Plasmonic nanobubbles can detect and kill only cancer cells

Author: staff

The first preclinical study of a new Rice University-developed anti-cancer technology found that a novel combination of existing clinical treatments can instantaneously detect and kill only cancer cells — often by blowing them apart — without harming surrounding normal organs. The research, which is available online this week Nature Medicine, reports that Rice’s “quadrapeutics” technology was 17 times more efficient than conventional chemoradiation therapy against aggressive, drug-resistant head and neck tumors. The work was conducted by researchers from Rice, the University of Texas MD Anderson Cancer Center and Northeastern University.

“We address aggressive cancers that cannot be efficiently and safely treated today,” said Rice scientist Dmitri Lapotko, the study’s lead investigator. “Surgeons often cannot fully remove tumors that are intertwined with important organs. Chemotherapy and radiation are commonly used to treat the residual portions of these tumors, but some tumors become resistant to chemoradiation. Quadrapeutics steps up when standard treatments fail. At the same time, quadrapeutics complements current approaches instead of replacing them.”

Lapotko said quadrapeutics differs from other developmental cancer treatments in that it radically amplifies the intracellular effect of drugs and radiation only in cancer cells. The quadrapeutic effects are achieved by mechanical events — tiny, remotely triggered nano-explosions called “plasmonic nanobubbles.” Plasmonic nanobubbles are non-stationary vapors that expand and burst inside cancer cells in nanoseconds in response to a short, low-energy laser pulse. Plasmonic nanobubbles act as a “mechanical drug” against cancer cells that cannot be surgically removed and are otherwise resistant to radiation and chemotherapy.


In prior studies, Lapotko showed he could use plasmonic nanobubbles alone to literally blow cells apart. In quadrapeutics, his team is using them to detect and kill cancer cells in three ways. In cancer cells that survive the initial explosions, the bursting nanobubbles greatly magnify the local doses of both chemotherapy drugs and radiation. All three effects — mechanical cell destruction, intracellular drug ejection and radiation amplification — occur only in cancer cells and do not harm vital healthy cells nearby.

To administer quadrapeutics, the team uses four clinically approved components: chemotherapy drugs, radiation, near-infrared laser pulses of low energy and colloidal gold.

“Quadrapeutics shifts the therapeutic paradigm for cancer from materials — drugs or nanoparticles — to mechanical events that are triggered on demand only inside cancer cells,” Lapotko said. “Another strategic innovation is in complementing current macrotherapies with microtreatment. We literally bring surgery, chemotherapies and radiation therapies inside cancer cells.”

The first component of quadrapeutics is a low dose of a clinically validated chemotherapy drug. The team tested two: doxorubicin and paclitaxel. In each case, the scientists used encapsulated versions of the drug that were tagged with antibodies designed to target cancer cells. Thanks to the magnifying effect of the plasmonic nanobubbles, the intracellular dose — the amount of the drug that is active inside cancer cells — is very high even when the patient receives only a few percent of the typical clinical dose.

The second component is an injectable solution of nontoxic gold colloids, tiny spheres of gold that are thousands of times smaller than a living cell. Quadrapeutics represents a new use of colloidal gold, which has been used for decades in the clinical treatment of arthritis. In quadrapeutics, the gold colloids are tagged with cancer-specific clinically approved antibodies that cause them to accumulate and cluster together inside cancer cells. These gold “nanoclusters” do nothing until activated by a laser pulse or radiation.

The third quadrapeutic component is a short near-infrared laser pulse that uses 1 million times less energy that a typical surgical laser. A standard endoscope delivers the laser pulse to the tumor, where the gold nanoclusters convert the laser energy into plasmonic nanobubbles.

The fourth component is a single, low dose of radiation. The gold nanoclusters amplify the deadly effects of radiation only inside cancer cells, even when the overall dose to the patient is just a few percent of the typical clinical dose.

“What kills the most-resistant cancer cells is the intracellular synergy of these components and the events we trigger in cells,” Lapotko said. “This synergy showed a 100-fold amplification of the therapeutic strength of standard chemoradiation in experiments on cancer cell cultures.”

In the Nature Medicine study, the team tested quadrapeutics against head and neck squamous cell carcinoma (HNSCC), an aggressive and lethal form of cancer that had grown resistant to both chemotherapy drugs and radiation. Quadrapeutics proved so deadly against HNSCC tumors that a single treatment using just 3 percent of the typical drug dose and 6 percent of the typical radiation dose effectively eliminated tumors in mice within one week of the administration of quadrapeutics.

Lapotko, a faculty fellow in biochemistry and cell biology and in physics and astronomy, said he is working with colleagues at MD Anderson and Northeastern to move as rapidly as possible toward prototyping and a human clinical trial. In clinical applications, quadrapeutics will be applied as either a stand-alone or intra-operative procedure using standard endoscopes and other clinical equipment and encapsulated drugs such as Doxil or Lipoplatin. Though the current study focused on head and neck tumors, Lapotko said quadrapeutics is a universal technology that can be applied for local treatment of various solid tumors, including other hard-to-treat types of brain, lung and prostate cancer. He said it might also prove especially useful for treating children due to its safety.

