Monthly Archives: September 2005

Ethyol Allows Greater Tolerability of Chemotherapy in Head and Neck Cancer

  • 9/29/2005
  • Boston, MA
  • staff
  • CancerConsultants (professional.cancerconsultants.com)

Researchers from Massachusetts General Hospital have reported that the dose of Taxol® (paclitaxel) given with hyperfractionated radiotherapy can be dose escalated in patients receiving Ethyol (amifostine). The details of this dose escalation trial were reported in the October 1, 2005, issue of Cancer .

Combined radiation therapy and chemotherapy are standard treatments for patients with advanced head and neck cancers, but most patients have recurrent disease after treatment. Ethyol is a radiation protector and the only drug of this class that has been approved by the FDA for this use in patients receiving radiation therapy for cancers of the head and neck.

Clinical trials have demonstrated that Ethyol can reduce both acute and late radiation-induced side effects. In the pivotal trial involving patients with head and neck cancer, Ethyol reduced the incidence of xerostomia but had no effect on the incidence or severity of oral mucositis. Ethyol has also been shown to reduce the incidence of grade 2-3 bladder and GI toxicities in patients receiving pelvic radiation therapy and more recently has been associated with decreased toxicities in patients receiving high-dose melphalan.

The current study was a multi-institution phase I clinical trial that included 36 patients with advanced head and neck cancer. Patients were treated with radiation therapy plus weekly Taxol. The number of doses of Taxol was escalated from a minimum of three to a maximum of six. Twenty-eight of these patients received Ethyol; eight received no Ethyol. Patients not receiving Ethyol tolerated four doses of Taxol while the average number of doses for the Ethyol group was five.

At approximately 30 months, both progression-free and overall survival was 66% in the whole group of patients. There were no differences in response rates between patients receiving and not receiving Ethyol.

These researchers concluded that Ethyol allows patients with advanced head and neck cancer who are also undergoing radiation therapy to tolerate an extra cycle of Taxol chemotherapy. Longer follow-up is necessary to determine if this will result in improved survival for these patients, and future randomized clinical trials are necessary to provide confirmed results.

Comments: Ethyol may increase the amount of Taxol that can be give concomitantly with radiotherapy, but the authors pointed out this is still not enough to significantly reduce distant relapses and more chemotherapy will have to be given before or after radiotherapy.

Reference:
Amrein P, Clark J, Supko J, et al. Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma. Cancer . 2005;104:1418-1427.

September, 2005|Archive|

Who’s Taking Care of the Caregiver?

  • 9/29/2005
  • Bethesda, MD
  • Ann O’Mara
  • Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6820-6821

Throughout the last decade, caring for a loved one with a cancer diagnosis has developed both in the sheer numbers of people providing the service and in the complexity of tasks required by cancer patients. Between 1997 and 2005, the number of Americans diagnosed with cancer has grown from 900,000 to 1.3 million, and the number of survivors has grown from 7.4 million to 9 million.1 With cancer care now routinely being delivered on an outpatient basis, informal caregivers’ responsibilities have gone far beyond the tasks of transportation, shopping, household chores, and personal care. Administering oral and parenteral medications, performing wound care, and monitoring signs and symptoms are a few of the more demanding, yet routine tasks.

The selection of an informal caregiver, like the diagnosis of cancer itself, is a random event, and there are no training programs to prepare individuals to be one. Thus, it comes as no surprise when we read of a new study, once again, highlighting the physical, emotional, and economic burdens that caregiving has placed on families and friends. What have these studies taught us throughout the years?

Just as we have learned that cancer is not one disease, but a constellation of many, informal caregiving is not a simple occurrence, as the caring reflects the variability associated with the type and stage of disease, age of the patient, and the treatment modalities. However, these variables that constitute the process of caregiving are only a part of the picture. What about the caregiver? What attributes does she (more than 80% are women) bring to this experience? What impact has the cancer diagnosis had on her and her family? What is the financial situation? These and many more questions have been explored for several decades, and a complex picture of the many variables affecting the caregiver and caregiving process is emerging. One example of this is found in a longitudinal study of 148 newly diagnosed colorectal cancer patients and their partners. Nijboer et al2 proposed a model that incorporated the interplay of patient and caregiver characteristics, as well as environmental resources to predict changes in a caregiver’s depression. They found that caregivers who scored low on their perceptions of their mastery of caregiver tasks, low on their level of daily emotional support, and perceived caregiving in a more negative way were identified as more depressed over time.

In this issue of the Journal of Clinical Oncology, Vanderwerker et al3 report the results of their interviews with 200 informal caregivers of patients with advanced-stage cancer to determine the prevalence of psychiatric disorders, as well as to gain a better understanding about referrals to and receipt of mental health interventions. The investigators’ approach to data collection, using a structured interview and asking caregivers about their use of mental health services before and after the diagnosis of cancer provides us with some interesting perspectives on the emotional health and needs of this growing population. In place of the more common approach to using validated symptom inventories such as the Profile of Moods Scale4 or the Center for Epidemiological Studies Depression Scale5 to ascertain the prevalence of depression, anxiety, and other psychiatric disorders, the investigators used the Structured Clinical Interview for the DSM-IV (SCID) Axis I Modules6 to diagnose current psychiatric disorders among their sample. This approach yielded findings that differed from other studies examining levels of emotional distress among caregivers7,8 in that investigators in the current study found lower rates of depression, but also new problems, most notably panic disorder. Data on caregivers’ use of mental health services before and after the diagnosis of cancer revealed that fewer than half of the caregivers with a current DSM-IV disorder had discussed their mental health with a clinician since the patient’s cancer diagnosis. Unlike Nijboer’s work, these investigators set out to more precisely determine the prevalence of depression, not examine the multiple stressors that may be contributing to its existence. They are not to be faulted for their narrow examination of the problem, but commended for pointing out how many vulnerable individuals slipped through the cracks. Numerous studies have repeatedly shown that caregivers are at risk for poor outcomes if their physical and emotional needs are left unattended.9-11

These data raise important and interesting clinical questions, both from a practice, as well as a research perspective. Where does the responsibility sit for asking cancer caregivers about their emotional well being? Does caring for our oncology patients also include asking simple, but pointed questions about their caregivers’ coping and emotional health? How should the data from this study guide the next set of research questions?

