How Do I Treat…?
Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.
Wednesday, July 09, 2014
By Elena Elimova, MD, MSC; Brian Badgwell, MD; Prajnan Das, MD, MS, MPH; Jeannelyn Estrella, MD; Aurelio Matamoros Jr., MD; and Jaffer A. Ajani, MD
Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10 percent realized by adjunctive treatments to surgery is unacceptable as more than 50 percent of patients with localized gastric cancer succumb to their disease.
Either postoperative chemoradiotherapy (in the United States), pre-and post-operative chemotherapy (in Europe), and adjuvant chemotherapy after a D2 resection (in Asia) can all be regarded as standards of care in the localized management of the disease. For patients with metastatic disease, the addition of trastuzumab to chemotherapy is standard of care in HER2-positive disease. In the HER2-negative population, the treatments remain limited.
In the first-line setting, the standard of care is a combination of fluoropyrimidine and platinum-containing chemotherapy, with or without epirubicin or docetaxel. Finally there is a minimal overall survival benefit in treating patients with metastatic disease in the second-line setting, with either irinotecan, docetaxel, or ramucirumab with or without chemotherapy.
Our approach to the treatment of patients with gastric cancer begins with appropriate clinical staging to determine if the cancer is localized or advanced. This involves full imaging, including CT of the chest/abdomen/pelvis, PET-CT, endoscopic ultrasound (EUS), and finally a staging laparoscopy.
EUS is the most reliable nonsurgical method to evaluate the depth of invasion, with concurrent evaluation of regional lymph nodes of primary gastric cancers and is therefore instrumental; however, things are not as simple as doing an EUS because this technique is really only useful in the hands of a skilled operator.
The PET/CT scan is most useful in detecting occult distant metastasis, thereby helping avoid high morbidity surgery in a sub-group of patients. Laparoscopy should be considered for patients who appear to have locoregional disease (other than stage IV, Tis or T1a stage) after conventional radiographic and EUS staging. However, because it is sometimes difficult to differentiate T2 and T3 lesions on EUS, it is reasonable to perform a laparoscopy for any medically fit patient who appears to have more than a T1 lesion on EUS, no histologic confirmation of stage IV disease, and who would not otherwise require a palliative gastrectomy because of symptoms. This is because 20 to 30 percent of patients with greater than T1 EUS disease will be found to have peritoneal metastasis despite having negative CT and PET scans.
In our center the clinical staging is followed by a multidisciplinary discussion in all localized gastric cancer cases:
Localized Gastric Cancer
In terms of localized gastric cancer, a curative resection (R0) offers the best chance of cure, and is best managed at high-volume centers and by high-volume surgeons. We strongly believe that a multidisciplinary approach and preoperative therapy is the cornerstone of management in the West.
Although gastrectomy is the recommended treatment in relatively early-localized gastric cancer (T1b), in more advanced disease (T2N0, T1aN+, or T1b-T3N+) we recommend adjunctive therapy in addition to gastrectomy. As previously mentioned, postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the management of localized gastric cancer. However, at our institution, we use a combination of these approaches in the pre-operative setting, because in our experience post-operative therapy is much harder to deliver.
Our general approach is to start with pre-operative chemotherapy with a platinum-based doublet or triplet (depending on the performance status of the patient) for two to three months, followed by chemoradiation also given preoperatively with 5-fluorouracil ± taxanes or platinum, finally followed by surgery. This approach is based on Phase II study data and results in R0 resection in 70 to 78 percent of our patients and five-year overall survival rates at least comparable to those reported in the Intergroup 0116 and MAGIC clinical trials.
In terms of post-treatment surveillance, there is no data to provide guidance, and arbitrary surveillance strategies are used.
Metastatic Gastric Cancer
In terms of our approach to metastatic gastric cancer, clearly in the context that this is no longer a curative situation our approach is to the palliation of symptoms and prolongation of life:
Otherwise, we would treat differently based on HER2 status. Clearly in HER2-positive gastric cancer there is an overall survival benefit to the addition of anti-HER2 therapy to first line chemotherapy.
It is our practice to typically use trastuzumab and not lapatinib because of the negative results of the lapatinib trial in combination with platinum-based doublet. Although no convincing data exists as to the benefit of the addition of HER2 therapy in gastric cancer, we extrapolate from the breast cancer trials and continue anti-HER2 therapy beyond progression, typically switching to an alternative agent such as pertuzumab.
