Tip: Use CTRL + F to find a map quickly. To upload or download maps from ENT, click here. 5th edition D&D Druid Handbook Version 4.2 Druids are full spell casters, and as such both powerful and versatile PCs. In addition, they sport a few other abilities.
Author by: Vera Stanley Alder Languange: en Publisher by: Weiser Books Format Available: PDF, ePub, Mobi Total Read: 86 Total Download: 689 File Size: 55,7 Mb Description: Vera Stanley Alder invites readers to test meditation by choosing a subject they don't know and learning about it by using the exercises and meditations in the book. He explores the variety of claims made about the effects of meditation what happens to the student, biologicaland physical changes, the practice of balanced living, and the phenomena that leads to ultimate fulfillment and achievement. Author by: David K. Miller Languange: en Publisher by: Light Technology Publishing Format Available: PDF, ePub, Mobi Total Read: 47 Total Download: 609 File Size: 52,8 Mb Description: Three forces must come together for a planetary healing to occur. The concept of the Sacred Triangle was introduced in David Miller's first book, Connecting with the Arcturians, which explored the fifth dimension and our relationship to higher Extraterrestrial groups. This new book explains how the Arcturian energy melds with that of the White Brother/Sisterhood and the Ascended Native American Masters to bring about planetary healing. David offers the reader an understanding of the soul, the nature of soul evolution, and how the human species is advancing towards the next evolutionary step.
'There will be many of you in this time who will be able to complete fantastic tasks. If I would declare to you what I see, you would be astonished that you could possibly carry out such tasks. You must think that you have the ability to do this. You have the personal power. I ask you to look at the Sacred Triangle and see what role you can play in this.
Others will be very interested when you explain this mission. I guarantee you there will be a very strong contingent that will ascend together as we are invited to join you in the Crystal Temple. We are very eager to meet you there as well. This is Chief White Eagle.' Author by: Vidya Frazier Languange: en Publisher by: First Edition Design Pub. Format Available: PDF, ePub, Mobi Total Read: 27 Total Download: 856 File Size: 51,7 Mb Description: Humanity has recently entered an extraordinary period of transition in which it is preparing to make a quantum, transformational leap to a higher level of consciousness and reality known as the Fifth Dimension--forever leaving behind all experiences of fear, conflict, pain, sorrow and duality.
As veils of forgetfulness and dysfunctional patterns begin to dissolve in this Shift, we are at the dawn of an entirely new era on the planet: life lived from love, peace, cooperation, abundance, and reverence for all existence. AWAKENING TO THE FIFTH DIMENSION is an indispensable guide for this journey into uncharted new territory in consciousness, which may include unprecedented experiences of freedom, joy and expansion as well as significant challenges of disorientation and rapid change.
We are invited here into conscious participation in an accelerated evolution as we ascend into the Fifth Dimension. In mapping the territory of this dimensional shift, it is also a call to co-create a New Earth that many of us have deeply longed for. Among its themes: • Common personal experiences during the Shift • Ways to navigate it with ease and grace • Understanding the Dimensions: Third, Fourth and the emerging Fifth • Physical, mental and emotional 'Ascension symptoms' • Raising and sustaining your vibration: well-being, happiness, freedom • Stepping into a new multi-dimensional identity • Discovering your mission for assisting the planet through the Shift. Author by: Pepper Lewis Languange: en Publisher by: Light Technology Publishing Format Available: PDF, ePub, Mobi Total Read: 85 Total Download: 734 File Size: 42,6 Mb Description: We, collective humanity, are one of Earth's resources. We cycle and recycle ourselves through lifetimes upon Earth, learning, sharing and contributing to Earth in a variety of ways.
Gaia truly benefits from our company, and her sentience enjoys the varied history we have shared with the planet. That being said, this is a time of great change for humanity and for Earth. We are on the cusp of a New Age, and time is running out on our present -- soon to be recent past -- age. Gaia cannot offer us complete solutions to our difficulties and dilemmas, but she can instill within us the knowingness to see through our predicaments to solve the puzzles of our time.
