Monthly Archives: February 2006

China Approves World’s First Oncolytic Virus Therapy For Cancer Treatment

  • 2/28/2006
  • Bethesda, MD
  • Ken Garber
  • Journal of the National Cancer Institute, Vol. 98, No. 5, 298-300, March 1, 2006

Oncolytic virus research got a welcome boost last November when Chinese regulators approved the world’s first oncolytic viral therapy for cancer, Shanghai Sunway Biotech’s genetically modified adenovirus H101.

“It’s fantastic for the field,” said John Bell, Ph.D., of the Ottawa Health Research Institute in Canada. “We needed to have something that was a success, and so I think this is a good first start.”

Oncolytic viruses are live viruses that selectively kill cancer cells. Shanghai Sunway Biotech expects to begin marketing H101 in July for treating head and neck cancer. The company is also testing the virus in lung cancer and has bought the rights to Onyx-15, an almost identical virus that Onyx Pharmaceuticals took into phase III trials in 2000 but later dropped after its marketing partner bailed out.

Now the Chinese effort has breathed new life into the Onyx virus. Sunway’s next step, says company president Hu Fang, M.D., is to compare it with H101 in a Chinese trial. The company will then apply to test one of the viruses in Europe and the United States. “The first choice is Onyx-15, but we can’t exclude the H101,” Hu said.

Virus Interruptus

The Chinese resurrection of Onyx-15 gives it a second chance after the aborted U.S. run that began in 1996. That year, Onyx biochemist Frank McCormick, Ph.D.—now the director of the University of California, San Francisco, Comprehensive Cancer Center—had the idea that an adenovirus without its E1B gene, which inactivates the host cell’s p53 gene, would selectively kill cancer cells. That’s because normal cells harboring the modified, defenseless virus would be subject to p53-mediated cell cycle arrest, preventing the virus from replicating. Cancer cells lacking p53 would be unable to halt viral replication and would be lysed, with the multiplied viruses bursting out to infect and destroy the entire tumor.

McCormick’s hypothesis was brilliant, but incorrect. It soon became clear that Onyx-15 was not specific for p53-null cells. But in early human trials, for then-unknown reasons, it still killed tumor cells preferentially and was superior to chemotherapy alone. Sunway’s H101 results, therefore, did not come as a surprise. In its phase III trial, Sunway reported a 79% response rate for H101 plus chemotherapy, compared with 40% for chemotherapy alone. “Those results are very similar to what we would have predicted with our phase III trial,” said David Kirn, M.D., who helped develop Onyx-15 and who now heads Jennerex Biotherapeutics in Mill Valley, Calif.

That trial barely got off the ground before it was suspended in 2000 by Pfizer, which had just acquired Onyx’s development partner, Warner-Lambert. Without funding to complete the trial on its own, Onyx discontinued the program. Kirn believes that complete phase III results would have led to U.S. Food and Drug Administration approval for Onyx-15. The virus “would have been made obsolete very quickly by much better viruses,” he said, “but … it would have been approved.” Such approval, he added, would have been “huge” for the field. Instead, the field was stigmatized, since many people assumed Onyx-15 didn’t work. “There’s this mistaken impression out there,” said Kirn. “In fact, the phase III was never done.”

Final Judgment

Sunway has now indirectly validated the Onyx approach. Hu, a former postdoctoral fellow in the laboratory of Michael Thaler, M.D., at the University of California, San Francisco, was fully aware of Onyx-15 when he formed Sunway Biotech in 1997. The company slightly modified the virus to obtain a patent in China and in 2000 began human testing. The only difference between the Chinese and American viruses is a slightly larger deletion in H101’s E3 gene, which affects immune response.

Part of H101’s success may be due to not treating manageable patient fevers in the phase III trial. After observing a high rate of responses in such patients in a phase II study, Hu reasoned that higher body temperature should aid viral replication and enhance the anticancer immune response. (Recent laboratory studies in the United States back this theory.)

Despite H101’s enhanced response rate over chemotherapy alone, the ultimate test of a drug’s worth is patient survival. Unfortunately, Sunway has not reported survival data because Chinese regulators at that time based their review on objective response rate, not survival. And although the company intends to report survival data, it can follow only a subset of the 140 evaluable patients in the phase III trial, because many of Sunway’s patients live in isolated rural areas and are never seen by their doctors again.

“This is our weakness in this clinical trial,” acknowledged Hu, who added that all current and future trials will have survival endpoints and plans for following up with patients. Approval for either H101 or Onyx-15 in Europe and the United States will depend on improving patient survival. Only then will final judgment be possible for these two adenoviruses.

A Rebounding Field

Onyx-15, in retrospect, was not the ideal oncolytic virus. For one thing, the E3 deletion probably hurt Onyx-15’s potency. “In the early days, we were all pretty naïve,” said Kirn. “We thought, ‘Boy, viruses replicate so fast, and they produce tens of thousands of virions per cell [so] you can just shoot an adenovirus in there and infect a few cells and eradicate the whole thing.’” Onyx scientists chose an E3-deleted adenovirus mutant off the shelf, not realizing their mistake until years later. “It definitely leads to more rapid clearance of the virus,” said Kirn.

Although some companies and labs continue to work with adenovirus, much of the field has switched to other viruses. “Adenovirus, it turns out now in retrospect, had a number of fundamental flaws,” said Kirn. “It spreads very slowly … and the packaging capacity to express other genes is extremely limited.” Also, adenovirus works poorly when given intravenously. Such systemic delivery is the field’s holy grail, since injecting the virus directly into primary tumors—the H101 and Onyx-15 approach—is unlikely to infect and eliminate distant metastases. “The real challenge, in cancer in general, is to get [at] disseminated disease,” said Bell. “That’s where we’re really not being successful.”