In the context of HER2-negative metastatic disease, our options continue to be limited. In a select subgroup of patients who have small-volume disease and who are asymptomatic, a careful watch-and-wait strategy is reasonable as long as the patient is comfortable with this approach. In symptomatic patients, a reasonable option in the first-line setting is a platinum-based doublet with the addition of docetaxel or epirubicin, depending on the performance status of the patient or clinical trials.
In the second-line setting, we often use irinotecan-based doublets, but with the recent approval of ramucirumab, this agent in combination with chemotherapy will have a role in our practice.
Genetic profiling of tumors is becoming a more widely used tool in the treatment of gastric cancer, as it is in other cancers. Patients are often found to have multiple and even more often non-targetable mutations. Even when a potentially targetable mutation is found and the patient is treated with a given drug, we have found that responses are rare--likely because of our poor knowledge of driver mutations. Therefore we do not consider a genetic evaluation a critical part of treatment, but rather emphasize the enrollment of patients into available clinical trials.
In summary, we strongly feel that all patients with localized gastric cancer in a potentially curable situation should be evaluated in a multidisciplinary way and in a high-volume center, so that they can have the benefit of a surgery performed by a high-volume surgeon. In metastatic disease at our institution we put emphasis of enrollment of patients on clinical trials in hopes of improving outcomes.
The authors are all from the University of Texas MD Anderson Cancer Center: Elena Elimova, MD, MSC, Department of Gastrointestinal Medical Oncology; Brian Badgwell, MD, Department of Surgical Oncology; Prajnan Das, MD, MS, MPH, Department of Radiation Oncology; Jeannelyn Estrella, md, Department of Pathology; Aurelio Matamoros Jr., md, Department of Diagnostic Radiology; and Jaffer A. Ajani, md, Department of Gastrointestinal Medical Oncology.
Saturday, July 05, 2014
BY Geoffrey R. Oxnard, MD
Assistant Professor of Medicine
Dana-Farber Cancer Institute
Harvard Medical School
T790M is a point mutation in the EGFR gene that is associated with resistance to epidermal growth factor receptor (EGFR) kinase inhibitors like erlotinib and gefitinib. Some of the most exciting results presented at this year’s American Society of Clinical Oncology Annual Meeting have to do with new inhibitors targeting the EGFR T790M mutation. Given that this appears to be an emerging biomarker in the treatment of lung cancer patients, it is worth reviewing the management of patients carrying this mutation. Importantly, it can be seen in several different clinical circumstances where it can mean different things.
Baseline EGFR T790M
The EGFR T790M mutation is rarely seen in a lung cancer at initial diagnosis, prior to treatment with an EGFR kinase inhibitor. The prevalence of baseline T790M is debated in the scientific literature, but using conventional testing methods it is generally though to occur in one to two percent of all EGFR-mutant lung cancers. When seen in this setting, it is most commonly identified in addition to a second drug-sensitive EGFR mutation. Despite that, lung cancers with baseline EGFR T790M are unlikely to respond to standard EGFR kinase inhibitors and should be treated in the first-line setting with standard chemotherapy. Interestingly, the presence of baseline T790M indicates a high likelihood of an underlying germline T790M mutation, discussed further below.
Acquired EGFR T790M
The more common setting where the T790M mutation is seen is as an acquired mutation in EGFR-mutant lung cancer after treatment with an EGFR kinase inhibitor. A repeat tumor biopsy in this setting can identify a new T790M mutation more than half the time. Previous data has suggested that T790M-mediated resistance can be associated with an indolent growth and a relatively favorable prognosis when compared with other types of resistance. Interestingly, there are some types of that resistance less likely to carry T790M – such as progression in the brain only, or recurrence after stopping adjuvant erlotinib – suggesting that these situations may not be fully resistant, and that further treatment with an EGFR kinase inhibitor might make sense.
While there was hope that irreversible EGFR kinase inhibitors like afatinib or dacomitinib might inhibit T790M, response rates to these drugs have been low in patients with resistance to erlotinib or gefitinib. A higher response rate of 30 percent was reported with afatinib plus the EGFR antibody cetuximab, though this activity was seen both in T790M positive and negative resistance.
At ASCO this year, data were presented regarding a new class of drugs called “mutant-selective irreversible EGFR kinase inhibitors” which target T790M-mediated drug resistance. These drugs potently inhibit mutant EGFR protein without inhibiting wildtype EGFR, aiming to induce responses while avoiding EGFR-related toxicities. Data from three trials of three different drugs in this class (AZD9291, CO-1686, and HM61713) were presented, and each drug reported dramatic tumor responses in patients with EGFR-mutant lung cancers after resistance to standard EGFR kinase inhibitors.