“The combination of aggressiveness and drug and radiation resistance is particularly problematic in tumors that cannot be fully resected, and new efficient solutions are needed,” said Dr. Ehab Hanna, a surgeon and vice chair of the Department of Head and Neck Surgery at MD Anderson, who was not involved with the testing or development of quadrapeutics. “Technologies that can merge and amplify the effects of surgery, drugs and radiation at the cellular level are ideal, and the preclinical results for quadrapeutics make it a promising candidate for clinical translation.”

1. Study co-authors included Rice research scientist Ekaterina Lukianova-Hleb, MD Anderson researchers Xiangwei Wu and Xiaoyang Ren and Northeastern researchers Vladimir Torchilin and Rupa Sawant.
2. The research was supported by the National Institutes of Health, the National Science Foundation and the Virginia and L.E. Simmons Family Foundation.

Low-dose IMRT may be safe for patients with HPV-positive head and neck cancer

Author: Laura Nikolaides

Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. “I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial,” he said. “This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities,” he added.

“We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors,” commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. “Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer,” he added.

Positive data announced for Reolysin in head and neck cancers

Author: staff

Oncolytics Biotech announced positive top line data in its double-blinded randomized Phase 3 clinical study examining Reolysin in combination with carboplatin and paclitaxel in second-line patients with platinum-refractory, taxane-naïve head and neck cancers. Reolysin is a proprietary formulation of the human reovirus.

A first analysis compared the relative percentages of patients in the test and control arms with tumors that had either stabilized or exhibited shrinkage. For the purposes of this endpoint, the definition of tumor stabilization was restricted to 0% growth only. Of the 105 total patients with evaluable metastatic tumors, 86% (n=50) of those in the test arm of the study exhibited tumor stabilization or shrinkage, compared with 67% of patients (n=55) in the control arm. This was statistically significant, with a p-value of 0.025.

A second analysis examined the magnitude of tumor response on a per patient basis using a comparison of percentage tumor shrinkage at six weeks in each patient with evaluable metastatic tumors. This analysis showed that Reolysin in combination with carboplatin and paclitaxel was statistically significantly better than carboplatin and paclitaxel alone at stabilizing or shrinking metastatic tumors, yielding a p-value of 0.03

December, 2012|Oral Cancer News|

Use of carbon nanoparticles paves way to customized cancer therapy

Author: Cameron Chai

A research study by Jeffrey Myers from the University of Texas MD Anderson Cancer Center and James Tour from the Rice University has reported that a combination of carbon nanoparticles and existing drugs has the capability to improve head-and-neck cancer treatment, particularly when coupled with radiation therapy.


The novel technique encapsulates chemotherapeutic drugs using carbon nanoparticles, which sequester the drugs until their delivery into the targeted cancer cells, opening the door to develop customized therapies based on the requirements of individual patients.

The researchers have developed a simple technique to mix Cetuximab, a targeting agent, and paclitaxel, a hydrophobic active chemotherapy agent marketed as Taxol, with hydrophilic carbon clusters that are functionalized with polyethylene glycol or PEG-HCC. According to the researchers, Cetuximab, paclitaxel and PEG-HCC ingredients combine easily and form a water-soluble compound that targets tumors more effectively than Taxol, while eliminating the toxic effects of Cremophor EL and paclitaxel on neighboring healthy cells.

Cremophor EL is a carrier based on castor oil that makes the hydrophobic paclitaxel into a water-soluble compound and delivers it to patients intravenously. Tour commented that the novel technique utilizes a very small quantity of chemotherapy drug. Myers informed that tests involving the use of Cetuximab, paclitaxel and PEG-HCC ingredients and radiation therapy on mice demonstrated a substantial increase in destroying tumors. The researchers’ hypothesis is paclitaxel detects the tumor cells to the radiation effects and Cetuximab and PEG-HCC augment the delivery of paclitaxel into the cancer cells, Myers explained.

Tour stated that the functionalized carbon clusters are nontoxic. Myers commented that this research has demonstrated the principle that carbon nanoparticles are capable of linking a chemotherapeutic drug non-covalently with a targeting antibody, which can supply the drug to target-specific cancer cells. This principle can be applied for delivering other drugs to other kinds of cells via target-specific cell surface receptors as a way of augmenting the therapeutic ratio, Myers concluded.

February, 2012|Oral Cancer News|

Taking out a cancer’s co-dependency: novel compound selectively kills cancer cells by blocking response to oxidative stress

Author: public release

A cancer cell may seem out of control, growing wildly and breaking all the rules of orderly cell life and death. But amid the seeming chaos there is a balance between a cancer cell’s revved-up metabolism and skyrocketing levels of cellular stress. Just as a cancer cell depends on a hyperactive metabolism to fuel its rapid growth, it also depends on anti-oxidative enzymes to quench potentially toxic reactive oxygen species (ROS) generated by such high metabolic demand.