In their review of the body of literature on caregivers, Thomas and Morris12 conclude that the caregiver is no longer a bystander in cancer care, but is an actual or potential “co-user” or “co-client” of services. If we are to accept this, what then are our explicit responsibilities? Rabow et al13 identify five areas of opportunity for physicians to be of service to family members caring for patients at the end of life. The authors point out that although a physician’s legal obligation is to the patient, the physician’s role should extend beyond what is required by law to provide the best possible care for the patient. The five areas include recognizing the burdens of family caregiving, communicating well, assisting with decision making, supporting home care, helping with caregiver emotions, and acknowledging bereavement. Simple screening questions such as, “how is the caregiving going for you?” or “how is the family doing” may help prevent some caregivers from slipping through the cracks. Responses to these questions can serve as the starting point for referrals to appropriate resources.

Despite our increasing understanding of the world of cancer caregivers, much remains to be explored and answered. For example, a diagnosis of advanced cancer no longer means imminent death, and this holds true in the current study. Despite their diagnosis of advanced cancer, the patients’ mean Zubrod score in the study of Vanderwerker et al1 was 1.3. What is the impact on the caregiver with this longer life span? How much more responsibility will the caregiver have to assume in reporting clinical data to health care providers, and how will these added responsibilities impact their day-to-day coping? Can health care providers improve caregiver outcomes by asking the few simple questions posed by Rabow et al,12 and refer appropriately? Studies are sorely needed to identify and test interventions that will prevent or alleviate the stress and distress of caregiving. A recent search of the National Institutes of Health’s Computer Retrieval of Information on Scientific Projects revealed more than 30 funded studies in informal cancer caregiving, ranging from testing interventions, to improving caregiver sleep patterns, to exploring informal caregiving in vulnerable and underserved populations.14

Informal caregiving is a fact of life in health care, and it will only become a larger factor in the world of decreasing resources. Meeting the needs of our informal caregivers is not just a medical problem, but a societal one requiring the expertise, creativity, and energies of many disciplines.

REFERENCES

1. American Cancer Society, Facts and Figures, 1997 and 2005. http://www.cancer.org/docroot/STT/stt_0.asp

2.Nijboer C, Tempelaar R, Triemstra M, et al: The role of social and psychologic resources in caregiving of cancer patients. Cancer 91:1029-1039, 2001

3. Vanderwerker LC, Laff RE, Kadan-Lottick NS, et al: Psychiatric disorders and mental health service use among caregivers of advanced cancer patients. J Clin Oncol 23:6899-6907, 2005

4. McNair DM, Lorr M, Droppleman LF: Manual for the profile of Mood States. Toronto, Ontario, Canada, Multi-Health Systems Inc, 1992

5. Radloff LS: The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Meas 1:385-401, 1977

6. Williams JBW, Gibbon M, First MB, et al: The structured clinical interview for DSM-III-R (SCID): II Multi-test-retest reliability. Arch Gen Psychiatry 49:630-636, 1992

7. Kozachik SL, Given CW, Given BA, et al: Improving depressive symptoms among caregivers of patients with cancer: Results of a randomized clinical trial. Oncol Nurs Forum 28:1149-1157, 2001

8. Nijboer C, Triemstra M, Tempelaar R, et al: Determinants of caregiving experiences and mental health of partners of cancer patients. Cancer 86:577-588, 1999

9. Navaie-Waliser M, Feldman PH, Gould DA, et al: When the caregiver needs care: The plight of vulnerable caregivers. Am J Public Health 92:409-413, 2002

10. Stein MD, Crystal S, Cunningham WE, et al: Delays in seeking HICV care due to competing caregiver responsibilities. Am J Public Health 92:1305-1311, 2002

11. Cameron JI, Franche RL, Cheung AM, et al: Lifestyle interference and emotional distress in family caregivers of advanced cancer patients. Cancer 94:521-527, 2002

12. Thomas C, Morris SM: Informal careers in cancer contexts. Eur J Cancer Care (Engl) 11:178-182, 2002

13. Rabow MW, Hauser JM, Adams J: Supporting family caregivers at the end of life: “They don’t know what they don’t know.” JAMA 291:483-491, 2004

14. Computer Retrieval of Information on Scientific Projects. Accessed June 1, 2005. http://crisp.cit.nih.gov/crisp/crisp_lib.query

September, 2005|Archive|

Cancer chemoprevention: lessons learned and future directions

  • 9/28/2005
  • Leicester, England
  • D E Brenner and A J Gescher
  • British Journal of Cancer (2005) 93, 735-739

The concept of delaying or preventing epithelial transformation remains a viable and attainable goal for the future. Drug-based strategies for chemoprevention of the future may predominantly rely upon targeted therapies with tolerable but defined toxicities for treatment of individuals diagnosed with intraepithelial neoplasias. Foods, diet manipulation strategies, or nutraceuticals may be more appropriate to delay or prevent carcinogenesis progression in healthy populations with genetic or epidemiologic evidence of risk for future transformation.

Three recent publications have demonstrated an unacceptable therapeutic index due to cardiovascular toxicity of selective cyclooxygenase-2 inhibitors when used for cancer preventive or anti-inflammatory indications (Bresalier et al, 2005; Nussmeier et al, 2005; Solomon et al, 2005). These data have focused the debate on whether pharmacologic interventions aimed at delaying or preventing the transformation of organ epithelia should proceed. Further, bad news for proponents of the cancer chemoprevention approach emerged recently from a trial of -tocopherol supplements in patients with stage I or II head and neck cancer treated by radiation therapy (Bairati et al, 2005). In these patients, the incidence of second primary cancers was higher (hazard ratio: 2.88) than that in patients who received the placebo. The corollaries of these clinical results have been amply debated (for example, see Alberts et al, 2005; Drazen, 2005; Meyskens and Szabo, 2005). In this minireview, we wish to distill some crucial issues from that debate, and re-evaluate current and prospective chemoprevention strategies considered promising in the light of these issues.

