Rectal and urinary toxicities are the principal limiting factors in delivering a high target dose to patients affected by prostate cancer. The verification of such toxicity is an important step before starting a dose-escalation program. The present observational study reports on the acute and late rectal and urinary toxicity in relation with dose-volume parameters in 104 patients with localized prostate cancer treated with 3-dimensional conformal radiation therapy.
Methods and study design
One hundred and four patients with stage T1b-T3b prostate cancer were treated with three-dimensional conformal radiation therapy to a total dose of 74 Gy, 2 Gy per fraction. Rigid dose constraints were applied for rectum and bladder. Acute and late rectal and urinary toxicities were analyzed also in relation to dose-volume histograms. Biochemical relapse-free survival was defined according to the American Society of Therapeutic Radiation Oncology (ASTRO) criteria and to the RTOG-ASTRO Phoenix Consensus Conference Recommendations using the Kaplan-Meier method.
Results
No grade 3 toxicity was observed. Acute and late grade 2 toxicity rates were 5.8% and 9.0% for rectum and 12.5% and 2.0% for bladder, respectively. Rectal V70 influenced the occurrence of late grade 2 toxicity. A relationship between acute and late urinary toxicity was also found. After a median follow-up of 30 months (range, 20–50), the actuarial overall and biochemical relapse-free survival rates were 84% and 77%, respectively, with a significant difference between low-intermediate and high-risk patients.
Conclusions
Conformal radiotherapy to the dose of 74 Gy was administered with good compliance. The incidence of acute and late toxicity was relatively low in accord with our dose constraints. Rectal V70 proved to be a reliable prognosticator of late toxicity. Overall survival and biochemical relapse-free survival rates were more favorable for low and intermediate-risk and significantly less favorable for high-risk patients.
QuagliaA., ParodyS., GrosclaudeP., Martinez-GarciaC., CoeberghJ.W., VercelliM.: Differences in the epidemic rise and decrease of prostate cancer among geographical areas in Southern Europe: an analysis of differential trends in incidence and mortality in France, Italy and Spain. Eur J Cancer, 39: 654–665, 2003.
2.
PollackA., ZagarsG.K., StarkschallG., AntolakJ.A., LeeJ.J., HuangE., von EschenbachA.C., KubanD.A., RosenI.: Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. IntJ Radiat Oncol Biol Phys, 53: 1097–1105, 2002.
3.
MagriniS.M., BertoniF., VavassoriV., VillaS., CagnaE., MaranzanoE., PerticiM., PradellaR., SpediacciM.A., ChiavacciA., AmbrosiE., LiviL., MagliA., BellavitaR., BossiA., BitiG.: Practice patterns for prostate cancer in nine central and northern Italy radiation oncology centers: a survey including 1759 patients treated during two decades (1980–1998). Int J Radiat Oncol Biol Phys, 52: 1310–19, 2002.
4.
HanksG.E., HanlonA.L., SchultheissT.E., PinoverW.H., MovsasB., EpsteinB.E., HuntM.A.: Dose escalation with 3D conformal treatment: five years outcome, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys, 41: 501–510, 1998.
5.
ZietmanA.L., CoenJ.J., DallowK.C., ShipleyW.U.: The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. Int J Radiat Oncol Biol Phys, 32: 287–292, 1995.
6.
MorrisD., EmamiB., MauchP.M., KonskiA.A., TaoM.L., NgA.K., KleinE.A., MohideenN., HurwitzM.D., FraasB.A., RoachM3rd, GoreE.M., TepperJ.E.: Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative. Int J Radiat Oncol Biol Phys, 62: 3–19, 2005.
7.
HanksG.E., HanlonA.L., PinoverW.H., HorwitzE.M., PriceR.A., SchultheissT.: Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys, 46: 823–832, 2000.
8.
ZelefskyM.J., FuksZ., HuntM., YamadaY., MarionC., LingC.C., AmolsH., VenkatramanE.S., LeibelS.A.: High-dose intensity-modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys, 53: 1111–1116, 2002.
9.
