The Testicular Cancer Resource Center

Testicular Cancer Treatments: Chemotherapy


History

Testicular cancer used to be a brutal killer. If you were diagnosed with nonseminoma, you had to have a complete Retroperitoneal Lymph Node Dissection because it was the only thing that could possibly cure the cancer. If you had Stage III testicular cancer, little could be done. Back in 1970, about 90% of testicular cancer patients died of their disease.

The 70's brought us the success of Cisplatin which, when used in combination with other chemotherapy drugs and the appropriate use of surgery, brought the cure rate to an astounding 80%! This chemotherapy is not pleasant, but it's profound success has allowed the doctors to decrease the toxicity of all of the various testicular cancer treatments because they know that they have a chemotherapy safety net. The surgeries used have become less drastic with fewer side effects; surveillance has become an option; and the chemotherapy, which was once given continuously for two YEARS, is now limited to 9-12 weeks. Yes, it is not perfect. People still die of their disease. But it is a far better world for testicular cancer patients than it was 30 years ago.

We asked one of our world class testicular cancer experts, Dr. Craig Nichols, to provide a little more history and an explanation as to why this chemotherapy works so well.

He tells us that this is, "Literally a Nobel Prize question. I can tell you why these agents were selected, but the actual mechanisms of action and why this combination works so well in this disease and hardly at all in others is unknown. In the pre cisplatin era, there were a variety of single agents that had some small level of activity in testis cancer. It was also noted that two agents in particular, vinblastine and bleomycin, seemed to have not just additive effects but synergism."

"In 1973 here at Indiana, Dr. Einhorn recognized that cisplatin had activity in testis cancer and also that it was a perfect drug for combining with the best agents of the time. Cisplatin had dominantly nausea/vomiting and kidney toxicity whereas vinblastine had bone marrow toxicity and bleomycin had lung toxicity. He realized that these agents could be combined in full doses and give the three best agents in this disease simultaneously. Therein lies the tale, because with the addition of cisplatin the cure rate went from 10% to 80% (with the addition of adjunctive surgery as necessary.) [Editor's note: Vinblastine was replaced by Etoposide in the 1980's. It has fewer side effects and is slightly more effective.]"

"We believe these agents kill the tumor cells by crosslinking DNA, disrupting the ability to divide and also accelerating programmed cell death. The trillion dollar question is what is unique about germ cells relative to other solid tumors that allows this exquisite sensitivity. This is not well understood (at this time)."

Agents and Protocols

The chemotherapy protocols used for testicular cancer vary from country to country and even from hospital to hospital. That makes life a little more complicated, but in general, there are two accepted chemotherapy protocols for good risk testicular cancer: Either 3 cycles of BEP (Bleomycin, Etoposide, and Cisplatin) or 4 cycles of EP (Etoposide and Cisplatin). The standard protocols used in the US call for the cisplatin and etoposide to be given, inpatient or outpatient, over a period of 5 days. Some other countries and some experimenters in the US have tried to give the chemo over a period of 1-3 days, but in my opinion, they are really trying to save money more than they are trying to benefit the patient. Also, in Europe they tend to use less Etoposide per cycle.

For intermediate and poor risk germ cell tumors, the standard protocol is 4 cycles of BEP. Some institutions use a protocol called VIP (Etoposide, Ifosfamide, and Cisplatin) and/or use high dose chemo with a stem cell transplant (Carboplatin and Etoposide) to treat poor risk patients. Typically, the stem cell transplant is not used outside of a clinical trial.

Please note that Carboplatin, while related to Cisplatin, is not as effective as Cisplatin. It should never be used to treat nonseminomatous germ cell tumors except during a stem cell transplant.