The recent cancer chemoprevention trial experiences have directed the focus on the following four pivotal issues:

(1) Acceptable therapeutic index for interventions in healthy populations: Individuals who are treated for a full-blown malignancy accept toxic therapies as a price for improved quality of life, survival, or both. In contrast, the acceptable therapeutic index for interventions intended for healthy individuals at risk of cancer in the future has ‘¼ been both underestimated and overestimated from failure to critically assess the parameter in relation to the modulation of the relevant biologic/biochemical/molecular end-points’ (Meyskens and Szabo, 2005).

In the case of cardiovascular disease prevention, the individuals and physicians accept treatment-induced toxicity if the recipient is convinced that a ‘disease’ such as hypertension or hvpercholesterolemia is being treated. In the case of neoplastic risk, healthy individuals at high risk for future development of a malignancy, for example, individuals with highly penetrant, low-frequency mutations (e.g. BRCA, familial adenomatous polyposis), are usually willing to tolerate surgical procedures such as colectomy, mastectomy, and oophorectomy to reduce cancer risk. Irritating, yet minor, adverse effects (e.g. hypokalemia associated with diuretics, headaches) are less acceptable for intervention in healthy populations, who are not ‘diagnosed’ with clear and imminent ‘disease’, but rather are approached to undergo an intervention on the basis of a conceptually abstract ‘epidemiologic risk profile’. Major toxicities such as the recently reported enhanced risk of cardiovascular events associated with the administration of cyclooxygenase-2 inhibitors are unacceptable for any intervention with chemopreventive intent. While these examples represent opposite ends of a continuum of risk-benefit for chemopreventive intervention, risk-benefit for the bulk of individuals at risk for sporadic neoplasms is less clear and poorly defined.

(2) Existence of preliminary data to rationalise trials in humans: Epidemiologic data, that is, hypotheses-generating associations, have not accurately predicted prospective cancer preventive outcomes to date with sufficient certainty to justify large-scale, high-cost trials with a cancer end-point (Meyskens and Szabo, 2005). Rodent models of carcinogenesis, either transgenic or chemically induced, provide tools to probe carcinogenesis mechanisms and to obtain preliminary evidence of potential preventive efficacy (Hawk et al, 2005). Nevertheless, the knowledge accrued thus far in such models suggests that their usefulness to predict therapeutic indices of cancer chemopreventive agents is rather doubtful (Corpet and Pierre, 2003).

(3) Trial design and progression of research in humans: The mixed record of success of the development of novel chemical entities by the pharmaceutical industry as cancer chemopreventive drugs points to the importance of design, implementation, and interpretation of phase I and II research in humans. An optimal cancer preventive dose cannot be extrapolated from doses used for different therapeutic indications. For example, in the chemoprevention of colorectal adenocarcinomas, higher doses of aspirin may be less effective than lower ones, which also protect against cardiovascular disease (Baron et al, 2003). Recent discussions have emphasised the importance of studying fundamental dose-response relationships in the field of cancer chemoprevention followed by extended biomarker-driven phase II efficacy trials in humans prior to embarking upon large, long, costly phase III risk reduction trials with cancer end-points (Alberts et al, 2005; Meyskens and Szabo, 2005).

(4) Importance of biomarkers as potential surrogates for preventive efficacy: Meyskens and Szabo (2005) cogently described the conceptual, syntactic, and scientific confusion currently surrounding biomarkers as potential chemoprevention end-points. Nevertheless, future definition of therapeutic efficacy of interventions designed to delay or prevent neoplastic progression requires discovery and validation of genetic or biochemical processes that reliably reflect the future potential of target epithelia to progress towards transformation. Current efforts by the US National Cancer Institute (NCI) to support and systematise biomarker discovery, validation, and application through the Early Detection Research Network (EDRN) (Verma and Srivastava, 2003) and Specialized Organ Research Effort (SPORE) mechanisms provide the necessary complex infrastructure. While splitting the development and validation of biomarkers from measurement of efficacy of preventive intervention reduces the rate of progress during the short term, such efforts will enhance the quality and speed of translational progress of new intervention products for preventive indications in the long run.

One might conclude that efforts to develop new chemopreventive interventions should be de-emphasised, and that resources should be redirected to more fundamental research. The experience gained in cancer chemoprevention trials to date provides important lessons that suggest a more rational, scientifically driven mode of development than that which has been often pursued until now. This process should enable a systematic, stepwise, phased exploration in preclinical models and in humans of newly emerging interventions. In the light of these considerations, we discuss below a chemopreventive agent selection strategy of novel drugs and a number of specific agents with putative cancer chemopreventive potential, of which some are currently under active clinical investigation and others originate from novel sources still at the stage of preclinical development.

Preventive Agent Selection for Development in Humans

The recent experiences gained in the development of drugs as cancer chemopreventive agents lead to the conclusion that the therapeutic index of proposed interventions should be titrated to relative risk of transformation. Individuals at high risk of developing malignancies with proven pathological evidence of potential transformation (‘intraepithelial neoplasia’), for example individuals with adenomatous polyps, atypical ductal hyperplasia, or oral leukoplakia, might be considered suitable candidates for ‘treatment of their disease’ using interventions consisting of single or combined drug-based approaches. Optimally, such drugs should target specific molecular carcinogenesis profiles obtained via genetic or proteomic profiling of that individual’s pathologic lesion. Drugs that target intracellular regulation of proliferation, survival, and angiogenesis may be suitable to be used in such individuals with preneoplasias as compared to those who suffer from advanced full-blown malignancies (i.e. transformed, invasive cancers). Such an approach might start with small, rapidly implemented and brief (60 days or less) translational clinical trials of biomarker modulation by multiple doses of a given intervention, alone or in combination with other mechanism-based agents. Subsequent biomarker-driven trials of drug combinations require duration of a year or more to assess both toxicity and continued biomarker effects prior to consideration of large, population-based cancer end-point trials. Toxicity profiles should include quality of life instruments to reflect the potential adverse nature of such interventions (Stanton et al, 2005).

