Radiotherapy to the Primary Tumor for Newly Diagnosed Metastatic Prostate Cancer


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Early-Stage Lung Ca: Better OS with Surgery?


Lobectomy seems to offer better long-term outcomes over radiotherapy, yet the latter is still gaining ground

An ongoing debate in the lung cancer community is whether patients with early-stage disease benefit more from surgery or from stereotactic body radiation therapy (SBRT). Radiation oncologists are certainly on board with SBRT in inoperable patients, and there is some data to back up that assertion, as highlighted in this ASCO Reading Room articlefrom last year.

Meanwhile, thoracic surgeons seem to be moving away from lobectomy, and have stumped for less aggressive surgical approaches, such as wedge resection and segmentectomy.

But any discourse gets that much livelier when there’s someone who is willing to offer a third opinion. Researchers at two University of California branches took on that monkey-wrench role with their study in U.S. veterans that compared lobectomy with SBRT — and decided that surgery was the winner. In an interesting twist, the authors are affiliated with radiation oncology — and not surgery — departments at their respective institutions.

“Our data suggest that the more aggressively we treat early lung cancer, the better the outcome,” noted Alex Bryant, of the University of California, San Diego, in a statement. “This study is one of the best-powered and detailed analyses to date and suggests that lobectomy is still the preferred treatment of this disease for most patients.”

Surgery Scores

Bryant and his colleagues identified early-stage non-small cell lung cancer (NSCLC) patients from the VA Informatics and Computing Infrastructure (VINCI). He described VINCI as “an extremely rich source of health information” from which the authors were able to gather detailed data related to a large, nationwide group of veterans.

The study population ultimately consisted of a little over 4,000 patients (97% male) who were diagnosed with clinical T1 or T2a (<5 cm in greatest dimension), N0 (no regional lymph node metastasis), M0 (no distant metastasis), biopsy-proven NSCLC. The diagnoses took place between Jan. 1, 2006 and Dec. 31, 2015.

Patients were treated definitively with either surgery or radiation. Those with a history of prior malignancy, those with a missing cause of death, those treated more than 6 months after diagnosis, and those with missing covariates were excluded. Covariates derived from VINCI were tumor size, tumor grade, histology, patient age, sex, race, and tobacco history. Having these data makes the registry particularly unique, Bryant noted.

“Factors such as these are often not available and have not been consistently addressed in previous studies, which sets this study apart.”

In terms of the procedures themselves, SBRT was defined as the delivery of one to five daily fractions of radiation directed at the lung (mean biologically equivalent dose of 124 Gy10), while the surgical groups were divided into lobectomy and sublobar resection. The latter included wedge and segmental resection; video-assisted thoracoscopic surgery and open surgeries were combined for this analysis.

The authors compared cancer-specific survival among patients receiving lobectomy, sublobar resection, or SBRT with univariable and multivariable competing risk analyses.

The unadjusted analysis revealed higher immediate post-procedural mortality in the surgery groups versus the SBRT group. While multivariable analysis that looked at long-term survival found higher cancer-specific mortality for SBRT compared with lobectomy (subdistribution hazard ratio 1.45, 95% CI 1.09-1.94, P=0.01), there was no survival difference between SBRT and sublobar resection (subdistribution HR 1.25, 95% CI 0.93-1.68, P=0.15).

“Despite the higher postoperative mortality risk, the lobectomy group had the lowest unadjusted risk of all-cause mortality at 5 years,” the authors wrote. “In the lobectomy group, the unadjusted 5-year overall survival [OS] was 70%, followed by sublobar resection at 56% and SBRT at 44%.”

In addition, the multivariable Cox proportional hazards model showed that SBRT was tied to a 38% increased risk of all-cause mortality versus lobectomy (HR 1.38, 95% CI 1.08-1.78, P=0.01).

