Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i851 (Published 02 March 2016) Cite this as: BMJ 2016;352:i851
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Dear Editor,
We read the article by Wallis CJD and colleagues (1), who identified an association between radiotherapy for prostate cancer and the development of secondary cancers of the bladder, colorectal tract, and rectum in a recently published systematic review and meta-analysis. Despite the efforts spent in a comprehensive and up-to-date review, as well as the attempts to account for the risk of selection’s bias through the use of the Newcastle-Ottawa scale, relevant limitations affect the quality of this study. Apart from the lack of information on smoking history and obesity – two well known factors involved in the development of colon (2) and prostate cancer (3), as the authors theirselves recognized – the control groups (surgery or no treatment) are not age-matched. Since patients assigned to radiotherapy tend to be generally older, it cannot be excluded that the increased risk of second malignancies after radiotherapy can be solely, or at least in part, simply attributed to aging, the single biggest risk factor for developing cancer (4,5).
Therefore, no reliable conclusions regarding the association between the risk of second malignancies and radiotherapy for prostate cancer can be drawn. Although the risk of an induced second malignancy resulting from the mutagenic potential of ionizing radiation is documented (6,7), the authors’ conclusion that “this information could be helpful in the decision making process regard in such treatment“ sounds like a serious warning against a potential harmfulness of radiotherapy. We believe that these concerns deserve to be investigated in thoroughly assessed analyses, aimed not only at the quantification of the risk but also at the outcomes of patients who develop second malignancies after radiotherapy, which might not be significantly different from those observed in the general population (8). Until now, the potential risk for development of a secondary malignancy after radiotherapy for prostate cancer remains a widely accepted misconception.
BIBLIOGRAPHY
1. Wallis CJD, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ 2016;352:i851
2. Frezza EE, Wachtel MS, Chiriva-Internati M. Influence of obesity on the risk of developing colon cancer. Gut2006;55:285-91.
3. Engeland A, Tretli S, Bjørge T. Height, body mass index, and prostate cancer: a follow-up of 950000 Norwegian men. Br J Cancer2003;89:1237-42.
4. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50:7-33, 2000.
5. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999.
6. Hall EJ and Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int. J Radiat. Oncol. Biol. Phys. Vol. 56, No. 1, pp. 83–88, 2003
7. Azzam EI, Colangelo NW, Domogauer JD, et al. Is Ionizing Radiation Harmful at any Exposure? An Echo That Continues to Vibrate. Health Phys. 2016 Mar;110(3):249-51.
8. Zelefsky MJ, Pei X, Teslova T, et al. Secondary cancers after intensity-modulated radiotherapy, brachytherapy and radical prostatectomy for the treatment of prostate cancer: incidence and cause-specific survival outcomes according to the initial treatment intervention. BJU Int. 2012 Dec;110(11):1696-701
Competing interests: No competing interests
Dear sir:
This review is very valuable with high clinical significance which reveals that radiotherapy for prostate cancer was associated with higher risks of some second malignancies.1 However, in the paper the author just reviewed the effect of external beam radiotherapy (EBRT) on the development of second malignancies and did not mention that interstitial brachytherapy (ISBT) such as the radioactive 125Iodine seed is also an important method in prostate cancer.
125Iodine possesses excellent radioactive property with low energy2-3 (radioactive radius=17 mm) and appropriate half-life time （T1/2=60.2 d)，which has a little impact on the normal tissue surrounding the prostate as the radiation is inversely proportional to the magnitude. As we know, EBRT could not avoid the radiation to the penetrating organs although the radiation has been reduced to a certain extent by using IMRT. Up to now，many clinical studies have confirmed that 125Iodine can provide excellent long-term results in clinically localized patients4-6 because ISBT can deliver high-dose radiation to the prostate gland without increasing doses to the surrounding normal tissues, and the National Comprehensive Cancer Network (USA) has recommended 125Iodine as a category 1 treatment method in the clinically localized prostate cancer since 2012 7. We believe ISBT will play an important role in clinically localized prostate cancer because of the low doses to the surrounding normal tissues. Finally, we look forward to further studies result with longer follow-up and especially the comparative studies with ISBT.
References
01. Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016 Mar 2; 352:i851. doi: 10.1136/bmj.i851.
