Prognostic Evaluation of Tumor Volume and Its Changes in Radical Radiotherapy of Advanced NSCLC
Condition: Non Small Cell Lung Cancer Stage III
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Observational

Summary: 
      The aim of the study is to retrospectively monitor the 'gross tumor volume' (GTV) before
      initiation of radiotherapy and its changes during radiotherapy and to correlate them with
      retrospectively recorded patient data, as well as with prognostic and therapeutic outcome
      after definite radiotherapy of locally advanced NSCLC in stage UICC III.
    

Detailed description: 
      The prognostic relevance of the 'gross tumor volume' (GTV) in radiotherapy of advanced
      non-small-cell lung cancer (NSCLC) in stage III is adressed in a limited number of studies in
      the literature. The review article by Dubben et al., that comprises data until 1998,
      highlights the GTV as an important indicator and influencing factor for the therapeutic
      success after radiotherapy, albeit not being dominant over the T-stage (Dubben et al. 1988).
      In general, an increase in tumor volume correlates with a higher T-stage (Martel et al.
      1997), but no congruence can neccessarily be assumed between the tumor volume and the
      T-determinator. Since the TNM-classification is primarily surgical however, it also does not
      provide sufficient information for prognosis when surgical therapy is not the first choice.

      Available evidence suggests that the GTV in particular at the beginning of therapy acts as a
      statistically significant prognostic indicator regarding overall survival and / or local
      tumor control (Martel et al. 1997; Bradley et al. 2002; Basaki et al. 2006; Etiz et al. 2002;
      Werner-Wasik et al. 2001; Wer-ner-Wasik et al. 2008; Stinchcombe et al. 2006; Dehing-Oberije
      et al. 2008; Willner et al. 2002; Ball et al. 2013). A direct comparison between different
      studies is, however, often hampered due to the large variation of measurement time points
      during therapy, as well as the employed definition of the tumor volume. For example, all
      studies include patients whose GTV was determined after (neoadjuvant) chemotherapy. In
      addition, three studies even combine the tumor volume of the primary tumor with affected
      lymph nodes (Etiz et al. 2002; Werner-Wasik et al. 2008; Dehing-Oberije et al. 2008).
      Furthermore, no agreements can be found in the literature concerning volume changes during
      therapy. Nonetheless, all studies report a volume reduction at the end of therapy, albeit not
      always significant. In a study containing 10 patients treated with helical Tomotherapy, the
      authors observed a relative median tumor reduction during therapy of 1.2% per day (0.6-2.3%)
      (Kupelian et al. 2005).

      The response of NSCLC to radiotherapy with or without chemotherapy is slow (Woodford et al.
      2007) with tumors reaching their maximum response or minimal volume after 5-11 months after
      exposure (Werner-Wasik et al. 2001). If the tumor volume is determined too early, i.e.
      directly after the end of therapy, the results can lead to misinterpretation resulting in an
      overestimation of the tumor volume or correspondingly an underestimation of the therapeutic
      response (Siker et al. 2006). According to Bell et al., the predictive value of tumor volume
      changes in the first 18 months after radiotherapy is of particular importance. During this
      time, a significantly increased mortality was observed for larger tumor volumes.

      Incorporation of a PET/CT in the context of the radiaton plan is advantageous with respect to
      the precise traget-volume definition and sparing of risk organs (Ruysscher et al. 2005;
      Nestle et al. 2006; Lavrenkov et al. 2005; van Baardwijk et al. 2007; Edet-Sanson et al.
      2012; Ruysscher und Kirsch 2010; As-hamalla et al. 2005; Bradley et al. 2004; van Baardwijk
      et al. 2006; Vanuytsel et al. 2000). The superiority of PET compared to stand-alone CT was
      also shown in two meta-analysis (Gould et al. 2001; Gould et al. 2003). The importance of the
      'standardized uptake value' (SUV) or the metabolic tumor volume (MTV) as well as the change
      in these parameters during radiotherapy has been repeatedly demonstrated (Berghmans et al.
      2008, Gillham et al. 2008; Zhang et al. 2011; van Elmpt et al. 2012; Edet-Sanson et al. 2012;
      van Baardwijk et al. 2007; Vera et al. 2014; Vanuytsel et al. 2000; Feifei Na et al. 2014;
      Lopez Guerra et al. 2012; Lee et al. 2007; Lee et al. 2012; Huang et al. 2011; Xiang et al.
      2012). These studies show partly a statistically significant correlation between tumorale
      FDG-accumulation before, during or after radiotherapy, or the decreasing accumulation during
      radiotherapy, respectively, and the overall survival. The results, however, suffer from a
      large uncertainty regarding the distinct influence corresponding to the SUV. Other studies
      report a significantly weaker association of the SUV and survival (Hoang et al. 2008;
      IKUSHIMA et al. 2010; Lopez Guerra et al. 2012). Due to the dynamic variations in the SUV and
      MTV during radiotherapy, a change in the prognostic validity during radiotherapy can be
      assumed. According to van Elmpt and others, the FDG uptake during the second (van Elmpt et
      al. 2012; Zhang et al. 2011) or fifth week of exposure is crucial for survival (Edet-Sanson
      et al. 2012). Work by van Baardwijk et al. shows an increase in the SUV in some patients
      during the first week of therapy, which is explained by radiation-triggered inflammation and
      tumor-biological changes due to radiotherapy (van Baardwijk et al. 2007). The results
      demonstrate that the appearance of tumor necrosis during radiotherapy or changes in the
      metabolic tumor situation or oxygenation affect the SUV parameter crucially (Hoang et al.
      2008, Huang et al. 2014; Huang et al. 2011). In this context, tumorhypoxia and the
      corresponding effects on the metabolism of glucose are of particularly importance: A
      hypoxia-simulated upregulation of the membranic glucose transporter with consecutive increase
      of cellular FDG uptage can lead to a false SUV value, calling for a combination of SUV or MTV
      with other prognostic parameters as well as hypoxia-specific imaging (FMISO-PET) (Ikushima et
      al. 2010, Berghmans et al. 2008). Consequently, the optimal timevpoint for carrying out a PET
      during / after radiotherapy is not well defined, especially when the protracted tumor
      response after completion of radiotherapy is taken into account, leaving the integration of
      additional PET measurements during radiotherapy exclusively to clinical studies.

      In conclusion, evidence from available literature regarding the prognostic and predictive
      value of tumor volume before and particularly its changes during radiotherapy of locally
      advanced NSCLC is conflicting and inconclusive. Currently available studies often include
      only a small number of patients with partly overlapping patient cohorts. Current data is
      additionally limited due to the highly heterogeneous GTV detection time points as well as the
      definition and detection methodology of tumor volumes.

      Based on the observation that a significant tumor volume reduction occurs during
      radiotherapy, a reevaluation of the tumor volume during radiotherapy could allow an
      adaptation of the target volumes with dose escalating in the tumor area, while at the same
      time, improving the protection of organs at risk.

      The prognostic or predictive significance of absolute tumor volumes or their change under
      radiotherapy is to be evaluated multicentrically and its integration into already existing
      prognostic models is to be multicentrically validated.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Locally advanced, inoperable stage III (A and B) non-small-cell lung cancer without prior
        surgery
      
Keywords: NSCLC; Radiotherapy; young DEGRO; tumor volume; lung cancer; radiochemotherapy; prognostic factors