Oncolytic viruses have met that challenge in preclinical studies by eliminating metastases in animals. “We just have to move now into humans,” Bell said. He added that he hopes to eventually accomplish this move with vesicular stomatitis virus (VSV), an enveloped RNA virus that is not a human pathogen. Since VSV is sensitive to the innate immune response triggered by interferon, Bell reasoned that tumors, which evolve to become resistant to the interferon response, should be a safe haven for VSV replication, whereas VSV in normal cells would be suppressed. Using VSV mutants unable to shut down the interferon response, Bell showed in 2003 that his viruses could eradicate advanced tumors in xenograft mouse models.

Meanwhile, Jennerex is moving its genetically modified vaccinia viruses into studies in humans. Vaccinia has been used over the last century to inoculate humans against smallpox, and, like VSV, vaccinia is inherently oncolytic, replicates efficiently, and can be delivered intravenously. Jennerex has added a gene coding for granulocyte–macrophage colony-stimulating factor (GM-CSF) to stimulate immune response to the tumor and deleted the gene for thymidine kinase, required for viral replication in normal cells (but not tumors). A phase I study of one such virus at Thomas Jefferson University in Philadelphia found that five of seven patients with metastatic melanoma had an objective response at the injection site, including one complete response. Some noninjected tumors also shrank. Jennerex is now testing this virus in cancer patients with a variety of tumors. Newer versions with additional tumor-targeting qualities should enter the clinic this year.

Overcoming Obstacles

Several other academic groups and small companies have oncolytic viruses in phase I studies or late preclinical development. The main obstacle for all these therapies is the human adaptive immune response, because antibodies invariably mobilize against the oncolytic viruses themselves. Can the viruses kill tumors faster than the body’s immune system kills the viruses? “That’s the big question,” acknowledges Kirn. If the viruses fall short, giving drugs to suppress B cells, or using multiple different oncolytic viruses in succession, are possible solutions.

Safety concerns about virulent strains arising during viral replication in tumors have not entirely disappeared. Nor has the memory of the massive immune and inflammatory reaction that killed Pennsylvania teenager Jesse Gelsinger in a 1999 gene therapy trial using an adenoviral vector. But recent human oncolytic virus trials have shown consistent safety, with most unable to even reach the maximum tolerated dose. Immune and inflammatory responses, Bell pointed out, are monitored especially closely, with at least one company using small doses of virus to desensitize patients to side effects before administering the therapeutic dose.

With the success in China, the newer viruses will have more chances to prove their worth in the clinic. “The people who’ve stuck with it are now developing things that are going to … have much greater impact than the local administration of an adenovirus,” said Kirn. “It’s an exciting time in the field.”

February, 2006|Archive|

Multiagent Concurrent Chemoradiotherapy for Locoregionally Advanced Squamous Cell Head and Neck Cancer: Mature Results From a Single Institution

  • 2/28/2006
  • Cleveland, OH
  • David J. Adelstein et al.
  • Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1064-1071

A retrospective review with long-term follow-up is reported from the Cleveland Clinic Foundation studying radiation and concurrent multiagent chemotherapy in patients with locoregionally advanced squamous cell head and neck cancer.

Patients and methods:
Between 1989 and 2002, 222 patients were treated with 4-day continuous infusions of fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d) during weeks 1 and 4 of either once daily or twice daily radiation therapy. Primary site resection was reserved for patients with residual or recurrent primary site disease after chemoradiotherapy. Neck dissection was considered for patients with N2 or greater disease, irrespective of clinical response, and for patients with residual or recurrent neck disease.

With a median follow-up of 73 months, the Kaplan-Meier 5-year projected overall survival rate is 65.7%, freedom from recurrence rate is 74.0%, local control without the need for surgical resection rate is 86.7%, and overall survival rate with organ preservation is 62.2%. Including patients undergoing primary site resection as salvage therapy, the overall local control rate is 92.4%. Regional control rate at 5 years is 92.4%. Among patients with N2-3 disease, regional control was significantly better if a planned neck dissection was performed. Distant control at 5 years was achieved in 85.4% of patients and was significantly worse in patients with hypopharyngeal primary sites and patients with poorly differentiated tumors.

Concurrent multiagent chemoradiotherapy can result in organ preservation and cure in the majority of appropriately selected patients with locoregionally advanced, nonmetastatic, squamous cell head and neck cancer. Distant metastatic disease was the most common cause of treatment failure. Late functional outcomes will require further investigation.

David J. Adelstein, Jerrold P. Saxton, Lisa A. Rybicki, Ramon M. Esclamado, Benjamin G. Wood, Marshall Strome, Pierre Lavertu, Robert R. Lorenz, Marjorie A. Carroll

Authors’ affiliations:
From the Departments of Hematology and Medical Oncology, Radiation Oncology, Biostatistics, and Otolaryngology and Communicative Disorders, The Cleveland Clinic Foundation; and the Department of Otolaryngology and Head and Neck Surgery, University Hospitals of Cleveland, Cleveland, OH

February, 2006|Archive|

Treatment of Advanced Head and Neck Cancer: What Lessons Have We Learned?

  • 2/27/2006
  • East Lansing, MI
  • Barbara A. Conley
  • Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1023-1025

Treatment of advanced squamous cell cancers of the head and neck (HNSCC) can be a frustrating endeavor. Early diagnosis may be missed by delay on the part of patients or their physicians and dentists. Patients are often elderly and have multiple medical or social comorbidities. HNSCC is an interdisciplinary disease, with optimum management requiring the input of the medical, radiation, and surgical oncologist, as well as pathologist, dentist, speech pathologist, social worker, and a dedicated home caregiver. The necessary specialists for optimum management may not be present near the patient’s home, necessitating ad hoc clinical teams or further delay and dislocation of the patient and caregiver for an extended treatment period.