In the largest trial, studying AZD9291, a striking difference in activity was seen between tumors with T790M-mediated resistance (a 65% response rate) and those with T790M-negative resistance (a 22% response rate). Additional phase II data will be needed to better understand any differences in activity between these drugs, but T790M does appear to be an emerging biomarker suggesting drug sensitivity.
Clinical trials are ongoing around the world (NCT01802632; NCT01526928; NCT01588145) and are an attractive alternative to standard chemotherapy for these patients.
Germline EGFR T790M
The rarest setting where EGFR T790M can be seen is as a germline mutation where it has been found to be associated with familial lung cancer, particularly in non-smokers. However, the risk of lung cancer in healthy individuals carrying such an inherited mutation is not well understood. Given how rare this condition is – associated with less than 1 in 1000 lung cancers – germline testing is not widely available and is not part of standard practice. In my practice, I only test for germline EGFR T790M when a patient presents with baseline EGFR T790M, a setting where the prevalence of germline mutations is estimated at approximately 50 percent.
To better understand this condition, and to offer patients free genetic counseling and germline testing, my institution has teamed up with the Addario Lung Cancer Medical Institute (ALCMI) to open a prospective trial titled INHERIT: Investigating Hereditary Risk from T790M. Individuals can present to the study website for more information: www.dana-farber.org/T790Mstudy/. If a lung cancer patient harboring baseline T790M undergoes germline testing and is found to be positive for an inherited mutation, they can then invite their relatives to be tested, allowing study of entire families. If we can demonstrate that these families are at a high risk of lung cancer, then perhaps they should be undergoing CT-screening much as is recommended for individuals with a significant smoking history.
Sunday, May 11, 2014
BY DAVID H. ILSON, MD, PHD
Globally esophageal cancer is the eighth leading cause of cancer-related death. Although squamous cancer is more common in the East, in Western Europe and the United States adenocarcinoma has emerged as the most common histology. The rate of increase of adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) has plateaued in recent years. These diseases continue to increase in incidence, and will overtake gastric cancer as the more common cancer of the upper gastrointestinal tract in the West.
Potential explanations for this increase include Western population trends of obesity, which may increase the rate of esophageal reflux disease; tobacco use; and the disappearance of Helicobacter pylori (HP) infection from Western populations. The decline in HP infection likely explains the decline in incidence of gastric cancer. Paradoxically, because HP infection may lead to atrophic gastritis and reduced stomach acid production, the disappearance of HP may actually lead to a population-wide increase in gastroesophageal reflux disease.
Screening for esophageal cancer is not feasible given that it occurs at less than 10 to 20 percent the incidence of more common cancers such as breast, prostate, and colorectal cancer. Endoscopic assessment is recommended for patients with chronic reflux, and patients identified with Barrett’s esophagus should undergo some form of regular surveillance endoscopy.
Recent population-based series indicate that, even in higher-risk patients with chronic reflux and Barrett’s esophagus, the rate of developing a cancer over 10 years may be even less than the reported one to two percent of patients. Only five percent of cases of esophageal cancer are detected by screening. Aspirin in conjunction with proton pump inhibitor therapy is the subject of ongoing trials as a cancer preventive therapy in Barrett’s esophagus. Use of life-long proton pump inhibitor therapy, however, is recommended in patients with Barrett’s esophagus as this may slow progression to dysplastic Barrett’s.
For Barrett’s esophagus with high-grade dysplasia, a population at high risk to develop esophageal adenocarcinoma in the short term, radiofrequency ablation (RFA) has replaced surgical resection as the therapy of choice. For early in situ cancers or early stage T1a cancers in the setting of Barrett’s esophagus, RFA can be combined with endoscopic mucosal resection as primary therapy.
Recent studies suggest there may be some familial predilection for both Barrett’s esophagus and esophageal adenocarcinoma, accounting for up to 10 to 15 percent of cases. Candidate genetic biomarkers, however, require further study and validation prior to routine clinical application. Esophageal or GEJ adenocarcinoma seen in the context of familial colorectal, uterine, or ovarian cancer should raise suspicion for Lynch Syndrome, which requires the identification of gene carriers who require specialized screening and follow-up.