Author by: Cathy Foster LM Languange: en Publisher by: Page Publishing Inc Format Available: PDF, ePub, Mobi Total Read: 89 Total Download: 487 File Size: 55,6 Mb Description: Where Is Our Path Taking Us? There is more to our identity than our physical bodies; our soul’s journey is an extremely important part of our life. When living within the energy of the 5th dimension, our hearts and souls are beginning to expand as time is forever changing. We can learn to evolve internally and externally, eliminating any limitations that we have placed upon ourselves by thinking out of the box. Social Booth Keygen Idm more. Approaching life by consciously monitoring our thoughts, feelings, and actions can lead to our soul’s growth and our soul’s advancements on a path of making small changes, which can result in major shifts in our level of consciousness that allows us to see the divine spark within, now viewing the impossible as possible. We can find peace with the chaos in our life by finding peace within our hearts, as we gradually learn to raise our vibrations by changing our perception and our way of thinking.
We can easily and effortlessly shift the course of our life when we tap into the divine knowledge and wisdom, drawing from our intuitive knowledge in order to align and empower our magnificent being. Through these changes, we can bring forth the potential to bridge the gap between the physical and spiritual worlds. We are about to venture off to a new journey to learn about our own unique higher self and our own personal quest for a deeper understanding of our own life. Through the world around us, we will be establishing a connection with the deeper sense of self by finding our true center, our balance, and gaining the ability to connect by interweaving the opportunities and possibilities of both the physical and spiritual worlds. Knowledge is power.
Only knowledge can assist us in finding the key to higher levels of consciousness. Author by: David K. Miller Languange: en Publisher by: Light Technology Publishing Format Available: PDF, ePub, Mobi Total Read: 51 Total Download: 111 File Size: 46,6 Mb Description: Three forces must come together for a planetary healing to occur. The concept of the Sacred Triangle was introduced in David Miller's first book, Connecting with the Arcturians, which explored the fifth dimension and our relationship to higher Extraterrestrial groups. This new book explains how the Arcturian energy melds with that of the White Brother/Sisterhood and the Ascended Native American Masters to bring about planetary healing.
David offers the reader an understanding of the soul, the nature of soul evolution, and how the human species is advancing towards the next evolutionary step. 'There will be many of you in this time who will be able to complete fantastic tasks. If I would declare to you what I see, you would be astonished that you could possibly carry out such tasks. You must think that you have the ability to do this. You have the personal power. I ask you to look at the Sacred Triangle and see what role you can play in this.
Others will be very interested when you explain this mission. I guarantee you there will be a very strong contingent that will ascend together as we are invited to join you in the Crystal Temple. We are very eager to meet you there as well. This is Chief White Eagle.'
Author by: Len Robertson Languange: en Publisher by: iUniverse Format Available: PDF, ePub, Mobi Total Read: 60 Total Download: 548 File Size: 46,9 Mb Description: Mary Brown, a divorced, forty year old housewife with five children suddenly finds herself eighteen years old, nude and lost in a land far different from anything she's ever seen. Then, she meets Fred and life gets infinitely more complicated. She's killed! Shortly afterward, she finds herself revived and pitted against Donovan Fausto in a life or death struggle. The best she can hope for is that she only gets herself killed.
A horrific nuclear winter and a new 'Dark Age' is far more likely. But first, Mary has to survive Boogey Monsters and their deadly short swords.
A knife of her own would help, not to mention clothing, boots and a few friends to help her survive her first day in Galatia. Still, considering she needs years of training and experience if she means to match Donovan Fausto and she only has three weeks in which to do it, maybe it might be simpler for Mary if she dies. That way, she can't be blamed for the catastrophe to follow. Author by: Ramma Kher Languange: en Publisher by: Xlibris Corporation Format Available: PDF, ePub, Mobi Total Read: 85 Total Download: 273 File Size: 51,5 Mb Description: The protagonist, Meera, emigrates from India to Canada as a newlywed. Unfortunately, her husband dies within a few months. Her dear friend, Jane, commits suicide soon after. To fulfill her last wishes, Meera adopts her illegitimate son, Rishi.