Numerous phase II and phase III studies have been performed with the hope of improving survival and preserving organ function in locally advanced disease. We now know that survival is improved by radiation administered concurrent with chemotherapy, but there are added toxicities.1 We also know that radiation with chemotherapy can result in survival that approximates the survival obtained by radical surgery followed by radiation therapy, especially if surgical salvage is performed at early signs of residual or recurrent disease.2,3 We know less about what the optimal radiation regimen or chemotherapy regimen should be for an individual patient.

Currently, standard therapy for locally advanced HNSCC could be radiation administered daily, twice daily, or in a concomitant boost regimen, with or without intensity-modulated radiation therapy, together with a platinum-based chemotherapy. When complete response is obtained, a planned neck dissection is often performed in those patients whose disease was at least N2 at presentation. If complete response is not obtained, resection of the primary and/or regional nodes is performed as is feasible. Standard care could also be surgery, followed by radiation therapy with or without concurrent chemotherapy. These modalities generally result in a 5-year survival rate of 20% to 65%, depending on stage and primary site. The choice of treatment is often dictated by the primary site, patient preferences (eg, organ preservation), and the experience of the treatment team.

Survival has slightly improved over that seen before 1990.4 Complete response and local control are generally high with combined-modality treatments. However, chemoradiotherapy is associated with severe acute toxicities, with approximately 80% of patients requiring a feeding tube during treatment. Late toxicities, such as loss of salivary function and soft tissue fibrosis, can lead to difficulty in speaking and eating. Over half of these patients are permanently disabled from work.5 Our goals must include not only improved survival but also reduction in morbidity.

The term unresectable is somewhat subjective and depends on the experiences of the treatment team, as noted in the article published in this issue by Adelstein et al.6 This review of the clinical experience of this consistent multidisciplinary team also notes the following: (1) some patients, notably those with oral cavity tumors, organ destruction, or bony involvement, are not considered for chemoradiotherapy therapy and are managed preferentially by surgery; (2) there was only one toxic death among 222 patients, although hospitalization was frequently required for hydration, antiemetics, and other supportive care; (3) local control, overall survival, and organ preservation could not be predicted by nodal status, stage, or primary site; (4) recurrence was more commonly distant than locoregional and correlated with hypopharyngeal primary site and poorly differentiated histology; and (5) 5-year projected survival rate was 65.7%, with a regional control rate of 92.4%. These data can be compared with a report from Brockstein et al7 of a series of trials carried out by this Chicago-based consortium. They noted that T and N stage independently predicted locoregional recurrence and overall survival, respectively, for patients treated with a regimen of concurrent chemoradiotherapy. In their series, the treating institution was also a significant factor for locoregional failure. Primary site was not investigated as a potentially significant prognostic factor. Overall 5-year survival rate was 47%. Hitt et al8 have published a phase III multicenter trial comparing induction regimens of cisplatin and fluorouracil with or without paclitaxel followed by chemoradiotherapy in responders and have found that the triple chemotherapy resulted in higher complete response rates but only improved overall survival in the group with unresectable disease.

As mentioned in the article by Adelstein et al6 in this issue, there may be selection bias in a referral center, with patients referred only if they have exceptional performance status. Note that in this report, the 5-year projected survival rate is 65.7%, whereas in the chemoradiotherapy arm of the intergroup trial comparing standard radiation and two schedules of concurrent chemoradiotherapy in patients with unresectable HNSCC, the 3-year projected survival rate for the best arm, cisplatin concurrent with radiation, is 37%.9 In the multicenter study by Hitt et al,8 the projected 5-year survival rate of the best arm is 45% to 50%.

Adelstein et al6 found that stage alone is not a predictor for efficacy of combined-modality treatment. As in other malignancies, analysis of the molecular characteristics of HNSCC has been undertaken to search for better prognostic and/or predictive factors, as well as for new therapeutic targets.

Epidermal growth factor receptor (EGFR) is overexpressed in the majority of HNSCC, and its expression has been noted as a prognostic factor for response in both radiation and chemoradiotherapy. Pivot et al10 found that lower EGFR levels predicted better disease-free interval in patients with laryngeal and hypopharyngeal cancers treated with induction chemotherapy followed by radiation. Hitt et al11 reported similar findings in their study of induction chemotherapy followed by chemoradiotherapy. Ang et al,12,13 using tissue samples from a phase III Radiation Therapy Oncology Group trial of radiation alone, noted that EGFR expression was a significant adverse prognostic factor for locoregional control and survival for patients treated with radiation. Recently, lower EGFR expression seemed to be predictive for response to cetuximab in relapsed HNSCC.14 Given these data and the favorable data on toxicity with the combination of cetuximab with radiation or chemotherapy,14-17 proceeding with a combination of radiation, chemotherapy, and cetuximab is a logical next step. However, Pfister et al18 have reported in this issue that cetuximab combined with cisplatin concurrent with concomitant boost radiation was too toxic to recommend at this time. There is some doubt that the two grade 5 toxicities and three other serious adverse effects seen were a result of the treatment. There was one fatal pneumonia, one bacteremia (in a patient with a port), one myocardial infarction, one atrial fibrillation, and one death from unknown cause among the 22 enrolled patients. Although a death rate of two of 22 patients is clearly of concern, the decision to stop the trial was difficult because any of these events could have occurred despite the chemoradiotherapy treatment. A phase I trial was not performed for this combination, but with the typical dose-escalation schema in a small number of patients (three to five per cohort), these events may not have been discerned. Serum concentrations of cetuximab had no correlation with toxicity. Cisplatin has been reported not to impact the pharmacokinetics of cetuximab.19 Although serum concentrations of cisplatin were not measured, the reported toxicities were not typical for cisplatin. Unfortunately, a safe and convenient method to assess impact of drug(s) or radiation on potential targets does not presently exist. For further elucidation, we await results from other trials of cetuximab with chemoradiotherapy.