There was no significant difference in OS between the SBRT and sublobar groups (HR 1.17, 95% CI 0.90-1.53, P=0.85), and there were no significant differences between groups when evaluating noncancer mortality based on univariable or multivariable analysis. There also was no difference in OS or cancer-specific survival between patients who received wedge versus segmental resection (P>0.09 in all unadjusted and adjusted analyses).

Finally, the authors noted that for every 10 Gy increase in biologically equivalent radiation dose, the risk of cancer-related death decreased by 7% (subdistribution HR 0.93, 95% CI 0.86-1.00, P=0.06).

A Resolution?

In spite of the perioperative mortality risks linked with surgery, lobectomy improved survival compared with SBRT in the long term, the researchers concluded. So did the group make the ultimate mic drop in favor of lobectomy? Not quite.

As one MedPage Today reader commented, SBRT is generally reserved for patients who are poor candidates for surgery. But a number of trials designed to compare SBRT with surgery in early-stage disease — STARS, ROSEL, RTOG 1021 — were shuttered early because of poor accrual.

“The probable reason that earlier prospective randomized trials failed to accrue was because surgeons who had operable stage I patients would not consider SBRT, and patients who were not surgical candidates didn’t qualify for randomization in the failed studies,” the reader pointed out.

That leaves the lung cancer community anticipating results from two recently launched trials — VALOR and STABLE-MATES.

The JoLT-Ca Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) for Lung Cancer (STABLE-MATES) trial aims to recruit 258 patients at more than 30 institutions, and has an estimated primary completion date of December 2021.

STABLE-MATES’ principal investigator, Robert Timmerman, MD, of UT Southwestern Medical Center in Dallas, explained in a statement that the “two therapies [surgery and SABR] are both fiercely competitive, like thoroughbreds in a race. Yet when not competing on the track, they reside together in a stable enjoying each other’s company — ready and eager to be called on for the next challenge.”

Meanwhile, the currently recruiting Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR) trial will compare the two modalities in 670 patients at 16 VA centers. The estimated primary completion date is September 2027.

VALOR co-principal investigator Drew Moghanaki, MD, MPH, of the VCU Massey Cancer Center in Richmond, VA, noted in a statement: “There is a lot of research that suggests stereotactic radiotherapy might be just as effective as surgery for lung cancer, or even better. Currently, more than 90% of lung cancers that are caught at an early stage can be controlled with this non-surgical treatment. We know it is often safer than surgery and, for this reason, cancer researchers now question whether surgery is still the optimal treatment for lung cancer.”

He added, however, that while this new treatment approach is promising, there has as yet been no successful comparison of stereotactic radiotherapy with surgery in a head-to-head trial to know how well it works in the long-term: “There are many oncologists who believe stereotactic radiotherapy might be the best way to treat lung cancer. But, until a study like the VALOR trial is completed we will not know what is the best treatment for all of our lung cancer patients.”

More on Surgery

Other recent research has also evaluated ways to refine lung cancer surgery:

  • Two investigators at Houston Methodist Hospital reported on the “five on a dice” port placement and technique to allow for minimal assistance during lobectomy
  • An Italian team explained why the technique for video-assisted thoracoscopic surgery (VATS) lymphadenectomy was the same as that of thoracotomy in early-stage lung cancer
  • Another group of Italian researchers found that VATS lobectomy for locally advanced-stage NSCLC was safe and effective in appropriately selected patients, ensuring perioperative results similar to those obtained in early-stage tumors
  • Japanese researchers reported on two patients in whom salvage VATS lobectomy was feasible after SBRT

The study by Bryant’s group was supported by the National Institutes of Health. Bryant disclosed no relevant relationships with industry; one co-author disclosed support from EMD Serano.

The VALOR trial is funded by the Veterans Affairs Cooperative Studies Program.

Turmeric’s ‘Smart Kill’ Properties Put Chemo & Radiation To Shame


The ancient Indian spice turmeric strikes again! A study finds turmeric extract selectively and safely killing cancer stem cells in a way that chemo and radiation can not.