Scientists at the Broad Institute and Massachusetts General Hospital (MGH) have discovered a novel compound that blocks this response to oxidative stress selectively in cancer cells but spares normal cells, with an effectiveness that surpassed a chemotherapy drug currently used to treat breast cancer. Their findings, based on experiments in cell culture and in mice, appear online in Nature on July 13.

The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don’t need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.

“Piperlongumine targets something that’s not thought to be essential in normal cells,” said Stuart L. Schreiber, a senior co-author and director of the Broad’s Chemical Biology Program. “Cancer cells have a greater dependence on ROS biology than normal cells.”

Sam W. Lee and Anna Mandinova, senior co-authors from the Cutaneous Biology Research Center (CBRC) at MGH, weren’t looking for a ROS inhibitor when they found PL. Their interest lay in the tumor suppressor gene p53, which is mutated in more than half of all cancer types. Teaming up with the Broad’s Chemical Biology Program and Platform to screen libraries of chemical compounds, they were looking for something that might increase levels of the properly functioning p53 gene.

When they saw a promising signal for PL, they assumed it worked by enhancing the p53 gene. But to their surprise, PL induced cancer cell death independent of the tumor suppressor gene’s activity. And when they tested PL in normal cells, the cells didn’t die.

“The novelty of this compound was that it was able to recognize cancer cells from normal cells,” said Mandinova, a Broad associate member and a faculty member at MGH and Harvard Medical School. “It has a mode of action that targets something especially important to the cancer cell.”

Their second surprise came after the Proteomics Platform’s quantitative analysis identified the target of PL. The researchers imagined that they might find a protein encoded by a cancer-causing gene was being inhibited in some way, but instead of an oncogene, they saw an indirect process on which cancer cells depend.

A small number of new cancer drugs target oncogenes directly, but this may not be the only promising new direction for treating cancers. Cancer genes do not act alone. PL exploits a dependency that develops after oncogenes transform normal cells into cancer cells.

“Our studies suggest that piperlongumine’s ROS-associated mechanism is especially relevant to the transformed cancer cell,” said co-author Andrew M. Stern, associate director of Novel Therapeutics at the Broad. “And this in part may underlie the observed selectivity of PL.”

The scientists tested PL against cancer cells and normal cells engineered to develop cancer. In mice injected with human bladder, breast, lung, or melanoma cancer cells, PL inhibited tumor growth but showed no toxicity in normal mice. In a tougher test of mice that developed breast cancer spontaneously, PL blocked both tumor growth and metastasis. In contrast, the chemotherapy drug paclitaxel (Taxol) was less effective, even at high levels.

“This compound is selectively reducing the enzyme activity involved in oxidative stress balance in cancer cells, so the ROS level can go up above the threshold for cell death,” said Lee, a Broad associate member and associate director of CBRC at MGH. “We hope we can use this compound as a starting point for the development of a drug so patients can benefit.”

While hopeful, the authors remain cautious. Much more work needs to be done to better understand how the ROS process differs between normal and cancer cells before clinical studies can even be launched. Further studies will focus on different forms of cancer and their genotypes, or genetic information.

“Our next set of goals is to learn if there are specific cancer genotypes that will be more sensitive to this compound than others,” said Alykhan F. Shamji, associate director of the Broad’s Chemical Biology Program. “We hope our experiments will help be predictive of whether patients with the same genotypes in their tumors would respond the same way. It would help us to pick the right patients.”

1. The research reported in Nature was funded by the National Cancer Institute and builds on work performed through the Initiative for Chemical Genetics and the Cancer Target Discovery and Development Network.

2. Paper cited: Raj L et al. Selective killing of cancer cells with a small molecule targeting stress response to ROS. Nature. Published online July 13, 2011. DOI: 10.1038/nature10167.

Plant stem cells pave way for low-cost cancer drug

Author: saff

A new study has suggested that a well-known cancer drug could be produced cheaply and sustainably using stem cells derived from trees.

University of Edinburgh researchers have isolated and grown stem cells from a yew tree whose bark is a natural source of the anticancer compound paclitaxel. The development could enable the compound to be produced on a commercial scale at low cost, with no harmful by-products.

Scientists and engineers behind the development say the drug treatment – currently used on lung, ovarian, breast, head and neck cancer – could become cheaper and more widely available. Currently, an extract from yew tree bark is used to industrially manufacture the compound paclitaxel. However, this process is expensive, requires supplies of mature trees, and creates environmentally damaging by-products.

Researchers claim that using stem cells-self-renewing tree cells which can be manipulated to produce large amounts of the active compound-would effectively create an abundant supply of the drug.