To minimize toxicity and improve efficacy in HNSCC, we need to redouble our efforts to find appropriate predictive and prognostic features that can be used to choose and modify the treatment given. With more than 80% of patients experiencing severe toxicity with current regimens, as well as enduring long-term effects from treatment, relapse, or metastasis, we clearly need to investigate agents directed to biologic targets of this disease and to enter patients onto trials on the basis of molecular or other characteristics that optimize the chance for success.


1. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data—MACH-NC Collaborative Group: Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949-955, 2000
2. Department of Veterans Affairs Cooperative Laryngeal Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991
3. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:855-856, 1996
4. Ries LAG, Eisner MP, Kosary CL, et al (eds): SEER Cancer Statistics Review, 1975-2002, National Cancer Institute, Bethesda, MD.
5. Taylor JC, Terrell JE, Ronis DL, et al: Disability in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 130:764-769, 2004
6. Adelstein DJ, Saxton JP, Rybicki LA, et al: Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: Mature results from a single institution. J Clin Oncol 24:1064-1071, 2006
7. Brockstein B, Haraf DJ, Rademaker AW, et al: Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: A 9-year, 337 patient, multi-institutional experience. Ann Oncol 15:1179-1186, 2004
8. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23:8636-8645, 2005
9. Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-98, 2003
10. Pivot X, Magne N, Guardiola E, et al: Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer. Oral Oncol 41:320-327, 2005[CrossRef][Medline]
11. Hitt R, Ciruelos E, Amador ML, et al: Prognostic value of the epidermal growth factor receptor (EGRFsic) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction therapy. Eur J Cancer 41:453-460, 2005
12. Ang KK, Berkey BA, Tu X, et al: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350-7356, 2002
13. Ang KK, Andratschke NH, Milas L, et al: Epidermal growth factor receptor and response of head and neck carcinoma to therapy. Int J Radiat Oncol Biol Phys 58:959-965, 2004
14. Burtness B, Goldwater MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group Study. J Clin Oncol 23:8646-8654, 2005
15. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005[Abstract/Free Full Text]
16. Herbst RS, Arquette M, Shin DM, et al: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23:5578-5587, 2005
17. Bonner JA, Giralt J, Harari P, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of the head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22(suppl):488, 2004
18. Pfister DG, Su YB, Kraus DH, et al: Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 24:1072-1078, 2006
19. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000

February, 2006|Archive|

Many patients survive cancer but still suffer from the cures

  • 2/27/2007
  • Norfolk, VA
  • Nancy Young

Freddie Cano had cancer. He doesn’t anymore.

In 1998, he noticed a lump on his neck. It turned out to be a tumor at the base of his tongue that wrapped all the way around his left carotid artery.

Surgery, chemotherapy, radiation and success followed. The cancer was killed.

But the treatment that vanquished the cancer also destroyed Cano’s salivary glands, so he constantly drinks water to keep his mouth from getting dry. It takes longer to eat, because of scar tissue in his throat that must periodically be thinned. For a time after the treatment, one foot “dropped” when he walked. “The chemo was short-circuiting the brain waves to my feet.”

The dream, Cano said, is “the treatments end and everything is fine again. It doesn’t happen.”

Like many cancer survivors, he’s not complaining about the side effects. The Norfolk resident is just happy about the main effect: He’s alive and making the most of it. He recently celebrated his 60th birthday by getting his first tattoo, a Navy anchor, on his left biceps.

But whether they complain or not, there’s growing concern that cancer survivors are not getting the care they need to live the fullest lives possible. In the past few years, national organizations including the Institute of Medicine and the Lance Armstrong Foundation have called for more systematic long-term follow-up for adult cancer survivors.

In the United States, men have a nearly 50-50 chance of developing cancer in their lifetimes, while for women it’s 1 in 3.

However, as preventive screenings catch the disease earlier and treatments have become more effective, a cancer diagnosis is no longer a likely death sentence.

The ranks of survivors have grown from about 3 million in the early 1970s to more than 10 million today. Last month, health officials announced the number of U.S. cancer deaths dropped in 2004, the most recent year for which statistics are available. That was the second straight year deaths declined, and it was hailed as the best sign yet that the tide has turned in the fight against the disease.

Having cancer can be a life-changing experience for the better, survivors say.

“Some people go a little bit crazy, the second chance of life,” Cano said. “I had a 30 percent chance to survive the next five years, and I’m eight years out.”

But survival comes at a cost. Surgery, powerful doses of chemotherapy and radiation can take a toll years or even decades later, resulting in problems such as secondary cancers, structural changes in the brain, infertility and diabetes.

“The cancer looks like it’s gone,” said Dr. Daniel Karak-la, a head and neck surgeon at Eastern Virginia Medical School who specializes in oncology. “That’s just the beginning of the story.”

And there’s more than just physiological side effects. Survivors also can experience long-lasting emotional problems and a perpetual sense of being lost. Where to find help is not as clear as it was during their active treatment – when there’s a systematic plan, protocols to follow and a team of medical professionals overseeing them.

“What I’m thinking now is we’re supposed to be doing the happy dance,” Carolyn Lawson of Morgans Corner, N.C., said at a support group at Chesapeake General Hospital earlier this month.

Lawson, 56, is nearing the end of her treatment for breast cancer. Her husband completed treatment for esophageal cancer last year. But the battles have left them scarred.

“Honey, even if you’re doing well, you can still feel sad,” Molly Feanny told Lawson. A 35 -year-old Chesapeake resident, Feanny has been fighting advanced non-Hodgkins lymphoma for four years. “There’s still a loss…. Life is never going to be the same after this.”

Cano, who is retired from the Navy, has found new life after the cancer by helping others. He volunteers with Lee’s Friends, a local group that helps cancer patients with many needs, including transportation to medical appointments. His connections have kept him up-to-date on treatments. For example, he’ll tell you there’s now medicine that can prevent the destruction of the salivary glands from radiation therapy.