Jane’s ruthless and wicked mother, Helena, has Rishi in an immoral and convoluted web of deceit. Rishi grows into a conflicted adolescent partly because of racism he experiences at school and partly due to Helena’s indoctrination against his mother. Rishi leaves Meera in spite of the sacrifices she made for him, refusing a marriage proposal twice. The protagonist is a highly moral and compassionate human who refuses to compromise her essence. Constantly striving to preserve some semblance of beauty and truth in her turbulent life, Meera’s story is about sacrifice, struggle and survival, decrepitude and triumph, and pain and transcendence by the Spirit, the fifth dimension. Author by: Dean Yang Languange: en Publisher by: Partridge Publishing Singapore Format Available: PDF, ePub, Mobi Total Read: 54 Total Download: 315 File Size: 45,7 Mb Description: When Keat—not an ordinary man but a high-ranking member of the triad that controls the Tanjung Bungah area on the tropical island of Penang—robs a goldsmith shop, his life takes quite a turn.
Though a hoodlum from childhood, Keat now finds himself the fugitive, hunted by the efficient and relentless Inspector Hassan along with the Sarawak Rangers. A chance encounter with an aborigine and the mysterious Bird Man changes Keat’s destiny. Meanwhile, meet a doctor whose interests lie outside of his medical field and who tries to understand the changing universe.
As the whole world faces an apocalypse, the only way out is to escape to another planet or into another dimension. To be successful, they’ll need the help of the extraterrestrials and the Agarthans and Lemurians from inner Earth. Set in Penang, Malaysia, Escape to the Fifth Dimension presents a fast-paced science fiction novel that offers a possible look into the near future. Author by: Arran Anderson Languange: en Publisher by: iUniverse Format Available: PDF, ePub, Mobi Total Read: 90 Total Download: 868 File Size: 40,5 Mb Description: Everything humanity has ever learned, finally comes down to this. 'What If God Were One Of Us?'
This is a new novel – with a new message – about a new time – for a new consciousness – in a new energy – when a new future depends on it. There is a New Energy which humanity has not yet learned to adapt to, because it requires higher consciousness in order to function at the increased vibration; so until humanity is willing to make that shift, senseless and non-winnable wars will continue to be fought, as people continue holding on to outdated beliefs that no longer serve them. It’s not about learning to deal with the reality of climate change; it’s about learning to change your beliefs about reality. “What If God Were One of Us?” is not only a cry to awaken, but also presents startling revelations about the destiny of the planet.
It’s an intriguing fictional novel about the expansion of human consciousness, offering the world a choice for the creation of a new and enlightened society. Author by: David K. Miller Languange: en Publisher by: Light Technology Publishing Format Available: PDF, ePub, Mobi Total Read: 29 Total Download: 872 File Size: 50,7 Mb Description: A shift in consciousness has occurred on the planet during the past twenty-five years, marking a new moment in the evolution of humanity’s consciousness concerning our relationship to Earth and to the cosmos. We now accept that human beings are interacting with a living planet, and we understand that this living planet has an energetic relationship to the galaxy. We have also come to understand that the entire biological and energy system of this beautiful planet we live on is totally dependent on how humans treat the planet, the environment, and other life forms on Earth. Biorelativity describes the ability of human beings to telepathically communicate with the spirit of the Earth. The goal of such communication is to influence the outcome of natural Earth events such as storms, volcanoes, and earthquakes.
This book is a collection of channeled lectures through Arcturian, Native American, and other mystical guides, transmitted in sessions from 2009 through early 2011, that describe the exercises and thought developments related to biorelativity, the planetary cities of light, and the Arcturian Tree of Life that together form new technology for Earth healing. Through these lessons, you can implement new planetary healing techniques right now, actively participating in exciting changes as Earth and humanity come together in unity and healing.
Methods We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. Results The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P.
Figure 1 Kaplan–Meier Estimates of Survival among the Study Patients with Oropharyngeal Cancer, According to Tumor HPV Status or p16-Expression Status. Data on overall survival and progression-free survival are shown according to stratification on the basis of tumor HPV status (Panels A and B, respectively) or p16-expression status (Panels C and D, respectively).
The Kaplan–Meier curves are shown in black, and the associated 95% confidence intervals in gray. Patients with HPV-positive tumors had significantly better overall survival and progression-free survival than did patients with HPV-negative tumors (P.
