Could p53 be a target for therapeutic suppression?

The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation-induced death of both differentiating and stem cells strongly depends on p53, suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53 does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development.     

Is there a role for chemosensitivity tests in head and neck cancer?

Despite many advances in predictive testing of human malignancies, we are far from using it routinely in clinical practice. Investigating the responsiveness of solid tumors to cytostatic drugs is particularly challenging. Nevertheless, for head and neck cancer, chemosensitivity testing is an increasingly attractive option, since chemotherapy has proven to have curative potential in the therapy of head and neck cancer, in particular in combination with radiation. The significant need for predictive methods to identify patients responsive to therapy, first of all in organ preservation programs, which is an alternative to first-line surgery, had recently renewed the discussion on a possible role of chemosensitivity testing in head and neck cancer. In this review, we discuss the current state of chemosensitivity testing in head and neck cancer. Recent methodological developments, in particular elimination of photochemical artifacts and inclusion of stromal cell response studies, may soon augment the value of ex vivo chemosensitivity testing for the management of head and neck cancer.     

Is home palliative care for head and neck cancer patients a possibility ?

It is likely that home palliative care for head and neck cancer patients could be treatable at general hospitals or clinics whereas combined joint efforts by medical cooperation from specialists, who are specialized in understanding of the singularity and how to cope with the symptoms, are existed.     

Is EGFR really a therapeutic target in head and neck cancers?

Epidermal growth factor receptor (EGFR) is overexpressed in 90% to 100% of squamous cell carcinoma of the head and neck (SCCHN). The overexpression of EGFR and its ligand transforming growth factor is associated with poorer survival. EGFR inhibitors such as Cetuximab (Erbitux) have shown a significant antitumoral effect in SCCHN and has improved locoregional control and as well as survival. Even though there was some success with Cetuximab, work with other EGFR inhibition has not been very fruitful and not really shown any promise. Mechanism of action of Cetuximab could be immune-mediated rather than EGFR inhibition and EGFR may not necessarily be a therapeutic target in SCCHN.     

Neoadjuvant chemotherapy in head and neck cancer: should it be revisited?

Locally advanced SCCHN (LA-SCCHN) is generally treated by a combination of chemotherapy, irradiation and/or surgery. Timing of the chemotherapy has for long been a matter of debate but concurrent chemoradiation was widely adopted as standard of care for locally advanced squamous cell carcinoma of the head and neck after the publication of a large meta-analysis which demonstrated that concurrent chemoradiation confers an absolute survival benefit of 8% at 2 and 5 years. Induction chemotherapy has some appealing advantages including the opportunity of assessing tumor response and selecting the patients who are candidates for organ preservation. The cisplatin-fluorouracil combination has been the induction regimen of choice for two decades but has recently been superseded by a combination of cisplatin, fluorouracil and a taxane which can be considered the standard regimen when induction chemotherapy is appropriate. Multiple large randomized trials designed to compare sequential induction, i.e., chemotherapy followed by CRT to CRT alone are currently underway. New challenges are the integration of targeted therapies into the current treatment strategies and the identification of prognostic biomarkers and of factors predicting the response to treatment which would help to select patients who are likely to benefit most from induction chemotherapy.     

C-reactive protein levels: a prognostic marker for patients with head and neck cancer?

Background

Recent advances in understanding complex tumor interactions have led to the discovery of an association between inflammation and cancer, in particular for colon and lung cancer, but only a very few have dealt with oral cancer. Therefore, the aim of the current study was to investigate the significance of preoperative C-reactive protein (CRP) levels as a parameter for development of lymph node metastases or recurrence.

Materials and methods

In 278 patients with oral cancer, preoperative CRP levels were compared with development of recurrence and metastasis.

Results

In 27 patients from the normal CRP group, and in 21 patients from the elevated CRP group, local recurrence was observed. Concerning lymph node metastases, 37 patients were in the normal group and 9 patients in the elevated CRP group. No significant correlation could be found between elevated CRP levels and metastasis (p = 0.468) or recurrence (p = 0.137).

Conclusion

Our findings do not appear to support a correlation between preoperative CRP levels and development of recurrence or metastases. In further studies, CRP levels in precancerous lesions and in Human Papilloma Virus (HPV) positive patients with oral squamous cell carcinoma (SCC) should be studied.

     

Induction chemotherapy for head and neck cancer: will history repeat itself?

Locally advanced squamous cell head and neck cancer remains a therapeutic challenge for multidisciplinary teams. Despite high objective response rates, induction chemotherapy has not resulted in tangible benefit in multiple randomized trials. In recent years, as most evidence solidified the role of concurrent chemotherapy and radiation as either primary or postoperative therapy for locally advanced head and neck cancer, induction chemotherapy fell out of scope and practice. The failure of older randomized trials to show a survival benefit from induction chemotherapy can be attributed to several factors. It is possible that the predominance of locoregional failure did not allow any added benefit from better systemic control to translate into a survival advantage. Alternatively, seemingly active chemotherapy regimens may have been suboptimal. Nevertheless, recent developments have altered our perception of head and neck cancer and its treatment. Locoregional control has dramatically improved with concurrent chemoradiotherapy. Of note is that none of the previously conducted randomized trials of induction chemotherapy used concurrent chemoradiotherapy in the control arm. Moreover, we witnessed the development of better combination regimens that improved efficacy in the induction setting. The previously standard cisplatin/5-fluoruracil (5-FU) combination is being replaced by the triple combination of taxane/ cisplatin/5-FU. Randomized trials showed that increased activity with the triplet regimen resulted in improved long-term disease control and survival. Finally, cetuximab, an active epidermal growth factor receptor inhibitor, is entering clinical practice and is expected to change the standard of therapy. With the emergence of more efficacious systemic therapies, the role of induction therapy warrants reevaluation. A number of randomized trials are planned or currently ongoing to investigate concurrent chemoradiotherapy with or without induction. These trials are anticipated to redefine the role of induction chemotherapy for head and neck cancer.     

Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention?

The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.     

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G(2) assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G(2) scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (相似文献   

Chemoradiotherapy for advanced head and neck cancer — Analysis of a prospective, randomized trial

Objective: To study the efficacy of neo-adjuvant chemotherapy followed by radiotherapy in advanced head and neck cancer.Study design: Randomised, prospective study.Setting: Tertiary academic referral center.Patients: One hundred and eighty patients of advanced head and neck squamous cell carcinoma.Intervention: Patients were randomized into two arms. The study arm (CT-RT arm) received 3 cycles of anterior chemotherapy with Inj. Cisplatin 100 mg/m² on D₁ and Inj 5F.U. 700 mg/m² on D₁-D₄ at an interval of 21 days, followed by external radiation. The control arm (RT arm) received external radiotherapy only. The dose of Radiotherapy was 64 to 68 Gy in conventional fractionation.Results: Patients of CT-RT showed better tumour control locally than patients who received only RT. Toxicities were commoner in CT-RT arm but they were manageable. 5 year survival is higher in the CT-RT arm (21% vs 16%; p value> 0.05).Conclusion: Anterior chemotherapy with Cisplatin and 5F.U. is associated with good clinical response which is translated into increased survival along with acceptable toxicities.