“Every year they come up with more stuff,” Cano said. “It just keeps getting better and better.”

Cancer specialists are increasingly thinking about long-term side effects before treatment begins.

When patients in their 30s come in for the first time, “I think, ‘What can I do so that in their 70s they can have as good a life as possible?’ ” said Dr. Mark Sinesi, chairman of the Radiation Oncology and Biophysics Department at EVMS. “We need to be as hard as we can on the cancer but as easy as we can on the person.”

Sinesi said the evolution of cancer care has given doctors the ability to mix and match treatments for a “superadditive” effect – one that kills cancer but minimizes the long-term side effects.

Some cancer treatments have well-known negative effects. For example, in testicular cancer, the radiation will almost certainly permanently destroy sperm production.

“We talk about that on the first visit so that they can bank sperm” if patient s want to have children later in life, said Dr. Paul Conkling, a medical oncologist at Virginia Oncology Associates in Norfolk.

Just how treatments will play out is often far from clear, however. New therapies are constantly being developed, and even those in use for some time have effects that aren’t immediately evident. Tamoxifen, a drug that can be effective in preventing recurrences of breast cancer, carries with it an increased risk of uterine cancer.

“We weren’t aware of that until it had been around for 15 years,” Conkling said. “It took a long time just to have enough data.”

Keeping up is challenging enough for oncologists. It’s even more difficult for primary care doctors, generalists who typically inherit the treatment of cancer survivors.

The relationship with a family doctor is crucial, said Dr. Cynthia Romero, a primary care physician in Virginia Beach.

Romero said that after her patients go for cancer treatment, often they call to see what she thinks or to ask questions they didn’t think about asking their oncologists.

“It hits you two hours later when you’re home lying in bed. I t hits you a week later,” Romero said. “We let them talk, then give them the resources they need to go beyond that discussion.”

When the cancer treatment is done, Romero said, her approach is, “Let’s get you back on track and get your whole health back together.”

A team approach involving specialists such as nutritionists and social workers, in addition to oncologists and family physicians, is key, Karakla said.

How long should cancer survivors get follow-up care?

“Forever,” Sinesi said. He said he gives his patients his cell phone number so they can call anytime with questions.

Too often, though, cancer patients get lost.

Ray and Wilhelmina Pearson had beaten cancer once, when Ray had his prostate removed in 1994.

“The way it was presented, once they took it, you were done with it,” Wilhelmina said. The Virginia Beach couple, who retired from teaching last year, went about their lives.

In 2005, they discovered the cancer had returned and had spread throughout his body.

At the low point of his second bout with cancer, Ray told his wife of 43 years to “just let me go.”

Though his condition has improved, the experience taught the Pearsons the importance of being more active in their care and finding doctors with whom they communicate well.

After his prostate surgery, Ray said, he wasn’t vigilant enough about scheduling follow-up tests and didn’t keep track of what they showed.

Long-term survivors at the late-effects cancer clinic at Children’s Hospital of The King’s Daughters in Norfolk don’t have to worry about those details. They know exactly what treatments they had, in what doses, and what to watch out for over the long haul. On their annual visits, they’re given a treatment summary they can share with all their doctors.

Only a few places in the country do for adult survivors of cancer what CHKD does for survivors of childhood cancers.

But Dr. Rebecca Byrd, who directs the late-effects clinic, is scheduled in March to give a lecture to physicians at EVMS. In it, she hopes to plant the seeds that could lead to CHKD’s patients getting the kind of attention as adults that they become accustomed to as children.

In Congress, some lawmakers are thinking along the same lines. Earlier this month, U.S. Rep. Tom Davis, R-Va., co-sponsored bipartisan legislation that would require Medicare to pay for the development of treatment plans for cancer survivors.

Such a treatment summary was at the center of 19-year-old Joe Buterbaugh’s annual checkup at CHKD’s clinic in January.

Buterbaugh, of Elizabeth City, N.C., was 6 when he was diagnosed and successfully treated for a rare cancer, known as Ewing’s sarcoma, in his leg.

Buterbaugh’s mother, Jenny Buterbaugh, said she gets anxious before the checkups, dreading bad news. But without the clinic, “it would get hard because it’s like, ‘Where do we go now?’ We wouldn’t know what to do.”

The news wa s good for Joe Buterbaugh – no return of the cancer. He’s generally healthy, though he’s on medicine for his heart and kidneys, which were damaged during his cancer treatment.

“The ifosfamide is probably what you can thank for your kidney problems,” said nurse Ellen Vasser, referring to one of the chemo drugs that helped save Buterbaugh’s life.

Vasser, the nurse coordinator of the CHKD clinic, went over Buterbaugh ‘s treatment summary. The document will be especially helpful to him when he reaches age 21 and no longer qualifies for the CHKD program.

Buterbaugh noted that one leg is noticeably smaller than the other. “Is there anything that can be done about that?”

Vasser said his legs will probably never be equal – and that, because of the increased risk of fracture, he should avoid lifting heavy weights. B ut he could try strengthening his legs with elastic bands used in Pilates and other exercise classes, she said.

The clinic also focuses on the non medical aspects of being a cancer survivor. Karen McKinley, an oncology social worker, asked how Buterbaugh is doing in school. She warned that, as a long-term effect of his treatment, he might have trouble concentrating.

He looks so healthy that teachers may not think about the cancer. “They think about it when you’re bald,” because of losing hair during chemo, “but then they forget,” McKinley said.

Buterbaugh said he still feels “frustrated” mostly, and his little problems get amplified by the “big things.”

“You’re going to have bumps in the road because of the treatment,” McKinley said. “You want to work on them right away so they don’t become overwhelming.”

She asked Buterbaugh to give her three wishes. If he could have anything in the world, what would it be?

