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Biologically effective dose and definitive radiation treatment for localized prostate cancer

Treatment gaps do affect the risk of biochemical failure

Biologisch effektive Dosis und definitiven Strahlentherapie des lokalisierten Prostatakarzinoms

Behandlungslücken beeinflussen das Risiko eines biochemischen Versagens

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Abstract

Background and purpose

It is not clear if prolongation of definitive external radiation therapy for prostate cancer has an effect on biochemical failure. The aim of this work was to evaluate whether the biologically effective dose (BED), and in particular the duration of radiotherapy, intended as overall treatment time, has an effect on biochemical failure rates and to develop a nomogram useful to predict the 6-year probability of biochemical failure.

Patients and methods

A total of 670 patients with T1–3 N0 prostate cancer were treated with external beam definitive radiotherapy, to a total dose of 72–79.2 Gy in 40–44 fractions. The computed BED values were treated with restricted cubic splines. Variables were checked for colinearity using Spearman’s test. The Kaplan–Meier method was used to calculate freedom from biochemical relapse (FFBR) rates. The Cox regression analysis was used to identify prognostic factors of biochemical relapse in the final most performing model and to create a nomogram. Concordance probability estimate and calibration methods were used to validate the nomogram.

Results

Neoadjuvant and concomitant androgen deprivation was administered to 475 patients (70 %). The median follow-up was 80 months (range 20–129 months). Overall, the 6-year FFBR rate was 88.3 %. BED values were associated with higher biochemical failure risk. Age, iPSA, risk category, and days of radiotherapy treatment were independent variables of biochemical failure.

Conclusion

A prolongation of RT (lower BED values) is associated with an increased risk of biochemical failure. The nomogram may be helpful in decision making for the individual patient.

Zusammenfassung

Hintergrund und Ziele

Es ist nicht geklärt, ob die Verlängerung einer definitiven Strahlentherapie bei der Behandlung von Prostatakarzinompatienten einen Effekt auf das biochemische Versagen hat. Die vorliegende Studie hat das Ziel zu evaluieren, ob biologisch die effektive Dosis und insbesondere die Gesamtdauer der Behandlung eine Wirkung auf das biochemisches Rezidiv haben könnte. Ferner wurde ein Nomogramm zur Vorhersage der 6-Jahres-Wahrscheinlichkeit von biochemischem Versagen entwickelt.

Patienten und Methoden

Insgesamt erhielten 670 Patienten im Tumorstadium T1–3, N0, eine Strahlentherapie mit einer Gesamtdosis von 72–79,2 Gy in 40–44 Fraktionen. Errechnete Werte der biologisch effektiven Dosis (BED) wurden mittels begrenzten kubischen Splines bearbeitet. Variablen wurden mit Spearman-Test hinsichtlich Kollinearität untersucht. Zur Abschätzung der Rate an „freedom from biochemical relapse” (Freiheit von biochemischen Versagen, FFBR) wurde die Kaplan-Meier-Methode angewendet. Mittels Cox-Regression wurden anhand des letzten am besten funktionierenden Models prognostische Faktoren für biochemisches Versagen identifiziert sowie ein Nomogramm etabliert. Durch Schätzung der Konkordanzwahrscheinlichkeit und mithilfe von Kalibrationsmethoden wurde das Nomogramm validiert.

Ergebnisse

Es erhielten 475 Patienten (70 %) neoadjuvant und begleitend eine Androgendeprivation. Der mediane Follow-up betrug 80 Monate (20–129). Insgesamt betrug die 6-Jahres-FFBR-Rate 88,3 %. BED-Werte waren mit höherem Risiko eines biochemischen Versagens assoziiert. Alter, initialer Wert des prostataspezifischen Antigens (PSA), Risikokategorie und Zeitraum der Strahlentherapie erwiesen sich als unabhängige Variable in Bezug auf biochemisches Versagen.

Schlussfolgerungen

Eine Verlängerung der Strahlentherapie (niedrige BED-Werte) ist mit einem steigenden Risiko eines biochemischen Versagen assoziiert. Das Nomogramm kann als Entscheidungshilfe in Bezug auf einzelne Patienten hilfreich sein.