Advanced Disease Therapy: Molecular Targets and the Emergence of Targeted Therapy
Chemotherapy for advanced esophageal and GEJ cancers has modest benefit, with responses in 30 to 40 percent of patients and a median survival of nine to 10 months. Standard chemotherapy combines a fluorinated pyrimidine and a platinum agent. The combination of (1) capecitabine with oxaliplatin or cisplatin, or (2) 5-FU and oxaliplatin on the mFOLFOX6 regimen, has emerged as global standards.
My practice in most patients is to use FOLFOX, given the chronicity of chemotherapy and the cumulative cutaneous toxicity of capecitabine. Triplet therapy adding a taxane to 5-FU and cisplatin adds modest benefits in response and survival at the cost of escalated toxicity; its use should be reserved for younger, higher functional status patients willing to tolerate greater treatment-related toxicity. Epirubicin added to flourinated pyrimidine and platinum therapy may be no better than FOLFOX, as seen in the recent CALGB 80403 Trial. Second line chemotherapy has now been validated to modestly improve survival, with data supporting the use of taxanes or irinotecan after disease progression on first-line chemotherapy.
The only validated molecular target in esophagogastric adenocarcinoma is HER2, with the recent TOGA trial showing enhanced response and survival when trastuzumab was combined with first-line chemotherapy in HER2-positive patients. All patients at diagnosis of esophagogastric adenocarcinoma should have documentation of HER2 status.
Standard practice is to perform IHC testing and if 3+, we declare the patient HER2 positive. If IHC 2+, we perform FISH testing and if positive, we consider HER2 positive. We consider IHC 0-1+ patients HER2 negative and do not perform FISH testing. Preliminary reports of phase III trials of the EGFr/HER2 tyrosine kinase inhibitor lapatinib, combined with first- and second-line chemotherapy in HER2-positive esophagogastric cancer, failed to improve overall survival.
Ongoing trials of novel HER2-targeted therapies include a randomized trial in first-line comparing chemotherapy and trastuzumab with or without the HER2-3 targeted agent pertuzumab (the JACOB Trial). Second-line paclitaxel is being compared with the trastuzumab conjugate agent TDM-1 after progression on trastuzumab-based first-line chemotherapy (the GATSBY Trial).
The positive results for the TOGA trial indicate the need to select patients with a biomarker predictive of a potential greater benefit from a new agent. This has been made painfully clear by recent large phase III trials of new agents in unselected patient populations. Multiple trials of EGFr targeted agents, including first-line trials combining chemotherapy with either cetuximab or panitumumab, or later-line therapy with gefitinib, failed to improve outcome.
Unlike colorectal cancer, where RAS mutation is commonly present and is predictive of resistance to EGFr therapy, no such biomarker for EGFr has been identified in esophagogastric cancer. A recent genomic analysis of a large series of esophagogastric adenocarcinomas indicated that, in contrast to colorectal cancer and non-small cell lung cancer, mutations in RAS, BRAF, and EGFr were rarely seen. On the other hand, a key role for gene amplification was seen, with nearly 40 percent of cancers having amplification in at least one of five important pathways: EGFr, HER2, MET, FGF, and KRAS.
Two large phase III trials are now evaluating the addition of MET-targeted therapies to first-line chemotherapy in MET-positive patients by IHC, including rilotumumab (which targets the MET receptor ligand hepatocyte growth factor) and onartuzumab (which blocks the MET receptor).
The large AVAGAST trial adding bevacizumab to first-line chemotherapy failed to improve survival, despite improvements in progression-free survival and anti-tumor response rate. An improvement in overall survival was limited to Western patients with no improvement in Asian patients. The higher utilization of second- and third-line chemotherapy in Asian patients may have undercut any survival benefit seen.
Resurgence in interest in VEGF-targeted therapy has now occurred with positive results reported for ramucirumab, a monoclonal antibody with blocks the VEGFr2 receptor. The REGARD Trial compared supportive care alone versus supportive care plus ramucirumab in second-line treatment of esophagogastric cancer. All endpoints were improved for ramucirumab, including progression-free and overall survival, leading to FDA approval of ramucirumab as monotherapy. Equally compelling results were recently reported for the RAINBOW trial, which compared second-line therapy with paclitaxel versus paclitaxel plus ramucirumab. Response rate, progression-free, and overall survival were improved with the combination of ramucirumab plus chemotherapy.