Scientists behind the project have also cultured stem cells from other plants with medical applications, indicating that the technique could be used to manufacture other important pharmaceuticals besides paclitaxel.

The study was published in Nature Biotechnology.

October, 2010|Oral Cancer News|

Neck response to chemoradiotherapy

Source: Arch Otolaryngol Head Neck Surg. 2009;135(11):1133-1136
Author: Alexander Langerman, MD et al.

Complete Radiographic Response Correlates With Pathologic Complete Response in Locoregionally Advanced Head and Neck Cancer

The role of neck dissection following chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer is an area of active debate. Patients who have a complete radiographic response may not need dissection, and the extent of neck dissection necessary for those patients with residual disease is unclear.

Retrospective review of data from a prospectively collected database of patients with locoregionally advanced head and neck cancer treated as part of a phase 2 study of induction chemotherapy followed by concurrent CRT. The results of post-CRT neck computed tomography (CT) imaging and pathologic analysis of the neck dissection specimens were compared to evaluate correlation between radiographic and pathologic response.

Forty-nine patients underwent 61 hemineck dissections. Overall, 209 neck levels were dissected. Radiologic complete response in the neck was achieved in 39 patients, all of whom had pathologic specimens negative for tumor cells. Ten patients (20%) had a total of 14 neck levels with residual disease on CT imaging. Five (50%) of these 10 patients were found to have residual tumor cells on pathologic analysis. Tumor cells were contained only to those levels found positive on CT imaging; they were present in 7 (50%) of the 14 positive levels.

Neck levels with residual disease on post-CRT CT imaging warrant removal. However, neck levels without evidence of disease on post-CRT CT imaging are unlikely to harbor cancer, which lends further support to the concept of basing neck dissection on post-CRT staging and performance of limited neck dissections for patients with limited residual disease.

The role of neck dissection following chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer is an area of active debate. Traditionally, many centers recommended a planned neck dissection for all patients based on the extent of pretreatment neck adenopathy. This was supported by studies that demonstrate improved survival in patients who undergo posttreatment neck dissection.1-2 Proponents argue that post-CRT neck dissection may remove subclinical residual nodal disease within treated lymph nodes, even in the setting of a complete radiographic response. However, other studies demonstrated no survival advantage of neck dissection for those patients with complete radiographic response,3-4 and, in a pooled Radiation Therapy Oncology Group analysis, post-CRT neck dissection was associated with long-term toxicity.5

Throughout this debate, few studies have correlated radiographic and pathologic response to determine potential response to therapy. Therefore, we analyzed a population of patients with locoregionally advanced head and neck cancer uniformly treated with induction chemotherapy and concurrent CRT and post-CRT neck dissection, to correlate posttherapy radiographic findings to pathologic response.

From November 1, 1998, to August 31, 2002, 222 patients with locoregionally advanced head and neck cancer (American Joint Committee on Cancer stage IV, except stage III base of tongue and hypopharynx cancers) were treated as part of a University of Chicago multi-institutional phase 2 study of induction chemotherapy followed by concurrent CRT. Patients with N2 or greater neck disease were recommended to undergo post-CRT neck dissection regardless of response to therapy. From the entire patient cohort, we restricted this analysis to patients treated at the University of Chicago (n = 130).

Treatment methods and outcomes for all patients have been previously reported.6 Briefly, all patients were treated with 2 cycles of induction carboplatin/paclitaxel followed by 5 cycles of concomitant hydroxyurea/fluorouracil/paclitaxel and 72 to 75 Gy of radiation. Patients underwent a post-CRT panendoscopy and biopsy of the primary site with frozen section analysis. Neck dissections were performed at the time of panendoscopy for patients with a complete response at the primary site.

Following CRT, all patients were restaged clinically and radiologically in a multidisciplinary conference with a contrast-enhanced computed tomography (CT) imaging of the head and neck. Patients with pretreatment N2 or greater neck disease or residual posttreatment disease underwent selective neck dissection. The extent of dissection was dictated by primary site and extent of prechemoradiation neck disease rather than postchemoradiation neck staging. At the time of the trial, a single, dedicated head and neck pathologist interpreted all neck dissection specimens.

Correlation of radiographic and pathologic response was performed in the following manner: post-CRT radiographic response for each patient was identified from study records. For completeness, CT imaging of patients with any evidence of lymphadenopathy was reviewed on a standard picture archiving and communication system workstation (Koninklijke Philips Electronics NV, Eindhoven, the Netherlands) that uses soft tissue windows. The location of pre-CRT and post-CRT lymphadenopathy was recorded for each patient. Lymphadenopathy was evaluated by means of criteria reviewed by Som.7 Nodes greater than 1 cm, with ill-defined or enhanced borders, or with areas of low attenuation suggestive of necrosis were considered pathologic. A complete response was defined as resolution of all evidence of radiographic disease. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of the involved lymph node.