A groundbreaking study published in the journal Anticancer Research reveals that one of the world’s most extensively researched and promising natural compounds for cancer treatment: the primary polyphenol in the ancient spice turmeric known as curcumin, has the ability to selectively target cancer stem cells, which are at the root of cancer malignancy, while having little to no toxicity on normal stem cells, which are essential for tissue regeneration and longevity.

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Titled, “Curcumin and Cancer Stem Cells: Curcumin Has Asymmetrical Effects on Cancer and Normal Stem Cells,” the study describes the wide range of molecular mechanisms presently identified by which curcumin attacks cancer stem cells (CSCs), which are the minority subpopulation of self-renewing cells within a tumor colony, and which alone are capable of producing all the other cells within a tumor, making them the most lethal, tumoriogenic of all cells within most if not all cancers.   Because CSCs are resistant to chemotherapy, radiation, and may even be provoked towards increased invasiveness through surgical intervention, they are widely believed to be responsible for tumor recurrence and the failure of conventional treatment.

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The study identified the following 8 molecular mechanisms by which curcumin targets and kills cancer stem cells:

  • Down-regulation of interleukin-6 (IL-6): IL-6 is classified as a cytokine (a potent biomolecule released by the immune system) and modulates both immunity and inflammation. It’s over expression has been linked to the progression from inflammation to cancer. Curcumin inhibits IL-6 release, which in turn prevents CSC stimulation.
  • Down-regulation of interleukin-8 (IL-8): IL-8, another cytokine, is released after tumor cell death, subsequently stimulating CSCs to regrow the tumor and resist chemotherapy. Curcumin both inhibits IL-8 production directly and indirectly.
  • Down-regulation of interleukin-1 (IL-1): IL-1, a family of cytokines, are involved in response to injury and infection, with IL-1 β playing a key role in cancer cell growth and the stimulation of CSCs. Curcumin inhibits IL-1 both directly and indirectly.
  • Decrease CXCR1 and CXCR2 binding: CXCR1 and CXCR2 are proteins expressed on cells, including CSCs, which respond to the aforementioned cytokines in a deleterious manner. Curcumin has been found to not only block cytokine release, but their binding to these two cellular targets.
  • Modulation of the Wnt signaling pathway: The Wnt signaling pathway regulates a wide range of processes during embryonic development, but are also dsyregulated in cancer. Curcumin has been found to have a corrective action on Wnt signaling.
  • Modulation of the Notch Pathway: The Notch signaling pathway, also involved in embryogenesis, plays a key role in regulating cell differentiation, proliferation and programmed cell death (apoptosis), as well as the functioning of normal stem cells. Aberrant Notch signaling has been implicated in a wide range of cancers. Curcumin has been found to suppress tumor cells along the Notch pathway.
  • Modulation of the Hedgehog Pathways: Another pathway involved in embryogenesis, the Hedgehog pathway also regulates normal stem cell activity. Abnormal functioning of this pathway is implicated in a wide range of cancers and in the stimulation of CSCs and associated increases in tumor recurrence after conventional treatment. Curcumin has been found to inhibit the Hedgehog pathway through a number of different mechanisms.
  • Modulation of the FAK/AKT/FOXo3A Pathway: This pathway plays a key role in regulating normal stem cells, with aberrant signaling stimulating CSCs, resulting once again in tumor recurrence and resistance to chemotherapy. Curcumin has been found
  • in multiple studies to destroy CSCs through inhibiting this pathway.

As you can see through these eight examples above, curcumin exhibits a rather profound level of complexity, modulating numerous molecular pathways simultaneously. Conventional cytotoxic chemotherapy is incapable of such delicate and “intelligent” behavior, as it preferentially targets fast-replicating cells by damaging their DNA in the vulnerable mitosis stage of cell division, regardless of whether they are benign, healthy or cancerous cells.   Curcumin’s selective cytotoxicity, on the other hand, targets the most dangerous cells – the cancer stem cells – which leaving unharmed the normal cells, as we will now learn more about below.