These positive results will likely change the standard of care for second-line chemotherapy in esophagogastric cancer, with the option of ramucirumab monotherapy or the combination with taxane-based chemotherapy.
Neoadjuvant Chemotherapy or Combined Chemoradiotherapy?
Endoscopic ultrasound (EUS)-staged T2-3 or node-positive patients are candidates for combined-modality therapy. The predominant approach in the U.S. is combined chemotherapy and radiotherapy followed by surgery, whereas in Europe, preop chemo alone is preferred. The Dutch CROSS trial reported in 2012 treated over 360 patients with EUS-staged esophageal squamous cell and adenocarcinoma.
Combined chemoradiotherapy, using a modern regimen of weekly carboplatin, paclitaxel, and 41.4 Gy of radiotherapy improved median overall survival by nearly a two-year increment over surgery alone. Other positive endpoints included an improved rate of R0 resection from 67 to 92 percent, a pathologic complete response rate of 27 percent, and an improved five-year overall survival of 13 percent. I feel that the CROSS trial established a new therapy standard for preoperative treatment in esophageal cancer.
Recent data from European studies indicate that early response observed on PET scan during preoperative chemotherapy may predict response at surgery and improved survival, and that PET scan non-responders can have preoperative chemotherapy discontinued and referral to immediate surgery without a detriment in outcome. Based on these observations, CALGB/Alliance Trial 80803 uses early PET scan to assess response to induction chemotherapy in esophageal and GEJ cancer. Patients are assigned randomly to receive either carboplatin/paclitaxel, or FOLFOX treatment. PET scan responding patients continue the same chemotherapy during subsequent radiotherapy; PET non-responding patients cross over to the other chemotherapy regimen.
The primary endpoint is to increase rates of pathologic complete response in PET scan non-responding patients who change chemotherapy during radiation.
Support also exists for the use of preop chemo without radiotherapy, but mixed positive and negative results of phase III trials have led to lesser acceptance of this approach in esophageal and GEJ cancers in the U.S. Positive preop chemo trials include the British MAGIC trial, employing perioperative chemo with ECF, and the French FFCD/FNLC trial using perioperative cisplatin/5-FU.
These trials, treating both esophageal and gastric adenocarcinoma, demonstrated a 13 to 14 percent improvement in five-year overall survival. The large British MRC OEO2 trial gave preop cisplatin/5-FU to 800 patients with squamous cell and adenocarcinoma of the esophagus. A six percent improvement in five-year overall survival was achieved with preop chemo. The largest negative trial of preop chemo was the U.S. Intergroup 113 trial, which failed to show improvement in any endpoint for preop chemo versus surgery alone. In my practice, I reserve the use of preop chemo for distal gastric cancer, and prefer the use of combined chemoradiotherapy in esophageal and GEJ adenocarcinoma.
DAVID H. ILSON, MD, PHD, is Attending Physician and Member of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College; and Chairman of the Intergroup Esophageal and Gastric Cancer Task Force Committee.
Monday, April 28, 2014
BY SARAH E. HOFFE, MD
Department of Radiation Oncology
Moffitt Cancer Center
Pancreatic cancer remains a difficult oncologic challenge, with the majority of patients presenting with locally advanced or metastatic tumors. A minority of patients present with tumors amenable to either upfront surgical resection or potential resection following neoadjuvant therapy. Although no universal criteria for borderline resectable pancreatic cancer (BRPC) exist, many institutions, like ours, follow the NCCN criteria.
When patients present to our multidisciplinary pancreatic team with a pancreatic mass, we advise endoscopic ultrasound to further characterize the lesion and perform fine needle aspiration (FNA) for diagnosis. Our workup includes a thin cut pancreatic protocol CT scan with both arterial and venous phases to assess the degree of vascular abutment and length of involvement.
PET/CT imaging ensures no evidence of occult metastasis, which we note can change management 11 to 22 percent of the time.1,2 All our patients are presented to our weekly multidisciplinary tumor board run by Dr. Mokenge Malafa, vice chair of the NCCN pancreas group.
Once the tumor board has agreed that the patient has a BRPC, we proceed with our institutional neoadjuvant approach. Nationally, there is no uniform standard of care approach in this setting.3 Our approach to facilitate margin negative resection was designed by medical oncologist Dr. Gregory Springett and begins with three cycles of GTX (gemcitabine, docetaxel, and capecitabine) chemotherapy.