His first wish was to have never had cancer, to go back “to the past, maybe when I was 6 years old,” he said. “Yeah, that’d be one of them.”

The second wish came quickly: “And a cure for it.”

Buterbaugh was stumped on the third. McKinley gave him the option of telling her next year when they’ll do it all again.

“I’ll probably save the last wish,” he said.

February, 2006|Archive|

Silibinin Inhibits Invasion of Oral Cancer Cells by Suppressing the MAPK Pathway

  • 2/25/2006
  • Taiwan
  • P.N. Chen et al.
  • This Article

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Here, we provide molecular evidence associated with the anti-metastatic effect of silibinin by showing a marked inhibition of the invasion and motility of SCC-4 tongue cancer cells, with 89% and 66.4% of inhibition, respectively, by 100 µM of silibinin.

This effect was associated with a reduced expression of MMP-2 and u-PA, together with an enhanced expression of TIMP-2 and PAI-1. Silibinin also exerted an inhibitory effect on the phosphorylation of ERK1/2. Additionally, pre-treatment of SCC-4 cancer cells with 10 and 20 µM of U0126, a specific MEK inhibitor, resulted in a reduced expression of MMP-2 (18.7 and 51.4%) and u-PA (19.2 and 48.9%) concomitantly with a marked inhibition of cell invasion (13.7 and 45.7%).

Finally, silibinin was evidenced by its inhibition of the metastasis of Lewis lung carcinoma (LLC) cells in vivo. These results suggested that silibinin can reduce the invasion and metastasis of tumor cells, and such a characteristic may be of great value in the development of a potential cancer therapy.

P.-N. Chen1,2, Y.-S. Hsieh1,a, C.-L. Chiang2, H.-L. Chiou3, S.-F. Yang1, and S.-C. Chu2,a

Authors’ affiliations:
1 Institute of Biochemistry,
2 Department of Food Science, Central Taiwan University of Science and Technology, No. 11 Pu-tzu Lane, Pu-tzu Road, Taichung 406, Taiwan
3 School of Medical Technology, Chung Shan Medical University, No. 110, Section 1, Chien Kuo N. Road, Taichung 402, Taiwan; and

February, 2006|Archive|

ImClone Systems Issues Statement Regarding Positive Opinion from CHMP for Use of ERBITUX(R) in Head and Neck Cancer

  • 2/23/2006
  • Larchmont, NY
  • press release
  • Genetic Engineering News (

ImClone Systems Incorporated today issued the following statement regarding the announcement that Merck KGaA, Darmstadt, Germany, has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the EMEA (European Medicines Agency), for its application to extend the use of ERBITUX(Cetuximab), an IgG1 monoclonal antibody, to the treatment of squamous cell carcinoma of the head and neck (SCCHN):

“We are pleased that our partners, Merck KGaA, may soon be able to offer ERBITUX to head and neck cancer patients in the European Union. This is the first new modality of treatment for this disease state since chemoradiation began use over thirty years ago,” stated Eric K. Rowinsky, M.D., Chief Medical Officer of ImClone Systems.

The CHMP opinion recommends marketing authorization by the European Commission for the use ERBITUX in combination with radiation in patients with locoregionally advanced SCCHN. The license application is based on the results from a randomized, international phase III trial (IMCL-9815), conducted by ImClone Systems and Merck KGaA, which examined the impact of combining ERBITUX with radiation on locoregional control and overall survival in 424 patients with locally or regionally advanced SCCHN.

About Head and Neck Cancer

In Europe alone, around 100,800 people are diagnosed with head and neck cancer and almost 40,000 die from the disease every year.(1) Head and neck cancer is the sixth most frequently occurring cancer worldwide.(2) Head and neck cancer includes cancers of the tongue, mouth, salivary glands, pharynx, larynx, sinus, and other sites located in the head and neck area. About 90 percent of head and neck cancers are of the squamous cell variety(3) and nearly all express epidermal growth factor receptor (EGFR), which is critical for tumor growth.(4)

About ERBITUX(R) (Cetuximab)

On February 12, 2004, the FDA approved ERBITUX for use in the United States in combination with irinotecan in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. The effectiveness of ERBITUX for the treatment of colorectal cancer is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in metastatic colorectal cancer patients.

ERBITUX binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.

Important Safety Information

Severe infusion reactions, rarely fatal and characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension, have occurred in approximately 3% (20/774) of patients with the administration of ERBITUX. Most reactions (90%) were associated with the first infusion of ERBITUX despite the use of prophylactic antihistamines. Severe infusion reactions require immediate and permanent discontinuation of ERBITUX therapy. Caution must be exercised with every ERBITUX infusion as there were patients who experienced their first severe infusion reaction during later infusions. A 1-hour observation period is recommended following the ERBITUX infusion. Longer observation periods may be required in patients who experience infusion reactions.

Severe cases of interstitial lung disease (ILD), which was fatal in one case, occurred in less than 0.5% of 774 patients receiving ERBITUX.

Dermatologic toxicities, including acneform rash (11% of 774 patients, grade 3/4), skin drying and fissuring, inflammatory or infectious sequelae (e.g., blepharitis, cheilitis, cellulitis, cyst) and paronychial inflammation (0.4% of 774 patients, grade 3) were reported. Sun exposure may exacerbate any skin reactions.

Hypomagnesemia has been reported with ERBITUX when administered as a single agent and in combination with multiple different chemotherapeutic regimens. The incidence of hypomagnesemia (both overall and severe (NCI CTC grades 3 & 4)) was increased in patients receiving ERBITUX alone or in combination with chemotherapy as compared to those receiving best supportive care or chemotherapy alone based on ongoing, controlled clinical trials in 244 patients. Approximately one-half of these patients receiving ERBITUX experienced hypomagnesemia and 10-15% experienced severe hypomagnesemia. Electrolyte repletion was necessary in some patients, and in severe cases, intravenous replacement was required. Patients receiving ERBITUX therapy should be periodically monitored for hypomagnesemia, and accompanying hypocalcemia and hypokalemia during, and up to 8 weeks following the completion of, ERBITUX therapy.