Curcumin and Normal Stem Cells

Normal stem cells (NSCs) are essential for health because they are responsible for differentiating into normal cells that are needed to replace damaged or sick ones. If curcumin were to kill normal cells, like radiation and chemotherapy, it would not provide a compelling alternative to these treatments.   The study addressed this point:

“The safety of curcumin has been long established, as it has been used for centuries as a dietary spice. The question arises as to why curcumin does not seem to have the same deleterious effects on normal stem cells (NSCs) as it does on CSCs. There are several possible reasons that curcumin has toxic effects on CSCs, while sparing NSCs.”

The study offered three potential explanations for curcumin’s differential or selective cytotoxicity:

  • Malignant cells take in much more curcumin than normal cells.
  • Curcumin alters the microenvironment of cells in such a way that is adverse to CSCs and beneficial to NSCs.
  • Curcumin may not only directly attack CSCs, but may encourage them to differentiate into non-lethal, more benign cells.

Concluding Remarks

 This study adds growing support to the idea that safe, time-tested, natural substances are superior to synthetic ones. Given the evidence that a safe and effective alternative may already exist, chemotherapy, radiation and even surgery may no longer be justified as the first-line standard of care for cancer treatment. In fact, a significant body of evidence now implicates these treatments in worsening prognosis, and in some cases driving cancer stem cell enrichment  in tumors. Radiotherapy, for instance, has been found to induce cancer stem cell like properties in breast cancer cells, essentially increasing their malignancy and tumoriogenicity by 30 fold.  This is hardly progress when one considers the role that CSCs play, especially in contributing to post-treatment secondary cancers.

Turmeric and its components, of course, are not FDA approved drugs, and by definition the FDA will not allow an unapproved substance, natural or synthetic, to prevent, treat, diagnosis or cure a disease.   This means that you will not be seeing it offered by an oncologist as an alternative to chemotherapy or radiation any time soon.   This does not, however, mean that it does not work. We have gathered over 1500 citations from the National Library of Medicine’s bibliographic database MEDLINE, accessible through pubmed.gov, and which can be viewed on our database here: Turmeric Research, showing that curcumin and related turmeric components possess significant anti-cancer activity.  Truth be told, the information is so extensive, revealing over 700 possible health benefits, that I believe this plant embodies a form of intelligence and even compassion. You can learn more about this supposition here: Turmeric’s Healing Power: A Physical Manifestation of Compassion?    I also discuss this concept in my lecture, Food As Medicine Rebooted, which you can watch below:

Of course, the point is not to wait until one has such a severe health problem that taking heroic doses of spices or herbs becomes the focus. It is important to remember that ancient cultures used spices like turmeric mainly in culinary doses, as part of their dietary practices. These smaller amounts, delivered mainly as whole food extracts, likely constituted effective preventive strategies – perhaps preventing the need for radical, heroic intervention later in life. If you read our previous article, Turmeric: A Wellness Promoting Tonic at Low Doses, Research Reveals, you’ll see this point explored in greater depth in light of a human clinical study.

If You Are a Cancer Survivor, This Is a Must Read .


Getting through cancer treatment successfully is something to celebrate. To stay in good health, doctors say you need to watch for other symptoms, including vision changes, headaches and problems with balance.

What many cancer survivors don’t realize is that 25 percent of people who survive some common cancers go on to develop a brain tumor. These brain tumors don’t originate in the brain but are actually cancerous cells from the original tumor that travel to the brain through the bloodstream. When this happens, doctors call these tumors brain metastases.

“About one-third of patients with the most common cancers — lung, breast and kidney cancer and melanoma — are at risk of developing brain metastases,” says Cleveland Clinic neurosurgeon Gene Barnett, MD.

When this happens, the resulting growth needs early treatment. Dr. Barnett says early detection can help people get the right treatment at the right time to avoid serious complications. This is why you need to be vigilant and pay attention to your symptoms.