When I joined the faculty at Moffitt in 2006, I instituted intensity-modulated radiation therapy (IMRT) delivery concurrently with infusional fluorouracil (5-FU). Initially, I delivered 45 Gy in 25 fractions to the gross tumor volume (GTV) delineated by 4D CT scan and a clinical target volume (CTV) including the regional nodes at risk. A cone down boost to 5.4 Gy in three fractions to the GTV ensured a total dose of 50.4 Gy. he IMRT strategy then expanded to a dose painted simultaneous integrated boost (SIB) technique over five weeks to deliver 45 Gy to the CTV and 50 Gy to the GTV.
During this time, the Stanford series reported by Koong et al was available and discussed delivery of a single fraction of stereotactic body radiation therapy (SBRT) for patients with locally advanced tumors.4 At our tumor board, my surgical colleagues were intrigued by this concept and wanted to know if we could do the same but focus more dose on the tumor/vessel abutment.
This collaboration led to an investigator-initiated prospective protocol with GTX and five-fraction SBRT to 25 Gy. Our experience with this early trial showed good toleration with an acceptably low toxicity profile and encouraged us that the five-fraction SBRT technique was feasible.
By 2009, we recruited Ravi Shridhar, MD, PhD, to our practice. Together, we have continued our work in the five-fraction SBRT model for BRPC. Our institution has now been employing this approach for more than five years with the support of our GI surgical oncology colleagues on our agreed-upon institutional pathway.
Our typical practice is to consult with the patient at initial diagnosis as part of the multidisciplinary team. We then arrange to see the patient again during the third cycle of GTX to coordinate endoscopic ultrasound evaluation and implantation of two to three fiducial markers into the pancreatic primary tumor.
Following implantation, the patient undergoes a conventional simulation so we can assess the degree of respiratory-associated tumor motion. If the motion is more than 5 mm, we assess the patient for a technique to decrease such motion. Our preferred techniques are either respiratory gating or abdominal compression.
The patient next undergoes 4D CT simulation. A full-body immobilization device is customized to patients with their arms over their head. An initial scan is done to visualize the fiducial markers and place isocenter. A second scan is done using 4D technique with IV/oral contrast.
We time image acquisition to start 60 to 90 seconds after contrast injection to capture the venous phase. After the images are processed, we review the 4D data. If we are gating, we determine the phase at which the tumor is at maximum expiration. We then choose that scan as the primary data set and fuse the phases at which the patient begins and exits exhalation. If available, we will fuse a 3D PET using soft tissue deformation or fuse a 4D PET to the appropriate phase.
If we are not gating, we would simulate the patient with abdominal compression and delineate the GTV in all phases as our internal target volume (ITV).
The radiotherapy technique varies depending on the clinical situation. We often use a 3D conformal multileaf collimator (MLC) delivery technique for our gated SBRT patients. For set up, we have patients fast three hours prior to treatment, and we do a cone beam CT (CBCT) on the day of preports to ensure no changes in the patient’s weight or fiducial marker position since the time of simulation.
We then proceed using kilovoltage (kv) imaging in the ap and lateral directions, matching the position of the fiducial marker in maximum exhalation phase on the machine to the position on the digitally reconstructed radiograph (DRR) from simulation. If there are significant shifts of more than 1 cm, we re-4D CT the patient. We fuse the dosimetry and contours from the initial plan to the updated CT to ensure that we do not need to adjust the plan.
In the setting where we choose an IMRT technique for SBRT delivery, we often use VMAT. Initially, we were concerned about potential dose degradation with a moving target and sliding MLC leaves; however, our physics colleagues have reported no such dose degradation up to 3 cm of motion.5
SBRT dosing is dependent on normal tissue constraints. Our philosophy is to deliver 30 Gy in 5 fractions to the planning volume encompassing the GTV and up to 40 Gy in 5 fractions to the GTV/vessel abutment. We have published our results and note a nearly 10% complete pathologic response (pCR) rate with this approach.6 In our report of 32 patients with BRPC, 31 (96.9%) underwent R0 resection with a median overall survival of 16.4 months and a 1 year overall survival of 72.2%, encouraging results in such a difficult disease.
Coronal view of planning CT showing radiation doses for stereotactic treatment plan.
1. Farma JM, Santillan AA, Melis M, et al. PET/CT fusion scan enhances CT staging in patients with pancreatic neoplasms. Ann Surg Oncol 2008;15:2465-2471.