LawtonC.A., WonM., PilepichM.V., AsbellS.O., ShipleyW.U., HanksG.E., CoxJ.D., PerezC.A., SauseW.T., DoggettS.R.: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys, 21: 935–939, 1991.
PeignauxK., TrucG., BarillotI., AmmorA., NaudyS., CréhangeG., MaingonP.: Clinical assessment of the use of the Sonarray system for daily prostate localization. Radiother Oncol, 81: 176–178, 2006.
12.
SpeightJ.L., RoachM.III: Advances in the treatment of localized prostate cancer: the role of anatomic and functional imaging in men managed with radiotherapy. J Clin Oncol, 25: 987–995, 2007.
13.
FiorinoC., SanguinetiG., CozzariniC., FellinG., FoppianoF., MenegottiL., PiazzollaA., VavassoriV., ValdagniR.: Rectal dose–volume constraints in high-dose conformal radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys, 57: 953–962, 2003.
14.
GrecoC., MazzettaC., CattaniF., TosiG., CastiglioniS., FodorA., OrecchiaR.: Finding dose-volume constraints to reduce late rectal toxicity following 3D-conformal radiotherapy (3D-CRT) of prostate cancer. Radiother Oncol, 69: 215–222, 2003.
15.
LiuM., PicklesT., BertheletE., AgranovichA., KwanW., TyldesleyS., McKenzieM., KeyesM., MorrisJ., PaiH.: Prostate cohort initiative. urinary incontinence in prostate cancer patients treated with external beam radiotherapy. Radiother Oncol, 74: 197–201, 2005.
16.
GeinitzH., ZimmermannF.B., ThammR., ErberC., MüllerT., KellerM., BuschR., MollsM.: Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer. Radiother Oncol, 79: 341–347, 2006.
17.
MarziS., ArcangeliG., SaracinoB., PetrongariM.G., BruzzanitiV., IaccarinoG., LandoniV., SorianiA., BenassiM.: Relationships between rectal wall dose-volume constraints and radiobiologic indices of toxicity for patients with prostate cancer. Int J Radiat Oncol Biol Phys, 68: 41–49, 2007.
18.
VavassoriV., FiorinoC., RancatiT., MagliA., FellinG., BaccoliniM., BianchiC., CagnaE., MauroF.A., MontiA.F., MunozF., StasiM., FranzoneP., ValdagniR.: Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D-CRT: results of a prospective multicenter study. Int J Radiat Oncol Biol Phys, 67: 1401–1410, 2007.
19.
SobinH., WittekingC.: TNM Classification of Malignant Tumors. UICC, 6th edn, Wiley-Liss, New York, 2002.
20.
National Comprehensive Cancer Network (NCCN)prostate cancer. In: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, version 1.2007.Jenkinstown, PA, National Comprehensive Cancer Network, March 2007.
21.
International Commission of Radiation Units and Measurements.ICRU Report 50: Prescribing, recording, and reporting photon beam therapy.Bethesda, MD: ICRU, 1993.
22.
International Commission on Radiation Units and Measurements.ICRU Report 62: Prescribing, recording, and reporting photon beam therapy (supplement to ICRU Report 50).Bethesda, MD: ICRU; 1999.
23.
CoxJ.D., StetzJ., PajakT.F.: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys, 31: 1341–1346, 1995.
24.
American Society for Therapeutic Radiology and Oncology Consensus Panel.Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys, 37: 1035–1041, 1997.
25.
RoachMIII, HanksG., ThamesH., SchellhammerP., ShipleyW., SokolG.H., SandlerH.: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys, 65: 965–974, 2006.
26.
DirixP., HaustermansK., JuniusS., WithersR., OyenR., Van PoppelH.: The role of whole pelvic radiotherapy in locally advanced prostate cancer. Radiother Oncol, 79: 1–14, 2006.
27.
BagshawM.A.: Radiotherapeutic treatment of prostatic carcinoma with pelvic node involvement. Urol Clin North Am, 11: 297–304, 1984.
28.
AsbellS.O., KrallJ.M., PipelichM.V., BaerwaldH., SauseW.T., HanksG.E., PerezC.A.: Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06. Int J Radiat Oncol Biol Phys, 15: 1307–1316, 1988.