Watch for these 9 signs

If you’ve had cancer and experience these symptoms, be sure to tell your doctor:

  1. Vision changes (such as double vision or partial vision loss)
  2. Headaches (possibly with nausea)
  3. Numbness or tingling in part of the body
  4. Paralysis or difficulty moving any part of the body
  5. Inability to walk
  6. Difficulty with balance and an increased incidence of falls
  7. Difficulty speaking (including slurred words or incoherent speech)
  8. Problems with mental acuity (such as not being able to read or tell time)
  9. Seizure or convulsions

Metastatic brain tumors tend to develop gradually, although severe episodes can occur. No matter what, it’s important to tell your doctor immediately so he or she can evaluate you and treat you early as needed.

Treatable brain tumors

For years, doctors believed that brain metastases were uniformly fatal. Treatment could only to relieve symptoms. Today, they know that such tumors are treatable, thanks to technological and medical advances. The key is early detection.

To help in this fight, Cleveland Clinic teamed with the Northern Ohio American Cancer Society to establish the B-Aware Program. “Our goal is to educate at-risk cancer patients so that brain metastases are detected as early as possible, when they have the greatest number of treatment options,” says Dr. Barnett.

Many treatments available

We’ve come a long way from the days when the only treatment option available for brain metastases was whole brain radiation. This often failed to control the tumors. Today, aggressive and precisely delivered treatments produce better outcomes with fewer side effects.

Treatment options depend on the location, type and extent of the tumor, and include:

  • Radiosurgery. Radiosurgery directs highly focused beams of radiation at the tumor with extreme precision. This will not destroy the tumor, but may succeed in stopping tumor growth. Surgeons deliver this radiation so precisely that they can spare the surrounding brain tissue. Gamma Knife surgery is a common form of radiosurgery.
  • Minimal access surgery. This type of surgery allows doctors to remove the tumor in a faster, simpler way. Surgeons make a very small incision in the skull or hidden in a nearby structure. This reduces postoperative complications, minimizes pain and scarring, and shortens recovery time.
  • Localized radiotherapy, or radiation therapy. Radiotherapy exposes the cancerous cells to ionizing radiation that injures or destroys them. Doctors often use radiotherapy before or in addition to radiosurgery.
  • Medical therapies. Chemotherapy uses drugs to kill tumor cells that are dividing most rapidly. Many drugs used successfully for tumors in the body cannot penetrate into the brain. However, in certain cases, chemotherapy or other medical treatments may secure control of certain brain metastases.

“We want to help patients ‘be aware’ of all management options, so they don’t blindly agree to a proposed treatment which may not be in their best interest,” says Dr. Barnett. “They always have the right to seek a second opinion.”

RT for Head and Neck Cancer: Humidifier Cuts Hospital Stay.


For patients with head and neck cancer who are undergoing radiotherapy, using a nasal mask to deliver humidified air to the mouth and throat region while they were sleeping appears to have reduced symptoms, and significantly shortened their hospital stay.

The results come from the RadioHUM study, a phase 3 trial conducted in 210 patients reported here at a plenary session during the 2014 Multidisciplinary Head and Neck Cancer Symposium. This study has just been published in the March 1 issue of theInternational Journal of Radiation Oncology * Biology * Physics.

Radiotherapy for head and neck cancer often results in mucositis, with patients developing painful inflammation and ulceration of the mouth and throat that can negatively affect their quality of life, explained principal investigator Andrew McCann, MBcHB, a radiation oncologist at Auckland City Hospital in New Zealand.

The trial investigated daily humidification of the mouth and throat region (using the Fisher & Paykel Healthcare MR880 humidifier) starting on the first day of radiotherapy. The humidified air is delivered through the nose via a mask-type of apparatus, which patients wear while they are sleeping or sitting. “This provides a greater level of humidification than has previously been available,” he said.“The rationale for humidification is based on the fact that moisturizing wounds generally helps them to heal faster,” he said during a press briefing.

In this trial, patients used this device for a mean of 3.6 hours per day (range, 1 – 14 hours).