Detailed pathology reports of neck dissection specimens were reviewed for evidence of viable tumor cells. The location of the viable tumor cells was recorded for each patient and compared to the location of pre-CRT and post-CRT lymphadenopathy.

Data were entered onto an Excel spreadsheet (Microsoft Corporation, Redmond, Washington). The 2-tailed t test was used to determine statistical significance with a threshold of P.05. This study was conducted with the approval of the institutional review board of the parent trial.6

Of the 130 patients treated at the University of Chicago, 94 (72.3%) were initially staged with N2 or greater disease. Sixty-five of these 94 patients (69.1%) had complete response at the primary site. Of these 65 patients, 13 (20.0%) had neck dissections performed before referral to our institution for CRT and received no further neck treatment. The remaining 52 (80.0%) underwent planned neck dissection at a median of 10 weeks after CRT. Of these, 3 patients had incomplete neck level data on pathologic records and were excluded from further study. The remaining 49 patients underwent 61 hemi-neck dissections of 209 neck levels. The prechemoradiation neck stage was N2a in 2 (4.1%), N2b in 23 (46.9%), N2c in 10 (20.4%), and N3 in 14 (28.6%). No eligible patients refused neck dissection.

Radiographic Response to CRT
Radiologic complete response in the neck was achieved in 39 of 49 patients (79.6%), and 10 patients had radiographic residual disease. Radiographic residual neck disease was identified in 14 neck levels, most commonly in level II: 1 (7.0%) in level I, 9 (64.0%) in level II, 1 (7.0%) in level III, 1 (7.0%) in level IV, and 2 (14.0%) in level V.

Pathologic Response to CRT:
All patients with a radiographic complete response also had a pathologic complete response. Five (50.0%) of the 10 patients with radiographic residual disease were found to have residual tumor cells on pathologic analysis. Tumor cells were contained only to those levels found positive on CT imaging, being present in 7 (50.0%) of the 14 positive levels but none of the 26 negative levels in these patients. Tumor cells were found only in level I in 1 patient, only in level II in 3 patients, and in level II/III/IV in 1 patient (Figure). Pathologic positivity was not related to pre-CRT N stage (P = .24).

Figure. Distribution of suspicious-appearing lymph nodes on postchemoradiation computed tomography imaging and positive pathologic diagnosis in 10 patients who underwent neck dissection. Gray areas represent extent of neck dissection. P indicates pathologically positive; N pathologically negative.

The necessity and extent of neck dissection following chemoradiation is controversial. At our institution and many others, the traditional method has been to perform a selective neck dissection appropriate for the primary site unless more extensive disease mandates more extensive dissection. For instance, an oral cavity tumor would warrant a supraomohyoid (levels I-III) neck dissection in the absence of disease beyond these levels. These criteria have been further refined by limitation of the neck dissection to only those patients with pre-CRT N2 or greater disease or residual disease post-CRT. In other words, in the majority of cases, the extent of dissection was dictated by primary site and extent of pre-CRT neck disease rather than post-CRT neck staging.

In the present study, all patients with a radiographic complete response also had a pathologic complete response. In those with a radiographic partial response, pathologically viable tumor cells were found in 50.0% of patients. Furthermore, pathologic residual disease was limited to levels restaged as positive on CT imaging.

Other series have reported a correlation of radiographic and pathologic complete response. Robbins et al8 analyzed 54 patients with advanced head and neck cancer who underwent neck dissection for evidence of persistent neck disease limited to a single level after combined intra-arterial chemotherapy and radiation. Their data demonstrated pathologically positive neck disease limited only to those neck levels that remained clinically positive by CT imaging in 52 of 54 patients (96.3%).

The above data, plus those included in this current report, suggest that radiographic residual neck disease should be dissected and that radiographically negative neck levels are unlikely to harbor disease. Although both the present data set and that of Robbins et al8 used CT imaging for restaging, considerable evidence has emerged in favor of positron-emission tomography (PET)9 or PET-CT.10-11 To the contrary, some have argued that PET adds little to CT.12 The relative merits of these modalities are beyond the scope of this article, but based on our and those of others, it appears that in centers where PET is unavailable or not used routinely, CT may be adequate to help surgeons decide whether or not to perform a post-CRT neck dissection.

Our data also suggest that a neck dissection limited to levels of radiographic involvement (ie, superselective neck dissection) constitutes adequate therapy following CRT. This concept was first suggested by Robbins et al.8 In their series, of the 2 patients whose CT scans failed to predict residual neck disease, 1 had neck disease in a contiguous level, which prompted the argument that it would have been discovered at the time of surgery, and which leaves only 1 patient for whom superselective neck dissection would have been inadequate. Robbins et al also reported that 100% of the radiographically positive neck disease was pathologically positive. Our data support this assertion because no patient was found to have disease other than at radiographically evident levels.