Other serious adverse events associated with ERBITUX in clinical trials (n=774) were fever (5%), sepsis (3%), kidney failure (2%), pulmonary embolus (1%), dehydration (5% in patients receiving ERBITUX plus irinotecan, 2% receiving ERBITUX as a single agent) and diarrhea (6% in patients receiving ERBITUX plus irinotecan, 0.2% with ERBITUX as a single agent).

Additional common adverse events seen in patients receiving ERBITUX plus irinotecan (n=354) or ERBITUX as a single agent (n=420) were acneform rash (88%/90%), asthenia/malaise (73%/48%), diarrhea (72%/25%), nausea (55%/29%), abdominal pain (45%/26%), vomiting (41%/25%), fever (34%/27%), constipation (30%/26%) and headache (14%/26%).

Full prescribing information, including boxed WARNING regarding infusion reactions, is available upon request or by visiting


1. April 2002.

2. Hunter KD et al. Profiling early head and neck cancer. Nat Rev
Cancer. 2005 Feb; 5 (2): 127-35.

3. Bourhis J and Pinto H. Redefining ‘State of the Art’ in Head
and Neck Cancer. Oral presentation, 6th International
Conference on Head and Neck Cancer 7-11 August 2004.

4. Forastiere A, Koch W, Trotti A, Sidransky D, et al. Head and
neck cancer. N Engl J Med 2001:345(26), 1890-1900.

February, 2006|Archive|

No pills to swallow with this treatment

  • 2/23/2006
  • Tampa Bay, FL
  • Christine R. Vaughn
  • Largo Leader (

For the estimated 15 million people in the U.S. diagnosed with dysphagia, the act of swallowing is a tremendous challenge. Taking a bite of a juicy steak or savoring the taste of a warm chocolate chip cookie is an unattainable pleasure of the past for such patients.

It was a tedious recovery for Phyllis Hamel, a former patient at East Bay Nursing Center. After respiratory failure, Hamel required a tracheotomy, which affected her ability to swallow. She could not eat or drink without choking. Most of her nutrition was given through a feeding tube inserted in her stomach.

At the nursing center, Hamel was treated with VitalStim Therapy, which is used in the treatment of swallowing disorders. Her muscles were re-educated to help her swallow properly.

“I noticed a difference after just a few sessions,” she said.

At the end of 15 sessions, Hamel was able to return home, where she is eating all her favorite foods again and has a nearly complete return of her muscle function.

The treatment was developed by Marcy Freed, a speech-language pathologist. The procedure utilizes electrodes placed on the neck, similar to those used during an EKG. The device sends a low-current electrical impulse that stimulates the nerve supply to the oropharyngeal muscles. Patients receive up to one hour of therapy each day until their swallowing function is restored to an acceptable level. It is the only such method cleared by the FDA to treat dysphagia and has been used successfully for more than 10 years.

However, many in the medical field regard the technique as too new or are unfamiliar with swallowing therapy.

Liz Boozer, a speech-language pathologist at the facility, is certified in the therapy. Since November, she has treated about 50 patients using the innovative technique.

“All of their conditions were upgraded and they all showed an improvement in their diet consistency,” Boozer said.

Outpatients generally are scheduled for three sessions a week.

“We see good results in the first three sessions,” she said.

Boozer fixes the problem by modifying the patient’s diet and correcting the reason for the swallowing problem with the therapy, she said.

Boozer has a master’s degree in speech and language pathology from the University of South Carolina. She is also certified by the American Speech/Language and Hearing Association.

Patients with dysphagia have difficulty or experience pain with swallowing. It is associated with multiple conditions and forms of debilitating neuromuscular diseases such as traumatic brain injury, amyotrophic lateral sclerosis, Parkinson’s and Alzheimer’s diseases, multiple sclerosis, and dementia. Almost 75 percent of stroke survivors develop some form of dysphagia.

Among those patients who undergo radiation therapy as a result of head and neck cancer, 75 percent also will develop dysphagia. It is not limited by age, since many infants are born with swallowing disorders.

It is estimated that almost 60,000 people die each year as a result of complications from dysphagia, and only 22 percent of patients affected by the condition are referred for swallowing evaluation, leaving feeding tube insertion as a primary medical intervention.

As the baby-boomer population ages, the problem is expected to escalate.

“We set up the VitalStim program because we wanted to give our patients an opportunity to get better and to know there is hope for their problem,” said Vesta Loucks, a nurse who is director of admissions at East Bay Nursing Center.

February, 2006|Archive|

Multikine Treatment Increases Survival in Cancer Patients

  • 2/22/2006
  • Vienna, VA
  • press release
  • PRNewswire (

CEL-SCI Corporation announces positive results from a long-term follow-up study of head & neck cancer patients treated with its drug Multikine(R) in a Phase II clinical trial. The follow-up study indicated that Multikine treatment resulted in a substantial increase in the survival of patients. In addition, Multikine treatment also improved local regional control of the patients’ tumors. Improved local regional control of the tumor is considered by many surgeons and oncologists to be an important measurement of the success of a head & neck cancer drug. Both survival and local regional control of the tumor are stated endpoints in CEL-SCI’s planned Phase III clinical trial.