Figure 2 Classification of the Study Patients into Risk-of-Death Categories and Kaplan–Meier Estimates of Overall Survival According to Those Categories. Recursive-partitioning analysis was used to identify prognostic factors with the most influential predictive significance in a proportional-hazards model of overall survival and to classify patients into categories of low, intermediate, or high risk of death. The prognostic factors in the analysis were age, tumor stage, nodal stage, race, smoking status, HPV status, anemia status, performance status, treatment assignment, and sex. Panel A shows the resulting classifications. Panel B shows data for overall survival in the classified patients. The Kaplan–Meier curves are shown in black, and the associated 95% confidence intervals in gray.
The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group. The majority of patients enrolled in therapeutic trials for squamous-cell carcinoma of the head and neck have oropharyngeal squamous-cell carcinoma, which in a subgroup of these patients is caused by infection with human papillomavirus (HPV). This subgroup is defined by the presence of high-risk types of HPV in tumor cells, predominantly HPV type 16 (HPV-16). Expression of viral E6 and E7 oncoproteins that inactivate the tumor-suppressor proteins p53 and the retinoblastoma protein (pRb), respectively, is necessary for malignant behavior of these tumors.
Several retrospective case series have shown that among patients with oropharyngeal squamous-cell carcinoma, patients with HPV-positive tumors have a better prognosis than patients with HPV-negative tumors. Similar findings were reported in a prospective analysis of data from a clinical trial. Because of the small sample, however, other favorable prognostic factors associated with tumor HPV status (e.g., early tumor stage or young age) could not be ruled out as an explanation for the observed difference in survival. We sought to evaluate the effect of tumor HPV status on survival in patients with oropharyngeal squamous-cell carcinoma who were enrolled in a clinical trial of sufficient size to account for potentially confounding factors, including smoking status. Our analysis was performed within a randomized clinical trial conducted by the Radiation Therapy Oncology Group (RTOG; the RTOG 0129 study).
Meta-analyses of clinical trials for patients with locally advanced squamous-cell carcinoma of the head and neck have shown that both accelerated-fractionation radiotherapy and concurrent cisplatin-based chemotherapy improved survival as compared with standard-fractionation radiotherapy alone. The RTOG 0129 study addressed the question of whether accelerated-fractionation radiotherapy is superior to standard-fractionation radiotherapy when each radiotherapy regimen is combined with concurrent cisplatin therapy. We report the results of this trial with an emphasis on the effect of tumor HPV status on survival among patients with oropharyngeal squamous-cell carcinoma. Study Protocol The RTOG 0129 study was registered with the National Cancer Institute and approved by the institutional review boards at the participating centers. All patients provided written informed consent. The authors attest to the fidelity of the article to the full protocol and statistical-analysis plan.
Eligibility criteria were the presence of untreated, pathologically confirmed, stage III or IV squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx without distant metastases (M0); Zubrod's performance status score of 0 or 1 (asymptomatic or symptomatic but ambulatory, respectively); age of 18 years or older; and adequate bone marrow, hepatic, and renal function. Lifetime tobacco exposure was determined at enrollment with the use of a standardized, self-administered questionnaire. Patients were stratified on the basis of the tumor site (larynx vs.
Other), nodal stage (N0 vs. N1, N2a, or N2b vs. N2c or N3), and Zubrod's performance status score (0 vs. 1) and were randomly assigned to receive high-dose cisplatin concurrently with either accelerated-fractionation radiotherapy (with the acceleration provided by means of concomitant boost radiotherapy) or standard-fractionation radiotherapy. The accelerated-fractionation radiotherapy consisted of the delivery of 72 Gy in 42 fractions over a 6-week period, with a concomitant boost of twice-daily irradiation for 12 treatment days (as previously reported ), and standard-fractionation radiotherapy consisted of the delivery of 70 Gy in 35 fractions (i.e., 2 Gy per fraction) over a 7-week period.