Strategies for the prevention of malignancies in patients at higher than normal risk of developing cancer but without evidence of pathologic progression can exploit concepts established in the treatment of cardiovascular risk factors. Hypertension and hypercholesterolaemia are considered ‘diseases’ that are treated by physicians despite the fact that these end-points are biomarkers for future cardiovascular events. Critical to the future implementation of cancer preventive interventions using drugs are the ability to alter public opinion and to prompt primary medical care providers to adjust their perception concerning high-risk cancer biomarkers – in analogy to treatment of cardiovascular biomarkers – and willingness to accept mild toxicity. For such individuals, a nutrition-based approach might be more acceptable and potentially efficacious.

Promising Drug-based Chemoprevention Approaches

Nonsteroidal anti-inflammatory agents (NSAIDs)

In the wake of the recent observations of unacceptable cardiovascular effects of selective cyclooxygenase-2 inhibitors, and mindful of the long-known gastro-intestinal irritation/damage associated with long-term consumption of NSAIDs, is this class of agent still viable as potential cancer chemopreventive intervention? We maintain that it is. Firstly, the epidemiological evidence that regular use of NSAIDs, such as aspirin, reduces cancer risk in a number of organs, especially the colorectum, is overwhelming, and it clearly supports the notion that cyclooxygenase inhibition has antineoplastic consequences (Thun et al, 2002). Secondly, prospective, randomised clinical trials using an intraepithelial neoplasia end-point suggest that two different NSAIDS, aspirin and sulindac, reduce recurrence of adenomatous polyps (Giardiello et al, 1993; Baron et al, 2003).

It is important to note that cyclooxygenase-independent mechanisms of action of NSAIDs may, at least in part, explain their anticancer activity (Thun et al, 2002). For example, the selective cyclooxygenase-2 inhibitor celecoxib has been demonstrated to inhibit AKT signalling and to induce apoptosis of human colorectal and prostate cancer cells in vitro in a cyclooxygenase-2-independent manner, by a mechanism involving direct inhibition of phosphoinositide-dependent kinase-1 (PDK-1) (Arico et al, 2002; Song et al, 2002). Whether this activity is relevant to the antineoplastic activity of celecoxib in vivo is unclear at present.

Currently, a number of clinical trials of the chemopreventive efficacy of the selective cyclooxygenase-2 inhibitors remain in analysis for colorectal adneocarcinoma, transitional cell carcinoma of the bladder, breast adenocarcinoma, cervical intra-epithelial neoplasia, lung cancer, skin cancer, and oral leukoplakia. While many of these trials have been disrupted following recognition of the cardiovascular toxicity of selective cyclooxygenase-2 inhibitors (Bresalier et al, 2005; Solomon et al, 2005), nevertheless, useful data will emerge from these studies, which will ultimately define the chemopreventive efficacy of these agents (Alberts et al, 2005). A more rigorous dose-response evaluation to ascertain the optimal dose and schedule required to delay or prevent cellular transformation may enable the use of lower doses that might not cause cardiovascular toxicity.

Molecular targeted approaches other than cyclooxygenases

ErbB tyrosine kinases, the most prominent among them being epidermal growth factor receptor (EGFR), when phosphorylated activates signal transduction pathways that enhance cell survival, motility, and proliferation. Inhibitors of EGFR activation via antibodies to the extracellular protein or via tyrosine kinase inhibitory molecules provide promising new approaches to both cancer treatment and prevention. Despite mixed results in cancer treatment, many dysplastic cells also have activated EGFR and are reasonable targets for these agents. Preclinical data in vitro and in vivo support the potential preventive efficacy of these agents, potentially in combination with NSAIDs for chemoprevention of colorectal and head and neck cancers (Shin et al, 1994).

P53 targeting with ONYX-015, an adenovirus that replicates only in p53-deficient cells, produced histologic resolution of dysplasis in seven of 19 patients with oral leukoplakia (Rudin et al, 2003). Other p53-deficient dysplasias or high-risk epithelial fields might be protected with this agent.

Peroxisome proliferation activated receptor (PPAR) gamma agonists, such as rosiglitazone, are currently in early phase chemoprevention development. These agents are of particular interest for targeting hormone receptor negative breast epithelial proliferations or dysplasia (Mehta et al, 2000).

Hypermethylation contributes to carcinogenesis by silencing downstream transcription of key tumour suppressor genes. That aging and carcinogenesis are linked through progressive changes in methylation patterns of key tumour suppressor genes suggests potential future chemoprevention targets. Pharmacologic inhibition with well-tolerated interventions that inhibit or reduce activity of methyltransferase and histone deacetylase proteins may reduce abnormal hypermethylation of key tumour suppressor gene promoters, thus reducing or delaying neoplastic transformation. Hydralazine is one potentially useful DNA methylation inhibitor (Deng et al, 2003). A number of synthesised hydroxamic acid inhibitor of histone deacetylase inhibitors are currently in clinical trials for cancer treatment (Marks et al, 2000).

Combined agents

The complexity and heterogeneity of known carcinogenesis mechanisms provides a strong rationale for combining drug interventions that might provide additive or synergistic anti-carcinogenesis effect. In addition to targeted anticarcinogenic mechanism-based approaches, population epidemiology and rodent models help in the choice of suitable agents for combinations. The most quoted example under investigation, the combination of inhibitors of EGFR signalling and cyclooxygenase (Torrance et al, 2000), which is currently under investigation in humans, may be modified due to the recent therapeutic index concerns for targeted cyclooxygenase inhibitors. Data in vitro and in vivo support the viability of combining HMG CoA reductase inhibitors and NSAIDs to increase apoptosis via enhanced caspase 3 activity in preneoplastic cells (Agarwal et al, 1999). DFMO and sulindac are currently in phase IIb clinical trial as a potential colorectal adenocarcinoma preventive combination (Gerner and Meyskens, 2004).

Prevention of Sporadic Epithelial Neoplasia In Populations Without High-risk Lesions

A population-based approach to chemopreventive intervention considers the gene-environmental risk of otherwise healthy populations. For example, individuals with high-frequency, low-penetrance polymorphisms such as the adenomatous polyposis coli II307K polymorphisms have a higher risk of developing colorectal adenocarcinoma, but this risk does not appear to become clinically apparent until later in life (Niell et al, 2003). Interventions or behaviour expected to reduce transformation risk have amplified protective effects in this cohort when compared to lower risk populations (Poynter et al, 2005).