The Phase II study, which used the same Multikine treatment protocol as proposed for the Phase III trial, included advanced primary head & neck cancer patients who were scheduled for their first cancer treatment. The Multikine treatment was administered for 3 weeks prior to the standard treatment for head & neck cancer, surgery or surgery plus radiation/chemotherapy. Results from this study were published in a leading cancer publication, the Journal of Clinical Oncology (Timar et al, JCO, 23(15): May 2005)

The median follow-up period for the patients was 3.2 years. The results of the Phase II trial follow-up study showed that the Multikine-treated patients had substantially increased survival rates and achieved a higher rate of 2-year local regional control as compared to the survival and the 2-year local regional control rates published in the scientific literature (39 clinical trials between 1987 and 2004 in a similar population of head & neck cancer patients). At this time, CEL-SCI cannot provide the detailed results of this long-term follow-up study of Multikine treatment as the data are currently being prepared for publication.

Maximilian de Clara, President of CEL-SCI, states, “These results suggest that Multikine has the potential to bring much needed benefit to patients with head & neck cancer, a disease that has significant morbidity and mortality and for which there has been little improvement in therapy over the last 20 years. We are very excited by these results and hope to repeat these very promising results in our Phase III clinical trial.”

CEL-SCI received the go-ahead for its proposed Phase III trial from the Canadian drug regulatory authority in August 2005. The same proposed Phase III trial was submitted to and discussed with the United States Food and Drug Administration (FDA) in two separate End of Phase II meetings held during 2005. Following each of these meetings the FDA requested that additional information be provided. CEL-SCI has recently completed the submission of all of the additional information the FDA requested and awaits the FDA’s response.

Head and neck cancer is an aggressive cancer that affects about 500,000 people per annum worldwide. About 92% of those cases are outside of the U.S., and about two thirds of all cases present with advanced disease.

Multikine is a patented immunotherapeutic agent consisting of a mixture of naturally occurring cytokines, including interleukins, interferons, chemokines and colony-stimulating factors, currently being developed for treatment of cancer.

February, 2006|Archive|

The sentinel node in cancer of the oral cavity, pharynx and larynx

  • 2/21/2006
  • Poland
  • D Mielcarek-Kuchta et al.
  • Otolaryngol Pol, January 1, 2005; 59(5): 683-8

Aim of the Study:
The evaluation of the importance of the prognostic of sentinel node biopsy in head and neck cancer with N0 neck.

Material and Methods:
Prospective study included 19 patients with squamous cell carcinoma of the oral cavity, pharynx and larynx without enlarged lymph nodes in ultrasound examination (N0). The study was carried out in ENT Department of Medical University in Pozna between 2001-2004. Each patient underwent lymphoscintigraphy after administration of radionuclide Technetium 99m (Nanocol). In case of detection of sentinel node, blue dye was injected into the tumour bed and dyed lymph nodes were removed. The specimens were evaluated histologically and immunohistochemically. The patients are still followed up.

So far 19 patients were included in our study. The tumours were classified from T1 to T4. In each case sentinel nodes were located. Metastases in removed lymphnodes were found in 5 patients. In one of them regional recidive was observed after 5 month. In the other patients no changes were found in follow up examination. In 14 cases in histological examination no metastases were found in sentinel nodes. In this group in one case local recurrence was observed and in another two lymph nodes metastases were confirmed. In patients with positive sentinel node elective neck dissection was performed. So far immunohistochemical examination has not provided us with any vital information. In no case with negative sentinel node we found micrometastases with the use of cytokeratin.

Based on our preliminary observation of the patients we have found that there is certain correlation confirming the fact that sentinel node may be reliable for the whole neck lymphatic system. Further clinical observation are needed based on a larger number of patients and longer observation period.
Publication Type:

D Mielcarek-Kuchta, W Szyfter, J Manasterskil, J Kaczmarek, JG Wojtowicz, and R Czepczynski

Authors Affiliation:
Katedra i Klinika Otolaryngologii i Onkologii Laryngologicznej AM w Poznaniu

February, 2006|Archive|

Spit Hides Clues to Disease

  • 2/19/2006
  • St. Louis, MO
  • Dan Ferber
  • ScienceNow Daily News (

Human saliva contains telltale markers of breast cancer, diabetes, and an autoimmune disease, according to new results presented here today at annual meeting of the American Association for the Advancement of Science (which publishes ScienceNOW). If the findings are validated in clinical trials, spit tests could make up a new non-invasive way to quickly diagnose these diseases.

To form saliva, the salivary gland uses the soluble component of blood, known as serum, as its starting material. Physicians have dreamed for years of using saliva-based tests instead of blood tests. Among other conveniences, such a shift would remove the need for needles. Last year, oral biologist David Wong of the University of California, Los Angeles, and his colleagues reported progress toward one saliva test, showing that levels of four of the 3000 messenger RNA molecules typically found in human saliva were consistently elevated in oral cancer patients, but not in healthy patients. Recently, the UCLA team had an accuracy of 94% when attempting to diagnose oral cancer in 320 patients using these 4 RNAs as markers.

But oral cancer was just the beginning. At the meeting yesterday, Wong reported that his team has also examined the saliva from groups of 10 people with either type II diabetes, breast cancer, or Sjogren’s syndrome, an autoimmune disease that afflicts mostly women and destroys the salivary gland and pancreas. By using a gene chip to compare the salivary RNA of people in each disease group to that of 10 healthy people, the researchers found candidate RNA markers linked to Sjogren’s syndrome (26 RNAs), type II diabetes (126 RNAs), and breast cancer (103 RNAs). Each set of candidate markers now needs to be tested in larger groups of patients to see if it can be used to accurately diagnose the corresponding disease.

The researchers have also developed a prototype hand-held device that uses nanotechnology to test tiny droplets of saliva for the presence of specific saliva RNA molecules. Wong plans to find a company to help develop a hand-held device that could test saliva in 20 minutes for Sjogren’s syndrome, oral cancer, breast cancer, and type 2 diabetes.

“It’s very exciting,” says oral biologist James Melvin of the University of Rochester School of Medicine and Dentistry in New York State. “It means that potentially any disease will have biomarkers in saliva.”

February, 2006|Archive|