Intravenous cisplatin was administered at a dose of 100 mg per square meter of body-surface area on days 1 and 22 in the accelerated-fractionation radiotherapy group and on days 1, 22, and 43 in the standard-fractionation radiotherapy group. Acute toxicity was evaluated weekly during the period of therapy according to the Common Terminology Criteria, version 2.0 (). To assess tumor status and late toxicity, according to RTOG criteria, physical examinations and imaging studies were performed every 3 months for the first 2 years, every 6 months during years 3 through 5, and annually thereafter. Laboratory Studies The analysis of tumor HPV status was restricted to patients with oropharyngeal squamous-cell carcinoma because of the low prevalence of HPV among nonoropharyngeal squamous-cell carcinomas. This post hoc subgroup analysis was not part of the study protocol. Formalin-fixed, paraffin-embedded tumor specimens were evaluated for HPV-16 DNA with the use of the in situ hybridization–catalyzed signal-amplification method for biotinylated probes (GenPoint, Dako). HPV-16–negative tumors were further evaluated for 12 additional oncogenic HPV types (18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) by means of a biotinylated-probe cocktail (GenPoint HPV Probe Cocktail, Dako).
An HPV-positive tumor was defined as a tumor for which there was specific staining of tumor-cell nuclei for HPV in either analysis. Tumor p16 expression was evaluated by means of immunohistochemical analysis with a mouse monoclonal antibody (MTM Laboratories) visualized with use of an autostainer (Ventana XT, Ventana) and a one-view secondary detection kit (Ventana). Positive p16 expression was defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells. Study End Points The primary end point was overall survival, defined as the time from randomization to death. Secondary end points included progression-free survival, defined as the time from randomization to death or the first documented relapse, which was categorized as local–regional disease (tumor at the primary site or regional nodes) or distant metastases.
Death from the primary cancer without a documented site of recurrence or death from an unknown cause was considered death from local–regional disease. Second primary tumors were evaluated separately. Progression-free survival and its components (local–regional disease and distant metastases) were reported instead of protocol-specified secondary end points (e.g., disease-free survival) to facilitate comparison with published meta-analyses.
Statistical Analysis With a sample of 720 patients, the RTOG 0129 study had 80% statistical power to detect a relative reduction of 25% in the rate of death in the accelerated-fractionation radiotherapy group as compared with the standard-fractionation radiotherapy group, assuming a 2-year rate of overall survival of 45% in the standard-fractionation radiotherapy group, with the use of a one-sided test at the 0.05 significance level. Rates of overall survival and progression-free survival were estimated by means of the Kaplan–Meier method and were compared between the two groups with the use of the log-rank test. The cumulative incidence method and Gray's test were used to estimate and compare rates of local–regional relapse, distant metastases, and second primary tumors. Cox proportional-hazards models were used to estimate hazard ratios; multivariable models were developed by minimizing Akaike's information criterion. Cox regression was performed with the use of data on tumor HPV status and smoking status, for patients for whom these data were available.
Unadjusted and adjusted hazard ratios for HPV-positive and HPV-negative status were compared between the two groups to estimate the proportion of the difference in survival that was attributable to covariates. To investigate potential bias in estimates due to missing data on HPV status, we repeated the analyses for the subgroup of patients with oropharyngeal squamous-cell carcinoma and for the entire RTOG study cohort (assuming the nonoropharyngeal squamous-cell carcinoma tumors were HPV-negative), using values imputed with the Markov chain Monte Carlo algorithm with a noninformative prior distribution (SAS/STAT software, with SAS OnlineDoc 9.1.3; SAS Institute). Twenty data sets were created, and the resulting analyses were combined per Rubin's formula. Recursive-partitioning analysis (for censored survival data) was performed with the use of S-Tree software () to identify the factors that were most influential for overall survival and to permit the classification of patients with oropharyngeal squamous-cell carcinoma as having a low, intermediate, or high risk of death. Characteristics of the Patients From July 2002 through May 2005, a total of 743 patients were enrolled in the RTOG 0129 study and randomly assigned to receive accelerated-fractionation radiotherapy or standard-fractionation radiotherapy. Analyses were restricted to the 721 patients who met the protocol study criteria (360 patients in the accelerated-fractionation radiotherapy group and the 361 patients in the standard-fractionation radiotherapy group); of the remaining 22 patients, 17 were found to be ineligible and 5 withdrew consent. The baseline characteristics of the two groups are listed in Table 1 Baseline Characteristics of the Study Patients and Their Tumors, According to Patient Group..