In a review article on management of the neck following radiation, Medina et al13 summarized what has remained otherwise unpublished data on 55 patients who underwent neck dissection for clinically or radiologically residual disease in the neck following radiation with or without chemotherapy. The full details with regard to neck level positivity were not reported, but all 5 patients with disease limited to level II on restaging had no pathologically positive disease beyond level II. Data were less convincing for patients with disease in multiple levels on posttherapy restaging, with 2 of those 10 patients having disease beyond that predicted by restaging. However, it is possible that not all of these patients were restaged radiographically. Overall, the yield of pathologically viable-appearing disease in the neck dissection specimens was 27%. Based on this data, Medina et al argued that disease limited to level II may be appropriate for superselective neck dissection.

The reliability of research into the response of the neck (and primary site) to CRT ultimately hinges on the pathologic interpretation in tissue from post-CRT surgical extirpation and two of us (A.L. and K.M.S.) are currently preparing a forthcoming formal review of the pathology of tumor response to CRT. We believe markers that indicate the progression of host response (eg, inflammatory markers and degree of fibrosis) as well as aspects of the tumor nidus (eg, nuclear changes and necrosis) can and should be incorporated into guidelines to standardize the interpretation of these specimens. Further careful study of radiographic partial responders without pathologic residual disease is warranted to identify characteristics that could limit surgery to those with higher risk of pathologic positivity.

This study is limited by its retrospective nature. Additionally, because the patients in this study all underwent neck dissections, the natural history of the neck disease cannot be determined, and it is unknown how the tumor detected in the neck pathologic specimens would have behaved in vivo. Furthermore, although a thorough pathologic analysis was conducted at the time of surgical extirpation, it is always possible that microscopic disease was undetected. Finally, it should be noted that, by protocol, only those patients who had a complete response at their primary site underwent the planned neck dissections analyzed in this study, and these results may not be applicable to patients who failed CRT at the primary site.

The high percentage of tumor cells in radiographically positive neck specimens suggests that neck levels with residual disease on post-CRT CT imaging warrant removal. Furthermore, neck levels without evidence of disease on post-CRT CT are unlikely to harbor cancer, which lends further support to the concept of basing neck dissection on post-CRT neck staging and performing superselective neck dissections for patients with limited residual disease.

1. Brizel DM, Prosnitz RG, Hunter S; et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;58(5):1418-1423. FULL TEXT | ISI | PUBMED
2. McHam SA, Adelstein DJ, Rybicki LA; et al. Who merits a neck dissection after definitive chemoradiotherapy for N2-N3 squamous cell head and neck cancer? Head Neck. 2003;25(10):791-798. FULL TEXT | ISI | PUBMED
3. Liauw SL, Mancuso AA, Amdur RJ; et al. Postradiotherapy neck dissection for lymph node–positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol. 2006;24(9):1421-1427. FREE FULL TEXT
4. Clayman GL, Johnson CJ II, Morrison W, Ginsberg L, Lippman SM. The role of neck dissection after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease. Arch Otolaryngol Head Neck Surg. 2001;127(2):135-139. FREE FULL TEXT
5. Machtay M, Moughan J, Trotti A; et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer. J Clin Oncol. 2008;26(21):3582-3589. FREE FULL TEXT
6. Salama JK, Stenson KM, Kistner EO; et al. Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels. Ann Oncol. 2008;19(10):1787-1794. FREE FULL TEXT
7. Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am J Roentgenol. 1992;158(5):961-969. FREE FULL TEXT
8. Robbins KT, Shannon K, Vieira F. Superselective neck dissection after chemoradiation: feasibility based on clinical and pathologic comparisons. Arch Otolaryngol Head Neck Surg. 2007;133(5):486-489. FREE FULL TEXT
9. Isles MG, McConkey C, Mehanna HM. A systematic review and meta-analysis of the role of positron-emission tomography in the follow up of head and neck squamous cell carcinoma following radiotherapy or chemoradiotherapy. Clin Otolaryngol. 2008;33(3):210-222. FULL TEXT | ISI | PUBMED
10. Rabalais AG, Walvekar R, Nuss D; et al. Positron emission tomography-computed tomography surveillance for the node-positive neck after chemoradiotherapy. Laryngoscope. 2009;119(6):1120-1124. FULL TEXT | ISI | PUBMED
11. Nayak JV, Walvekar RR, Andrade RS; et al. Deferring planned neck dissection following chemoradiation for stage IV head and neck cancer: the utility of PET-CT. Laryngoscope. 2007;117(12):2129-2134. FULL TEXT | ISI | PUBMED
12. Tan A, Adelstein DJ, Rybicki LA; et al. Ability of positron-emission tomography to detect residual neck node disease in patients with head and neck squamous cell carcinoma after definitive chemoradiotherapy. Arch Otolaryngol Head Neck Surg. 2007;133(5):435-440. FREE FULL TEXT
13. Medina JE, Vasan NR, Krempl GA. Management of the neck after treatment with radiation with or without chemotherapy. Curr Treat Options Oncol. 2007;8(3):261-264. FULL TEXT | PUBMED

