Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

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Approximately 12% of enrolled patients were excluded from efficacy analyses for various reasons, which may bias the results in favor of the treatment. The results of this trial can represent patients who were highly selected: those who might benefit substantially from treatment were more likely to be enrolled. Patients with positive paraaortic lymph nodes, who historically have a poorer prognosis, were excluded. 3,4 Although they are treated in the same manner at most institutions, why were the patients with adenocarcinoma of the cervix not included in this study? Previous studies have suggested that patients with cervical adenocarcinoma bear a worse prognosis and lower OS. 5 It is also possible that the high response rate observed in the study by NogueiraRodrigues et al 1 could be related to improvements in radiotherapy techniques, better patient selection, and a stage migration effect. We also would like to point out that the landmark studies used for comparison in Table 3 of the article were performed more than a decade ago. 1 With the use of platinum-based chemoradiation as a standard of care for patients with locally advanced disease, the search for non-platinum-based therapy is important. In modern oncology, we are experiencing a paradigm shift toward novel targeted agents. To our knowledge, no biological agent to date has been approved for use in patients with cervical cancer. However, a significant improvement in OS recently was observed among patients with advanced cervical cancer who were treated with antiangiogenic therapy. 6 Furthermore, the results of ongoing studies assessing the role of epidermal growth factor receptor inhibition in combination with chemoradiation would be helpful (ClinicalTrials.gov identifiers: NCT00104910 and NCT00957411). We do need treatments that improve survival, and build on the small steps that have been made in this area of unmet need. The quest for improved cure rates for patients with locally advanced cervical cancer is paramount and future research that 1) includes a true control group, 2) involves patients with both squamous and adenocarcinoma histology, 3) uses disease-free survival or OS as the primary endpoints, and (4) is adequately powered will further elucidate the value of this regimen in the management of patients with advanced cervical cancer.

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