. A 1–2% absolute difference in the 2-year rates still exists (p < 0.02).
Local recurrence rates at 2 and 5 years for radically resected patients in Sweden and Norway.
The proportions who developed distant metastasis over a 5-year period have decreased from slightly above to slightly below 20%, with no difference between the countries (Supplementary Fig. 3). The 5-year RS increased in both countries from about 77% in 1996 to about 81% in 2009, with no difference between countries (Fig. 5). A decrease with time was seen in both cancer deaths and non-cancer deaths, with no difference between countries (Supplementary Fig. 4). A separate analysis of 5-year RS for low tumors did not reveal any difference (data not shown).
Relative survival at 2 and 5 years for radically resected patients in Sweden and Norway.
The countries used two different approaches to rectal cancer treatment, preoperative radiotherapy plus TME to many patients in Sweden, and TME alone to most patients initially followed by an increased use of preoperative CRT during recent years in Norway. With these two different approaches, no survival differences could be detected. However, the local recurrence rates were initially lower in Sweden, until the use of CRT increased in Norway. In recent years, although RT regimens and rates differ, the local recurrence rates have been comparable at a very low level (4% after 5 years).
The data from the two countries are population-based. There was no randomization, but all patients with rectal cancer have been analyzed, giving “real life data” from two countries with a total of 14 million citizens. When analyzing population-based data, it is difficult to fully understand the selection mechanisms to treatment options. However, national guidelines have been followed due to a focus on rectal cancer treatment over these two decades, treatment in public hospitals, and generally a very good adherence to guidelines.
It is known that both RT and surgery for rectal cancer have acute and late adverse effects, and a main purpose of this study was to evaluate which strategy for RT appeared most optimal, the Swedish or the Norwegian. Any gains in local recurrence rates and potentially in survival must be balanced against expected adverse effects. These have been studied extensively in both countries, albeit with the radiation techniques used in those time periods , , and . There is no increased risk of 30 or 60 days mortality after (C)RT, unless improperly given, but following an APE there is an increased risk for perineal wound infections , , and . However, there are late effects of (C)RT, such as compromised bowel function , , and  and sexual dysfunction in men and women , , and . There may be a slightly increased risk of a second malignancy, although minor in recent studies  and .
During the first half of the 20-year period, when there was a large difference in the proportion of patients irradiated (40% overall in Sweden compared to 10–15% in Norway), the absolute difference in 5-year local recurrence rates was 4%. During the most recent years, when the proportions irradiated differed less (about 50% in Sweden, about 40% in Norway), no difference was seen after 5 years, but still a minimal difference of 1–2% after 2 years.
Does then a 4% absolute difference in local recurrence rate, as seen during the first half of the period, motivate a several-fold difference in the use of (C)RT? Is it reasonable to irradiate almost half of the patients when the local recurrence rates have decreased to about 4%, as in the latter part of the time period? Given the results of the multiple trials that have explored the value of adding preoperative (C)RT to surgery, it is beyond doubt that many patients with rectal cancer need (C)RT to obtain a high probability of local control. The markedly different utilization of preoperative (C)RT between Sweden and Norway illustrates how different trial results can be interpreted, as does the marked variation in RT use seen in a British survey .
During this period MRI has become standard of care for preoperative staging and an important factor for treatment decisions. In Sweden, rectal cancers are divided in three groups based on MRI, ‘early or good’, ‘intermediate or bad’ and ‘locally advanced or ugly’. The ‘good’ tumors are T1-T3a-b and N0 (N1 if upper rectum), and no RT is given. The ‘bad’ tumors are T3c-d, N+ and preoperative 5 × 5 Gy is recommended. ‘Ugly’ tumors are cT3 with compromised or threatened (⩽1 mm) mesorectal fascia and cT4b where standard care is CRT. In Norway, patients in the intermediate group are normally not irradiated unless the margin to the mesorectal fascia is ⩽2 mm (3 mm during the latter part of the investigated time period) on MRI . Therefore, the Norwegian treatment of most patients with an intermediate rectal cancer, i.e. surgery alone, appears to give comparable results as in Sweden with more RT. Taken into account the late effects of RT it urges reducing the RT rate in Sweden. In Norway, it could be discussed if an absolute reduction in local recurrence rates from 10–12% to 4% motivates an increase in preoperative (C)RT from 10–15% to about 40%, and whether more patients could have 5 × 5 Gy. However, a meticulous audit is necessary for monitoring that local recurrence rates remain low if RT rates are reduced.
There was no difference in the rate of distant metastases in radically resected patients between the countries. Since local control is achieved with modern surgery and selective RT, the next crucial step must be to prevent metastatic disease, where only slight improvement has been observed. The RAPIDO trial is a Swedish-Dutch trial (with two Norwegian centers participating) with the aim of increased survival, where patients with locally advanced rectal cancer (some “bad”, all “ugly”) are randomized to preoperative CRT followed by surgery and optional adjuvant chemotherapy or to an experimental treatment with 5 × 5 Gy followed by 6 cycles of CAPOX and surgery . A Polish group recently reported better OS in patients with locally advanced rectal cancer who received neoadjuvant short-course RT and 2 months of FOLFOX versus CRT . The results of these studies may result in new treatment strategies for patients with high-risk rectal cancer.
Another important observation during this period of almost 20 years is the centralization of rectal cancer surgery. In 1995, rectal cancer was operated in 71 hospitals in Sweden and 40 hospitals in Norway. Since 2012, only 35 hospitals in Sweden and 20 in Norway operate rectal cancer.
Swedish and Norwegian surgeons had learned the TME technique prior to the initiation of this study. Further improvements in surgical technique during the 18-year period can have contributed to the continuously improved survival. Population-based screening has been performed to a limited extent in the countries, but there may have been greater symptom awareness. Better staging, increased use of (C)RT, and more active surgery and more effective chemotherapy for metastatic disease have likely also contributed to the improved survival. The latter is likely a major reason for the improved survival in patients with metastatic disease (Supplementary Fig. 2) . Adjuvant chemotherapy was used sparsely, and has limited survival gains in rectal cancer  and .
Over a time period of 19 years, population-based rectal cancer registry data from Sweden and Norway have shown that different treatment strategies have had an impact on local recurrence rates, but not on survival. At present, there are still differences in the use and choice of regimens of preoperative therapy, but both countries have similar good outcomes in terms of local recurrence and survival.
Conflict of interest
None of the authors have any conflict of interest to report.
Late Professor Lars Påhlman for his dedicated work to improve treatment and prognosis for rectal cancer patients worldwide and for his contribution to this work initially. Financial support was received from the Swedish Cancer Society, Sweden.
Appendix A. Supplementary data
Radiotherapy (RT) for patients with non-metastatic disease (M0 (above)) and for radically resected patients (below) in Sweden and Norway.
Overall survival at 2 and 5 years for patients with primary metastatic disease (M1) in Sweden and Norway.
Distant metastases at 2 and 5 years for radically resected patients in Sweden and Norway.
Proportion of cancer deaths and non-cancer deaths with time in Sweden and Norway.
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a Department of Immunology, Genetics and Pathology, Uppsala University, Sweden
b Department of Registration, Cancer Registry of Norway, Oslo, Norway
c Department of Radiation Sciences, Oncology, Umeå University, Sweden
d Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
e Department of Oncology and K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norway
⁎ Corresponding author at: Department of Immunology, Genetics and Pathology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
© 2016 Published by Elsevier B.V.