Alexander Langerman, MD; Colleen Plein, BA; Everett E. Vokes, MD; Joseph K. Salama, MD; Daniel J. Haraf, MD; Elizabeth A. Blair, MD; Kerstin M. Stenson, MD

Authors’ affiliations:
Author Affiliations: Sections of Otolaryngology–Head and Neck Surgery (Drs Langerman, Blair, and Stenson and Ms Plein) and Hematology–Oncology (Dr Vokes), Department of Radiation and Cellular Oncology (Drs Vokes, Salama, and Haraf), and Department of Surgery, Cancer Research Center (Drs Vokes, Salama, and Haraf), University of Chicago, Chicago, Illinois.

Author Contributions:
Dr Langerman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Langerman, Vokes, Haraf, Blair, and Stenson. Acquisition of data: Langerman, Plein, and Haraf. Analysis and interpretation of data: Langerman, Plein, Salama, and Stenson. Drafting of the manuscript: Langerman. Critical revision of the manuscript for important intellectual content: Plein, Vokes, Salama, Haraf, Blair, and Stenson.

November, 2009|Oral Cancer News|

Oncolytics’ Phase III borrows adaptive design in SPA trial

Author: Catherine Hollingsworth

Oncolytics Biotech Inc. reached agreement with the FDA on the design of a Phase III trial of Reolysin in head and neck cancer, marking the first such agreement for an intravenously administered oncolytic virus.

The Phase III trial will be conducted in two stages and will cost an estimated $15 million, Matt Coffey, Oncolytics’ chief operating officer, told BioWorld Today. The Calgary, Alberta-based company has the cash to get through the first half of the study on its own, but it hopes to secure a partner to take Reolysin the rest of the way, he said.

The trial uses an adaptive design in which “the endpoint is not fixed going in,” CEO Brad Thompson said during a conference call. He said it was “a major advantage” getting the FDA to sign off on the study design up front under a special protocol assessment.

Thompson said that the adaptive design already is in use in the area of infectious disease, and he said he believes that there will be “a big push” by the FDA for more adaptive trials to be conducted in oncology.

The trial will assess the intravenous administration of Reolysin with the chemotherapy combination of paclitaxel and carboplatin vs. chemotherapy alone. The drug likely will be studied in about 275 patients whose cancer has progressed while on or after prior platinum-based chemotherapy.

The first stage of the trial is nonadaptive and is designed to enroll 80 patients. The second stage is adaptive, and is designed to enroll between 100 and 400 patients with the most probable statistical enrollment being 195 patients.

According to Oncolytics, the Phase III adaptive trial allows frequent data evaluation to determine if the probability of reaching a statistically significant endpoint has been achieved.

The primary endpoint for the trial is overall survival, and secondary endpoints include progression-free survival, objective response rate (complete response plus partial response) and duration of response and safety and tolerability of Reolysin when administered in combination with paclitaxel and carboplatin.

The decision to pursue a Phase III trial in head and neck cancers was based on positive results seen in preclinical work and the company’s UK Phase I and Phase II combination studies of Reolysin and paclitaxel/carboplatin. Interim results of the U.K. Phase I/II trial reported in March demonstrated an overall response rate of 42 percent and a total clinical benefit rate of 75 percent. Updated Phase II results are expected to be presented later this quarter.

First-in-class Reolysin, a proprietary formulation of the reovirus, could be “as significant as the introduction of the antibody therapy,” Coffey said.

Reolysin is designed to replicate in cancer cells that have an activated RAS pathway, seen in about two-thirds of all cancers. Oncolytics sees an opening with Reolysin in metastatic cancers, including colorectal and non-small-cell lung cancers, and in patients with a mutated KRAS gene who are unlikely to respond to treatment with anti-EGFR monoclonal antibodies.

Under recent labeling revisions, the EGFR class of antibodies is not recommended in colorectal patients who have KRAS mutations in their tumors because they do not respond to EGFR-blocking antibodies.

Head and neck cancer is primarily treated with radiation and surgery and chemotherapy is typically used in advanced cases.

Oncolytics has several other ongoing clinical trials of Reolysin, including a Phase II study in NSCLC with K-RAS or EGFR-activated tumors.

October, 2009|Oral Cancer News|

Early postoperative Taxol® may improve outcomes in high-risk head and neck cancer

Author: staff

Researchers involved in the RTOG 0024 study have reported that the administration of early adjuvant Taxol® (paclitaxel) followed by concurrent chemoradiotherapy may improve local control and improve disease-free survival in patients with high-risk head and neck carcinoma. The details of this study appeared in the Journal of Clinical Oncology early online on August 31, 2009.[1]

There have been several randomized and non-randomized clinical trials that suggest that the concomitant administration of platinum-based chemotherapy and radiotherapy (RT) is superior to RT alone for the treatment of patients with advanced head and neck cancer for local and regional control. Most, but not all, have also shown a survival advantage for combined treatment.