One may consider the I1307K polymorphism as a paradigm for other single nucleotide polymorphisms associated with enhanced transformational risk. Otherwise healthy individuals who are found to carry such polymorphisms would reject high-cost, mildly toxic pharmaceutical interventions but might be receptive to dietary interventions or nutriceutical interventions.

Nutriceuticals

Could there be ‘nontoxic alternatives’ to drugs with unacceptable therapeutic indicies such as NSAIDs or targeted therapeutic agents? Some recent results tentatively suggest that certain nutriceuticals may constitute such an alternative. Considerable evidence supports the hypothesis that flavonoids and other polyphenolic phytochemicals contained in certain foodstuffs, for example onions, red grapes, nuts and green tea, mediate, or contribute to, the putative cancer chemopreventive properties of their dietary sources. One potential approach is to deliver chemopreventive substances as a food supplement that is grown consistently between years to deliver constant concentrations of micronutrients. For example, black raspberries, which contain substantial concentrations of phenolic acids such as ellagic acid and ferulic acid, flavonoids such as anthocyanins, vitamins and minerals, may be grown with standardized content within and between years. When tested in rodent models, freeze-dried and frozen formulations of black raspberries inhibit colon tumours and aberrant crypt foci at concentrations of individual anticarcinogenesis constituents that are 10-fold less than the concentration of each individual constituent necessary to block aberrant crypt foci when given as a purified product (Harris et al, 2001). A whole food, given fresh or freeze dried as a capsule, containing multiple components thought to be anticarcinogenic is an efficient, nontoxic delivery system for potential anticarcinogenic compounds.

Alternatively, purified chemical isolates of foodstuffs may also be useful as preventive ‘drugs’. Such purified substances are commonly ingested in the food supply, sometimes in substantial quantities. Examples of such agents are curcumin, a constituent of curry, and resveratrol, contained in red grapes and berries. A plethora of mechanistic studies in cells in vitro suggests that polyphenolic phytochemicals can undermine oncogenic signalling cascades germane to tumour promotion and progression in a variety of ways (Manson et al, 2005). Both curcumin and resveratrol interfere with the cyclooxygenase-catalysed production of prostanoids from arachidonic acid by downregulation of arachidonic system catabolic enzymes (cyclooxygenases and lipoxygenases) and can reduce cancers in multiple rodent model systems of epithelial tumours (Leu and Maa, 2002; Aggarwal et al, 2004).

In the light of issue 2 outlined in the introduction, it seems most important to find out whether the potency difference in rodent colonic carcinogenesis models between NSAIDs and polyphenolic phytochemicals (Gescher, 2004) translates into a similar difference in the ability to achieve adenoma regression in humans. Alternatively, it is conceivable that efficacy in rodent models just ‘signals’ potential for activity in humans without potency implications, implying that a positive result for an intervention in the preclinical model renders its preliminary investigation in humans definitely worthwhile.

Diet modification

Diets rich in fruits and vegetables, specifically diets rich in citrus fruits, dark green vegetables, and cruciferous vegetables, reduce risk of cancer. Recent data document success in diet modification using extensive prepared materials, staff effort, intensive intervention with the targeted population over a 1-year (Resnicow et al, 2001; Pierce et al, 2004) or 4-year period (Schatzkin et al, 2000). Diet can be modified in medically well-served (Schatzkin et al, 2000; Resnicow et al, 2001; Pierce et al, 2004) and medically underserved populations (Resnicow et al, 2001). The entire diet can be modified to enhance fruit and vegetable intake (Schatzkin et al, 2000; Resnicow et al, 2001; Pierce et al, 2004). Dietary interventions utilising motivational interviewing performed by minimally trained lay members of a community can successfully disseminate cancer protective diets to large populations at minimal cost (Resnicow et al, 2004).

A prospective, 4-year diet modification trial failed to reduce adenoma recurrence (Schatzkin et al, 2000). Similarly, an intervention with fibre also failed to reduce colorectal adenoma recurrence (Alberts et al, 2000) The former trial was criticised because the serum biomarker of diet modification, serum carotenoids, did not change in the treated group while the dose and type of fibre used was criticised in the later trial. The ongoing WHEL project (Pierce et al, 2004) tests the question of dietary modulation impact upon cancer preventive and treatment efficacy in a population of women with early-stage breast cancer (Pierce et al, 2004). The tools and procedures necessary to effect a dietary change in a large population (thousands) are available at reasonable cost. While attempts to modify human carcinogenesis with diet modification to date have been disappointing, the effects of these interventions may require much longer term follow-up (beyond 4 years). Alternatively, intervention prior to the appearance of a late carcinogenesis neoplastic event, such as a dysplastic lesion, in individuals with low-penetrance, high-frequency genetic haplotypes predictive for increased risk of an epithelial cancer may be required to demonstrate cancer preventive efficacy. Given the low toxicity, low cost, and relative ease of implementation, diet modification should be considered as a preferred preventive intervention in the healthy but a higher than normal risk population.

Summary

Recent publications have identified major weaknesses in the developmental strategies of cancer chemopreventive agents that have resulted in negative trial outcomes. Pivotal issues have included (1) concerns over the concept of acceptable therapeutic index for interventions in healthy populations; (2) the necessary preliminary data set required to support the development and implementation of research in humans; (3) the design and progression of research in humans aimed at defining preventive efficacy; and (4) the discovery and validation of biomarkers as potential surrogates for preventive intervention efficacy. Addressing these issues requires reorientation of the selection process of individuals at risk for a future cancer. Individuals at high risk for future transformation are more likely to accept the toxicity risks and financial costs of treatment-related toxicity in exchange for delay of cancer occurrence. Individuals without a known tissue or molecular high-risk factor for cancer will not tolerate toxicity that reduces quality of life female tadalafil.