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Acknowledgments

The authors thank Dr. Loreta Sanpaolo for helping us with this manuscript and the editor and reviewers for their helpful comments.

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Conflict of interest

P. Sanpaolo, V. Barbieri, and D. Genovesi state that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Radiation Oncology Department, CROB, Via Padre Pio 1, 85028, Rionero in Vulture, PZ, Italy

    P. Sanpaolo & V. Barbieri

  2. Radiation Oncology Department, “G. D’Annunzio” University, Chieti, Italy

    D. Genovesi

Authors
  1. P. Sanpaolo
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  2. V. Barbieri
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  3. D. Genovesi
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Corresponding author

Correspondence to P. Sanpaolo.

Appendix

Appendix

Three possible examples of therapy interruption are described for a theoretical patient undergoing radiotherapy of 76 Gy in 38 fractions, 5 fractions per week, OTT of 52 days.

Example 1

His treatment starts on 18 November 2013 and should end on 8 January 2014, but because of interruptions on 25–26 December 2013, 1 and 6 January 2014 and included weekends, his treatment ends on 14 January, adding 6 days to his treatment (OTT 58 days).

On the basis of Eq. (2), BED = n•d•[1 + d/(α/β)]−[(0.693/α)•(T/Tpot)], the ideal BED is 153.5 Gy. The first break is after 27 fractions and 37 days (24 December 2013) with BED = 109 Gy (defined as BED pre-gap).

Eleven fractions in 21 days are still to be delivered with a BED of 41.7 Gy (defined as BED post-gap). The new BED value is therefore 109 + 41.7 = 150.7 Gy, with a difference of 2.8 Gy and 1.8 % of loss of dose. The BED value of 153.5 Gy has to be maintained so we introduce this equation:

BED pre-gap + BED post-gap = 153.5 Gy

BED = 27 • 2 • [1 + 2 / ( 1.5 ) ]− [(0.693/0.036)•(37/42)] + 11•d•[1 + d/(1.5)]−[(0.693/0.036)•(21/42)] = 153.5 Gy

where d is the new dose per fraction to be administered during the remaining 11 fractions in order to reach the ideal prescribed BED value.

The solution for d is d = 2.07 Gy. The new dose per fraction is not higher than the dose prescribed and the BED value could be easily compensated.

Example 2

The patient starts treatment on a Monday and breaks are required in weeks 5 and 6. The prescribed BED value is 153.5 Gy; OTT is 66 days.

The first break is after 20 fractions and 28 days with BED = 80.5 Gy (define as BED pre-gap). Thus, 18 fractions in 24 + 14 days are still to be delivered with a BED of 66.5 Gy (define as BED post-gap). The new BED value is therefore 80.5 + 66.5 = 147 Gy, with a difference of 6.5 Gy and 4.2 % of loss of dose.

Using the same equations of example 1, the new d value is d = 2.1 Gy. In this situation, the new dose per fraction is not higher than the dose prescribed and the BED value could be easily compensated.

Example 3

The patient starts on a Monday and is not able to complete the last eight fractions (1 week plus 3 days) that are administered after a 30-day interval. The prescribed BED value is 153.5 Gy; the OTT is 82 days.

The first break is after 30 fractions and 42 days with BED = 120.7 Gy (defined as BED pre-gap). Eight fractions in 10 + 30 days are still to be delivered with a BED of 19 Gy (defined as BED post-gap). The new BED value is therefore 120.7 + 19 = 139.7 Gy, with a difference of 13.8 Gy and 8.9 % of loss of dose.

Using the same equations of example 1, the new d value is d = 2.44 Gy. In this situation, the new dose per fraction becomes higher than the dose prescribed and the compensation of BED value should take into account surrounding normal tissue to PTV.

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Sanpaolo, P., Barbieri, V. & Genovesi, D. Biologically effective dose and definitive radiation treatment for localized prostate cancer. Strahlenther Onkol 190, 732–738 (2014). https://doi.org/10.1007/s00066-014-0642-0

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