The majority of enrolled patients (60.1% [433 of 721]) had oropharyngeal squamous-cell carcinoma, and HPV status was determined in 74.6% of these patients (323 of 433). Tumor specimens were not available for study in 94 patients, and tissue specimens from 16 patients did not contain tumor tissue. No significant differences in baseline characteristics, overall survival, or progression-free survival were found between patients in whom HPV status was determined and those in whom it was not, arguing against significant selection bias (see the, available with the full text of this article at NEJM.org). HPV DNA was detected in 63.8% of patients' tumors (206 of the 323) by means of in situ hybridization, and 96.1% of the samples (198 of 206) were positive for HPV-16. HPV-positive oropharyngeal cancer was more common among patients who had never smoked and those with a lower number of cumulative pack-years of tobacco smoking than among those with a history of heavier smoking and was also significantly associated with several favorable prognostic factors, including younger age, white race, better performance status, absence of anemia, and smaller primary tumors ( ).
The two treatment groups were balanced with regard to tumor HPV status. Survival and Toxicity There were no significant differences between the accelerated-fractionation radiotherapy group and the standard-fractionation radiotherapy group with regard to the rate of death within 30 days after the start of therapy (3.3% and 1.9%, respectively; P=0.26) or the overall rates of grade 3 or 4 acute toxic events (80.0% and 83.7%, respectively; P=0.21) and late toxic events (25.7% and 21.1%, respectively; P=0.18). At the data cutoff point (August 2009), 418 patients were alive.
After a median follow-up of 4.8 years (range, 0.3 to 6.5), there was no significant difference in the 3-year rate of overall survival between the accelerated-fractionation radiotherapy group (70.3%; 95% confidence interval [CI], 65.6 to 75.1) and the standard-fractionation radiotherapy group (64.3%; 95% CI, 59.3 to 69.2; P=0.18). There was a nonsignificant reduction of 10% in the risk of death for the accelerated-fractionation radiotherapy group as compared with the standard-fractionation radiotherapy group (hazard ratio, 0.90; 95% CI, 0.72 to 1.13), with a similar reduction in the subgroup of patients with HPV-positive cancer (11%; hazard ratio, 0.89; 95% CI, 0.51 to 1.55) and in the subgroup with HPV-negative cancer (9%; hazard ratio, 0.91; 95% CI, 0.69 to 1.19).
The accelerated-fractionation radiotherapy group and the standard-fractionation radiotherapy group did not differ significantly with regard to progression-free survival or the pattern of relapse (see the ). HPV Status and Survival For analysis of the association of tumor HPV status with survival, we combined the data for all patients with oropharyngeal squamous-cell carcinoma, since the survival rates were similar in the two treatment groups. In a Kaplan–Meier analysis, patients with HPV-positive cancer had better overall survival and progression-free survival than patients with HPV-negative cancer (P10) and then nodal stage (N0 to N2a vs. N2b to N3), for HPV-positive tumors, or tumor stage (T2 or T3 vs.
T4), for HPV-negative tumors ( Figure 2 Classification of the Study Patients into Risk-of-Death Categories and Kaplan–Meier Estimates of Overall Survival According to Those Categories. Recursive-partitioning analysis was used to identify prognostic factors with the most influential predictive significance in a proportional-hazards model of overall survival and to classify patients into categories of low, intermediate, or high risk of death. The prognostic factors in the analysis were age, tumor stage, nodal stage, race, smoking status, HPV status, anemia status, performance status, treatment assignment, and sex. Panel A shows the resulting classifications. Panel B shows data for overall survival in the classified patients. The Kaplan–Meier curves are shown in black, and the associated 95% confidence intervals in gray. The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group.