An intergroup trial with participation of RTOG, ECOG, and SWOG compared post-operative radiotherapy alone or with concurrent Platinol® (cisplatin) for patients with high-risk head and neck cancer. This study showed that the addition of adjuvant Platinol decreased local recurrences but had no significant impact on metastatic disease or overall survival. An EORTC trial showed that the addition of Platinol to RT improved progression-free and overall survival by 10% and improved overall survival by the same degree.

The current study (RTOG 0024) sought to improve the results of adjuvant chemoradiotherapy in high-risk head and neck cancer patients by administering Taxol postoperatively on weeks 2, 3, and 4 prior to RT. Taxol and Platinol were administered concomitantly with RT after week 4. This study was compared to the previous RTOG trial 9501, which administered Platinol alone with RT.

The current study enrolled 70 patients with high-risk head and neck carcinoma, which was defined as positive surgical margins, extracapsular nodal extension, or multiple positive lymph nodes. The median follow-up was 3.3 years. This regimen appeared to be reasonably well tolerated with a compliance rate of 75.4%. There was one death during the concurrent chemoradiotherapy part of treatment due to myocardial infarction.

The estimated two-year loco-regional relapse rate was 12.4%. New primary tumors occurred in 13.8%. The estimated two-year disease-free survival was 59.5%. The estimated two-year overall survival was 64.7%. A comparison to RTOG trial 9501 suggested an improvement in overall survival and disease-free survival. These authors suggest that this earlier treatment may represent an improvement over previous studies. They suggest that even earlier administration of chemotherapy postoperatively or prior to surgery (neoadjuvant administration) should be explored.

Comments: These data suggest that the addition of a taxane to high-risk patients treated with adjuvant Platinol and RT was of significant benefit.

1. Rosenthal DI, Harris J, Forastiere AA, et al. Early postoperative paclitaxel followed by concurrent paclitaxel and cisplatin with radiation therapy for patients with resected high-risk head and neck squamous cell carcinoma: Report of the Phase II Trial RTOG 0024. Journal of Clinical Oncology [early online publication]. August 31, 2009.

September, 2009|Oral Cancer News|

Oncolytics Biotech(R) Inc. collaborators present positive head and neck results in phase I/II combination

Author: press release

Oncolytics Biotech Inc. announced that interim clinical results from its Phase I/II U.K. trial of Reolysin(R) combined with paclitaxel/carboplatin for patients with advanced cancers were presented at the Fifth International Meeting on Replicating Oncolytic Virus Therapeutics. The meeting is being held in Banff, Alberta from March 18th to 22nd, 2009. The principal investigator for the trial is Dr. Kevin Harrington of The Institute of Cancer Research.

To date, fifteen head and neck cancer patients have been treated in the Phase I/II trial. All but one patient had prior platinum treatment. Of 12 patients evaluable for clinical response, five have experienced Partial Response (PR) and four have experienced Stable Disease (SD) ranging from two to six months. For patients who have been followed for at least six months since their initial treatment, the median progression-free survival (PFS) is currently six months, while the overall survival is currently seven months. The literature suggests that platinum refractory patients typically have a PFS of approximately two months and a median survival ranging from 4.5 to 6.5 months. The overall survival figure may evolve as many of the patients are still alive.

“In patients previously treated with platinum agents, where the response rate (PR and Complete Response (CR)) is generally in the 3-10% range, a response rate of 42% and a 75% clinical benefit rate (SD, PR, and CR) are dramatic,” said Dr. Karl Mettinger, Chief Medical Officer for Oncolytics.

The Phase I/II trial has two components. The first is a Phase I, open-label, dose-escalating, non-randomized study of Reolysin(R) given intravenously in combination with paclitaxel and carboplatin every three weeks. In this portion of the trial, standard dosages of paclitaxel and carboplatin are delivered to patients with escalating intravenous dosages of Reolysin(R). Eligible patients include those who have been diagnosed with advanced or metastatic solid tumours such as head and neck, melanoma, lung and ovarian that are refractory (have not responded) to standard therapy or for which no curative standard therapy exists. The second component of the trial is a Phase II, 14-patient, single arm, open-label, dose-targeted, non-randomized trial of Reolysin(R) given intravenously in combination with a standard dosage of paclitaxel and carboplatin. Eligible patients include those with advanced or metastatic head and neck cancers that are refractory to standard therapy or for which no curative standard therapy exists.

An independent, confirmatory Phase II trial using the same combination of Reolysin(R) and carboplatin/paclitaxel for patients with head and neck cancers is currently underway in the U.S. Interim results from both the U.K. and the U.S. study formed the basis of the Phase III pivotal program now being developed for Reolysin(R) in combination with carboplatin/paclitaxel in this patient population.

March, 2009|Oral Cancer News|