Risk Seminomatous tumors Nonseminomatous tumors

Good Any primary site
    and
No nonpulmonary visceral metastasis
    and
Normal AFP,
any hCG,
any LDH level
Testicular or retroperitoneal primary tumor
    and
No nonpulmonary visceral metastasis
    and
Good markers (all of the following):
    AFP <1,000 ng/mL
    hCG <5,000 mIU/mL
    LDH <1.5 x ULN

Intermediate Any primary site
    and
Nonpulmonary visceral metastasis
    and
Normal AFP,
any hCG,
any LDH level
Testicular or retroperitoneal primary tumor
    and
No nonpulmonary visceral metastasis
    and
Intermediate markers (any of the following):
    AFP 1,000-10,000 ng/mL
    hCG 5,000-50,000 mIU/mL
    LDH 1.5-10 x ULN

Poor None Mediastinal primary tumor
    or
Nonpulmonary visceral metastasis
  (brain, liver, bone, etc.)
    or
Poor markers (any of the following):
    AFP >10,000 ng/mL
    hCG >50,000 mIU/mL
    LDH >10 x ULN

AFP, alpha-fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; ULN, upper limit of normal.

Adapted from International Germ Cell Cancer Collaborative Group    

Some countries in Europe (particularly the UK and Germany) plus a few sites in the US are now recommending 2 cycles of adjuvant chemo for patients with high risk stage I nonseminoma. Their thought is that if they can't see the spread of cancer on CT scan, but the pathology report indicates that it is likely to have spread, then they can save the patient from surgery or excessive chemo by giving them just two cycles of BEP chemo right away. Unfortunately, neither I nor most of the experts I have talked with agree with this thinking.

In recent years, particularly in Europe, one or two cycles of adjuvant Carboplatin are being recommended to treat Stage I seminoma. Studies do exist implying that this treatment is just as effective as radiation in reducing short term recurrences, but there is less evidence that it is as effective in reducing long term recurrences. Nevertheless, most men with Stage I Seminoma are cured by the orchiectomy alone, and while this Carboplatin treatment is very quick and relatively painless, it still is chemotherapy and can lead to other side effects. Surveillance should always be considered as a viable option for men with Stage I disease.

To Chemo or Not to Chemo...

So, who needs chemo? Well, in my opinion, men with documented Stage II or III testicular cancer are candidates for chemotherapy. Some with stage II seminoma can be treated with chemotherapy or radiation. Some with Stage II nonseminoma can be treated with surgery or chemotherapy. Men with Stage III seminoma or nonseminoma and men with Stage I nonseminoma and abnormal tumor markers that have not dropped to normal (Stage IS) must be treated with chemotherapy.

Men with Stage IS and Stage II cancer should probably receive 3 cycles of BEP or four cycles of EP. Depending on the severity of the disease, most men with Stage III cancer can be also cured with one of these standard protocols. Men with advanced Stage III cancer or a mediastinal extragonadal germ cell tumor should probably get 4 cycles of BEP or investigate a clinical trial into the use of high dose chemotherapy. If there is ever any question as to how much chemo you really need, please have your doctor consult with one of our experts!

The two protocols (EP and BEP) are essentially identical in terms of cure rate. They are different in terms of length and possible side effects. The BEP protocol uses less Cisplatin and Etoposide, but uses Bleomycin. Bleomycin can cause lung fibrosis in older patients (over fifty) and can be a problem in patients with extensive lung metastases or existing lung problems. Etoposide can cause leukemia many years down the road (at the levels given during standard chemo, the risk is less than 1 percent.) and Cisplatin can cause neuropathy and hearing loss, so there is some impetus to reduce the number of cycles of these drugs. Which should YOU choose? Well, you usually won't be asked. These protocols typically vary from hospital to hospital. Memorial Sloan Kettering strongly prefers EP while Indiana University prefers BEP. If you have any concerns, please discuss them with your doctor before starting chemotherapy...

John S, one of the TC survivors on our email support list, did some research into the bleomycin question. He asked a couple of doctors about problems associated with oxygen exposure. He learned that the more Bleo you receive, the greater the risk of this pulmonary toxicity. Most doctors don't worry too much about this side effect until you're up in the 300-400 units range. His doctor recommended a MedicAlert bracelet for a year or two just in case you're knocked unconscious and they decide to put you on oxygen. However, he said that if it's life-threatening situation, it's best to get the oxygen. Ditto for oxygen masks on an airplane. If they drop down, put them on.