To address these two groups, which represent opposite poles of a risk continuum, development of multiagent pharmacologic interventions for high-risk individuals is warranted. Future combinations of pharmaceutical cancer preventives might consist of agents targeted to specific signal transduction pathways associated with specific epithelial cellular targets. Diet modification, and food or nutritional extracts (‘nutriceuticals’) with known anticarcinogenesis activity may be more acceptable to healthy populations with known genetic risk based upon gene-environment interactions.

References:

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Aggarwal BB, Bhardwaj A, Aggarwal RS, Sceram NP, Shishodia S & Takada Y. (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24: 2783−2840.

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Alberts DS, Potter JD, Martinez ME, Hess LM, Stopeck A & Lance P. (2005) What happened to the coxibs on the way to the cardiologist? Cancer Epidemiol Biomarkers Prev 14: 555−556.

Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P & Ogier-Denis E. (2002) Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer IIT-29 cell line. J Biol Chem 277: 27613−27621.

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Authors:
D E Brenner(1) and A J Gescher(2)

Authors’ affiliations:
(1) Division of Hematology-Oncology, Department of Internal Medicine, Department of Pharmacology, University of Michigan & VA Medical Center, Ann Arbor, MI 48109, 0930, USA

(2) Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 2LX, UK

September, 2005|Archive|

Quit smoking to save teeth

  • 9/26/2005
  • United Kingdom
  • staff
  • British Dental Journal (2005); 199, 323. doi: 10.1038/sj.bdj.4812840

Smokers who give up are much less likely to lose their teeth prematurely than those who don’t kick the habit, according to research conducted at the University of Newcastle-upon-Tyne. Dental researchers observed a group of cigarette smokers with chronic gum disease over one year and found some symptoms were more likely to improve in the people who quit during the study period.

The researchers’ findings were revealed in the Journal of Clinical Periodontology, and the study, The effect of quitting smoking on chronic periodontitis by PM Preshaw et al, followed 49 smokers with chronic gum disease over one year. All were encouraged to stop smoking through counselling and, in some cases, using nicotine replacement therapy and/or medication. All of the patients also received treatment for their gum disease. One-fifth of the patients quit smoking, and in those patients, gum health was significantly improved compared to those who continued to smoke over the 12 months.

Dr Philip Preshaw a clinical lecturer in periodontology with Newcastle University’s School of Dental Sciences, led the research. He said, “Our study shows that people should stop smoking now if they want to increase their chances of keeping their teeth into old age. Dentists have known for some time that smokers have worse oral and gum health than non-smokers but for the first time we have shown that quitting smoking together with routine gum treatment results in healthier gums.”

The Department of Health has promoted the idea of smoking cessation counselling by dentists, and dental students at Newcastle University are now taught how to counsel patients on this issue as part of their degree course.

September, 2005|Archive|

Mitomycin and Fluorouracil in Combination with Concomitant Radiotherapy: A Potentially Curable Approach for Locally Advanced Head and Neck Squamous Cell Carcinoma

  • 9/26/2005
  • Japan
  • Madhup Rastogi et al.
  • Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyi155

Objective:
The purpose of this study was to evaluate the efficacy of radiotherapy and concurrent mitomycin-C (MC) plus 5-fluorouracil (5FU) infusion in locally advanced squamous cell carcinoma of head and neck (SCCHN).

Methods:
Sixty-nine patients with SCCHN (6 Stage III and 63 Stage IV patients) were treated with external beam radiotherapy (70 Gy) and simultaneous intravenous chemotherapy with 5FU (600 mg/m2/day, Days 1-5) and MC (10 mg/m2, Days 5 and 36).

Results:
After a mean follow-up of 28.5 months, 59.4% of patients were alive without disease. Complete response was seen in 76.8% of patients. The 3 years overall survival, locoregional relapse-free survival and disease-free survival was 62.3, 89.8 and 49.5%, respectively. Treatment was well tolerated (Grade III mucositis in 43.5% and Grade II leukopenia in 5.8%).

Conclusions:
This concurrent chemoradiotherapy regimen offers a curative option for our patients where primary and nodal disease is fairly large resulting in hypoxic radioresistant tumors.

Authors:
Madhup Rastogi 1, Madhu Srivastava 1, Kundan S. Chufal 2, M. C. Pant 1, Kirti Srivastava 1, and Madanlal B. Bhatt 1

Authors’ affiliations:
1 Department of Radiotherapy, King George’s Medical University, Lucknow, Uttar Pradesh, India
2 Department of Oncology, Batra Hospital and Medical Research Center, New Delhi, India

September, 2005|Archive|

Young hit by mouth cancer increase

  • 9/26/2005
  • Scotland
  • staff
  • News.scotsman.com

Increasing numbers of young people are being hit by mouth cancer, sparking new warnings about the disease. Mouth cancer was once considered to mostly affect older men, but it is now becoming more common in younger people and women.

It is possible that binge-drinking and smoking could be helping to fuel rising rates of the disease as these are key risk factors.

Now the British Dental Health Foundation (BDHF) is warning people of all ages that they need to start checking their mouths regularly if rising rates of mouth cancer are to be stopped.

The ratio of women to men suffering mouth cancer has grown by a third in the last 10 years, although men are still twice as likely to develop the disease.

Mouth cancer is sometimes called oral cancer and can affect the lips, tongue, cheeks and throat. Every year in the UK, there are 4,300 new cases diagnosed and 1,700 deaths.

The most common causes of mouth cancer are smoking and drinking alcohol to excess – people who do both are up to 30 times more likely to develop the condition than those who do not. Having a poor diet is also linked to the disease.

But the BDHF said about 25% of mouth cancer cases in younger people involved none of these common risk factors. The foundation said this meant it was vital people learnt to be aware of the possible symptoms, even if they led a healthy lifestyle.

September, 2005|Archive|

Intensity-modulated radiation treatment for head-and-neck squamous cell carcinoma-the University of Iowa experience

  • 9/25/2005
  • Iowa City, IA
  • M Yao et al.
  • Int J Radiat Oncol Biol Phys, October 1, 2005; 63(2): 410-21

Purpose:
To review the University of Iowa experience with intensity-modulated radiotherapy (IMRT) in the treatment of head-and-neck squamous cell carcinoma.