Discussion This study provides strong evidence that tumor HPV status is an independent prognostic factor for overall survival and progression-free survival among patients with oropharyngeal squamous-cell carcinomas, which is consistent with the hypothesis that HPV-positive and HPV-negative oropharyngeal squamous-cell carcinomas are distinct and have different causes, risk-factor profiles, and survival outcomes. On the basis of our data, we believe that future clinical trials should be designed specifically for patients with HPV-positive or HPV-negative squamous-cell carcinoma of the head and neck or patients who have been stratified according to HPV status. Moreover, additional information could be gleaned from completed clinical trials, by means of reanalysis, to determine whether imbalances in tumor HPV status between treatment groups affected the outcomes and thus the therapeutic implications. Our analysis of the association of HPV status with survival was performed in a clinical trial of locally advanced squamous-cell carcinoma of the head and neck that did not show a significant difference in overall survival between a concomitant-boost accelerated-fractionation regimen of radiotherapy and a standard-fractionation regimen, combined with concurrent, high-dose cisplatin. Therefore, either regimen could serve as the comparison for a new therapy being investigated. We observed strong agreement between tumor HPV status, as determined by in situ hybridization, and expression of p16, an established biomarker for the function of the HPV E7 oncoprotein. Our HPV-16 in situ hybridization assay has sensitivity for single viral copies, and a positive result is strongly correlated with expression of the HPV E6 and E7 oncogenes — the standard for defining a tumor as being associated with HPV.
A limitation of our method is the unknown sensitivity of the probe cocktail for non–HPV-16 types, which account for an estimated 5 to 10% of HPV-positive oropharyngeal squamous-cell carcinomas. Thus, the misclassification of HPV-positive tumors as HPV-negative tumors probably explains the slightly larger reduction in the risk of death when the analysis was based on status with respect to p16 expression rather than HPV presence.
A strength of the p16-expression assay is that it is not specific for HPV type, unlike the in situ hybridization assays; therefore, p16-expression status is a very good surrogate for tumor HPV status. The superior prognosis for HPV-positive oropharyngeal squamous-cell carcinoma, as compared with that for the HPV-negative cancer, appears to have multifactorial underpinnings. Known favorable prognostic factors associated with the HPV-positive subgroup account for approximately 10% of the detected difference in outcome. The higher survival rate among patients with HPV-positive cancer is due in part to greater local–regional control, reflecting higher intrinsic sensitivity to radiation or better radiosensitization with the use of cisplatin. Although rates of response to induction chemotherapy are higher among patients with HPV-positive tumors than among those with HPV-negative tumors, single-agent cisplatin therapy did not appear to differentially affect the elimination of occult distant metastases. Second primary tumors, which are largely related to smoking, were less frequent among patients with HPV-positive tumors, a finding that is consistent with the lower exposure to tobacco in this subgroup. However, the rates of death from second primary tumors were similar in the HPV-positive and HPV-negative subgroups and therefore do not account for the overall differences in survival rates.
Our data clearly indicate that HPV status and status with respect to tobacco smoking are major independent prognostic factors for patients with oropharyngeal squamous-cell carcinoma, probably because they determine the molecular profile of the cancer and thus the response to therapy. The contents of this article are the sole responsibility of the authors and do not necessarily represent the official views of the NCI or NIDCR. Supported by grants (RTOG U10 CA21661, CCOP U10 CA37422, and P01 CA06294) from the National Cancer Institute (NCI), a grant (DE016631) from the National Institute of Dental and Craniofacial Research (NIDCR), and the Oral Cancer Foundation. Future Islands Wave Like Home Rar on this page. Provided by the authors are available with the full text of this article at NEJM.org. This article (10.1056/NEJMoa0912217) was published on June 7, 2010, at NEJM.org. References • 1 Gillison M, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus 16-negative head and neck cancers.
J Natl Cancer Inst 2008;100:407-420 • 2 Rampias T, Sasaki C, Weinberger P, Psyrri A. E6 and E7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 2009;101:412-423 • 3 Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 2007;121:1813-1820 • 4 Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial.
J Natl Cancer Inst 2008;100:261-269 • 5 Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843-854 • 6 Pignon J-P, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
Radiother Oncol 2009;92:4-14 • 7 Fleming I, Cooper J, Henson D, et al., eds. AJCC cancer staging manual. Philadelphia: Lippincott-Raven, 1997. • 8 Oken MM, Creech RH, Tormey DC, et al.
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655 • 9 Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.
Int J Radiat Oncol Biol Phys 2000;48:7-16 • 10 Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 19-1346.