29.
AsbellS.O., MartzK.L., PilepichM.V., BaerwaldH., SauseW.T., DoggettR.L., PerezC.A.: Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG 77-06, a phase III study for T1bN0M0 (A2) and T2N0M0 (B) prostate. Int J Radiat Oncol Biol Phys, 17: 945–951, 1989.
30.
PilepichM.V., KrallJ.M., JohnsonR.J., SauseW.T., PerezC.A., ZinningerM., MartzK.: Extended field (periaortic) irradiation in carcinoma of the prostate-analysis of RTOG 75–06. Int J Radiat Oncol Biol Phys, 12: 345–351, 1986.
31.
RoachMIII, DeSilvioM., LawtonC., UhlV., MachtayM., SeiderM.J., RotmanM., JonesC., AsbellS.O., ValicentiR.K., HanS., ThomasC.R.Jr., ShipleyW.S.: A phase III trial comparing whole pelvic versus prostate only radiotherapy and neoadjuvant concurrent versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group (RTOG) 9413. J Clin Oncol, 21: 1904–1911, 2003.
32.
RoachMIII, DeSilvioM., ValicentiR., GrignonD., AsbellS.O., LawtonC., ThomasC.R.Jr., ShipleyW.U.: Whole-pelvis, “mini-pelvis”, or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol Biol Phys, 66: 647–653, 2006.
33.
LawtonC.A., DesilvioM., RoachMIII, UhlV., KirschR., SeiderM., RotmanM., JonesC., AsbellS., ValicentiR., HahnS., ThomasC.R.Jr.: An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys, 69: 646–655, 2007.
34.
StoreyM.R., PollackA., ZagarsG., SmithL., AntolakJ., RosenI.: Complications from radiotherapy dose escalation in prostate cancer: Preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys, 48: 635–642, 2000.
35.
VargasC., MartinezA., KestinL.L., YanD., GrillsI., BrabbinsD.S., LockmanD.M., LiangJ., GustafsonG.S., ChenP.Y., ViciniF.A., WongJ.W.: Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys, 62: 1297–1308, 2005.
36.
PeetersS.T., LebesqueJ.V., HeemsbergenW.D., van PuttenW.L., SlotA., DielwartM.F., KoperP.C.: Localized volume effects for late rectal and anal toxicity after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys, 64: 1151–1161, 2006.
37.
KupelianP.A., WilloughbyT.R., ReddyC.A., KleinE.A., MahadevanA.: Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland clinic experience. Int J Radiat Oncol Biol Phys, 68: 1424–1430, 2007.
38.
KubanD.A., TuckerS.L., DongL., StarkschallG., HuangE.H., CheungM.R., LeeA.K., PollackA.: Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys, 70: 67–74, 2008.
39.
ValdagniR., ItaliaC., MontanaroP., LanceniA., LattuadaP., MagnaniT., FiorinoC., NahumA.: Is the alpha-beta ratio of prostate cancer really low? A prospective non-randomized trial comparing standard and hyperfractionated conformal radiation therapy. Radiat Oncol, 75: 74–82, 2005.
40.
SkalaM., RosewallT., DawsonL., DivanbeigiL., LockwoodG., ThomasC., CrookJ., ChungP., WardeP., CattonC.: Patient-assessed late toxicity rates and principal component analysis after image-guided radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys, 68: 690–698, 2007.
41.
DaleW., CampbellT., IgnacioL., SongP., KopnickM., MamoC., RayP., VijayakumarS.: Self-assessed health related quality of life in men being treated for prostate cancer with radiotherapy: instrument validation and its relation to patient assessed bother or symptoms. Urology, 53: 359–366, 1999.
42.
KubanD.A., TuckerS.L., DongL., StarkschallG., HuangE.H., CheungM.R., LeeA.K., PollackA.: Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys, 70: 67–74, 2008.
43.
ValdagniR., RancatiT., FiorinoC., FellinG., MagliA., BaccoliniM., BianchiC., CagnaE., GrecoC., MauroF.A., MontiA.F., MunozF., StasiM., FranzoneP., VavassoriV.: Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT. Int J Radiat Oncol Biol Phys, 71: 1065–1073, 2008.