Methods and Materials:
From October 1999 to April 2004, 151 patients with head-and-neck squamous cell carcinoma were treated with IMRT for curative intent. One patient was lost to follow-up 2 months after treatment and therefore excluded from analysis. Of the remaining 150 patients, 99 were treated with definitive IMRT, and 51 received postoperative IMRT. Sites included were nasopharynx, 5; oropharynx, 56; larynx, 33; oral cavity, 29; hypopharynx, 8; nasal cavity/paranasal sinus, 8; and unknown primary, 11. None of the patients treated with postoperative IMRT received chemotherapy. Of 99 patients who had definitive IMRT, 68 patients received concurrent cisplatin-based chemotherapy. One patient received induction cisplatin-based chemotherapy, but no concurrent chemotherapy was given. Three clinical target volumes (CTV1, CTV2, and CTV3) were defined. The prescribed doses to CTV1, CTV2, and CTV3 in the definitive cohort were 70-74 Gy, 60 Gy, and 54 Gy, respectively. For high-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 64-66 Gy, 60 Gy, and 54 Gy, respectively. For intermediate-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 60 Gy, 60 Gy, and 54 Gy.

Results:
The median follow-up was 18 months (range, 2-60 months). All living patients were followed for at least 6 months. There were 11 local-regional failures: 7 local failures, 3 regional failures, and 1 failure both in the primary tumor and regional lymph node. There were 16 patients who failed distantly, either with distant metastasis or new lung primaries. The 2-year overall survival, local progression-free survival, locoregional progression-free survival, and distant disease-free survival rates were 85%, 94%, 92%, and 87%, respectively. The median time from treatment completion to local-regional recurrence was 4.7 months (range, 1.8 to 15.6 months). Only one marginal failure was noted in a patient who had extensive tonsil cancer with tumor extension into the orbit and cavernous sinus. Patients with oropharyngeal cancer did significantly better than patients with oral cavity and laryngeal cancer, with a 2-year local-regional control rate of 98%, compared with 78% for oral cavity cancer and 85% for laryngeal cancer (p = 0.005). There was no significant difference in local-regional control for patients who received postoperative radiation or definitive radiation (p = 0.339) and for patients who had chemotherapy or not (p = 0.402). Neither T stage nor N stage had a significant effect on local-regional control (p = 0.722 and 0.712, respectively).

Conclusions:
Our results have confirmed the effectiveness of IMRT in head-and-neck cancer. It offers excellent outcomes in local-regional control and overall survival. More studies are necessary to further improve the outcomes of laryngeal cancer as well as oral cavity cancer.

Authors:
M Yao, KJ Dornfeld, JM Buatti, M Skwarchuk, H Tan, T Nguyen, J Wacha, JE Bayouth, GF Funk, RB Smith, SM Graham, K Chang, and HT Hoffman

Authors’ affiliations:
Department of Radiation Oncology, University of Iowa Health Care, Iowa City, Iowa, USA; Department of Otolaryngology, University of Iowa Health Care, Iowa City, IA

September, 2005|Archive|

Radiation depresses head, neck cancer patients

  • 9/25/2005
  • Virginia, USA
  • staff
  • myDNA (www.mydna.com)

Upper aerodigestive tract cancer patients used to have few treatment options. Fortunately, radiation therapy (RT) has proven to be an effective treatment – either on its own or in combination with surgery. But, despite the benefits, RT can also be associated with several long-term side effects, including depression.

Many cross-sectional and longitudinal studies have looked at the impact that this treatment modality can have on the long-term quality of life of head and neck cancer survivors. On the other hand, few studies have assessed the effect of acute toxicities of radiation therapy on the quality of life during the treatment process. These acute toxicities can be more severe when chemotherapeutic agents that have a synergistic effect on the cancerous and normal tissues are used concomitantly.

The quality of life of head and neck cancer patients during radiation has not been explored before. British researchers planned a prospective study to assess the impact that radiation therapy has on the quality of life during the treatment process. They speculated that the health related quality of life would decrease over the period of radiation therapy and that patients would be increasingly depressed as the treatment progressed caused by the side effects of the treatment.

The authors of “Deterioration in Quality of Life and Depressive Symptoms during Radiation Therapy for Head and Neck Cancer,” are Mr. Vinidh Paleri FRCS, Carol Downes, and Charles Kelly FRCR, all from the Freeman Hospital, University of Newcastle upon Tyne, United Kingdom. Their findings are to be presented at the 109th Annual Meeting and OTO EXPO of the American Academy of Otolaryngology – Head and Neck Surgery Foundation, being held September 25-28, 2005, at the Los Angeles Convention Center, Los Angeles, CA.

All patients who were to receive radiation or chemoradiation as part of the treatment for head and neck cancer were selected for the study. The primary sites included squamous cell carcinomas of the upper aerodigestive tract mucosa including the nasopharynx.

The University of Washington QoL (UW-QOL) version 3 was the instrument chosen to assess quality of life. The self-administered questionnaire consists of ten domains that describe important areas of daily living that may be affected by treatment of head and neck cancer. These domains are pain, appearance, activity, recreation/entertainment, employment, chewing, swallowing, speech and shoulder disability.

The Hospital Anxiety and Depression Scale (HADS) was developed to detect anxiety and depression in a non-psychiatric hospital setting, but since its inception the questionnaire has been used and validated in other, non-hospital settings, including in oncologic work. The UW-QOL and the HADS questionnaire were administered before treatment, at the mid-treatment point and after treatment. Subsequently, all two-year survivors were sent a further questionnaire.

Between August 2001 and February 2003 some 202 patients consented to the study. The mid-treatment data and end of study data was available for 113 and 68 subjects respectively. Datasets at all three time points were available for 63 patients, while 68 patients completed a questionnaire at the beginning and at the end of the study. Eighty-four patients filled out only one questionnaire at the beginning of the study and subsequently dropped out of the study.

The distribution of primaries in the cohort is as follows: paranasal sinus (2.25 percent), oral cavity (19.66 percent), oropharynx (20.22 percent), hypopharynx (10.67 percent), larynx (41.01 percent), nasal cavity (1.1.2 percent), nasopharynx (3.37 percent) and unknown primary (1.69 percent).