02. Popescu CC, Wise J, Sowards K, et al. Dosimetric characteristics of the Pharma Seed model BT-125-I source. Med Phys. 2000 Sep; 27(9):2174-81. http://dx.doi.org/10.1118/1.1289897
03. Ling CC. Permanent implants using Au-198, Pd-103 and I-125: radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys. 1992; 23(1):81-7. doi:10.1016/0360-3016(92)90546-T
04. Sekiguchi A, Ishiyama H, Satoh T, et al. 125Iodine monotherapy for Japanese men with low- and intermediate-risk prostate cancer: outcomes after 5 years of follow-up. J Radiat Res. 2014 Mar 1;55(2):328-33. doi: 10.1093/jrr/rrt113
05. Kittel JA, Reddy CA, Smith KL, et al. Long-Term Efficacy and Toxicity of Low-Dose-Rate 125I Prostate Brachytherapy as Monotherapy in Low-, Intermediate-, and High-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2015 Jul 15;92(4):884-93. doi: 10.1016/j.ijrobp.2015.02.047.
06. Yorozu A, Kuroiwa N, Takahashi A, et al. Permanent prostate brachytherapy with or without supplemental external beam radiotherapy as practiced in Japan: outcomes of 1300 patients. Brachytherapy. 2015 Mar-Apr;14(2):111-7. doi: 10.1016/j.brachy.2014.06.008.
07. http://www.jnccn.org/
Competing interests: No competing interests
Presumably, similar iatrogenically induced pelvic second malignancies will also appear after excessive radiotherapeutic sessions for endometrial/ovarian/cervical/uterine cancers.
Further studies on women with gynecologic cancers are needed to confirm this unfortunate trend.
Current treatment protocols should be revised in order to avoid increasing mortality of beamed women.
Competing interests: No competing interests
Presumably, similar iatrogenically induced pelvic second malignancies will also appear after excessive radiotherapeutic sessions for endometrial/ovarian/cervical/uterine cancers.
Further studies on women with gynecologic cancers are needed to confirm this unfortunate trend.
Current treatment protocols should be revised in order to avoid increasing mortality of beamed women.
Competing interests: No competing interests
We read with interest the BMJ research article, “Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis” by Wallis et al.1 The authors report that external beam radiotherapy (but not brachytherapy or surgery) for prostate cancer is associated with higher risks of developing second malignancies of the colon and rectum, as well as the bladder. The authors speculate that the higher integral dose imparted by external beam radiation therapy could explain the higher second cancer rates. However, there is an important and unaccounted for confounding variable that might invalidate their conclusions.
Long-term androgen deprivation therapy for prostate cancer is associated with an increased risk of colorectal cancer.2 Long-term adjuvant androgen deprivation therapy is often used with external beam radiation therapy, especially for locally advanced and high-risk patients.3,4 In contrast, long-term androgen deprivation therapy is not frequently with surgery or brachytherapy (and may even be contraindicated).5 Therefore, the use of androgen deprivation therapy in patients receiving external beam radiotherapy may be a major confounding variable that would explain the results of Wallis et al. The fact that the authors did not stratify their results based on androgen deprivation therapy calls into question their conclusion that external beam radiation therapy was the cause for the increased colorectal cancer rates. Unless such stratification is performed, it remains possible that the true culprit for the increased colorectal cancers was androgen deprivation therapy.
1. Wallis CJ, Mahar AL, Choo R, Herschorn S, Kodama RT, Shah PS, Danjoux C, Narod SA, Nam RK. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016 Mar 2; 352:i851. doi: 10.1136/bmj.i851.
2. Gillessen S, Templeton A, Marra G, Kuo YF, Valtorta E, Shahinian VB. Risk of colorectal cancer in men on long-term androgen deprivation therapy for prostate cancer. J Natl Cancer Inst. 2010;102:1760-70. doi: 10.1093/jnci/djq419.
3. Warde P, Mason M, Ding K, et al Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011; 378:2104-11. doi: 10.1016/S0140-6736(11)61095-7.
4. Zapatero A, Guerrero A, Maldonado X, Alvarez A, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015; 16:320-7. doi: 10.1016/S1470-2045(15)70045-8.
5. Stone NN, Stock RG. 15-year cause specific and all-cause survival following brachytherapy for prostate cancer: negative impact of long-term hormonal therapy. J Urol. 2014;192:754-9. doi: 10.1016/j.juro.2014.03.094.
Competing interests: No competing interests
Re: Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis
This article was interesting because the radio therapy generates high probability of cancers such as prostate and the development of secondary cancers of bladder, colorectal tract, and rectum compared to the association of lung cancer, the statistical differences regarding other types of cancer are significant, in addition to the different types of radiation, and the comparison group. This article also provides evidence of the current knowledge about the risk of secondary cancer increases with time unlike other alternative treatments such as surgery.
Competing interests: No competing interests