The other question he had concerned scuba diving. After all, you're not breathing concentrated oxygen, just compressed oxygen. He consulted with Daniel A. Nord from the DAN Medical Staff. DAN (Diver's Alert Network) is an organization dedicated to dive safety and medical issues. Daniel wrote back explaining that, "Bleomycin is a cytotoxic drug of particular importance to divers as it causes pulmonary toxicity in generally 4% of patients, usually in the form of pneumonitis/fibrosis. Even in patients with no obvious pulmonary toxicity, the lungs are sensitized to raised levels of inspired oxygen, causing an adult respiratory distress syndrome. In general, anyone who has had bleomycin should not be exposed to partial pressures of oxygen greater than 0.3 ata's, approx. 15 feet salt water on normoxic air. Sorry to have to advise that from a medical perspective, diving is not recommended. If you would like to discuss this in further detail, please feel free to contact this office directly at (919) 684-2948."

We asked Dr Nichols about the issues associated with bleomycin. He told us, "that patients who received bleomycin should always make sure that, now and forever, their doctors and anesthesiologists should be reminded about this before any surgery or sedation. I suspect the risk of O2 toxicity declines over time, but as far as I know this is unknown. I don't think any additional information need be related to medical personnel and always, if oxygen is required in a life threatening emergency (eg heart attack or respiratory arrest etc.) it should be given." We have also asked Dr Lawrence Einhorn at Indiana University about the same thing, and his position is that the a good part of bleomycin toxicity issue is overstated and the negative aura has grown over time without any medical evidence.

So there you have it: Put on the mask, sell your respirator and tanks, and buy a medical alert bracelet or necklace! Or not... Keep your eyes open. I hope to give this issue more space in the near future.

Salvage Chemotherapy

Salvage chemo. It doesn't have a nice ring to it, does it? Well, truth be told, not everyone with testicular cancer is going to be cured by the first attempt at chemotherapy. But just because the first chemo fails to cure does not mean that all is lost. Depending on the type and timing of the recurrence, many patients can still be cured of their disease.

No matter when the recurrence, be it 1 month or 10 years after chemotherapy is finished, I strongly recommend that the patient's doctor contact one of the experts on our experts list to learn about the proper way to treat the problem. There is a lot of research in this area, and new treatments are being tried all of the time. Be aware that more than one study has determined that getting treated by an expert will improve your chances for survival. The experts know what they are doing and are willing to share this information. Please make use of them. The articles and links listed below also have some good information.

This may sound stupid, but it is very important that salvage therapy is not given unless a relapse is clearly occurring and is documented by a biopsy or a clearly rising and significant levels of markers. It is not that rare for patients to be mistakenly classified as having recurrent disease based on false-positive markers or abnormal x-ray results. Some of these false-positive results may be due to a growing teratoma (which still would require surgery), pseudonodules from bleomycin-induced pulmonary disease, or elevated markers from other causes such as elevated b-HCG from marijuana usage or cross-reactivity with luteinizing hormone, or elevated AFP associated with hepatitis or liver dysfunction. Tests can and should be done to ensure that a slightly positive marker level is really due to cancer and not something else! Another cause of persistently elevated markers is a tumor sanctuary site (eg, in the testis or brain). Now, this is still cancer, but it may be treated differently than recurrent cancer in the abdomen.

Most salvage chemotherapy for testicular cancer is VeIP with or without high dose therapy, and this protocol results in 30-50% of patients being cured assuming that they are not cisplatin refractory. During this type of therapy, it is generally routine to prescribe G-CSF. Be aware that chemo may not be a solution, so it is important that you explore surgical options as well.

A Few Important Final Tips

Chemotherapy is a complicated subject. The drugs used can make you sick, typically much sicker than you felt from the cancer alone. There are many different drugs used and many different ways to use those drugs. Oncology may seem like a cookie cutter / recipe driven way to cure cancer, but it is not. Experience does count, and if your doctor does not have a lot of experience with testicular cancer, you might want to ask them review your treatment with their peers and with an expert.

Over the years, we have learned a few things about the administration of chemotherapy for testicular cancer. Discuss this information with your doctor, and make sure that both of you agree how to deal with these issues before starting chemo.

For more detailed information on chemotherapy and testicular cancer, please check out the following links:


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This page was last updated on Dec 05, 2012
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