44.
PeetersS.T., HeemsbergenW.D., KoperP.C., van PuttenW.L., SlotA., DielwartM.F., BonfrerJ.M., IncrocciL., LebesqueJ.V.: Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol, 24: 1990–1996, 2006.
45.
FiorinoC., CozzariniC., VavassoriV., SanguinetiG., BianchiC., CattaneoG.M., FoppianoF., MagliA., PiazzollaA.: Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: Analysis of a large group of patients pooled from three institutions. Radiother Oncol, 64: 1–12, 2002.
46.
KoperP.C., JansenP., van PuttenW., van OsM., WijnmaalenA.J., LebesqueJ.V., LevendagP.C.: Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: observations of a randomized trial. Radiother Oncol, 73: 1–9, 2004.
47.
StasiM., MunozF., FiorinoC., PasquinoM., BaiottoB., MariniP., MalinverniG., ValdagniR., GabrieleP.: Emptyng the rectum before treatment delivery limits the variations of rectal dose-volume parameters during 3DCRT of prostate cancer. Radiother Oncol, 80: 363–370, 2006.
48.
HarsoliaA., VargasC., YanD., BrabbinsD., LockmanD., LiangJ., GustafsonG., ViciniF., MartinezA., KestinL.L.: Predictors for chronic urinary toxicity after the treatment of prostate cancer with adaptive three-dimensional conformal radiotherapy: dose-volume analysis of a phase II dose-escalation study. Int J Radiat Oncol Biol Phys, 69: 1100–1109, 2007.
49.
NakamuraR.A., MontiC.R., CastilhoL.N., TrevisanF.A., ValimA.C., ReinatoJ.A.: Prognostic factors for late urinary toxicity grade 2–3 after conformal radiation therapy on patients with prostate cancer. Int Braz J Urol, 33: 652–661, 2007.
50.
DearnaleyD.P., SydesM.R., LangleyR.E., GrahamJ.D., HuddartR.A., SyndikusI., MatthewsJ.H., ScraseC.D., JoseC.C., LogueJ., StephensR.J., RT01 Collaborators: The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: results from the MRC RT01 trial (ISRCTN47772397). Radiother Oncol, 83: 31–41, 2007.
51.
MoiseenkoV., LiuM., KristensenS., GelowitzG., BertheletE.: Effect of bladder filling on doses to prostate and organs at risk: a treatment planning study. J Appl Clin Med Phys, 12: 55–68, 2006.
52.
EadeT.N., HanlonA.L., HorwitzE.M., BuyyounouskiM.K., Hanks, PollackA.: What dose of external-beam radiation is high enough for prostate cancer?Int J Radiat Oncol Biol Phys, 68: 682–689, 2007.
53.
KubanD., ThamesH., LevyL., HorwitzE., KupelianP., MartinezA., MichalskiJ., PisanskyT., SandlerH., ShipleyW., ZelefskyM., ZietmanA.: Failure definition-dependent differences in outcome following radiation for localized prostate cancer: can one size fit all?Int J Radiat Oncol Biol Phys, 61: 409–414, 2005.
54.
D'AmicoA.V., ManolaJ., LoffredoM., RenshawA.A., Della CroceA., KantoffP.W.: 6-month androgen suppression plus radiation therapy vs. radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA, 292: 821–827, 2004.
55.
BrunsF., FranzkiC., WegenerG., KarstensJ.H.: Definitive conformal radiotherapy for localized high-risk prostate cancer: a long-term follow-up study with PSA course. Anticancer Res, 27: 1847–1851, 2007.
56.
ThamesH., KubanD., LevyL., HorwitzE.M., KupelianP., MartinezA., MichalskiJ., PisanskyT., SandlerH., ShipleyW., ZelefskyM., ZietmanA.: Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995. Int J Radiat Oncol Biol Phys, 57: 929–943, 2003.
57.
ViciniF.A., KestinL.L., MartinezA.A.: The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys, 45: 553–561, 1999.
