Related to: [¹⁸F]Fluorodeoxyglucose-positron emission tomography/computed tomography response evaluation can predict histological response at surgery after induction chemotherapy for oligometastatic bladder cancer

With the worldwide use of chemotherapy in muscle-invasive bladder cancer (MIBC) patients, there is a need for non-invasive tools to evaluate response. Kollberg et al. assessed the value of [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in response evaluation after induction chemotherapy in the largest cohort of patients with lymph-node (LN) positive MIBC so far [1].

A total of 50 patients was analyzed. Forty-three of them had LN-positive MIBC and received induction chemotherapy followed by (at least) a pelvic LN dissection.

FDG-PET/CT was performed after three courses of chemotherapy and classified all but one patient as responders. Histopathology, however, found that six patients had not responded, only one of whom was identified by FDG-PET/CT. Hence, a high sensitivity of FDG-PET/CT for detecting LN response (100%) was reported, in contrast to a remarkably low specificity (17%) [1]. This indicates that FDG-PET/CT can predict (any) histological response of LN-positive MIBC to chemotherapy, but fails to identify non-responders.

What do we really want to know when restaging LN-positive MIBC patients after induction chemotherapy and what can we learn from this study? In essence, we want to answer the question of whether subsequent surgery (or any other consolidating therapy) after chemotherapy is worthwhile. This is not a trivial question, considering both the major impact of surgery on quality of life and the poor prognosis of patients with LN-positive MIBC in general (5 year survival after chemotherapy: 5–20%) [2].

In almost 25% of patients with LN-positive MIBC, a complete pathological response (pCR) to induction chemotherapy is found after surgery. It is this subgroup of complete responders that benefits most from consolidating surgery with significant survival benefit, achieving a 5 year cancer-specific survival of over 60% [3].

Can this group of patients be identified preoperatively? Maybe more importantly: can patients who do not respond or, even worse, progress under chemotherapy, be identified reliably? Their prognosis is dismal and it has been suggested that surgery has no therapeutic value for these patients [4]. Alternative second line therapies (experimental therapies, immunotherapy) or palliative treatment instead of surgery should be offered to patients with persisting LN metastases that are unresponsive to chemotherapy.

FDG-PET/CT cannot distinguish patients with pCR from patients with residual disease. In a pilot cohort, it was found that FDG-PET/CT only correctly distinguished pCR from patients with residual disease in 68% of cases [5]. This indicates that in cases of persistent nodal FDG activity, radical cystectomy (RC) specimens reveal a pCR, and vice versa. Can FDG-PET/CT identify progression under induction chemotherapy? Kollberg et al. report a low specificity of only 17%, indicating that FDG-PET/CT overestimates the response to chemotherapy. However, as Kollberg et al. followed the treatment paradigm in which only patients who progressed did not receive consolidation surgery, it cannot be concluded that FDG-PET/CT fails to detect the patients with progressive disease. In their study, three patients with progressive disease under chemotherapy were detected by FDG-PET/CT during response evaluation. According to the aforementioned treatment strategy, these patients did not undergo subsequent surgery and were, unfortunately, not included in the diagnostic accuracy calculation.

What are the lessons for daily practice? First of all, FDG-PET/CT cannot accurately enough prove pCR, and RC should not be cancelled based on FDG-PET/CT alone. Secondly, progressing patients under chemotherapy should not undergo RC; FDG-PET/CT may be able to detect some of them. Thirdly, with the low specificity of FDG-PET/CT, a number of non-responding patients will probably be operated on in vain. This is the price to be paid for the poor performance characteristics of FDG-PET/CT.

It is clear that improvements in response evaluation are necessary. Will other nucleotides be able to do that? Other questions that remain unanswered are: How does FDG-PET/CT perform compared with CT? What would be the ideal timing of imaging response in general? And are there better ways to predict the response to systemic therapies as early as possible (ultimately, before the start of treatment)?

As stated in the European guidelines, evidence is accruing in the literature suggesting that FDG-PET/CT may have potential clinical use for staging metastatic MIBC [6]. Its use, however, for response evaluation after chemotherapy for MIBC seems far from perfect. Single-institutional data, like the present article by Kollberg et al., will encourage researchers to further elucidate and improve this in international collaborations.

Disclosure statement

No potential conflict of interest was reported by the authors.