2. Yao J, Gan G, Farlow D, et al. Impact of F18-fluorodeoxyglycose positron emission tomography/computed tomography on the management of resectable pancreatic tumours. ANZ J Surg 2012;82:140-144.
3. Katz MH, Crane CH, Varadhachary G. Management of Borderline Resectable Pancreatic Cancer. Semin Radiat Oncol 2014;24:105-112.
4. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;58:1017-1021.
5. Stambaugh C, Nelms BE, Dilling T, et al. Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments. Med Phys 2013;40:091710.
6. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys 2013;86:516-522.
Sunday, March 09, 2014
BY KENNETH R. HANDE, MD
Professor of Medicine (Hematology/Oncology)
Professor of Pharmacology
Vanderbilt-Ingram Cancer Center
On the surface, it may seem relatively easy to make appropriate chemotherapy dose modifications for patients with renal insufficiency. We generally have pharmacokinetic studies measuring renal clearance. We can estimate a patient’s renal function using a serum creatinine or glomerular filtration rate (GFR). If we have a patient who has half normal renal function and a chemotherapeutic drug where renal clearance accounts for 50 percent of overall clearance, we should make a dose reduction of 25 percent. If the drug is not cleared by the kidney, no dose reduction should be made.
Unfortunately, things are not as simple as one might think. Several variables make dose adjustments for renal insufficiency more complicated. How do we accurately measure renal function? What is normal renal function? Are drug metabolites formed? Are metabolites active? Are there multiple mechanisms for drug clearance? Can renal failure impact non-renal drug clearance?
I believe that most oncologists initially use a serum creatinine as a measure of renal function. However, a normal serum creatinine may not indicate “normal” renal function. Creatinine comes from skeletal muscle. If muscle mass remains steady and dietary creatinine intake remains steady (conditions that are not always met in cancer patients), the serum creatinine concentration is inversely proportional to creatinine clearance.
However 10 to 40 percent of urinary creatinine is secreted by the renal tubule. In early renal insufficiency, tubular secretion of creatinine will increase as GFR falls. Once a serum creatinine exceeds 1.5-1.8 mg/dl, the creatinine secretory process is saturated. In early renal failure, a small change in serum creatinine can mean a large drop in GFR. An increase in serum creatinine from 0.9 to 1.2 mg/dl corresponds to a decrease in creatinine clearance from 120 to 70 ml/min. Half of patients with a GFR < 60 ml/min have a “normal” creatinine so that oncologists should not assume that all patients with a serum creatinine under 1.5 mg/dl will have a GFR above 60 ml/min.
Measurement of Creatinine Clearance
Measurement of creatinine clearance (GFR) is a better indicator of renal function. GFR can be calculated by collecting a 24-hour urine sample and comparing the urine creatinine concentration with a serum creatinine (GFR = UCr x Volume/SCr). However, measuring creatinine clearance in the clinic is not practical due to time constraints and patients frequently not collecting all urine over 24 hours.
Estimates of creatinine clearance have been devised using serum creatinine and clinical variables. The Cockcroft-Gault and the MDMR (Modification of Diet in Renal Disease) estimates have been validated; they correlate well with each other and with some exception, make a reasonable estimate of GFR. Both can be used for dose modification in patients with renal failure.
However, the Cockcroft-Gault and MDRD estimates are less accurate in patients with unusual body mass (obesity, amputees) and in certain ethnic groups (specifically Asians). Patients with unusual diets or extremes of body weight may need to have a measured creatinine clearance.
It is also important to remember that the MDMR is normalized to a 1.73 m2 body surface area (BSA). An MDMR-estimated GFR needs to be multiplied by a patient’s BSA to obtain a GFR in ml/min. A “normal” GFR varies considerably among normal individuals and depends on body size, sex, and age.
An average person’s GFR declines by 0.75 ml/min per year. A normal GFR for someone under 40 is roughly 100-120 ml/min, but by age 70, the GFR may average 60-70 ml/min. Although not scientifically sound, in practical terms most individuals seen in an oncology clinic with a GFR over 60 ml/min are considered to have “normal” renal function. Even with this loose definition of “normal,” approximately 12 to 20 percent of cancer patients presenting for chemotherapy will have an abnormal GFR
If we have an accurate measure of a patient’s renal function, can we simply measure the percentage of renal drug clearance for that drug and adjust the dose for our patients based on these measurements? This would make sense if the parent drug were the only active moiety and if non-renal clearance of drug was not affected by renal failure. However, active metabolites are often present, and non-renal clearance may be changed in patients with renal insufficiency.