The composite score, and domain scores for pain, appearance, recreation, swallowing, chewing, taste and saliva show a steady decrease in time over the radiation period. This difference was statistically significant. The Friedman test was used to assess within subject change of quality of life scores over this period; this showed a significant deterioration in total quality of life scores over the treatment period for the three groups. Attrition of patients led to data being not available at all time points. Comparison of the within subject scores during the first two time points (n=113) showed a significant deterioration even by the mid-point of the treatment period.

There was also a significant increase in depression scores on the HADS scale over the three treatment periods but not in anxiety levels. To assess if poor QoL and depression at the beginning of treatment was related to the attrition, we compared response rates at the second time point between patients who scored above and below the median score prior to start of treatment. There was marginally significant difference in the response rates between the groups with respect to the initial composite scores, but patients with higher depression scores on the HADS scale prior to start of treatment were more likely to drop out.

Conclusions: The researchers found:

1. The primary reasons for patients not completing the questionnaires were the side effects, especially when this was significant enough for treatment interruption due to reactions or admission to ward.

2. This study also validates the anxiety domain of the UWQOL and also shows that depressed patients are likely to drop out of the study, but not those with poor quality of life.

3. Approximately 24.2 percent of patients are depressed prior to start of treatment and this underlines the need for good psychological support in this population. This figure increases with time and given that depressed patients are less likely to respond to questionnaires, the problem is being underestimated as well.

September, 2005|Archive|

Beta-Carotene Associated With Higher Risk of Tobacco-Related Cancers in Women Smokers but Not in Nonsmokers

  • 9/25/2005
  • Bethesda, MD
  • press release
  • Journal of the National Cancer Institute, Vol. 97, No. 18, 1315, September 21, 2005

A new study of French women has found that high beta-carotene intake—through a combination of diet or supplementation—is associated with a higher risk of tobacco-related cancers in smokers, but the risk of these cancers decreases with increasing beta-carotene intake in nonsmokers. The study appears in the September 21 issue of the Journal of the National Cancer Institute.

Some observational studies have found that beta-carotene consumption is associated with a decreased risk of cancer. However, some intervention studies have suggested that high doses of the antioxidant, given through supplementation, may be associated with an increased risk of lung cancer and digestive cancers in smokers.

To investigate the relationships of beta-carotene intake from both diet and supplementation with the risk of tobacco-related cancers—which include colorectal, thyroid, ovarian, cervical, and lung cancers in addition to less common cancers—Marie-Christine Boutron-Ruault, M.D., Ph.D., of INSERM in Villejuif, France, and colleagues used information from questionnaires given in 1994 to nearly 60,000 women from the French Etude Epidémiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) prospective study. The researchers assessed diet, supplement use, and smoking status in these women and followed them for a median of 7.4 years.

During the follow-up period, 700 women developed a type of cancer known to be related to smoking. Among women who never smoked, beta-carotene intake was inversely associated with the risk of developing a tobacco-related cancer, with a dose-dependent relationship across the considered beta-carotene categories (tertiles of dietary beta-carotene, and supplement use as the fourth category). However, among women who had ever smoked, the results were reversed: cancer risk was highest among women in the high beta-carotene intake group.

In the population studied, the authors calculated that the absolute rates of tobacco-related cancers over 10 years for nonsmokers with low and high beta-carotene intakes were 181.8 and 81.7 cases per 10,000 women, respectively. Among smokers, these rates were 174.0 cases per 10,000 women for those who had low beta-carotene intake and 368.3 cases per 10,000 women for those who had high intake.

“Although beta-carotene may act as a cocarcinogen, there is no evidence that smokers should avoid consuming beta-carotene-rich foods such as fruit and vegetables, in which other components, such as vitamins C and E, may counteract a potentially deleterious interaction of beta-carotene with smoking,” the authors write.

In an editorial, Susan T. Mayne, Ph.D., of the Yale University School of Medicine and Yale Cancer Center in New Haven, Conn., and Scott M. Lippman, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, write that “evidence suggesting that tobacco exposure modifies the chemopreventive efficacy of nutrients/nutrient derivatives continues to mount.” However, this new research “should not alter our current policy recommendations with regard to nutrients and cancer risk. Rather, this new research emphasizes the need to examine current, former, and never smokers separately in studies of nutrient supplements and other preventive agent classes in a wide spectrum of cancer prevention settings,” they write.

September, 2005|Archive|

Imperial buys tobacco product banned in EU

  • 9/22/2005
  • England
  • Rachel Stevenson
  • The Independent (news.independent.co.uk)

Imperial Tobacco, the group behind the Regal, John Player and Superkings cigarette brands, said yesterday it was entering the market for smokeless tobacco despite a ban on the product in the EU.

The company has bought a 43.2 per cent stake in Skruf, a Swedish manufacturer of smokeless tobacco known as “snus”. The EU banned “snus” and most other forms of smokeless tobacco in 1992, but Sweden, where the product is hugely popular, negotiated an exemption from the ban when it joined the EU in 1995.

“Snus”, sold in tins, is moist, loose tobacco put in small teabag-like pouches that are placed under the lip. They produce a similar experience to smoking a cigarette. The product was banned because it was deemed attractive to children, who could become easily hooked and move on to cigarettes. There is also research to suggest the product could increase the risk of oral cancer.

Imperial hopes to capture some of the huge Swedish demand for “snus”. While cigarette sales have been in decline there, more than 200 million tins of “snus” are sold every year and rising.

Skruf’s chairman and founder, Adam Gillberg, said: “With this alliance, we will get the resources and the muscles that we need to grow.” The company has 1 per cent of the Swedish market.

The tobacco industry claims “snus” is far less harmful than cigarettes, containing less of the carcinogenic chemicals that are in cigarettes. It also eradicates the danger of passive smoke inhalation. British American Tobacco (BAT) has also launched a “snus” product in Sweden and claims that lung cancer deaths in Sweden are the lowest in Europe. BAT is also running a trial of “snus” in South Africa.

September, 2005|Archive|