However, the authors note that only 43 patients (42%) in the humidification group met a defined benchmark for humidifier compliance. Only these patients contributed to the per protocol analysis, so although the results were in the direction of less symptom severity, most of the time points did not reach significance. Nevertheless, they say there were “efficacy signals consistent with a role for humidification in reducing symptom burden from mucositis,” and this included the patient reports in a self-assessment questionnaire.

However, several of the results did reach statistical significance.

Patients who used the humidifier had a significantly shorter hospital stay (mean of 2.3 vs 4.1 days in the control group; P = .017), and fewer of them required hospital readmission (0.31 vs 0.55; P = .013).

This effect of reducing hospitalization may make this approach cost-effective, the authors comment.

In addition, significantly fewer patients who had used a humidifier needed an eating tube, and a nutritional status assessment at 20 weeks after the radiotherapy showed that significantly more patients in this group had returned to near-normal eating patterns.

“The results are encouraging, particularly given the signal favoring humidification was seen across clinician-reported outcomes, patient-reported outcomes, and independent data such as hospitalizations,” the authors note.

“This is important,” Dr. McCann suggested, “because when you see signals across these different types of outcomes, there is some independent corroboration there.”

Patients didn’t use the humidifier as much as we had hoped, Dr. McCann commented. Some of the issues with compliance are similar to those seen with the use of continuous positive airway pressure machines in patients with sleep apnea, he said. “Our next step is to work to increase the proportion of patients who use the humidifier effectively,” he added.

MRI visualizes proton dose distribution.


“How can proton therapy not be clinically better than intensity-modulated radiation therapy?” That was the question posed by Thomas Bortfeld, PhD, speaking at the recent European Society for Radiotherapy and Oncology (ESTRO) annual meeting in Barcelona, Spain.

The answer lies in uncertainty over the range of the proton beam, surmised the Harvard Medical School professor of medical physics and director of the physics research division of the Massachusetts General Hospital (MGH) Department of Radiation Oncology and its Francis H. Burr Proton Therapy Center in Boston.

This uncertainty can be reduced by measuring the proton range in vivo. Several techniques are being investigated for this purpose, including dosimetry in body cavities; other possibilities are PET and prompt gamma imaging, which detect secondary particles created as the proton beam travels through the patient. But another option is the use of MRI to visualize the proton dose distribution, by imaging radiation-induced tissue changes, Bortfeld told ESTRO attendees.

The idea is to use MRI to image tissue changes that occur on a molecular level following proton irradiation. The technique has already been successfully used to infer the delivered dose in proton therapy of the spine. Here, irradiation causes the blood-producing bone marrow to be replaced by fat, which shows up as areas of increased intensity in post-treatment MR images.

While this MR imaging method works well for treatment of bony structures, can it be used elsewhere? Bortfeld cited an example in which contrast-enhanced MRI was used to observe changes in liver tissue following brachytherapy.

After treatment, a reduction in contrast uptake was seen in the treated areas of the liver. “We expected to see a similar effect for proton therapy, and we did,” he noted.

Bortfeld described a study performed at Massachusetts General Hospital in which MR images were recorded 2.5 months after five fractions of proton therapy. A reduced signal was seen in central parts of the liver. Contours of the area of signal reduction were in good agreement with the high-dose region in the treatment plan.

Bortfeld’s research group is also trying to understand the underlying molecular process, and believes that radiation-induced and cytokine-mediated changes of the irradiated liver cells disable the active contrast media uptake.

The main advantages of MRI range imaging are better spatial resolution and improved signal-to-noise ratio compared with PET. In comparison with prompt gamma imaging, MRI can offer 3D information combined with anatomical information. The main disadvantage at present is the delay between the start of treatment and the observation of changes in the MR image.

The key question now, therefore, is whether similar changes in MR images can be observed after just a few days of treatment. If this is possible, then small misalignments could be detected between proton fractions and compensated for in later treatments. He said that Christian Richter, PhD; Joao Seco, PhD; and colleagues from MGH are currently running a trial to determine the time point in the treatment process at which such changes can be observed.

Source: Radiation Oncology Digital Community.