For example, cytosine arabinoside is primarily metabolized to uracil arabinoside, which has been felt to be a non-toxic metabolite. However, ara-U is cleared by the kidney and studies have suggested that high plasma concentrations of ara-U in renal failure patients receiving high dose ara-C may increase toxicity.
Irinotecan and imatinib are primarily cleared by hepatic metabolism. There is a suggestion that uremic toxins may decrease hepatic transport or metabolism of imatinib and irinotecan leading to increased toxicity. Thus, renal failure can impact clearance even if the parent drug does not undergo renal excretion. Conversely, drug toxicity may not increase in patients with renal insufficiency even if the drug has significant renal excretion.
Over 50 percent of oxaliplatin undergoes renal excretion. However, studies evaluating toxicity in patients with renal failure have found no measureable increase in toxicity down to a creatinine clearance of less than 20 ml/min. Thus, drug pharmacokinetics with estimates of renal clearance may not provide enough information to make appropriate dose adjustments in patients with renal insufficiency.
Studies measuring drug toxicity and efficacy in a significant number of cancer patients with renal insufficiency, in addition to pharmacokinetics measurements, would provide better information to make informed dosing decisions. Unfortunately, such studies are rare. For some drugs, no toxicity or efficacy data is available. Toxicity evaluations in patients with renal insufficiency are sometimes available but often in very small series. Information that dose modifications for renal impairment result in similar antitumor responses (response rates, PFS, and overall survival) is almost never available.
Given the lack of perfect information to make recommendations for dose adjustments for renal failure patients, what do I recommend when presented with a patient needing chemotherapy that has a creatinine clearance below 60 ml/min?
I would first review the package insert and/or ask my pharmacist if there is any information regarding studies of this drug in patients with renal insufficiency. Pharmaceutical companies may be a good source of information. I generally recommend using a drug where we have fairly good information (carboplatin is an example) or using a drug with minimally renal excretion (less than 20% of total clearance).
It is important to know what the goals of treatment are. For palliation, minimizing risk by avoiding a drug with potential for increased toxicity may be a better plan. If the goal is potential cure, then using a drug with the potential for high risk of toxicity may be justified. Chemotherapy is sometimes appropriate for patients on dialysis. In addition to dose adjustments for lack of any renal function, it is important to remember that drugs may be cleared by dialysis. Chemotherapeutic agents should generally be administered just following a dialysis session.
There are many review articles and book chapters providing suggestions as to dose modifications for renal insufficiency. These suggestions are at times based only on “expert opinion.” I categorize the information regarding the need for dose adjustments of chemotherapy drugs into three groups:
· Grade 1 evidence is that a drug (or active metabolite) is renally excreted, that there is evidence of increased toxicity using standard doses in patients with renal failure and that there is some data as to dose adjustments for renal failure. Chemotherapy drugs falling into that category include: capecitibine, carboplatin, cisplatin, lenalidomide, methotrexate, and oxaliplatin. For carboplatin, oxaliplatin, and lenalidomide, good data for dose adjustment exist, and I would be comfortable using these agents. Equations for adjusting carboplatin doses based on GFR are well-known. Oxaliplatin can safely be used down to a GFR of 20 ml/min. Dosing guidelines for lenalidomide are available. In myeloma patients with renal insufficiency, lenalidomide therapy may improve renal function. I tend to avoid cisplatin and methotrexate in patients with renal insufficiency as the risks are just too great without good information for dose adjustments. The risk of standard-dose cisplatin is worsening renal insufficiency to the point of dialysis. If there is no concern about worsening renal function, then cisplatin is a reasonable choice.
· My Grade 2 evidence includes drugs that are excreted via the kidney and for which there are case reports or small series suggesting increased drug toxicity in renal failure. Suggested dose modifications are only guesses without much data or where toxicity studies are conflicting. Category 2 drugs include: arsenic trioxide, bleomycin, high-dose cytarabine, etoposide, fludarabine, imatinib, melphalan, pentostatin, sorafanib, sunitinib, topotecan, and vandetinib.
· Category 3 drugs either have significant renal excretion or a case report noting increased toxicity in a patient with renal toxicity but minimal or conflicting information. Category 3 drugs include chorambucil, cyclophosphamide, daunorubicin, epirubicin, erbulin, ifosfamide, irinotecan, lomustine, nitrosoureas, and pemetrexed.